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. 2025 Sep 8;39:e071. doi: 10.1590/1807-3107bor-2025.vol39.071

Salivary flow rate in children and teenagers with Down syndrome: Systematic review and meta-analysis

Wilmer RAMÍREZ-CARMONA (a), Beatriz DÍAZ-FABREGAT (a), Antonio Hernandes CHAVES-NETO (b), Douglas Roberto MONTEIRO (c), Juliano Pelim PESSAN (a), Ana Cláudia de Melo Stevanato NAKAMUNE (b)
PMCID: PMC12419198  PMID: 40929398

Abstract

The purpose of our review was to group the evidence and attempt to provide a consensus on the behavior of salivary flow rate in patients with Down syndrome. Observational studies evaluating salivary flow rate in children and teenagers with Down syndrome compared with non-syndrome individuals were selected. Ten sources of information were researched. The risk of bias was assessed by using the Newcastle Ottawa Scale tool . Inverse Variance was ty the SMD (95% Confidence Interval). The certainty of the evidence was determined according to the GRADE approach. Fourteen studies were evaluated. The results showed, with a very low certainty of evidence, that children and teenagers with Down syndrome present a lower salivary flow rate compared with non-syndrome controls (SMD: -1.71, 95%IC: -2.81; -0.60, p < 0.05), with significant differences in the saliva collection methods (p < 0.05) (Unstimulated saliva, SMD -5.07, 95%CI: -7.96; -2.18, p < 0.01; Stimulated saliva, SMD -0.80, 95%IC: -1.78; 0.17, p = 0.11). The behavior of the salivary flow rate is not significantly different between the age groups (p = 0.60) (up to 5 years old, SMD -1.85, 95%CI: -2.90; -0.81, p < 0.01; 2 to 18 years old, SMD -1.51, 95%CI: -2.24; -0.78, p < 0.01), and the sex (p = 0.70) (Male, SMD -1.77, 95%CI: -2.39; -1.16, p < 0.01; Female, SMD -1.53, 95%CI: -2.58; -0.48, p < 0.01). Children and teenagers with Down syndrome present a lower salivary flow rate with an unstimulated saliva collection method compared to non-syndrome.

Keywords: Adolescent, Chromosome Disorders, Disabled Children, Saliva, Salivary Glands, Systematic Review

Introduction

Down syndrome is a chromosomal disorder derived from an effective trisomy of chromosome 21 meaning, so that instead of having 46 chromosomes, the person has 47. This condition is associated with intellectual disabilities and a wide variety of additional factors. 1 Hypotonia, intellectual and learning disability, cervical instability, autism spectrum disorder, epilepsy, cerebrovascular disease, Alzheimer’s disease, and neuropsychiatric disease are the main clinical conditions of the neurological complications reported in Down syndrome patients. 2

Evidence from studies has shown differences in parameters related to saliva and oral health in this population. For example, although there is no high-level scientific evidence to support the hypothesis that people with Down syndrome have a lower experience of dental caries, 3,4 the possible trend towards a decrease in the caries index; This , In turn, is accompanied by common gingival and periodontal diseases. 5 Children with Down syndrome have lower indices of pH, α-amylase, and of buffer capacity in the saliva, compared with control non-syndrome children. 6,7 Furthermore, high levels of oxidative stress biomarkers, such as superoxide dismutase activity and malondialdehyde, 8 and higher values of cytokines, such as IL-1β and IL8 are also reported in this population. 5 Salivary parameters, especially salivary flow rate, seem to be a comparative factor in analyses. 6-8

Saliva is a fluid with a complex composition, which results from the mixture of secretions from major and minor salivary glands, crevicular gingival fluid, microorganisms, desquamated epithelial cells, and food remains. 9 Age, sex, collection method, medication use, pre-existing medical conditions, or diseases can affect salivary composition and flow rate. 10-12

There is, however, no consensus in the scientific community about the influence of Down’s syndrome on salivary flow rate. 6-8,13 Some authors have reported a significantly lower salivary flow rate in this population, 7,8 while another study has stated that there was no difference 13 , or even that there is a tendency to a higher salivary flow rate in these patients. 6 The proposal of our review was to group the evidence on the subject, and try to provide a consensus on the salivary flow rate behavior in children and adolescents with Down syndrome. The results of this review could help us clarify the salivary flow behavior in this population, especially as a risk factor for oral diseases. 3-5 Thus, our review question is as follows: Is the salivary flow rate altered in children and teenagers with Down syndrome compared with non-syndrome controls?

Methods

Registration and protocol

This systematic review was carried out in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses (Prisma) guidelines updated in 2020, 14 and was registered under the CRD42022344856 (Prospero, https://www.crd.york.ac.uk/prospero) in July 2022.

Eligibility criteria

Observational studies (cohort, case-control, and cross-sectional studies) evaluating salivary flow rate in children and teenagers with Down syndrome compared with non-syndrome controls were selected for this systematic review. The eligible population was children and adolescents (up to 18 years old), without sex restrictions; previously diagnosed with Down syndrome were considered to be the Exposure Group, while the comparison group (control?) consisted of the systemically healthy population without Down syndrome. The salivary flow rate was considered as the main outcome. Studies that assessed/performed salivary flow rate, but did not report the results, or results reported with other dichotomizations were excluded. Clinical registry studies and studies that were not concluded were not considered for inclusion. Parotid saliva alone was an exclusion criterion for our review. Moreover, children and teenagers with altered salivary flow rate due to conditions (except Down Syndrome) or medications/treatments that may be associated with a decrease or an increase in salivary flow rate were excluded. There were no restrictions in terms of language, year of publication of the study, ethnicity, or country.

Information source

The sources of information were based on main databases such as PubMed / Medline, Scopus, Web of Sciences, Embase, and the Cochrane Library. Regional databases such as Lilacs and BBO accessed from the Virtual Health Library were also included. Open Grey (https://onlinelibrary.london.ac.uk/resources/databases/opengrey), Google Scholar (first 100 articles), and the Catalog of Theses and dissertations of the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Capes) were assessed.

Search strategy

The search strategy was elaborated according to the Population AND Exposure AND Outcome structure, for which mesh terms and entry terms were used. The data referring to the strategy used are described in Table 1. The date of the last search was 03/01/2024. The search strategy was validated from studies obtained in an exploratory search of the topic. The sensitivity of the search to identify all studies considered clearly eligible was high. The search process was carried out in pairs (researchers ACN and BDF). Any disagreements were settled by consensus with the help of a third investigator (WRC).

Table 1. Search strategy.

Search strategy
#1 #1 MeSH descriptor: [Child, Preschool]
#2 MeSH descriptor: [Child]
#3 MeSH descriptor: [Adolescent]
#4 (Preschool Child OR Children, Preschool OR Preschool Children OR Children OR Adolescents OR Adolescence OR Teens OR Teen OR Teenagers OR Teenager OR Youth OR Youths OR Adolescents, Female OR Adolescent, Female OR Female Adolescent OR Female Adolescents OR Adolescents, Male OR Adolescent, Male OR Male Adolescent OR Male Adolescents):ti,ab,kw
#1 OR #2 OR #3 OR#4
#2 #1 MeSH descriptor: [Down Syndrome]
#2 (Down Syndrome OR Syndrome, Down OR Mongolism OR Trisomy G OR Downs Syndrome OR Trisomy 21 OR Trisomy 21, Mitotic Nondisjunction OR Down Syndrome, Partial Trisomy 21 OR Partial Trisomy 21 Down Syndrome OR Trisomy 21, Meiotic Nondisjunction):ti,ab,kw
#1 OR #2
#3 #1 MeSH descriptor: [Saliva]
#2 (Saliva OR Salivas OR Salivary flow):ti,ab,kw
#1 OR #2
#1 AND #2
#1 AND #2 AND #3
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* Contact by email with a faculty where the study was presented to obtain the full text, and it was not available in the online version to make available. Diagram available from: Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. doi: 10.1136/bmj.n71

Selection process

The selection process was carried out in pairs in all phases. In the first phase, the studies were selected by title and abstract, and in the second phase, the full text was read according to the eligibility criteria. Any disagreements were settled by consensus. Articles in languages other than Spanish, Portuguese, and English were translated using the Google translator tool.

Data collection process and data items

Data were collected by two independent reviewers (BDF and WRC) and verified by a third investigator (AH) who resolved possible disagreements. Data were collected on the authors, year of publication, country, study design, total number of participants, age, sex, characteristics of the children, saliva collection methods, salivary flow rate, funding, limitations or bias reported, and conflict of interest.

Study risk of bias assessment

The risk of bias was assessed by using the Newcastle Ottawa Scale tool (NOS) modified for cross-sectional studies. 15 This tool assesses the selection, comparability, and outcome process according to bias for these types of studies. This process was carried out by two researchers in pairs and individually (BDF and WRC), and doubts or disagreements were resolved by consensus. Regarding the risk of bias, individual studies were assessed as low risk (≥ 7 stars) or high risk (< 7 stars). 16

Effect measures

The salivary flow rate (mean and standard deviation) was evaluated as a continuous variable, expressed in mL of saliva (stimulated or unstimulated) per minute (mL/min). The measure evaluated was the Standardized Mean Difference (SMD) between the exposed and control groups, due to the variability of saliva collection methods. The data provided in median and ranges were transformed into mean and standard deviation. 17

Synthesis methods

The Standardized Mean Difference was measured using Inverse Variance (IV) as the statistical method, with a 95% confidence interval (CI). The chi-square test and I 2 statistic were used to assess the heterogeneity in the studies (p < 0.10). The overall effect was assessed using the Z statistic at a 5% significance level. The Tau 2 was used to interpret the data variability of effect size, and the analysis model was carried out using the random effect model 18 . In cases of high heterogeneity in the results, this was explored with subgroup analysis considering saliva collection methods (stimulated or unstimulated), age of participants (years old), and sex (male or female). The analysis was adjusted by risk of bias (low risk of bias). Statistical analyses were performed in Review Manager version 5.4.

Publication bias assessment

Small study effects and publication bias were assessed by Egger’s test (p < 0.10) for pooling up to 10 studies, and the funnel plot graph. 19 The ‘trim and fill’ method was performed to identify and correct for funnel plot asymmetry arising from publication bias. 20,21 Statistical analyses were carried out in R version 4.1.3.

Certainty of the evidence assessment

The certainty of evidence was determined according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. 22 Cross-sectional studies start with low evidence. Parameters such as the risk of bias, inconsistency, indirectness, imprecision, publication bias, effect size, absence of confounding factors, and dose-response effect were assessed for classification. 23 The certainty of the evidence was classified as very low, low, moderate, or high. GRADEpro software (gradepro.org) was used to perform the analysis and to generate the results.

Results

Study selection

A total of 500 studies were identified from the databases, as follows: PubMed / Medline (n = 83), Scopus (n = 107), Web of Sciences (n = 73), Embase (n = 63), Cochrane Library (n = 8), Lilacs (n = 7), BBO (n = 1), Open Grey (n = 56), Google Scholar (n = 100), and CAPES Catalog (n = 2). Subsequently, 240 duplicate studies were removed and 220 other studies were excluded according to the eligibility criteria. Of the 39 eligible studies, 25 studies were excluded for the following reasons: age range for exposed and control groups different from under 18 years; salivary flow rate assessed or performed, but not reported in the results; results reported with other dichotomizations; clinical registry study, and study not concluded. Finally, 14 clinical studies were included in the current review (Figure 1).

Figure 1. Flow-Diagram.

Figure 1

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Study characteristics and individual results

This systematic review included 14 studies with a cross-sectional design. The studies were conducted in developed and underdeveloped countries on four continents, with seven in Brazil and one each in the Kingdom of Saudi Arabia, Portugal, Indonesia, New Zealand, Türkiye, Iraq, and India, respectively. The studies evaluated a total of approximately one thousand children and adolescents. Samples or records of participants with Down syndrome were obtained from centers and schools for special children, dental clinics, pediatric hospitals, the Association of Parents and Friends of Exceptional People, and national databases. Controls were siblings or healthy children and teenagers from preschools and elementary schools, dental clinics, and hospitals in the same city or region. A wide variety of saliva collection methods were used. The individual results are described (Table 2).

Table 2. Characteristics of studies included.

Study identification Country Study design Participants Characteristics of Children and adolescents Saliva collection methods Salivary flow rate (mL/min) Funding Limitations or bias reported Conflict of interest
Mean (standard deviation)
Alzughaibi, Filimban, & Arafa, 20176 Kindom of Saudi Arabia Cross-sectional study DS: 100 children and adolescents DS: Special needs centers Unstimulated saliva 0.80 (0.66) Faculty of Dentistry in Umm Al-Qura University. Does not justify the sample size. It does not describe in detail, how the evaluation process was performed. None
Areias et al., 201230 Time: 9 to 11 am  
Bachtiar, Salmiah, & Luthfiani, 20187 Fasting: 2 h (drink and food) Control: 0.64 (0.45)
Control: 103 children and adolescents Control: Non-syndrome children and adolescents from elementary and kindergarten schools   p < 0.05
Age: 4 to 15 years old      
Sex: Matched between groups      
Areias et al., 2012 30 Portugal Cross-sectional study DS: 44 children and adolescents Portuguese national database Stimulated saliva 0.30 (0.24) The Faculty of Dental Medicine of the University of Porto, Portugal. Does not justify the sample size. No detailed description provided of how the evaluation process was performed None
Stimulus: Masticatory (paraffin)  
Time: 8 am Control: 0.47 (0.29)
Fasting: 2 h (eating, tooth brushing, or mouth washing)  
Control: 44 children and adolescents Control: The sibling   p < 0.05
  DS: closest in age who was living in the same household was used as the matched control.    
Age: 6 to 18 years old      
Sex: Not reported      
Bachtiar, Salmiah, & Luthfiani, 20187 Indonesia Cross-sectional study 30 children and adolescents (17 males and 13 females) Medan Helvetia and Medan Timur district Unstimulated saliva DS: 0.35 (0.13) No reported Does not justify the sample size. No detailed description provided of how the evaluation process was performed None
   
Time: 9 to 11 am  
  Control: 0.47 (0.17)
Fasting: Not reported  
Control: 30 children and adolescents (17 males and 13 females) Control: Non-syndrome children and adolescents. (Medan Helvetia and Medan Timur district)   p < 0.05
Age: 6 to 18 years old    
Balaji et al., 2016 13 New Zealand Cross-sectional study DS: 19 children and adolescents DS: Participants were contacted through the Pediatric Dentistry Clinic Unstimulated saliva (Preweighed Salivette ®) DS: 1.10 (0.50) New Zealand Dental Association and Ministry of Health Does not justify the sample size. Fewer participants in the experimental group than the minimum necessary. No description of the sampling strategy. It does not describe how the evaluation process was in detail. None
  Time: Not reported    
  Fasting: Not reported Control: 1.0 (0.30)  
Control: 10 children and adolescents Control: Sibling of closest age.   p > 0.05  
Age: 2 to 12 years old      
Sex: Matched between groups      
Cogulu et al., 2006 31 Türkiye Cross-sectional study DS: 73 children and adolescents (38 males and 35 females) DS: Department of Pediatrics Stimulated saliva DS: None Does not justify the sample size. No detailed description provided of how the evaluation process was performed None
    1.05 (0.17)
  Stimulus: Masticatory (paraffin)  
  Time: 9 to 12 am Control: 1.04 (0.17)
  Fasting: 2 h (eat or drink)  
Control: 70 children and adolescents (33 males and 37 females) Control: Non-syndrome children and adolescents.   p > 0.05
  (State schools in Izmir)    
Age: 7 to 12 years old      
Domingues et al., 2017 8 Brazil Cross-sectional study DS: 18 children and adolescents (8 male and 10 female) DS: APFE Stimulated saliva DS: 0.25 (0.10) Brazilian Financing Agency FAPESP (São Paulo Research Foundation––grant 2013/18010-2) and the Association of Parents and Friends of People with Disabilities (APAE) in Araraquara. Fewer participants in the experimental group than the minimum necessary. No detailed description provided of how the evaluation process was performed None
  Stimulus: Masticatory (paraffin)    
  Time: 9 to 11 am Control: 0.63 (0.23)  
  Fasting: 2 h (eat)    
Control: 23 children and adolescents (9 males and 14 females) Control: Non-syndrome children and adolescents (Pediatric Clinic)   p < 0.05  
Age: 6 to 12 years old      
Habibe et al., 2020 5 Brazil Cross-sectional study DS: 22 children and adolescents DS: AFPE Unstimulated saliva (Preweighed Salivette ®) DS: 0.28 (0.23) São Paulo Research Foundation (Fundação de Amparo à Pesquisa do Estado de São Paulo, FAPESP), National Council for Scientific and Technological Development (CNPq) and National Institute of Science and Technology in (CNPq/CAPES/FAPEMIG). Theranostics and Nanobiotechnology. Does not justify the sample size. No detailed description provided of how the evaluation process was performed None
        Convenience samples.
  Time: Not reported      
    Control: 0.36 (0.14)    
  Fasting: 1 h (eating, drinking liquids or brushing their teeth)      
Control: 22 children and adolescents Control: Non-syndrome children and adolescents   p < 0.05    
Age: 7 to 18 years old        
Sex: Matched between groups        
Jafer, 2009 24 Iraq Cross-sectional study DS: 50 children DS Stimulated saliva DS: 0.47 (0.08) None No detailed description provided of how the evaluation process was performed None
Stimulus: Not reported*   *contact by email with a faculty where the study was presented to obtain the full text, and it was not available in the online version to make available.
  Control:
Time: Not reported* 0.92 (0.65)
Fasting: Not reported*  
  p < 0.05
Control: 50 children Control: Non-syndrome children    
Age: 7 to 10 years old    
Sex: Not reported*    
Raurale et al., 2013 32 India Cross-sectional study DS: 30 children and adolescents DS: Hospital Ahmednagar Unstimulated saliva DS: 0.30 (0.03) None Does not justify the sample size. No detailed description provided of how the evaluation process was performed None
  Time: 8 to 10 am Control: 1.26 (0.05)
  Fasting: Not reported  
Control: 30 children and adolescents Control: Non-syndrome children and adolescents   p > 0.05
Age: 8 to 14 years old    
Sex: Not reported    
Schutz et al., 2013 25 Brazil Cross-sectional study DS: 30 adolescents DS: Down’s syndrome diagnosed. (City special schools) Stimulated saliva DS: 0.32 (0.25) None Does not justify the sample size. No description of the sampling strategy No detailed description provided of how the evaluation process was performed None
Stimulus: Masticatory (latex)  
   
Fasting: 2 h (eat)  
Control: 30 adolescents Control: Non-syndrome adolescents   p < 0.05
Age: 10 to 15 years old    
Sex: Matched between groups    
Siqueira & Nicolau, 2002 26 Brazil Cross-sectional study DS: 17 children (8 males and 9 females) DS: APFE Stimulated saliva DS: 0.38 (0.15) Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq). Does not justify the sample size. No description given of the sampling strategy. No detailed description provided of how the evaluation process was performed None
  Stimulus: Masticatory (paraffin) Male: 0.41 (0.19)  
    Female: 0.36 (0.13)  
  Time: 9 to 11 am Control: 0.88 (0.26)  
  Fasting: 2 h (eat)    
    Male: 0.93 (0.25)  
    Female: 0.82 (0.27)  
    p < 0.05  
Control: 18 children (9 males and 9 females) Control: Non-syndrome children      
Age: 6 to 10 years old        
Siqueira et al., 2004 27 Brazil Cross-sectional study DS: 22 children (12 males and 10 females) DS: APFE Stimulated saliva DS: 0.37 (0.13) Conselho Nacional de Desenvolvimento Científico e Tecnologico (CNPq). Does not justify the sample size. No description of the sampling strategy. It does No detailed description provided of how the evaluation process was performed None
  Stimulus: Masticatory (paraffin)    
    Male: 0.41 (0.17)  
    Female: 0.35 (0.19)  
  Time: 8 to 10 am    
    Control: 0.95 (0.21)  
  Fasting: Not reported    
    Male: 0.97 (0.36)  
    Female: 0.84 (0.25)  
Control: 21 children Control: Non-syndrome children   p < 0.05  
(11 males and 10 females)      
Age: 6 to 10 years old      
Siqueira et al., 2005 28 Brazil Cross-sectional study DS: 25 children (11 males and 14 females) DS: APFE Unstimulated saliva DS: 0.34 (0.14) Not reported Does not justify the sample size. No description of the sampling strategy. No detailed description provided of how the evaluation process was performed. None
  Time: 9 to 10 am Male: 0.37 (0.14)
    Female: 0.32 (0.19)
  Fasting: 2 h (eat)  
    Control: 0.56 (0.18)
    Male: 0.63 (0.22)
    Female: 0.47 (0.27)
Control: 21 children (10 males and 11 females) Control: Non-syndrome children   p < 0.05
Age: 2 to 60 months    
Siqueira et al., 2007 29 Brazil Cross-sectional study DS: 20 children DS: APFE Unstimulated saliva (using slight suction through a soft plastic catheter) DS: 0.32 (0.10) CAPES (Brazilian Ministry of Education) Does not justify the sample size. No description of the sampling strategy. No detailed description provided of how the evaluation process was performed None
  Time: 9 to 10 am Control: 0.58 (0.11)  
  Fasting: 2 h (eat)    
    p < 0.05  
    Control: 18 children Control: Non-syndrome children. (Dental Clinic)          
Age: 12 to 60 months
Sex: Not reported
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DS: Down’s syndrome diagnosed; AFPE: Association of Parents and Friends of Exceptional.

Risk of bias in studies

The studies were evaluated according to the risk of bias; 8 were classified as high risk of bias 5,13,24-29 , and 6 as low risk of bias 6-8,30-32 (Table 3). The main biases detected in the selection of the participants were no justification of the sample size 5-7,13,25-29,30-32 ; no description of the sampling strategy; 13,25-29 and convenience samples 5 . Regarding the comparability between the groups, the majority of the studies were comparable in the characteristics between them, except two studies 8,13 that had fewer participants in the experimental group than the minimum necessary. According to the outcome assessed, none of the studies described the evaluation process in detail, for example, if the person who collected the saliva was the same one who evaluated it and knew which group the participant was from, or if a code was created to carry out the blinding, etc.

Table 3. Risk of bias in individual studies.

Study identification Selection Comparability Outcome Total Risk of bias
(5 stars) (2 stars) (3 stars) (10 stars)
Alzughaibi, Filimban, & Arafa, 20176 4:00 AM 2 1 b 7 Low risk of bias
Areias et al., 2012 30 4:00 AM 2 1 b 7 Low risk of bias
Bachtiar, Salmiah, & Luthfiani, 20187 4:00 AM 2 1 b 7 Low risk of bias
Balaji et al., 2016 13 3 a, c 1 d 1 b 5 High risk of bias
Cogulu et al., 2006 31 4:00 AM 2 1 b 7 Low risk of bias
Domingues et al., 2017 8 5 1 d 1 b 7 Low risk of bias
Habibe et al., 2020 5 3 a, f 2 1 b 6 High risk of bias
Jafer, 2009 24 3 g 2 1 b 6 High risk of bias
Raurale et al., 2013 32 4:00 AM 2 1 b 7 Low risk of bias
Schutz et al., 2013 25 3 a, c 2 1 b 6 High risk of bias
Siqueira & Nicolau, 2002 26 3 a, c 2 1 b 6 High risk of bias
Siqueira et al., 2004 27 3 a, c 2 1 b 6 High risk of bias
Siqueira et al., 2005 28 3 a, c 2 1 b 6 High risk of bias
Siqueira et al., 2007 29 3 a, c 2 1 b 6 High risk of bias
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The risk of bias was assessed by using they Newcastle Ottawa Scale (NOS) , modified version for cross-sectional studies. Regarding the risk of bias, individual studies were assessed as low risk (≥ 7 stars) or high risk (< 7 stars). a does not justify the sample size. b No detailed description provided about how the evaluation process was performed ,Flow- c No description of the sampling strategy. d Fewer participants in the experimental group than the minimum necessary. f Convenience samples. g Contact by email with a faculty where the study was presented to obtain the full text and no answers.

Results of syntheses

The meta-analysis showed that children and teenagers with Down syndrome have a lower salivary flow rate compared to non-syndrome (SMD -1.56, 95%CI -2.23; -0.89, p < 0.05, I 2 95%) (Figure 2). When adjusted by low risk of bias, the results are similar (SMD -1.71, 95%CI -2.81; -0.60, p < 0.05, I 2 97%), but with significant differences (p < 0.01) in behavior between the subgroups of the saliva collection methods (Unstimulated saliva, SMD -5.07, 95%CI -7.96; -2.18, p < 0.01, I 2 98%; Stimulated saliva, SMD -0.80, 95%CI -1.78; 0.17, p = 0.11, I 2 92%) (Figure 3). In the results by age groups, significant differences were not observed in the salivary flow rate behavior between the ages (p = 0.60) (up to 5 years old, SMD -1.85, 95%CI -2.90; -0.81, p < 0.01, I 2 74%; 2 to 18 years old, SMD -1.51, 95%CI -2.24; -0.78, p < 0.01, I 2 95%) (Figure 4). In the same way, similar results were observed when adjusting for the risk of bias (2 to 18 years old, SMD -1.71, 95%CI -2.87; -0.60, p < 0.01, I 2 97%) (Figure 5). In addition, the male and female sexes presented similar behavior in salivary flow rate between the subgroups (p = 0.70), being lower in the experimental group (SMD -1.63, 95%CI -2.18; -1.08, p < 0.05, I 2 39%) (Male, SMD -1.77, 95%CI -2.39; -1.16, p < 0.01, I 2 0%; Female, SMD -1.53, 95%CI -2.58; -0.48, p < 0.01, I 2 67%) (Figure 6).

Figure 2. Forest plot comparing the difference in salivary flow rate (mL/min) between groups of children and adolescents with Down syndrome and non-syndrome by saliva collection method.

Figure 2

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Figure 3. Forest plot comparing the difference in salivary flow rate (mL/min) between groups of children and adolescents with Down syndrome and non-syndrome by saliva collection method and adjusted by risk of bias.

Figure 3

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Figure 4. Forest plot comparing the difference in salivary flow rate (mL/min) between groups of children and adolescents with Down syndrome and non-syndrome by age.

Figure 4

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Figure 5. Forest plot comparing the difference in salivary flow rate (mL/min) between groups of children and adolescents with Down syndrome and non-syndrome by age and adjusted by risk of bias.

Figure 5

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Figure 6. Forest plot comparing the difference in salivary flow rate (mL/min) between groups of children and adolescents with Down syndrome and non-syndrome by sex.

Figure 6

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Reporting biases

The funnel plot graph showed visually detected asymmetry, and after performing the Egger’s test, publication bias was corroborated (p < 0.01) (Figure 7.1). The analysis was adjusted by the ‘trim and fill’ method to estimate missing studies due to publication bias (p = 0.74) (Figure 7.2).

Figure 7. (A). Standard Error (x axis) and Standardized Mean Difference (y axis). Funnel plot shows an asymmetry detected. Egger test (t = -6.60, df = 12, p-value < 0.0001). (B). Standard Error (x axis) and Standardized Mean Difference (y axis). Funnel plot shows publication bias adjusted by the ‘trim and fill’ method. Egger test (t = -0.33, df = 18, p-value = 0.7430). Fill points estimate the number of missing studies.

Figure 7

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Certainty of evidence

Regarding the main outcome, the certainty of the evidence of the results was very low, due principally to the risk of bias (sample size), high heterogeneity, imprecision, and the design of the studies (cross-sectional). According to analysis by sex, the evidence was very low due to the low number the studies and participants and the high risk of bias (Table 4).

Table 4. The certainty of the evidence assessed by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach.

Outcome Study design (n) Risk of bias Inconsistency Indirectness Imprecision Other considerations Certainty Explanations
Salivary flow rate (See Figure 2 and 4) Cross-sectional studies (n = 14) very serious1 very serious2 not serious serious3 Publication bias4. Dose-response gradient was not assessed. Confounding factors were evaluated5. Very large effect (SMD > 0.8 or SMD < -0.8). ⨁◯◯◯ 1 More than half of the studies were high risk of bias (See Table 4).
Very low 2 High heterogeneity due to the age ranges of participants verified by subgroup analysis (See Figure 4).
  3 Total number of people evaluated was 990, and Confidence Interval (CI) more than CI ± 0.5.
  4 Publication bias detected (See Figure 7).
  5 Subgroups analysis (saliva collected methods, age and risk of bias)
Salivary flow rate adjusted by low risk of bias (See Figure 3 and 5) Cross-sectional studies (n = 6) not serious very serious6 not serious serious7 Publication bias not applicable (n < 10). Dose-response gradient was not assessed. Confounding factors were evaluated8. Very large effect (SMD > 0.8 or SMD < -0.8). ⨁◯◯◯ 6 High heterogeneity due to the age ranges of participants verified by subgroup analysis (See Figure 5).
Very low 7 Total number of people evaluated was 595, but CI more than ± 0.5.
  8 Subgroups analysis (saliva collected methods)
Salivary flow rate by sex (See Figure 6) Cross-sectional studies (n = 3) very serious9 not serious10 not serious very serious11 Publication bias not applicable (n < 10). Dose-response gradient was not assessed. Confounding factors were evaluated12. Very large effect (SMD > 0.8 or SMD < -0.8). ⨁◯◯◯ 9 All studies were high risk of bias (See Table 4).
Very low 10 Low heterogeneity
  11 Total number of people evaluated was 124. CI more than ± 0.5.
  12 Subgroups analysis (only by sex)
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Discussion

The results of this meta-analysis suggested that the salivary flow rate was lower in patients with Down syndrome, but that there were differences between collection methods. The quantity of non collected was lower in individuals with Down syndrome, while the stimulated saliva collected showed no differences.

Saliva is secreted by three pairs of major salivary glands, the parotid, submandibular, and sublingual, by a pair of tubarial glands located in the oropharynx, and by hundreds of minor salivary glands. 33 Control of the secretions of these glands involves afferent pathways for conducting signals to the central nervous system, efferent pathways of the autonomic, sympathetic, and parasympathetic nervous systems, responsible for conducting signals to the glands. In the absence of stimuli and the presence of the individual’s awareness, salivary secretion is controlled by minor reflex activities of the central nervous system. 34

The volume of saliva produced under these conditions as a function of time in minutes is called resting, basal, or unstimulated salivary flow. 35 The submandibular, sublingual, parotid, and minor glands contribute to this flow. The salivary flow produced in response to the stimulus of chemo and/or mechanoreceptors is called stimulated. The responses of different types of glands to stimuli differ, with the parotid glands being more strongly stimulated by mastication, and the submandibular and sublingual glands being more responsive to gustatory stimuli. Whereas the smaller glands flow practically continuously , but are influenced by the circadian rhythm. 34 Unstimulated salivary flow is more important for assessing glandular function, as changes in function do not always affect unstimulated flow. 36

The literature has shown conflicting data regarding salivary flow rate in patients with Down syndrome, when compared with non-syndrome individuals. Part of the discrepancies result from the fact that some studies were conducted with unstimulated saliva and others with flow, mostly after mechanical stimulation. The unstimulated flow varies as a function of the health status and physiological conditions of individuals 35 . The submandibular and sublingual glands contribute to approximately 75% of this flow, while the parotid glands account for 15–20% and the minor glands for 5–8%. The reduction in unstimulated salivary flow seen in Down syndrome may result, at least in part, from the decreased reflex activity of the central nervous system 34 or the difficulty of spitting in this population. The absence of a significant difference in the stimulated salivary flow rate of individuals with Down syndrome compared with non-syndrome individuals suggests that the lower mastication force, due to the reduction in electrical potential in muscles involved in this process, 37 tongue hypotonia, and temporomandibular disorders 38 common in the syndrome. These factors do not interfere with the secretory capacity of the parotid glands, which contribute to 50% of the mechanically stimulated salivary flow. 9,39,40 In contrast,, it should be considered that this population, as well as the child population under 5 years of age, have difficulties with spitting, so methods such as light suction through a soft plastic catheter or other device would facilitate collection and are recommended methods. 29

The electrolyte concentration gradient, maintained by the active transport of sodium and potassium, in combination with the polarized distribution of membrane transport proteins also influences the secretion of fluids by acinar cells of the salivary glands, and so does the modification of these glands by the duct cells. 41 There is no evidence, however, that the reduction in salivary flow rate after mechanical stimulation in patients with Down syndrome results from the higher sodium concentration observed in these conditions. 26,27

The time when the saliva samples were obtained may have interfered with the results, as salivary secretion is influenced by the circadian rhythm. 34 To eliminate this possible bias, all studies included in the review reported sample collection in the morning. In addition, age can interfere with salivary gland secretion 39 and people with Down syndrome may experience accelerated neurological aging 42 caused by an increase in the oxidative state, 43 so analyses were carried out to assess the impact of these biases on the results. From birth to adolescence, there are variations in the composition of saliva that reflect the development and maturation of the salivary glands 44,45 and these factors can be associated with the different stages of dentition; i.e., deciduous, mixed, and permanent dentition. 46,47 It is known that unstimulated salivary flow is higher at 30 and 42 months of age than at 18 months 48 and decreases throughout life. 40,43,49 With aging, there is a reduction in the glandular secretory epithelium, an increase in intraglandular lipid and connective tissue deposits, and a reduction in blood perfusion. 50 Moreover, all of these changes compromise the salivary flow, whether stimulated or not. The studies included in this review collected saliva from a broad age groups, and it was not possible to perform subdivisions for data analysis with the lower range of ages. Despite this, we were able to verify that the salivary flow was lower in patients with Down syndrome, irrespective of age.

Sex is another factor that can interfere with salivary flow results. Lower unstimulated flow values have been described in females compared with males in different age groups. 46 This difference is attributed to the smaller size of the salivary glands in women, 51,52 including the submandibular gland. 53 Furthermore, estrogen is an important factor in maintaining salivary flow. 54,55 In this review, it was not possible to certify the effects of sex on salivary flow, due to the low number of studies presenting these values and the very low certainty of the evidence provided.

Despite the inclusion of a broad search strategy in several databases, including the gray literature, publication bias was evident. This method of analysis may have limitations when the studies present important methodological deficiencies. 19 Studies with higher methodological quality and that control of confounding factors, such as age ranges and sex are necessary. Considering the implications of saliva as lubrication, protection, and maintenance of the balance of the oral microbiota for the health of patients with Down syndrome, 56,57 preventive actions that reinforce oral hygiene, in view of the increased risk of periodontal diseases, 5,58 are considered timely strategies in this population. Relative to dental caries, the results suggested that hyposalivation in patients with Down syndrome does not necessarily imply a higher number of dental caries cases. 30

Conclusion

With regard to the very low evidence, children and teenagers with Down syndrome have a lower salivary flow rate with an unstimulated saliva collection method compared with non-syndrome controls. Saliva collection methods can interfere with salivary flow analysis. The salivary flow rate can vary according to the age groups evaluated, generating high heterogeneity. In contrast, sex does not appear to interfere with salivary flow rate behavior.

Acknowledgements

The authors are grateful for the support provided in the form of a study grant by the Coordination for the Improvement of Higher Education Personnel (CAPES). Finance code 001. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Funding Statement

The authors are grateful for the support provided in the form of a study grant by the Coordination for the Improvement of Higher Education Personnel (CAPES). Finance code 001. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability:

The authors declare that all data generated or analyzed during this study are included in this published article.

References

  • 1.Bull MJ. Down Syndrome. N Engl J Med. 2020 Jun;382(24):2344–2352. doi: 10.1056/NEJMra1706537. [DOI] [PubMed] [Google Scholar]
  • 2.Santoro JD, Pagarkar D, Chu DT, Rosso M, Paulsen KC, Levitt P, et al. Neurologic complications of Down syndrome: a systematic review. J Neurol. 2021 Dec;268(12):4495–4509. doi: 10.1007/s00415-020-10179-w. [DOI] [PubMed] [Google Scholar]
  • 3.Deps TD, Angelo GL, Martins CC, Paiva SM, Pordeus IA, Borges-Oliveira AC. Association between dental caries and down syndrome: a systematic review and meta-analysis. PLoS One. 2015 Jun;10(6):e0127484. doi: 10.1371/journal.pone.0127484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Moreira MJ, Schwertner C, Jardim JJ, Hashizume LN. Dental caries in individuals with Down syndrome: a systematic review. Int J Paediatr Dent. 2016 Jan;26(1):3–12. doi: 10.1111/ipd.12212. [DOI] [PubMed] [Google Scholar]
  • 5.Habibe CH, Yoshida RA, Gorjão R, Gutierrez GM, Heller D, Birbrair A, et al. Comparison of salivary cytokines levels among individuals with Down syndrome, cerebral palsy and normoactive. J Clin Exp Dent. 2020 May;12(5):e446–e451. doi: 10.4317/jced.56336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Alzughaibi OS, Filimban LA, Arafa AA. Assessment of Salivary Immunoglobulin A, a-amylase, pH and flow-rate effects on dental caries experience of down's syndrome children in Makkah, Saudi Arabia. Int J Health Sci Res. 2017;7(3):143–149. [Google Scholar]
  • 7.Bachtiar ZA, Salmiah S, Luthfiani C. Comparison of caries status and saliva condition (pH, Buffer Capacity, Flow Rate, and Volume) among Down Syndrome and normal children aged 6-18 years old in SLB C Medan Helvetia and Medan Timur District Proceedings of the International Dental Conference of Sumatera Utara. Advances in Health Science Research. 2017 doi: 10.2991/idcsu-17.2018.86. [DOI] [Google Scholar]
  • 8.Domingues NB, Mariusso MR, Tanaka MH, Scarel-Caminaga RM, Mayer MP, Brighenti FL, et al. Reduced salivary flow rate and high levels of oxidative stress in whole saliva of children with Down syndrome. Spec Care Dentist. 2017 Nov;37(6):269–276. doi: 10.1111/scd.12258. [DOI] [PubMed] [Google Scholar]
  • 9.Edgar WM. Saliva: its secretion, composition and functions. Br Dent J. 1992 Apr;172(8):305–312. doi: 10.1038/sj.bdj.4807861. [DOI] [PubMed] [Google Scholar]
  • 10.Bel'skaya LV, Sarf EA, Kosenok VK. Age and gender characteristics of the biochemical composition of saliva: correlations with the composition of blood plasma. J Oral Biol Craniofac Res. 2020;10(2):59–65. doi: 10.1016/j.jobcr.2020.02.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Pedersen A, Sørensen CE, Proctor GB, Carpenter GH. Salivary functions in mastication, taste and textural perception, swallowing and initial digestion. Oral Dis. 2018 Nov;24(8):1399–1416. doi: 10.1111/odi.12867. [DOI] [PubMed] [Google Scholar]
  • 12.Topkas E, Keith P, Dimeski G, Cooper-White J, Punyadeera C. Evaluation of saliva collection devices for the analysis of proteins. Clin Chim Acta. 2012 Jul;413(13-14):1066–1070. doi: 10.1016/j.cca.2012.02.020. [DOI] [PubMed] [Google Scholar]
  • 13.Balaji K, Milne TJ, Drummond BK, Cullinan MP, Coates DE. A comparison of salivary IgA in children with Down syndrome and their family members. Arch Oral Biol. 2016 Jul;67:39–45. doi: 10.1016/j.archoralbio.2016.03.005. [DOI] [PubMed] [Google Scholar]
  • 14.Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. 89Syst Rev. 2021 Mar;10(1) doi: 10.1186/s13643-021-01626-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Modesti PA, Reboldi G, Cappuccio FP, Agyemang C, Remuzzi G, Rapi S, et al. Panethnic differences in blood pressure in Europe: a systematic review and meta-analysis. PLoS One. 2016 Jan;11(1):e0147601. doi: 10.1371/journal.pone.0147601. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Martins JR, Díaz-Fabregat B, Ramírez-Carmona W, Monteiro DR, Pessan JP, Antoniali C. Salivary biomarkers of oxidative stress in children with dental caries: systematic review and meta-analysis. Arch Oral Biol. 2022 Jul;139:105432. doi: 10.1016/j.archoralbio.2022.105432. [DOI] [PubMed] [Google Scholar]
  • 17.Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. 135BMC Med Res Methodol. 2014 Dec;14(1) doi: 10.1186/1471-2288-14-135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Barili F, Parolari A, Kappetein PA, Freemantle N. Statistical primer: heterogeneity, random- or fixed-effects model analyses? Interact Cardiovasc Thorac Surg. 2018 Sep;27(3):317–321. doi: 10.1093/icvts/ivy163. [DOI] [PubMed] [Google Scholar]
  • 19.Sterne JA, Gavaghan D, Egger M. Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature. J Clin Epidemiol. 2000 Nov;53(11):1119–1129. doi: 10.1016/s0895-4356(00)00242-0. https://doi.org/10.1016/S0895-4356 (00)00242-0 [DOI] [PubMed] [Google Scholar]
  • 20.Duval S, Tweedie R. Trim and fill: A simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000 Jun;56(2):455–463. doi: 10.1111/j.0006-341X.2000.00455.x. [DOI] [PubMed] [Google Scholar]
  • 21.Taylor SJ, Tweedie RL. Practical estimates of the effect of publication bias in meta-analysis. Australas Epidemiol. 1998;5:14–17. [Google Scholar]
  • 22.Schünemann H, Brozek J, Guyatt G, Oxman A. The GRADE Working Group GRADE handbook for grading quality of evidence and strength of recommendations. 2013. [cited 2022 Mar 1]. https://guidelinedevelopment.org/handbook
  • 23.Higgins JP, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, et al. Cochrane handbook for systematic reviews of interventions version 6.2 Cochrane. 2021. [cited 2022 Mar 1]. https://www.training.cochrane.org/handbook
  • 24.Jafer N. Oral health status in relation to nutritional analysis and salivary constituents among a group of children with Down's Syndrome, in comparison to normal children. Baghdad: College of Dentistry, University of Baghdad; 2009. thesis. [Google Scholar]
  • 25.Schutz AK, Utumi AN, Ignácio SA, Brancher JA, Fregoneze AP. Análise sialométrica em indivíduos portadores da síndrome de Down. Arch Oral Res. 2013;9(2):165–170. doi: 10.7213/archivesoforalresearch.09.002.AO03. [DOI] [Google Scholar]
  • 26.Siqueira WL, Jr, Nicolau J. Stimulated whole saliva components in children with Down syndrome. Spec Care Dentist. 2002;22(6):226–230. doi: 10.1111/j.1754-4505.2002.tb00276.x. [DOI] [PubMed] [Google Scholar]
  • 27.Siqueira WL, Oliveira E, Mustacchi Z, Nicolau J. Electrolyte concentrations in saliva of children aged 6-10 years with Down syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004 Jul;98(1):76–79. doi: 10.1016/j.tripleo.2004.04.007. [DOI] [PubMed] [Google Scholar]
  • 28.Siqueira WL, Bermejo PR, Mustacchi Z, Nicolau J. Buffer capacity, pH, and flow rate in saliva of children aged 2-60 months with Down syndrome. Clin Oral Investig. 2005 Mar;9(1):26–29. doi: 10.1007/s00784-004-0282-3. [DOI] [PubMed] [Google Scholar]
  • 29.Siqueira WL, Siqueira MF, Mustacchi Z, Oliveira E, Nicolau J. Salivary parameters in infants aged 12 to 60 months with Down syndrome. Spec Care Dentist. 2007;27(5):202–205. doi: 10.1111/j.1754-4505.2007.tb00347.x. [DOI] [PubMed] [Google Scholar]
  • 30.Areias C, Sampaio-Maia B, Pereira ML, Azevedo A, Melo P, Andrade C, et al. Reduced salivary flow and colonization by mutans streptococci in children with Down syndrome. Clinics (Sao Paulo) 2012 Sep;67(9):1007–1011. doi: 10.6061/clinics/2012. 09. 04. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Cogulu D, Sabah E, Kutukculer N, Ozkinay F. Evaluation of the relationship between caries indices and salivary secretory IgA, salivary pH, buffering capacity and flow rate in children with Down's syndrome. Arch Oral Biol. 2006 Jan;51(1):23–28. doi: 10.1016/j.archoralbio.2005.06.001. [DOI] [PubMed] [Google Scholar]
  • 32.Raurale A, Viddyasagar M, Dahapute S, Joshi S, Badakar C, Mitesh K, Purohit V. Evaluation of oral health status, salivary characteristics and dental caries experience in Down's Syndrome children. NJIRM. 2013;4(6):59–65. [Google Scholar]
  • 33.Valstar MH, de Bakker BS, Steenbakkers RJ, de Jong KH, Smit LA, Klein Nulent TJ, et al. The tubarial salivary glands: a potential new organ at risk for radiotherapy. Radiother Oncol. 2021 Jan;154:292–298. doi: 10.1016/j.radonc.2020.09.034. [DOI] [PubMed] [Google Scholar]
  • 34.Proctor GB, Carpenter GH. Regulation of salivary gland function by autonomic nerves. Auton Neurosci. 2007 Apr;133(1):3–18. doi: 10.1016/j.autneu.2006.10.006. [DOI] [PubMed] [Google Scholar]
  • 35.Navazesh M, Christensen C, Brightman V. Clinical criteria for the diagnosis of salivary gland hypofunction. J Dent Res. 1992 Jul;71(7):1363–1369. doi: 10.1177/00220345920710070301. [DOI] [PubMed] [Google Scholar]
  • 36.Becks H, Wainwright WW. Human saliva; the effect of activation on salivary flow. J Dent Res. 1939;18(5):447–456. doi: 10.1177/00220345390180050601. [DOI] [Google Scholar]
  • 37.Szyszka-Sommerfeld L, Sycinska-Dziarnowska M, Machoy M, Wilczynski S, Maglitto M, Cernera M, et al. Electromyographic Study of Masticatory Muscle Function in Children with Down Syndrome. J Clin Med. 2022 Jan;11(3):506. doi: 10.3390/jcm11030506. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Kaczorowska N, Kaczorowski K, Laskowska J, Mikulewicz M. Down syndrome as a cause of abnormalities in the craniofacial region: a systematic literature review. Adv Clin Exp Med. 2019 Nov;28(11):1587–1592. doi: 10.17219/acem/112785. [DOI] [PubMed] [Google Scholar]
  • 39.Humphrey SP, Williamson RT. A review of saliva: normal composition, flow, and function. J Prosthet Dent. 2001 Feb;85(2):162–169. doi: 10.1067/mpr.2001.113778. [DOI] [PubMed] [Google Scholar]
  • 40.Sreebny LM. Saliva in health and disease: an appraisal and update. Int Dent J. 2000 Jun;50(3):140–161. doi: 10.1111/j.1875-595X.2000.tb00554.x. [DOI] [PubMed] [Google Scholar]
  • 41.Proctor GB, Shaalan AM. Disease-induced changes in salivary gland function and the composition of saliva. J Dent Res. 2021 Oct;100(11):1201–1209. doi: 10.1177/00220345211004842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Lott IT, Doran E, Nguyen VQ, Tournay A, Movsesyan N, Gillen DL. Down syndrome and dementia: seizures and cognitive decline. J Alzheimers Dis. 2012;29(1):177–185. doi: 10.3233/JAD-2012-111613. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Xu F, Laguna L, Sarkar A. Aging-related changes in quantity and quality of saliva: where do we stand in our understanding? J Texture Stud. 2019 Feb;50(1):27–35. doi: 10.1111/jtxs.12356. [DOI] [PubMed] [Google Scholar]
  • 44.Ben-Aryeh H, Fisher M, Szargel R, Laufer D. Composition of whole unstimulated saliva of healthy children: changes with age. Arch Oral Biol. 1990;35(11):929–931. doi: 10.1016/0003-9969(90)90075-L. [DOI] [PubMed] [Google Scholar]
  • 45.van der Linden MS, Vucic S, van Marrewijk DJ, Ongkosuwito EM. Dental development in Down syndrome and healthy children: a comparative study using the Demirjian method. Orthod Craniofac Res. 2017 May;20(2):65–70. doi: 10.1111/ocr.12139. [DOI] [PubMed] [Google Scholar]
  • 46.Forcella L, Filippi C, Waltimo T, Filippi A. Measurement of unstimulated salivary flow rate in healthy children aged 6 to 15 years. Swiss Dent J. 2018 Dec;128(12):962–967. doi: 10.61872/sdj-2018-12-472. [DOI] [PubMed] [Google Scholar]
  • 47.Tucker AS. Salivary gland development. Semin Cell Dev Biol. 2007 Apr;18(2):237–244. doi: 10.1016/j.semcdb.2007.01.006. [DOI] [PubMed] [Google Scholar]
  • 48.Dezan CC, Nicolau J, Souza DN, Walter LR. Flow rate, amylase activity, and protein and sialic acid concentrations of saliva from children aged 18, 30 and 42 months attending a baby clinic. Arch Oral Biol. 2002 Jun;47(6):423–427. doi: 10.1016/s0003-9969(02)00032-8. https://doi.org/10.1016/S0003-9969 (02)00032-8 [DOI] [PubMed] [Google Scholar]
  • 49.Gutman D, Ben-Aryeh H. The influence of age on salivary content and rate of flow. Int J Oral Surg. 1974;3(5):314–317. doi: 10.1016/S0300-9785(74)80069-4. [DOI] [PubMed] [Google Scholar]
  • 50.Ekström J, Khosravani N, Castagnola M, Messana I. In: Dysphagia. medical radiology. Ekberg O, editor, editor. Cham: Springer; 2017. Saliva and the control of its secretion; pp. 19–47. [Google Scholar]
  • 51.Heintze U, Birkhed D, Björn H. Secretion rate and buffer effect of resting and stimulated whole saliva as a function of age and sex. Swed Dent J. 1983;7(6):227–238. [PubMed] [Google Scholar]
  • 52.Percival RS, Challacombe SJ, Marsh PD. Flow rates of resting whole and stimulated parotid saliva in relation to age and gender. J Dent Res. 1994 Aug;73(8):1416–1420. doi: 10.1177/00220345940730080401. [DOI] [PubMed] [Google Scholar]
  • 53.Scott J. Age, sex and contralateral differences in the volumes of human submandibular salivary glands. Arch Oral Biol. 1975 Dec;20(12):885–887. doi: 10.1016/0003-9969(75)90071-0. [DOI] [PubMed] [Google Scholar]
  • 54.Leimola-Virtanen R, Salo T, Toikkanen S, Pulkkinen J, Syrjänen S. Expression of estrogen receptor (ER) in oral mucosa and salivary glands. Maturitas. 2000 Aug;36(2):131–137. doi: 10.1016/s0378-5122(00)00138-9. https://doi.org/10.1016/S0378-5122 (00)00138-9 [DOI] [PubMed] [Google Scholar]
  • 55.Srivastava A, Wang J, Zhou H, Melvin JE, Wong DT. Age and gender related differences in human parotid gland gene expression. Arch Oral Biol. 2008 Nov;53(11):1058–1070. doi: 10.1016/j.archoralbio.2008.05.006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Qian J, Lu J, Huang Y, Wang M, Chen B, Bao J, et al. Periodontitis salivary microbiota Worsens Colitis. J Dent Res. 2022 May;101(5):559–568. doi: 10.1177/00220345211049781. [DOI] [PubMed] [Google Scholar]
  • 57.Lysik D, Niemirowicz-Laskowska K, Bucki R, Tokajuk G, Mystkowska J. Artificial Saliva: Challenges and Future Perspectives for the Treatment of Xerostomia. Int J Mol Sci. 2019 Jun;20(13):3199. doi: 10.3390/ijms20133199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Rondón-Avalo S, Rodríguez-Medina C, Botero JE. Association of Down syndrome with periodontal diseases: systematic review and meta-analysis. Spec Care Dentist. 2024;44(2):360–368. doi: 10.1111/scd.12892. [DOI] [PubMed] [Google Scholar]

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