Association between sickle cell disease and dental caries: a systematic review and meta-analysis

ABSTRACT

Objectives: Although dental caries has been widely reported in individuals with sickle cell disease (SCD), there is still controversial in the literature regarding the association between SCD and dental caries. The aim of this systematic review was to investigate whether individuals with SCD have more dental caries than individuals with non-SCD.

Methods: PubMed and Embase databases were searched for eligible studies. The parameters of the permanent decayed, missing and filled teeth (DMFT) index and the permanent decayed, missing and filled surface (DMFS) index were considered as outcome measures. The overall meta-analyses of the DMFT and DMFS index and various subgroup analyses (caries components, age, and genotypes) of DMFT index were performed to calculate the weighted mean differences (WMD) between patients with SCD and non-SCD individuals.

Results: A total of 9 studies covering 1478 individuals were included in this meta-analysis. The results of overall meta-analyses indicated that the scores of the DMFT and DMFS index were not significantly different between patients with SCD and non-SCD participants. The results of subgroup analyses by caries components, age, and genotypes showed no significant difference in most items. The result of the missing teeth was significantly lower in patients with SCD than in non-SCD individuals (WMD, −0.14; 95% confidence interval [CI], −0.25 to −0.03; P = 0.01).

Discussion and Conclusions: The results revealed that compared with non-SCD individuals, patients with SCD did not suffer from worse dental caries. Considering the limitations, further well-designed studies are necessary to reveal the association between SCD and dental caries.

KEYWORDS:

• Sickle cell disease
• sickle cell anemia
• dental caries
• oral health
• sickle hemoglobin S
• decayed, missing and filled teeth
• decayed, missing and filled surface
• meta-analysis

Introduction

Sickle cell disease (SCD) is one of the most prevalent hemoglobinopathies associated with the replacement of normal hemoglobin with sickle hemoglobin S (HbS) [1–3]. SCD is recognized as a public health issue worldwide that has affected at least 20–25 million people worldwide [4]. As a chronic progressive disease, SCD is a chronic vascular disorder that leads to hemolytic anemia, ongoing organ damage and susceptibility to infection, which are related to high childhood mortality, a considerable financial burden and low quality of life [5–7]. The characteristics of chronic low inflammation of SCD and drug treatments for the disease are considered to be associated with several oral manifestations [8].

Common oral manifestations have been described in SCD patients, including lower salivary flow [9,10], increased levels of biofilm [11,12], hypomineralization of the enamel [13] and dental caries [6,14]. In addition, frequent admission, drug treatments, and diminished oral hygiene are high-risk factors for caries, which contribute to more dental caries in SCD patients [15–17]. Dental caries can destroy hard tissues of the teeth and may lead to pulpitis and periapical periodontitis, which can even become a source of infection in sickle cell crisis due to an insufficient blood supply [18,19]. Dental caries is a common oral manifestation in individuals with SCD [20,21]. Moreover, the association between SCD and dental caries has aroused great interest from clinical doctors and researchers.

Recently, Al-Alawi found significantly higher numbers of decayed teeth among SCD individuals compared with non-SCD individuals [15]. Brandao observed reduced salivary flow in individuals with SCD who had more dental caries than non-SCD controls [9]. However, several other investigators have not noted any statistically significant results in the comparison of dental caries between groups. Therefore, there is a lack of consensus in the literature regarding the association between SCD and dental caries [22,23]. This inconclusive evidence is not advantageous for facilitating oral hygiene management and the prevention of dental caries among SCD individuals.

Therefore, it is necessary to summarize current evidence on the association of dental caries in those with SCD for preventive policies against dental caries. We conducted this systematic review and meta-analysis to evaluate the association between SCD and dental caries.

Materials and methods

Guidelines and registration

We conducted and reported this meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [24] and registered it in PROSPERO (CRD42019132139).

Focused question

Is there any relationship between SCD and dental caries?

Literature search

We conducted an electronic search of PubMed and Embase up to August 2019. We used the following search terms: (1) ‘sickle cell anemia’ or ‘sickle cell diseases’, and (2) ‘dental caries’ or ‘oral manifestation’ or ‘oral health’. In addition, we also identified additional citations by reviewing the reference lists of included studies and pertinent reviews. We contacted the original authors through e-mail for extra data if necessary. The detailed search strategy is illustrated in supplementary file S1.

Inclusion and exclusion criteria

Studies were included if they (1) met a cohort, case-control, or cross-sectional study design and were published in English; (2) diagnosed with or without SCD irrespective of ages; (3) had clear diagnostic criteria for SCD; (4) reported measures of dental caries such as the decayed, missing and filled permanent/deciduous teeth (DMFT/dmft) index; the decayed, missing and filled permanent/deciduous surface (DMFS/dmfs) index; and the decayed permanent/deciduous teeth (D/d), the missing permanent/deciduous teeth (M/m) and the filled permanent/deciduous teeth (F/f) indexes between patients with SCD and non-SCD participants; and (5) data on measures of dental caries were analyzed and were expressed as continuous variables.

Reviews, case reports, and studies provided unavailable, overlapping data and original data expressed as figures were excluded.

Study selection

To select the studies, two reviewers first excluded duplicate studies. After scrutinizing the titles and abstracts of all identified studies, we excluded apparently ineligible studies and selected the potential eligible ones. Then, two reviewers read full papers carefully and analyzed the inclusion and exclusion criteria for further eligible studies. After completing the selection, we included all eligible studies in which the investigators reported measures of dental caries between patients with SCD and non-SCD participants. During the selection and eligibility screening process, two reviewers independently assessed the studies and we resolved any disagreements by means of discussion. If we could not reach a consensus, a third reviewer decided whether the study would be included.

Data extraction

Two reviewers independently performed data extraction from each of the eligible studies. A third reviewer checked the result for accuracy. The main information is as follows: family name of the first author; year of publication; study country; study design; age and number of enrolled participants; diagnostic methods of SCD; outcomes of measuring dental caries; and P values.

Quality assessment

Two reviewers used the Newcastle-Ottawa scale (NOS) to evaluate the methodological quality of cohort studies and case-control studies [25,26]. This assessment scale comprises selection, comparability, and outcome. We used the three broad categories to appraise the quality of the cohort and case-control studies, with a maximum of 9 points. For cross-sectional studies, we used the Agency for Healthcare Research and Quality (AHRQ) recommended criteria to evaluate the methodological quality [27]. The criteria use 11 items, and each item has an answer of either ‘YES’, ‘NO’ or ‘UNCLEAR’. We would score ‘0’ if the item was answered 'NO' or ‘UNCLEAR’ and we would score ‘1’ if the item was answered ‘YES’. Two (items d and k) of the 11 items in the AHRQ recommended criteria were not suitable in our study. The cross-sectional studies also scored a maximum of 9 points. Two reviewers independently completed the quality assessment of the included studies, and we resolved any disagreements by means of discussion. If we could not reach a consensus, a third (Bo Hu) reviewer would decide the outcome.

Statistical analysis

We used software (RevMan 5.3, Cochrane Collaboration) to perform statistical analysis of the included studies. We pooled the weighted mean difference (WMD) with a confidence interval (CI) of 95% from each study to explain the relationships between SCD and dental caries measured by the DMFT or DMFS indexes. We used I² to estimate between-study heterogeneity [28]. An I² of more than 75.0% indicated high heterogeneity; an I² of between 50.0% and 75.0% indicated moderate heterogeneity, and an I² of less than 50.0% indicated low heterogeneity. We used the fixed-effect model when low heterogeneity was found. Otherwise, we used a random-effect model. Sensitivity analysis was conducted by the exclusion of any single study in turn to analyze the stability of the pooled results, if at least 5 studies were included in the comparison. Funnel plots were used to assess any potential publication bias in at least 10 studies.

Analysis of subgroups

We conducted a subgroup analysis by components of the DMFT indexes to calculate the WMDs between patients with SCD and non-SCD participants. We conducted subgroup analyses by each item of the DMFT indexes to further identify the association between SCD and dental caries. We used subgroup analyses of DMFT by age and genotype of the SCD groups and explored the potential source of heterogeneity. First, we divided the patients with SCD into 2 age groups: children/adolescents and adults. Second, in some of the included studies, the investigators divided patients with SCD into different genotype groups. So, we divided the patients with SCD into 2 common genotype groups: the HbSS genotype and HbSC genotype.

Results

Study selection

Figure 1 illustrates the flow diagram of the study selection process. According to our search strategy, we comprehensively retrieved and identified 78 and 41 articles from PubMed and Embase, respectively. We reviewed 13 full-text articles; however, the investigators of one of the 4 studies did not provide available data [11,16,29,30]. Although we sent emails to contact the corresponding authors of these studies, we received no reply. Moreover, we noted that 2 publications were the same by Fernandes but provided case arms for children and teens separately, and data from the matched control group were used in more than one comparison [22,31]. Ultimately, we included a total of 9 studies within 8 publications featuring a comparison group included in the systematic review and in the meta-analysis [9,15,16,22,23,32–34].

Figure 1. Flow diagram of the study selection process.

Summary of the included studies

Table 1 summarizes the main characteristics of the included studies [9,15,16,22,23,32–34]. The publication year ranged from 2002 to 2018. The included publications were 6 cross-sectional [9,15,16,22,23,33] and 2 retrospective cohort studies [32,34]. The investigators conducted three studies [32–34] in the USA, four [9,16,22,23] in Brazil, and one [15] in Saudi Arabia. The investigators evaluated a total of 545 patients with SCD and 967 non-SCD healthy control participants. No study reported the dmfs index. The authors of one study reported the dmft index and found that patients with SCD had more significantly scores than non-SCD children controls [9]. Authors of six [9,15,22,23,33,34] studies reported the scores of the DMFT index; the same authors of two cohort studies [32,34] reported the scores of the DMFS index and authors of one study [34] reported the scores of both the DMFT index and DMFS index; authors of one study only reported the scores of decayed teeth. Investigators in most of the included studies [9,15,16,22,23] used the World Health Organization (WHO) criteria to measure the DMFT index. Investigators in two studies used retrospective records to measure the DMFS index [32,34].

Table 1. Characteristics of the studies included.

(Study, year); Country	Study design	SCD diagnosis	Setting		Sample total (cases AND controls)	Mean age (SD or range)	Measures for dental caries and calibration	Data (mean ± SD)			Statistic	P-value	Study quality
			SCD	Non-SCD				SCD		Non-SCD
(Laurence, Reid et al. 2002) USA	Retrospective cohort	Medical records	Howard University’s College of Dentistry	Howard University’s College of Dentistry	175: 35 SCA; 140 controls	30.4 (19.4) y 30.4(19.0) y	DMFS DMFT K = no definition	33.0(32.3) 12.0(8.3)		26.2(27.7) 9.9(6.9)	t-tests	0.21 0.12	High
(Laurence, George et al. 2006) USA	Retrospective cohort	Medical history	Howard University Hospital in Washington, D.C and Johns Hopkins Hospital in Baltimore	The same University College of Dentistry with SCD	152: 102 SCD; 50 controls	30.4 (19.4) y 30.4(19.0) y	DMFS Number of examiners; K = 0.90	28.01 (1.35)		28.26 ± 1.34	chi-square tests	-	High
(Passos, Santos et al. 2012) Brazil	Cross-section	Electrophoresis	Laboratory of Genetics of Professor Edgar Santos University Hospital or the School of Pharmacy of Federal University of Bahia	The same University with SCD	180: 51 HbSS; 48 HbSC; 91 controls	31.51(10.16) y 34.19(13.02) y 34.05(11.89) y	Decayed Teeth Missing Teeth Filled Teeth DMFT Intra-examiner; K = 0.82	HbSS 4.23(4.19) 4.52(5.74) 3.13(3.59) 11.8(6.16)	HbSC 3.27(2.98) 4.47(4.72) 3.47(3.22) 11.22(6.57)	2.91(3.07) 4.79(5.76) 3.68(3.93) 11.3(6.93)	Chi-square or Fisher’s Exact test	0.07 0.93 0.64 0.63	Moderate
(Ralstrom, da Fonseca et al. 2014) USA	Cross-section	Medical history	the sickle cell and the adolescent medicine clinics	no definition	106: 54 SCD; 52 controls	14(6)y 16(4)y	DMFT; Intra-examiner; K = no definition	1.94 (2.70)		2.96 (4.10)	chi-square test or Fisher’s exact test	0.10	Moderate
(Al-Alawi, Al-Jawad et al. 2015) Saudi Arabia	Cross-section	Medical history	Al-Qatif Central Hospital	general population	66: 33 SCD; 33 controls	24.52(4.611)y 24.58(6.124)y	Decayed teeth Missing teeth Filled teeth DMFT; one examiner; K = no definition	5.30 (3.861) 0.85 (0.972) 1.70 (1.403) 7.85 (4.071)		3.33 (3.594) 0.67(1.08) 2.97 (2.568) 6.97 (3.729)	Chi-square test	0.036 0.475 0.015 0.364	Moderate
(Fernandes, Kawachi et al. 2015a) Brazil	Cross-section	Medical history	Referral Center for Hematology and Transfusion Services in the State of Minas Gerais	100 schools	261: 56 SCD; 205 controls	8.9 (0.87)y 8.9 (0.8)y	Decayed teeth Missing teeth Filled teeth DMFT Intra- examiner; K = 0.87	0.9 (1.8) 0 0.4 (1.2) 1.3 (2.1)		1.1 (1.5 ) 0.2 (0.6) 0.5 (1.0) 1.8 (2.0)	Mann Whitney U test	- - - -	High
(Fernandes, Kawachi et al. 2015b) Brazil	Cross-section	Medical history	Referral Center for Hematology and Transfusion Services in the State of Minas Gerais	100 schools	261: 50 SCD; 180 controls	12.0 (1.08)y 11.9 (1.0) y	Decayed teeth Missing teeth Filled teeth DMFT; Intra- examiner; K = 0.87	1.0 (1.4) 0.1 (0.6) 0.4 (0.8) 1.5 (1.9)		1.0 (1.7) 0.2 (0.7) 0.8 (1.7) 2.1 (2.8)	Mann Whitney U test	- - - -	High
(Brandao, Oliveira et al. 2018) Brazil	Cross-section	Hb electrophoresis and/or high-performance liquid chromatography	Hematology and Hem-therapy Foundation in Bahia	State School Francisco da ConceiçãoMenezes	124: 61 SCD; 63 controls	12.4 (2.9)y 11.1 (2.9)y	Decayed teeth Missing teeth Filled teeth DMFT; dmft two examiner; K = 0.71	1.5 ( 2.38) 0.8 ( 0.33) 0.5 (1.0) 2 (2.7) 2.3(2.6)		0.8 ( 1.23) 0.98 (0.3) 0.24 ( 0.7) 1.1 (1.7) 0.88(1.2)	Student’s t-test	0.003 0.620 0.004 0.013 0.018	High
(Kalbassi, Younesi et al. 2018) Iran	Cross-section	Medical history	Tehran, Mashhad, Isfahan and Tabriz cities, central hospitals	private offices	155: 55 SCA; 100 controls	19.2 (2.91)y 19.3 (3.211)y	Decayed teeth three examiner; K = no definition	6.10 ( 3.620)		2.33 (1.221)	Chi-squared test	<0.05	High

Quality assessment

We evaluated the quality of the 2 cohort studies [32,34] using NOS and found a score of 7 in the cohort studies; we thus considered them to be high-quality studies. We assessed the quality of the 6 cross-sectional studies [9,15,16,22,23,33] by the AHRQ recommended criteria. For item ‘a’ and item ‘g’, all answers were ‘YES’. For items ‘b’ and ‘h’, all answers were ‘YES’. For item e, all answers were ‘NO’. We found a score of 5 in 3 studies and a score of 6 in 3 studies. We considered them to be moderate- and high-quality studies. The methodological assessment evaluation of the cohort studies and the cross-sectional studies shows in Tables 2 and 3, respectively.

Table 2. Methodological quality scores of the selected articles.

	Selection*				Comparability**		Exposure***
Study	Is the case definition adequate?	Representativeness of the cases	Selection of controls	Definition of controls	Comparability of cases and controls on the basis of the design or analysis		Ascertainment of exposure	Same method of ascertainment for cases and controls	Non-response rate	Total	quality
Laurence and Colleagues, 2002	*	*	*	*	*	–	*	*	*	8	High
Laurence and Colleagues, 2006	*	*	*	*	*	–	*	*	*	8	High

*a maximum of 1 point for each item; **a maximum of 2 points for each item; ***a maximum of 1 point for each item****a maximum of 9 points.

*1 point.

1 (a) yes, with independent validation*, (b) yes, egrecord linkage or based on self-reports*, (c) no description.

2 (a) consecutive or obviously representative series of cases *, (b) potential for selection biases or not stated.

3 (a) community controls or school controls *, (b) hospitalor dental clinical controls, (c) no description.

4 (a) no history of disease (endpoint) *, (b) no description of source.

5 (a) the exposures of interest (dental caries and periodontal diseases) were adjusted for one confounder (demographic confounder: sex or age) *, (b) the exposures of interest (dentalcaries and periodontal diseases) were adjusted for two or more confounders (demographic confounder: sex or age and socioeconomic confounder: hygiene or income) **, (c) nodescription related to the adjustment analysis for confounding factors.

6 (a) secure record (e.g. surgical records) *, (b) structured interview where blind to case/control status*, (c) interview not blinded to case/control status (d) written self-report or medical record only, (e) no description.

7 (a) yes *, (b) no.

8 (a) same rate for both groups *, (b) non respondents described, (c) rate different and no definition.

Table 3. Methodological quality scores of the selected articles.

Study, year	a	b	c	d	e	f	g	h	i	j	k	Total	Quality
Al-Alawi and colleagues, 2015	√	√	×	–	×	?	?	√	?	√	–	5	Moderate
Brandão and colleagues, 2018	√	√	×	–	×	√	?	√	?	√	–	6	High
Fernandes and colleagues, 2015	√	√	√	–	×	√	?	√	?	√	–	6	High
Kalbassi and colleagues, 2018	√	√	√	–	×	√	?	√	?	√	–	7	High
Passos and colleagues, 2012	√	√	×	–	×	√	?	√	?	√	–	5	Moderate
Ralstrom and colleagues, 2014	√	√	×	–	×	√	?	√	?	√	–	5	Moderate

Notes: Item a–k represents the 11 items of the AHRQ recommended criteria. ‘√’ means ‘YES’, ‘×’ means ‘NO’, ‘?’ means ‘UCLEAR’, ‘–’ means ‘not suitable’.

Meta-analysis

Investigators of 5 studies [9,15,22,33,34] including a total of 673 non-SCD healthy control participants and 289 patients with SCD estimated the relationship between dental caries and SCD measured by levels in the DMFT index. Investigators of 2 cohort studies [32,34] including a total of 243 non-SCD healthy control participants and 137 patients with SCD estimated the relationship between dental caries and SCD measured by levels in the DMFS index. The results of separate meta-analyses indicated that the DMFT and DMFS scores were not significantly different between patients with SCD and non-SCD healthy control participants (WMD, −0.11; 95% CI, −0.47, 0.26; P = 0.56; and WMD, −0.77; 95% CI, −4.10, 5.64; P = 0.20, respectively). Considering the low heterogeneity of the DMFS index (I² = 29%) between studies, we selected a fixed-effects model for the meta-analysis. However, we considered the heterogeneity between the studies of the DMFT index to be moderate (I² = 61%), so we conducted a random-effects model for the meta-analysis. When conducting a sensitivity analysis by the exclusion of any single study in turn from the meta-analysis, the results remained significantly unchanged, indicating that the meta-analysis of the DMFT is robust. The information on the results of the meta-analysis evaluating DMFT and DMFS is provided in Figures 2 and 3, respectively.

Figure 2. Forest plot presenting weighted mean differences (WMD) of the permanent decayed, missing and filled teeth (DMFT) between patients with SCD and non-SCD participants. CI: Confidence interval. SCD: Sickle cell disease. Non-SCD: participants without sickle cell disease.

Figure 3. Forest plot presenting weighted mean differences (WMD) of the permanent decayed, missing and filled surface (DMFS) between patients with SCD and non-SCD participants. CI: Confidence interval. SCD: Sickle cell disease. Non-SCD: participants without sickle cell disease.

The information on the results of the subgroup analyses is provided in Table 4. We conducted a subgroup analysis by each item of the DMFT index. Investigators of 3 studies [9,15,22] reported the permanent missing teeth (M) index. The results of the meta-analysis showed that patients with SCD had lower M scores than non-SCD participants (WMD, −0.14; 95% CI, −0.25, −0.03). Investigators of four articles [9,15,16,22] reported the D index and three articles [9,15,22] evaluating the F index were included in the study. However, no statistically significant difference between individuals with SCD and non-SCD was found for scores of the D index (WMD, 1.14; 95% CI, −0.04 to 2.33) and the F index (WMD, −0.22; 95% CI, −0.66 to 0.21) of the DMFT index. In addition, the sensitivity analysis of the D index was stable. We selected a random-effects model for subgroup analyses by each item of the DMFT index.

Table 4. Results of subgroup analyses.

Character		No. of trails	Heterogeneity		Meta-analysis
			p	I^2 (%)	WMD (95% CI)	p
Components	Decayed teeth	5	<0.001	93%	1.14(−0.04, 2.33)	0.06
	Missing teeth	3	0.33	10%	−0.14(−0.25, −0.03)	0.01
	Filled teeth	4	0.003	78%	−0.22(−0.66, 0.21)	0.31
Age	Children/Adolescents	4	0.01	73%	−0.26(−0.64, 0.12)	0.17
	Adults	2	0.50	0%	−0.18(−0.55, 0.18)	0.13
Genotypes	HbSS	5	0.41	0%	−0.42(−0.84, 0.00)	0.05
	HbSC	2	0.27	17%	−1.17(−2.47, 0.13)	0.08

We conducted a subgroup analysis of the DMFT index by age group of the participants (children/adolescents, adults). There was no significant difference for the subgroup of DMFT in SCD patients (children/adolescents: WMD = −0.26, 95% CI, −0.64, 0.12, adults: WMD, 1.23; 95% CI, −0.36, 2.82).

We conducted a subgroup analysis of DMFT by two genotypes of SCD individuals. Four studies [22,23,33,34] reported the HbSS genotype of SCD patients, and two studies [23,33] reported the HbSC genotype of SCD patients in evaluating the DMFT index compared to that of non-SCD subjects. No significant difference was observed for the subgroups of DMFT in SCD patients with genotype HbSS (WMD, −0.42; 95% CI, −0.84, −0.00) or HbSC (WMD, −1.17; 95% CI, −2.47, −0.13) compared with non-SCD subjects, which showed low heterogeneity between the studies of the DMFT index in the HbSS and HbSC genotypes in SCD patients. A fixed-effects model was conducted. The sensitivity analysis revealed that the results are stable.

Discussion

This systematic review assessed the association between dental caries and SCD in affected individuals. Dental caries is a chronic and destructive condition of dental tissues and may lead to the complications of pulpitis, periapical periodontitis and acute pain, which, if left untreated, may even lead to loss of teeth [35]. Dental caries remains a disease associated with significant health effects, financial costs and low quality of life. Dental caries is one of the dental manifestations commonly reported in individuals with SCD. The complications of pulpitis and periapical periodontitis due to insufficient blood supply may become a source of infection in sickle cell crisis in SCD individuals [18,19]. Recently, the association between dental caries and SCD has sparked great interest among dental researchers and affected patients. However, there are inconsistencies based on the current research findings [9,15,16,22,23,32–34]. This inconclusive evidence may hinder oral hygiene management and the prevention of dental caries in individuals with SCD. Therefore, we conducted a systematic scientific review and meta-analysis in an attempt to elucidate the association between SCD and dental caries.

The DMFT/DMFS index represents caries severity and prevalence, which is considered a lifetime cumulative burden of dental caries [36]. Individuals with SCD commonly reported hypomineralization of enamel, diminished oral hygiene, and low salivary flow rate, and drug treatments containing sugar were found in SCD patients [17,37], suggesting that the association of risk factors may lead to susceptibility to dental caries in these affected individuals. However, in this systematic review, no statistically significant differences were found in the scores of dental caries between SCD patients and the non-SCD group as measured by the mean DMFT and DMFS indexes. On the one hand, SCD patients are usually asked to drink plenty of water to prevent sickle cell pain crisis, possibly leading to fluoride exposure through the water supply due to public health policies in some regions [33]. Fluoridated water may promote the remineralization of dental enamel and neutralization of acid substances, which is an effective measure for the prevention of caries disease [38]. On the other hand, SCD patients may have lower sugar consumption in the diet for fear of weakening their blood [21]. Additionally, lower sugar intake can reduce the development of dental caries [39].

The components of the DMFT index consist of the decayed, missing and filled teeth. And we conducted subgroup analyses of components of the DMFT index. No significant difference was found in most of the components, apart from the M index. Although the result of the M index was significantly lower in patients with SCD than in non-SCD participants, we believe that this result may exhibit bias. Authors of six [9,15,22,23,33,34] reported the scores of the DMFT index, three of which reported the M index. One study reported a higher M index in the SCD group but no difference was found [15]. Two of the studies reported lower M indices in SCD patients, one of which was not significantly different [9], and the other one was significantly different [22]. We carefully analyzed the article with statistical significance and found that the investigators of the study concluded that the reason for lower M is that SCD patients had free access to oral health care provided by the government in the regions [22]. This may be the reason for the reduction of dental caries. Therefore, interpretation of the meaningfulness of the M in this meta-analysis should be considered with caution.

Both SCD and dental caries are characterized by chronic and progressive conditions, and they may share common confounders, such as age and economic status [40]. Although understanding the association between SCD and non-SCD subjects from different economic statuses could be beneficial, due to the insufficient information provided by the included studies, we could not assess the effects of the economic status on the overall effects. Considering that 6 studies focused on different age groups of participants, ranging from 3 to 68 years old in our meta-analysis, dental caries and SCD were found to be associated with age groups [22]. Therefore, we conducted an age subgroup analysis to further evaluate dental caries in SCD patients and non-SCD subjects. In the analysis of DMFT by subgroups of children/adolescents and adults, non-SCD children/adolescents did not have significantly higher scores than children/adolescents with SCD. No statistically significant difference between SCD and non-SCD adults was found for DMFT.

SCD is a disease that is a group of autosomal recessive disorders, including hemoglobin SS disease (HbSS genotype), sickle cell hemoglobin C disease (HbSC genotype), and homozygous beta-thalassemia [3]. HbSS and HbSC are the most common genotypes of SCD, and the former is the most severe form. Studies have shown that the clinical severity or genotype of SCD (HbSS or HbSC) may be associated with dental caries [34,41]. Therefore, we conducted a subgroup analysis of SCD genotypes using the DMFT index. In the analysis of DMFT by subgroups of HbSS and HbSC, the subgroups of individuals with SCD with the genotype HbSS and genotype HbSC showed that these affected people exhibited a significant difference in the DMFT index compared to those without SCD.

In this paper, moderate levels of heterogeneity between studies were found (Pheterogeneity = 0.02, I² = 61%) in the overall meta-analysis of the DMFT index; therefore, we used a random-effects model in the comparison. The variation in results among studies may be due to there were multiple confounders, including different countries with different socioeconomic factors, especially, the inconformity of age, as well as the genotypes of SCD (HbSS and HbSC). First, dental caries is associated with different age groups. Thus, we performed a subgroup analysis of DMFT by age group (children/adolescents and adults). Additionally, according to the change in heterogeneity compared with the overall analysis, we could not explain the source of heterogeneity from the age groups. Second, we conducted a subgroup analysis for genotypes of SCD. We found a decrease in the level of heterogeneity from moderate to low (HbSS, I² = 0%, P = 0.41; HbSC, I² = 17%, P = 0.27) upon the subgroup analysis, indicating that genotypes of SCD may explain mainly the observed heterogeneity across studies. Additionally, a mild heterogeneity still existed (HbSC, I² = 17%). This finding may be explained by different economic statuses. Despite all of the above confounding factors, the heterogeneity of our meta-analyses is acceptable.

To the best of our knowledge, this systematic review and meta-analysis elucidate for the first time the current evidence on associations between SCD and dental caries. In this meta-analysis, the effect of the DMFT and DMFS indexes were analyzed to compare dental caries between the SCD and non-SCD groups. In addition, for the analysis of DMFT, subgroups of age and genotype of SCD participants were further evaluated, which provides more information for understanding the relationship between SCD and dental caries. Simultaneously, several limitations of the present study should be acknowledged. First, moderate levels of heterogeneity were found; therefore, we used a random-effect model in the comparison of some indexes. In addition, the sensitivity analysis revealed that the results of the DMFT index are stable. And subgroup analyses of DMFT by age and genotype of SCD were conducted. Second, because of the limited number of papers, we could not evaluate publication bias. Third, due to the limited information provided by the included studies, we could not analyze the effects of the common risk factors (such as health/dental care systems, socioeconomic and behavioral factors) shared by dental caries and SCD on the overall effects. More well-designed longitudinal studies are needed in the future to clarify the association between dental caries in SCD patients.

In conclusion, the results of the studies revealed that patients with SCD did not suffer from worse dental caries than did non-SCD healthy control participants. In addition, the subgroup analyses of DMFT by age and genotype of the SCD groups of participants failed to show a significant difference in the association between SCD and dental caries. Considering the limitations of the current study, the interpretation of the meaningfulness of this meta-analysis should be considered with caution. Therefore, it is still necessary to pay constant attention to SCD patients’ dental health in clinical work. More well-designed longitudinal studies evaluating the association between SCD and dental caries are encouraged.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by Program for Innovation Team Building at Institutions of Higher Education in Chongqing in 2016.