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Risk factors for temporomandibular disorders: a systematic review of

cohort studies

Cecı́lia Doebber Da-Cas , Lı́gia Figueiredo Valesan ,

Luiza Pereira do Nascimento , Ana Cristina Scremin Denardin ,
Eduardo Januzzi , Giovana Fernandes ,
Juliana Stuginski-Barbosa , Beatriz Dulcineia Mendes de Souza

PII: S2212-4403(24)00326-2
DOI: https://doi.org/10.1016/j.oooo.2024.06.007
Reference: OOOO 5293

To appear in: Oral Surg Oral Med Oral Pathol Oral Radiol

Received date: 30 August 2022

Revised date: 19 April 2024
Accepted date: 9 June 2024

Please cite this article as: Cecı́lia Doebber Da-Cas , Lı́gia Figueiredo Valesan ,
Luiza Pereira do Nascimento , Ana Cristina Scremin Denardin , Eduardo Januzzi ,
Giovana Fernandes , Juliana Stuginski-Barbosa , Beatriz Dulcineia Mendes de Souza , Risk factors
for temporomandibular disorders: a systematic review of cohort studies, Oral Surg Oral Med Oral
Pathol Oral Radiol (2024), doi: https://doi.org/10.1016/j.oooo.2024.06.007

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 Risk factors for temporomandibular disorders: a systematic review of cohort studies
Authors: Cecília Doebber Da-Cas1, Lígia Figueiredo Valesan1, Luiza Pereira do
Nascimento2, Ana Cristina Scremin Denardin1, Eduardo Januzzi3, Giovana Fernandes4,
Juliana Stuginski-Barbosa5, Beatriz Dulcineia Mendes de Souza6
1
Postgraduate Program of Dentistry, Federal University of Santa Catarina, Florianópolis,
Brazil.
2
Postgraduate Program of Dentistry, Federal University of Santa Maria, Santa Maria, Brazil.
3
Coordinator of the Orofacial Pain Center, Hospital Mater Dei, Belo Horizonte, Brazil.
4
Department of Dental Materials and Prosthodontics, Araraquara School of Dentistry,
University Estadual Paulista, Araraquara, Brazil.
5
Bauru Orofacial Pain Group, University of São Paulo, Bauru, SP, Brasil.
6
Multidisciplinary Center of Orofacial Pain (CEMDOR), Federal University of Santa
Catarina, Florianopolis, Brazil.

Corresponding author: Cecília Doebber Da-Cas

Department of Dentistry, Federal University of Santa Catarina
University Campus, Mailbox 476 – Trindade, Florianópolis, Santa Catarina, Brazil
Zip code: 88040-900
Telephone number: +55 48 37214952
E-mail: [email protected]

Declaration of interest
None.

Word count Abstract: 201

Word count text: 5190
Number of references: 75
Number of figures: 2
Number of Tables: 2
Number of Supplementary materials: 4

Abstract

1
Objective: A systematic review was performed to synthesize and identify the risk factors

involved in TMD onset. Study Design: Electronic searches were conducted in PubMed, Web

of Science, Scopus, Embase, PsyInfo and Lilacs databases, as well as in three gray literature

databases (Google Scholar, ProQuest and Open grey). The studies were blindly assessed by

two reviewers and selected by a pre-defined eligibility criterion. Risk of bias of included

studies was assessed using the Joanna Briggs Institute Critical Appraisal Checklist for Cohort

Studies. Grading of Recommendations Assessment, Development and Evaluation (GRADE)

was evaluated for the most related factors. Results: Twenty-one cohort studies were

included. Some of the significant factors were female gender, symptoms of depression and

anxiety, perceived stress, sleep quality, symptoms of obstructive sleep apnea and presence of

any comorbidity, such as irritable bowel syndrome, lower back pain, headache frequency,

tension-type headache, migraine and mixed headache. Moreover, high estrogen and low

testosterone levels in utero, greater pain perception, jaw mobility pain, pain during palpation,

orofacial anomalies, as well as extrinsic and intrinsic injuries were also significant.

Conclusions: Several factors seems to be involved in TMD onset, however, more studies

with standardized methodology are necessary to affirm each one of them.

Keywords: Temporomandibular disorder. Risk factors. Systematic Review. Causality.

Orofacial Pain. Musculoskeletal Diseases.

INTRODUCTION

The umbrella expression, temporomandibular disorders (TMD), is comprised of a

group of conditions that affect the stomatognathic system such as masticatory muscles,

2
temporomandibular joint (TMJ), and associated structures1. TMD affects approximately 10%

of the general population1,2 and, according to the American Academy of Orofacial Pain

(AAOP), the most frequent signs and symptoms of TMD are muscle pain and/or TMJ during

palpation or normal function, TMJ sounds and asymmetric or restricted mandibular

movements1.

There are some international tools that can be used for the assessment and diagnosis

of TMD such as guidelines proposed by the AAOP1. In addition, the Research Diagnostic

Criteria (RDC/TMD)3 was proposed in 1992 to standardize research in this field; its revised

version (2014), the Diagnostic Criteria for TMD (DC/TMD)4, enables the use of this tool not

only in research but also in clinical assessment4. The diagnosis of TMD based on these

criteria is evaluated in two major axes: Axis I is related to physical assessments and Axis II is

related to psychosocial appraisal4.

Currently, the most accepted theories about the etiology of TMD are based on the

biopsychosocial model of pain which, as the name implies, involves a combination of

psychological, social, and biological factors1. Similarly, the management of these conditions

should include a multimodal approach, addressing behavioral, environmental, and

psychosocial risk factors involved5.

According to the World Health Organization (WHO), “health risk is defined as a

factor that raises the probability of adverse health outcomes”6. Until now, a single and

universal cause for the etiology of TMDs has not been identified, since cause-and-effect

relationships are difficult to be determined in chronic diseases, which is why TMD is

considered to have a multifactorial etiology7. The risk factors for TMD include modifiable

and non-modifiable factors, e.g. gender, parafunctional habits, psychosocial factors, sleep

quality and disturbances, genetic arrangements, and emotional and physical trauma, among

3
others8. Therefore, it is important for the clinician to know and identify mainly the modifiable

factors in order to avoid TMD onset and/or its chronicity.

In order to evaluate a cause-effect relationship, the cohort study design is the most

reliable option among the observational studies9. A well-known cohort study in this field, the

“Orofacial Pain: Prospective Evaluation and Risk Assessment (OPPERA)”8, evaluated

several risk factors related to TMD. However, the analyses of more cohort studies in different

populations may result in new insights and guide future primary studies.

Further, TMD is the main cause of pain of non-dental origin in the orofacial region1, 7.

Thus, the detection of possible variables that have an influence on TMD onset is fundamental

for the effective management and prevention of TMD, as well as its chronicity. It is also

important in developing public health strategies in this field. Moreover, individuals with

TMD present limitations in their daily life activities and report a negative impact on their

quality of life7.

Some systematic reviews have already explored a few associated aspects predisposing

an individual to TMD, e.g., chewing dysfunction, occlusion alterations, bruxism, genetic

arrangments10,11,12,13,14,15. However, they presented only limited information because these

factors were analyzed separately, without considering the multifactorial nature of TMDs.

Hence, the present systematic review has been performed to answer the research question

“Which are the putative risk factors involved in TMD onset?”.

MATERIAL AND METHODS

Eligibility criteria

The following inclusion criteria were applied: cohort studies with a sample over 18

years old (y.o.) without TMD at baseline, with at least one year of follow-up, and with TMD

4
outcome assessed by a clinical examination based on RDC/TMD3, DC/TMD4 or following

the guidelines of the AAOP1. No time restrictions were applied.

The exclusion criteria consisted of 1) Samples under 18y.o.; 2) Studies not evaluating

TMD; 3) Studies using a diagnostic tool other than RDC/TMD, DC/TMD, or AAOP

guidelines; 4) Samples with TMD at baseline; 5) Presence of interventions in the study

sample; 6) Studies without a minimum follow-up of one year; 7) Studies that did not report

association rates or p-values 8) Randomized controlled trials, case-control, cross-sectional,

before-after, abstracts, reviews, case reports and series, protocols, short communications,

personal opinions, letters, posters, conference abstracts, and laboratory research (in vivo and

in vitro studies); 9) Full-text not available; 10) Articles not written in the Latin-roman

alphabet.

Information sources and search strategy

Search strategies were developed for PubMed (including MedLine), EMBASE, Latin

American and Caribbean Center on Health Sciences (LILACS), PsyInfo, Web of Science,

and Scopus. An additional search in gray literature was performed on Google Scholar, Open

Grey, and ProQuest. The Google Scholar search was limited to the first 100 most relevant

articles published in the last 10 years. All searches were conducted on April 23, 2021. Also,

all references were included in Reference Management software (EndNote X8, Thomson

Reuters, Philadelphia, PA) to exclude duplicated articles and organize references.

In addition, a screening of reference lists from included articles and Experts were

consulted in order to improve search findings16. More information regarding search strategies

is provided in Supplementary Table SI.

Selection process

The study selection was performed in two phases. In phase one, after the exclusion of

duplicated articles, two reviewers (CDC and LFV) evaluated titles and abstracts

5
independently, using the online software RayyanⓇ17 (Qatar Computing Research Institute,

Doha, Qatar). Then, potentially eligible studies were blindly appraised in full text by the

same authors, applying eligibility criteria. The reason for elimination was registered (a list of

excluded articles and reasons is available in Supplementary Table SII). A meeting for

consensus on retained articles was performed in both phases and if there was any

disagreement, the third author (LPN) was requested to obtain a final decision.

If a full text was not available for assessment, the contact by e-mail or “research gate

website” of the corresponding author was attempted twice. If this was not successful, or an e-

mail/contact was not available, the study was excluded and justified by “full text not

available”.

Data collection process and data items

The first reviewer (CDC) collected data from included studies. To ensure the integrity

of contents, the second reviewer (LFV) confirmed the gathered information. Any

disagreements were discussed with the third reviewer (LPN).

Some articles also presented data from a case-control design. However, only data

from the cohort design was assessed and gathered. Data collected included: study

characteristics (authors, year of publication, country, time of follow-up, diagnostic criteria

used for TMD diagnosis), population characteristics (mean age at baseline, sample size,

gender distribution), risk factors assessed by each study, and main findings. Hundreds of

variables were investigated by the included studies, thus, in order to enable synthesis and

discussion about the topic, the variables that showed statistical significance in the included

studies were assessed in this systematic review.

Risk of bias (RoB) assessment

Risk of bias (RoB) was individually evaluated by two blind reviewers (CDC and

LFV) using the Joanna Briggs Institute Critical Appraisal Checklist for Cohort Studies17.

6
RoB was categorized as follows: “High” (up to 49% score “yes”); “Moderate” (50% to 69%

score “yes”) and “low” (more than 70% score “yes”). After judgment, the two reviewers held

a decision meeting, and any discordance was discussed with the third reviewer (LPN). The

figure was produced using the RevMan 5.3 software (Review Manager 5.3, The Cochrane

Collaboration).

Effect measures

Effect measures such as Odds Ratio (OR), Incidence Density Ratio (IDR), Rate Ratio

or Risk Ratio (RR), Hazard Ratio (HR), and its 95% confidence intervals (95% CI) were

considered, as well as p-values for significant putative risk factors.

Synthesis Methods

Due to the heterogeneity of the results, only descriptive analysis of the results was

performed. In order to simplify the understanding and enable some comparisons, putative risk

factors were compiled according to the area involved. For example, variables related to sleep

included all variables related to sleep cited by the included studies, such as OSA and sleep

quality.

Certainty assessment

Grading of Recommendations Assessment, Development, and Evaluation (GRADE)

criteria was used in order to analyze the overall strength of evidence of the most cited risk

factors19. This analysis rated the strength of evidence of main risk factors as high, moderate,

low, or very low. For example, a high index of evidence means that the variable has a high

degree of reliability. This index is calculated automatically by the software (GRADEpro

GDT, Copenhagen, Denmark), considering judgments made by the authors about the risk of

bias, imprecision, and heterogeneity for each of the most cited risk factors. A summary of

findings is presented in Table II and the entire table, generated using online software

7
(GRADEpro GDT, Copenhagen, Denmark) provided by the GRADE Working Group, is

available in supplementary material Table IV (SIV).

RESULTS

Study selection

All database searches were performed on April 23, 2021. The searches resulted in

2,625 records, after duplicate removal, and 196 were selected for the second phase. At this

phase, 175 studies were excluded and 21 were included following the eligibility criteria. An

overview of the selection process is available in Figure 1.

Study Characteristics

Twenty-one cohort studies were included. They were published between 2005 and

2021. The majority of the studies used RDC/TMD to diagnose TMD; one used DC/TMD38

and one used AAOP guidelines32. The results for TMJ and muscular disorders were

distinguished in only four articles32,35,36,38

The main information about included studies is presented in Table I and the

significant findings are available in Supplementary Table III (SIII).

Risk of bias within studies

Thirteen studies presented a low risk of bias21, 22,23,24,25,26,27,28,30,31,32,34,37, seven studies

were judged with a moderate risk of bias20,29,33,35,36,38,40 and one presented a high risk of bias39

(all judgments are presented in Figure II). The most relevant question that increased the risk

of bias within studies was “Was the outcome measured in a valid and reliable way?” since

some studies stated that the examination was performed by calibrated researchers. However,

these studies did not explain how the calibration was performed, nor the kappa values that

came from the calibration.

In addition, concerning the question “Was the exposure measured in a valid and

reliable way”, several putative risk-factors were presented, and most of them were assessed

8
through self-reported questionnaires. For specific diseases or conditions, a clinical

examination or a diagnosis by specialized professionals is necessary. Hence, an unclear risk

of bias was considered in most of the articles in this section. Further information about the

risk of bias assessment from the included studies can be found in Figure II.

Results of individual studies

A qualitative analysis was performed on major topics in order to compare studies and

synthesize their factors.

Non-modifiable Factors

Female gender was indicated as a risk factor for TMD by six studies35,36,37,26,27,29, with

a hazard ratio varying from 1.3 to 4.9. However, it was not significant in seven studies that

examined this variable.

Age was another frequently studied variable. Studies from OPPERA presented a

higher incidence of TMD onset in the 35-44y.o group23,26,27,29, however, younger groups (18-

24 and 25-34y.o) demonstrated a higher incidence when psychological factors21, such as

other pains or health conditions27, were added in the analyses. Yet, among studies comprising

samples of those over 44y.o, the risk was not significant in people over 40y.o33,34.

Also, African Americans demonstrated a higher risk for TMD in comparison with

white people24,29,25,26 in seven studies derived from OPPERA. However, in two studies this

was not significant. Similarly, low levels of satisfaction regarding material life standards also

indicate a higher risk for TMD29.

Concerning genetic factors, COMT haplotype demonstrated an effect on TMD onset

in two studies20,40. No specific Single Nucleotide Polymorphisms (SNP) were significantly

associated directly with TMD onset; however, some genes present indirect effects because

they have an influence on pain phenotypes. As an example, SCN1A and ACE2 were

associated with non-painful orofacial symptoms; a SNP in the PTGS1 gene was associated

9
with psychosocial factors. Also, a SNP in the APP gene was associated with stress and

negative affectivity, while a MPDZ gene was associated with the QST phenotype (heat pain

temporal summation)30.

Modifiable Factors

General Health Factors

Throughout the Short Form 12 Health Survey v2 (SF-12v2) questionnaire, people

who considered their general health as „poor or fair‟ presented a 2.5 times greater risk of

TMD than people who indicated „excellent‟27. Another significant factor was the past usage

of three or more medications (not specified by the study), indicating about a 40% chance of

increase in TMD onset27.

Mean arterial pressure higher than 85 units of millimeters of mercury (mmHg)26 and a

heart rate22,26 higher than 69 beats per minute were also significant for TMD development, as

well as obesity26,27 and osteoporosis33,34. Moreover, a higher D2:D4 digit ratio (representing

lower testosterone and higher estrogen exposure in prenatal life) was considered a significant

predictor of TMD27.

Furthermore, a history of neurosensory conditions (e.g.: earache; ringing in ears;

hearing loss; fainting or dizzy spells; epilepsy, seizures, or convulsion; psychiatric treatment)

or respiratory conditions (asthma, sinus trouble, allergies or hives, tuberculosis, breathing

difficulties) can also predict TMD onset27.

Former and current smokers presented around twice the risk of TMD than those who

never smoked in both studies which comprised these variables 26,27.

Comorbidities and Other Painful Conditions

The presence of pains, such as menstrual pain, chest pain, joint soreness or pain,

muscle soreness or pain, and abdominal pain, in general, were indicated as predictors of

10
TMD onset39. In addition, the presence of more than two comorbidities (painful or

nonpainful) was also a significant factor27.

Genital pain (presence of pain on contact but absence of genital itching during the last

3 months)27 was also a predictor of TMD. Similarly, Irritable Bowel Syndrome (IBS) or more

than 3 IBS symptoms (bowel movements and experiencing discomfort or pain in the

abdomen that lasted at least 1 day per week during the previous 3 weeks) were positively

associated with TMD27.

Although back pain had been measured by different methods among studies, it was

significantly associated with TMD in all studies where this variable was examined27,33,37,39. In

addition, one of the studies reported that current low back pain at a baseline of more than five

episodes in one year, also predicts TMD27. Further, when spinal back pain was compared

between genders, the female gender demonstrated a higher risk of TMD37.

The presence of headaches was also significantly associated with TMD onset39,27,31,

including the frequency and severity of headaches events. Among headache types, tension-

type (TTH)27, migraine31 and mixed headache31 demonstrated significant effects on TMD

onset. However, migraine was not considered a predictor only in one study27.

Physical trauma

People who had a history of jaw injury due to prolonged mouth opening were more

likely to develop TMD23. The number of injuries (only one injury or two or more injuries)

was also significant and presented a higher risk of TMD onset28.

Injuries can be divided into macro trauma, which includes extrinsic injuries - e.g.

tooth extraction or dental treatments, motor vehicle accidents, oral intubation, sports injuries,

accidents resulting in whiplash, head, neck or shoulder injuries - all being significantly

related to TMD onset28; and microtraumas, including intrinsic injuries - e.g. yawning only,

sustained mouth opening only, yawning and sustained mouth opening28, self-reported

11
parafunctional habits23 (measured by Oral Behaviors Checklist – frequency of 21 activities,

such as clenching and chewing gum) - also all being significant predictors of TMD onset, as

well as teeth grinding or clenching for both TMJ disorders35 and myofascial pain36. However,

parafunctional habits, such as grinding and clenching, were not significant in all studies that

comprised these variables38.

Facial Symptoms

A history or recent inability to open the jaw wide23 and self-reported TMJ sounds23,35

exhibited significant effects on TMD, the latter specifically for TMJ disorders. Facial pain23

was also indicated to predispose an individual to TMD, as well as higher pain sensitivity

from mechanical and heat stimuli22. In addition, people with scores of 2-4 episodes of pain or

disability due to orofacial pain, as measured with the Grade Chronic Pain Scale (GCPS),

increased the risk of TMD by four times23.

Pain from palpation on the temporalis22,23, masseter22,23, and the lateral pterygoid area,

as well as greater tender points in the neck and body, were significantly associated with TMD

onset. Further, the presence of non-specific orofacial symptoms (jaw stiffness, cramping,

fatigue, pressure, soreness or aches) in the preceding month were significant23, as well as the

presence of jaw mobility pain when opening the mouth: unassisted or assisted un-

terminated23.

Occlusal-related Factors

The presence of unilateral contact in the centric relation and mandibular instability in

the intercuspal position were significant for both TMJ disorders35 and Myofascial pain36.

However, crossbite and any deviation of morphological occlusion were positively associated

only with TMJ disorders35.

Sleep-Related Factors

12
 Poor sleep quality was associated with TMD24,25,26 through the analysis of the

Pittsburgh Sleep Quality Index (PSQI) and the Sleep Quality Rating Scale (SQ-NRS)

questionnaires. In addition, the variation on SQ-NRS along quarterly periods of the study was

also significant, and even when perceived stress was added as a mediator, sleep quality

presented a direct and indirect effect on TMD onset25. Moreover, people with a higher

likelihood of Obstructive Sleep Apnea (OSA) presented a higher risk for TMD26.

Psychosocial Factors

Symptoms of depression were measured by the Brief Symptom Inventory (BSI) 40,

Composite International Diagnostic Screener (CID-S)32 and Symptom Checklist 90-Revised

(SCL90R)21 and were considered significant for TMD onset. In addition, the symptoms of

depression were more relevant for TMJ disorders than muscular ones32. These symptoms

presented significance even when adjusted for the presence of the Catecholamine-O-

methyltransferase (COMT) gene, demonstrating an independent effect on TMD onset40.

Similarly, symptoms of anxiety were also described as a predictor for TMD, which

was measured by the State-Trait Anxiety Inventory (STAI), SCL90R21, and CID-S32.

Through the analysis of these questionnaires, symptoms of anxiety were considered

significant to TMD onset even when State and Trait types of anxiety were disconnected.

Unlike symptoms of depression, symptoms of anxiety were more significant predictors of

muscular disorder development32.

Perceived stress was also explored by the studies and measured by the Perceived

Stress Scale (PSS); it was found to be significant in TMD onset21,25,40.

Fillingim et al. (2013) presented other relevant psychological factors such as somatic

symptoms (The Pennebaker Inventory of Limbic Languidness – PILL), general psychological

symptoms (greater scores for SCLR90 subscales and the Eysenck Personality Questionnaire-

Revised - EPQ-R Neuroticism), negative mood (Profile of Mood States- BiPolar – POMSbi),

13
and multiple measures of stress, such as Post Traumatic Stress Disorder (PTSD) symptoms

(PTSD Checklist-Civilian Version – LSL/PCL-C) and recalled life events (The Life

Experiences Survey – LES). People who present high levels of “Global Psychological and

Somatic Symptoms” (high scores on SCL90R, LES, and LSL/PCL-C PTSD scales) and high

levels of “Stress and Negative Affectivity” (high scores on STAI, PSS, POMS Negative

affect and EPQR-Neuroticism) are more likely to develop TMD. However, in a multivariate

analysis, high levels of “Stress and Negative Affectivity” were significant only when “Global

Psychological and Somatic Symptoms” were low. Further, younger individuals with high

levels of “Global Psychological and Somatic Symptoms” have more risk of TMD than the

35-44y.o group21.

Certainty of evidence

According to GRADE criteria, confidence in cumulative evidence was considered

“high” for sleep-related, smoking history and trauma; “moderate” for female gender, age-

related, race-related, facial symptoms, symptoms of depression, symptoms of anxiety and

headache-related variables; “low” for parafunctional habits, perceived stress, and genetic

factors; and “very low” for back-pain related and occlusal related variables. Inconsistency

was considered serious because identification of the exposures was assessed by different

tools or by self-report questionnaires. Similarly, imprecision was also judged as serious due

to different results observed across studies regarding the possible association between some

putative risk factors and TMD onset. A summary of the strength of evidence from the main

risk factors is available in Table II and the complete table is available in Supplementary

Table IV (SIV).

DISCUSSION

The present SR explored the existing evidence concerning risk factors related to TMD

onset. TMD is multifactorial, and clinicians must know all the potential risk factors cited in

14
this article in order to prevent the onset or chronicity of these disorders. Only one factor is

not enough to develop TMD symptoms; however, the knowledge about what is behind the

minimal symptoms is important to guide patients and manage these symptoms. There are two

main types of analysis of risk factors in included studies. The univariate (UV) analysis is the

simplest way to evaluate the influence of one variable in TMD onset. Conversely,

multivariate (MV) analysis is comprised of confounders that may impact the results, such as

the use of medications, and psychosocial impairments41. Due to the multifactorial nature of

TMD, MV analyses are more relevant to evaluate risk factors related to these disorders. Thus,

in this SR, some non-modifiable (such as age, race, and gender) and modifiable factors (such

as physical trauma, facial symptoms, sleep-related factors, comorbidities, and psychosocial

factors), which were part of the MV analysis of primary studies, were discussed.

Female gender was considered a relevant risk factor by several studies26,27,29,35,36,37.

This suggests that women are at higher risk for developing TMD than males and supports the

higher prevalence of TMD in this population42,43,44. This can be explained by a greater

likelihood of seeking treatments42, a greater tendency of hypermobility45, and higher levels of

psychosocial symptoms and pain perception46. Hypermobility, for example, can be a risk

factor for the luxation and subluxation of TMJ4. Moreover, female hormones, such as

estrogen, could be a factor, since it plays a role in orofacial pain47, on the other hand,

testosterone appears to play a role in preventing this condition48. Estrogen seems to be

involved in pain modulation, inflammatory modulation of TMJ, and the nociceptive response

of the peripheral and central nervous systems49. Further, it corroborates another finding – a

higher D2:D4 digit ratio, representing high levels of estrogen and low levels of testosterone

exposition during the 14th week in utero (when the formation of digit cartilage occurs)27.

Although age presented significance to TMD onset21,23,26,27,29,33, a reliable comparison

was difficult due to the different age group ranges presented in each article. Most of the

15
included studies presented a sample age range of 18-44 y.o., and only two included samples

over 44 y.o33,34. In addition, the literature presents two-main age peaks for TMD, which are

different for muscular and articular disorders50. However, these conditions were not

differentiated by most of the studies. Thus, the indication of a specific age group for the

highest TMD risk was not possible.

A strong predictor of TMD was physical trauma, which can be divided into indirect

(e.g., whiplash) and direct (subdivided into macro trauma, such as a punch in the face; or

microtrauma, defined as prolonged or repeated force over time)1, and both types were

significant to TMD onset. The findings from direct and indirect traumas agreed with other

studies regarding injuries caused by, for example, dental treatments 50,51 and whiplash

injury53,54. As dental clinicians, it is important to know the reduction maneuver of the

mandible in cases of luxation of TMJ, as well as how to perform it, primarily in acute disc

displacement without reduction cases, prescribing an appropriate pharmacological therapy

and referring the patient to multidisciplinary management, such as physiotherapy1. Further, if

myalgia occurs in long treatments, orientation about self-massage and/or specific

pharmacological therapy should be applied.

An interesting fact presented by the study by Sharma et al (2019) is that 80% of

incident TMD cases pointed out the “intrinsic injury only” option28, including yawning or

sustained mouth opening. It is important to highlight, through self-perception and orientation

from health professionals about possible complications, that this type of injury is mostly

avoidable. Also, when the patient presents some type of disc complex disorder, like

hypermobility, they have a higher chance of developing trauma in the region, such as

luxation and disc dislocation1. Thus, it is important to reduce the time in which the mouth is

open during dental treatments and consider non-invasive treatments (such as cognitive

behavioral therapy, self-care management, multimodal care with physiotherapy,

16
pharmacological therapy and/or a flat-plane intraoral device), which also includes education

to avoid TMD onset or its chronicity55. Similarly, although bruxism35,36 and other

parafunctional habits23,38 did not present significant values in MV analysis, it is important to

point out that they are also microtraumas in the orofacial region. These conditions should be

studied more deeply, and clinicians should alert the patients about the risk of these habits for

the orofacial region (such as nail and lip biting, yawning, or chewing gum), as well as spread

this knowledge to increase awareness about the topic.

Sleep-related factors were also associated with TMD in all four studies that examined

these variables. Most of the results came from PSQI and SQN-R questionnaires, both

validated and adequate methods to investigate the sleep quality of patients56,57. Sleep quality

is indicated as an important regulator of our physiological and psychological system58,59. It

presents a bidirectional relationship with TMD58 and, despite the complexity of this

connection, the increased likelihood of TMD could be explained by sleep deprivation

possibly affecting the pain sensitivity threshold, since it alters the function of key endogenous

pain modulation pathways60. A higher likelihood for OSA26, for example, was indicated as a

specific risk factor for TMD, due to sleep fragmentation caused by this condition - in an

attempt to reestablish the air passage on the upper airway61, which has an influence on sleep

quality.

Additionally, some symptoms of TMD such as jaw mobility pain, pain from

palpation, and other facial symptoms22,23 were also described as risk factors for TMD onset.

Although these symptoms are common in TMD patients, the thresholds for being diagnosed

with TMD and these studies were not met. The authors suggested that these symptoms could

indicate an important systemic dysregulation and a pre-clinical condition, contributing to

posterior acute TMD23. Although the differentiation of muscular and articular disorders was

not cited by the included studies, they present some differences, affecting specific structures

17
and with different signs and symptoms4. Also, both could be present simultaneously or

separately. Furthermore, TMD disorders can include pain, decreasing the quality of life of

patients, but can also be present initially without pain involved7. The DC/TMD is a

diagnostic tool with clinical characteristics for each type and subtype of TMD, helping the

clinician give a precise diagnosis4.

Low back pain and headaches were indicated as risk factors for TMD by the included

studies. Low back pain33,39,37,27 and primary headaches27,31,39 (including tension-type and

migraine), when chronic, are known as comorbidities of TMD62,63,64 because they share

similar pain pathways as those of TMD conditions64. Moreover, migraine, for example, was

demonstrated as a risk factor for TMD and, although TMD is not considered a risk factor for

primary headaches, it plays a role in their chronification31. Similarly, pain and dysfunction in

innervated areas of the trigeminal nerve, such as neck pain, headache, and orofacial pain are

commonly reported by patients. There are several hypotheses attempting to explain these

associations, including neuronal convergence, central sensitization, and inhibition of the

descending pain downregulation mechanisms37,64. Thus, the identification and control of each

one of these modifiable factors are important to control TMD, because they share similar pain

pathways influencing the treatment of all these comorbidities64.

Another comorbidity positively associated with TMD onset is the Irritable Bowel

Syndrome (IBS) disease, which possibly shares a dysfunction in endogenous pain inhibition,

present in most chronic pain conditions65. In addition, people with IBS and TMD presented

greater pain perception compared with healthy individuals22,66. Hence, the presence of any

comorbidity was an important variable related to an increased risk for TMD onset, presenting

a cumulative risk when increased levels are present27.

All the aforementioned variables can be mediated by psychosocial aspects. Symptoms

of depression32,21,40, perceived stress21,25,40, symptoms of anxiety21,32, and the presence of

18
somatic symptoms21 were significantly associated with TMD onset. The findings are in line

with the high prevalence of depressive symptoms and somatization in patients with TMD67,68.

In addition, symptoms of anxiety presented a stronger link with myofascial pain 69. Although

the role of these factors in TMD is not fully understood70, it seems to contribute to TMD

onset because it increases pain perception and changes the individual‟s coping capacity71.

Further, it presents a bidirectional link with TMD, playing a role in pain pathway modulation

and chronication72. Hence, knowledge about potential risk factors and a multimodal

approach is essential for the management of TMD disorders, addressing behavioral,

environmental, and psychosocial aspects5.

In order to enhance the reliability in assessing the potential risk factors involved in

TMD onset, cohort studies were chosen9. However, this type of study (where patients are

observed during a period of time) is expensive and involves a temporal framework,

depending on the patient‟s availability and willingness, making them more susceptible to

withdrawals and bias9. Due to all these difficulties, the number of cohort studies assessing

similar variables was minimal. As a result, a meta-analysis could not be performed since
21,22,23,24,25,26,27,28,29,30,31
eleven included studies were drawn from an OPPERA study , using a

unique sample for several analyses, and leading to possible population overlap. In addition,

variables were assessed by different forms and tools among included papers, which also

hampered a reliable comparison by a meta-analysis. Thus, from the available literature about

the topic, a quantitative comparison was not possible and future studies should evaluate the

variables related to TMD following international guidelines and/or validated questionnaires.

Due to the multifactorial nature of TMD, more than one risk factor is needed for its

development, and several factors must be investigated to achieve a precise diagnosis or

prevent this condition1. Thus, the clinician must know all the potential factors. Further, a

19
multimodal approach is essential for the management of TMD disorders, mainly when

psychological aspects are involved73.

Limitations

The distinction between muscle and articular disorders, or pain-related or pain-free

disorders, was not possible due to the general assessment of TMD by the included studies.

Each one of the putative risk factors may present singular influences for each type of TMD;

thus, this differentiation is important to fully understand how and which of them have an

influence in each type of TMD.

Due to the heterogeneity of studies, a risk of over-generalization of results is

recognized as a consequence of the type of review presented. Hence, the presentation of these

results should be done with caution.

For future studies, we recommend the standardized evaluation of TMD, subdivisions of TMD

based on DC/TMD, and the evaluation of confounding factors, e.g., psychological factors,

medications, and other comorbidities including them in MV analysis.

CONCLUSION

Although several factors seem to be involved in TMD onset, this SR did not find

enough evidence to compare and affirm each of them as a risk factor. Thus, more cohort

studies with standardized methodology in different populations are necessary to affirm each

of them.

Acknowledgements

Grateful to MSc. Gilberto Melo for assisted in data analysis and to librarian Maria Gorete

Monteguti Savi, for assisted in search strategy. The authors of this study C.D.C [grant

number 88882.437764], L.F.V [grant number 88882.437769], L.P.N [grant number

888822428240], A.C.S.D [grant number 88882.437761] were supported by Coordination for

20
the Improvement of Higher Education Personnel (CAPES), Bras lia, DF, Brazil - Finance

Code 001. The authors declare no conflict of interest.

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Legends of tables

Table I. Main characteristics of included studies (n=21)

Table II. Summary of evidence certainty of the variables most assessed based on “Grading of
recommendations assessment, development, and evaluation summary of findings table”

Legends of figures

31
Figure I. Flow Diagram of Literature Search and Selection Criteria (adapted from Preferred

Reporting Items for Systematic Reviews and Meta-Analysis – PRISMA)

32
Figure II. Risk of bias of included studies assessed by Joanna Briggs Institute Critical
Appraisal Checklist for Cohort Studies (generated using the software Review Manager 5.3)
Legend: (+) =yes; (-) =no; (?) =unclear

33
Table I – Main characteristics of included studies (n=21)
Mean
Author, Diagnostic
age/SD
Country Follow-up Sample Characteristics Criteria
at
(year) for TMD
baseline
Data Collection: 1998-
Final Sample: 170 F
2000
Diatchenko 58 subjects: Low COMT activity
Follow-up: 3 years
et al., USA (HPS and/or APS) 18-34 y. o RDC/TMD
(3-month intervals
(2005) 112 subjects: at least one “high
interviews and annual
activity” haplotype (LPS)
examination)
Follow-up: Average of 2.8
Fillingim et years (Until 5.2 years) 27.1 y.o
Final Sample: 2737
al., USA Follow-up examination: (SD=7.8) RDC/TMD
(1630F/1107M)
(2013) 2006-2011 (3-month 18-44 y.o
intervals evaluation)
Follow-up: Average of 2.8
Greenspan years (Until 5.2 years)
Final Sample: 2737
et al., USA Follow-up examinations: 18-44 y.o RDC/TMD
(1630F/1107M)
(2013) 2006-2011 (3-month
intervals evaluation)
Enrolled: 4308
Joint Pain: 3006
Muscle: 3034
Data Collection:1997-
Kindler et Follow-up drop-outs: 1008 (231
2001 49 y.o (20-
al., died, 129 moved away, 541
Follow-up: 5 years 81y.o) AAOP
Germany refused, 107 other reasons)
Follow-up
(2012) Final Sample: 3300
Examination:2002-2006
(1589M/1711F) – 3006 joint pain
analysis/ 3034 muscle pain
analysis
Lee et al.,
Retrospective Cohort Final Sample: 260,484
Taiwan 20-70 y.o RDC/TMD
Follow-up: 15 years (128,068F/132,416M)
(2020)
Lee et. al, Final Sample: 13,163 with COPD
Follow-up: 15 years
Taiwan and osteoporosis and 39,489 with 30-70 y.o RDC/TMD
(2000-2015)
(2021) COPD without osteoporosis
Lim et al.,
Follow-up: 3 years Final Sample: 266 F 18-34y.o RDC/TMD
N/A (2010)
Marklund
Data Collection: 1998- Initial sample: 371 23 y.o (SD
et al.,
2005 1year follow-up: 308 (114M/ 4.9/18- RDC/TMD
Sweden
Follow-up: 1 year 194F) 48y.o)
(2007)
Marklund
Data Collection: 1998- Initial sample: 371 (142M/229F) 23 y.o (SD
et al.,
2005 1year follow-up: 308 (112M/ 4.9/18- RDC/TMD
Sweden
Follow-up: 1 year 196F) 48y.o)
(2008)
Marklund Initial Sample: 372 (92 drop-outs
23 y.o (SD
et al., Follow-up: 2 year (1-year due interruption of education)
4.9/18- RDC/TMD
Sweden intervals examination) Sample: 280 dental students
43y.o)
(2010) (98M/182F)
Follow-up: Average of 2.8
Orbach et
years (Until 5.2 years) Final Sample: 2737
al., USA 18-44 y.o RDC/TMD
Follow-up examination: (1630F/1107M)
(2013)
2006-2011 (3-month

34
 intervals evaluation)
Olliver et Baseline: children
al., New Examinations at 15y.o
Final Sample: 892 45 y.o DC/TMD
Zealand and 45y.o
(2020) Follow-up: 30 years
Follow-up: Average of 2.8
Sanders et years (Until 5.2 years)
Final Sample: 2453
al., USA Follow-up examination: 18-44 y.o RDC/TMD
(1471F/982M)
(2016) 2006-2011 (3-month
intervals evaluation)
Follow-up: Average of 2.8
Sanders et years (Until 5.2 years)
Final Sample: 2722
al., USA Follow-up examination: 18-44 y.o RDC/TMD
(1623F/1099M)
(2017) 2006-2011 (3-month
intervals evaluation)
Follow-up: Average of 2.8
Sanders et years (Until 5.2 years)
Final Sample: 2,604
al., USA Follow-up examination: 18-44 y.o RDC/TMD
(1547F/1057M)
(2013a) 2006-2011 (3-month
intervals evaluation)
Follow-up: Average of 2.8
Sanders et years (Until 5.2 years)
al., USA Follow-up examination: Final Sample: 2722 (N/A) 18-44 y.o RDC/TMD
(2013b) 2006-2011 (3-month
intervals evaluation)
Follow-up: Average of 2.8
Sharma et years (Until 5.2 years)
Final Sample: 1729
al., USA Follow-up examination: 18-44 y.o RDC/TMD
(1047F/682M)
(2019) 2006-2011 (3-month
intervals evaluation)
Follow-up: Average of 2.8
years (Until 5.2 years)
Slade et al., Final Sample: 2737
Follow-up examination: 18-44 y.o RDC/TMD
USA (2013) (1630F/1107M)
2006-2011 (3-month
intervals evaluation)
Initial sample: 254 F enrolled
Follow-up: up to 3 years
Slade et al., Blood sample and written consent
(up to 42 months – every 18-34y.o RDC/TMD
N/A (2007) for genotyping: 212
3 months)
Final Sample: 171
Follow-up: Average of 2.8
Smith et years (Until 5.2 years)
Final Sample: 2737
al., USA Follow-up examination: 18-44 y.o RDC/TMD
(1630F/1107M)
(2013) 2006-2011 (3-month
intervals evaluation)
Follow-up: Average of 2.8
Tchivileva years (Until 5.2 years)
Final Sample: 2410
et al., USA Follow-up examination: 18-44 y.o RDC/TMD
(1443F/967M)
(2017) 2006-2011 (3-month
intervals evaluation)
Abbreviations: AAOP, American Academy of Orofacial Pain; APS, Average Pain
Sensitivity; COMT, Catecholamine-O-methyltransferase;
COPD, chronic obstructive pulmonary disease; F, female; HPS, High Pain Sensitivity; LPS,
Low Pain Sensitivity; M, male; N/A, not available; RDC/TMD, Research Diagnostic Criteria
for Temporomandibular Disorders; SD, Standard Deviation; y.o, years old;

35
Table II – Summary of evidence certainty of the variables most assessed based on “Grading of
recommendations assessment, development, and evaluation summary of findings table”

High (n/n) Moderate (n/n) Low (n/n) Very Low (n/n)

Sleep-Related (4/5) Female gender (6/13) Parafunctional Habits Back Pain related
(4/5) (4/4)
Smoking history Age-related (6/12) Perceived Stress (3/3) Occlusal – related
(2/2) (3/2)
Trauma (2/2) Race- Related (5/7) Genetic factors (3/2)
Facial Symptoms (3/3)
Symptoms of Depression
(3/3)
Headaches- related (3/3)
Symptoms of anxiety (2/2)
n/n = number of studies where the variable was significant/number of studies that the variable
was assessed

Statement of Clinical Relevance:

TMD is a multifactorial and a chronic condition that impacts the patient's quality of life in the

long term. Identifying and treating early-onset risk factors helps reduce the chronicity of the

condition.

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