Brian Laurence, DDS," Britt C. Reid, DDS, PhD,2 Ralph V. Katz, DDS, PhD3 'Howard University College of Dentistry, Restorative Department, 600 W Street, NW, Washington, DC 20059; 2University of Maryland School of Dentistry, Baltimore; and 3New York University College of Dentistry, New York, NY; *corresponding author, blaurence@howard.edu

Sickle cell anemia and dental caries: a literature review and pilot study

Spec Care Dentist 22(2):70-74, 2002

ABSTRACT The purpose of this cohort study was to determine whether individuals with sickle cell anemia (SCA) were more susceptible to dental caries than non- sickle-cell control subjects. A review of the literature suggests several reasons why individuals with SCA may be at increased risk. Thirty-five cases of SCA aged 6 years and older were identified from a screening of 15,900 current patient files at the Howard University College of Dentistry Dental Clinic. A total of 140 non-SCA control subjects (four per case), ffequency-matched on enrollment period (+ 5 yrs) and age (f 2 yrs if under age 21, or f 5 yrs if 21 or over), was selected by a nonbiased method from the same dental clinic files. SCA cases and controls were identical on mean age (30.4 + 19 yrs, ranging from 5 to 92 yrs) and were similar in sex distribution (males: 34% of SCA cases, 40% of controls). The mean number of permanent teeth present was very similar for SCA cases and controls (23.4 % 6.4 vs. 24.2 f 6.4). The mean DMFT was 21% higher in the SCA cases (12.0 f 8.4 vs. 9.9 % 6.9), and the mean DMFS was 26% higher in the SCA cases (33.0 * 32.3 vs. 26.2 % 27.7). While there was virtually no difference in DMFS between SCA cases and controls for 6- to 19-year-olds, for subjects aged 20 and older, the DMFS was 30.4% higher in the SCD cases. For all ages, the M component for SCA cases was 40.7% higher, and the D component was 20.0% higher, while the F component was only 3.5% higher than for controls. Untreated decay (the D/D+F surfaces ratio) was 24.4% higher in the SCA cases. The findings from this pilot study suggest that SCA cases have a higher susceptibility to dental caries and/or that SCA patients may have different treatment pathways once caries is detected. While none of the observed differences was statistically significant, these findings were of clinical interest and should be pursued in future large-scale studies.

KEY WORDS: dental caries, epidemiology, human subjects, sickle cell anemia.

INTRODUCTION ickle cell anemia is an inherited disorder of hemoglobin formation that S predominantly affects African-Americans in the United States. Sickle cell

anemia (SCA) occurs in persons homozygous for the sickle-cell gene, and about 50,000 African-Americans, or less than 1%, have sickle cell anemia, while 8% have sickle-cell trait, one normal gene and one mutant sickle hemoglobin gene. Sickle cell disease (SCD) is the broader term often used to describe several autosomal disorders caused by abnormalities of hemoglobin, including hemoglobin SS (homozygous) disease or sickle cell anemia, sickle cell hemoglobin C disease, and the homozygous P-thalassemias. I

SCA is characterized by abnormal hemoglobin where valine is substituted for glutamic acid on the sixth position of the beta chain of hemoglobin in the homozygous sickle cell individual. The red blood cells assume unusual shapes, becoming more rigid and making it more difficult for them to pass through small blood vessels, which results in increased blood viscosity and tissue hypoxia. This distortion in shape is due to low oxygen tension as the sickle- shaped erythrocytes accumulate, occluding the microvasc~lature.~~~ When this occurs, it is referred to as a sickle-cell crisis and is characterized by severe pain, ranging in duration from three to four days for most ep i~odes .~ The areas most commonly afflicted by this acute pain are the lower back, chest, head, abdomen, and hip joint. Some of the other symptoms include jaundice with fever, tachycardia, tachypynea, and occasional hypertension. The blood disorder affects almost every organ in the body, and the more common manifestations of the disease include hepatomegaly, splenomegaly, pulmonary infarction, chronic leg ulcers, and liver dy~function.~,'

The literature was reviewed for all studies relevant to caries for the years. Discussed below are three articles on orofacial pain, two on histology, one on radiographic change, and two on dental caries. Several studies on the behavioral science aspect of depression and its effect on the oral tissues are also briefly discussed.

Three published studies have examined the relationship between SCD and orofacial or maxillofacial pain. In 1984, Cox' compared 25 cases with SCA with 25 individuals without the disease in a hospital dental clinic and found a statistically significant increased risk of self-reported pain in patients with SCA.

In 1990, O'Rourke and Mitropoliss measured pain as an outcome among three matched groups, 19 cases with SCD, 19 individuals with sickle cell trait, and 21 normal patients. The study concluded that the group with SCD had significantly more pain, more frontal headaches, and more head and neck injuries. Most recently, in 1998, O'Rourke and Hawley" examined orofacial and dental pain among 5 1 patients with SCD in Jamaica and 5 1 non-sickle- cell controls. The study concluded that having sickle cell disease was associated with a six-fold increase in the self-reporting of maxillary or mandibular pain. These three studies all drew similar conclusions. They suggested that vaso-occlusion within the vasculature of the pulpal tissue may account for the pain experience of SCD sufferers, and that the same infarction process that afflicts other organs in the body may also affect the dental tissue. Further, the two most recent of these studies made clinical recommendations

70

Spec Care Dentist 22(2) 2002 Sickle Cell Anemia and Dental Caries: An Update 71

that caution should be exercised with regard to clinical treatment when a patient with SCA presents with pain.

Two studies'"," have examined histological changes in the dental tissue with regard to SCA and serve to substantiate the results of the pain studies. In 1966, Sonil" stated that the pulp chamber of the teeth of SCA patients contained denticle-like bodies, likely due to blood vessel occlusion. There was evidence of enamel hypomineralization, accentuated incremental lines, and interglobular dentin due to poor mineralization. The author states that the changes observed are not pathognomonic but defined the changes as significant.

In 1984, Cox and Soni" found linear calcifications in the pulp canals of patients with SCA. In addition, pulp stones and excessive interglobular dentin formation were observed. Sickle-shaped cells were observed in the vessels of the pulp of teeth from patients 24 to 96 hrs after an acute sickle cell crisis attack. The authors concluded that significant pathological changes were observed in the dentin and pulp and suggested that they were most likely due to stasis of the sickle cells in the capillaries, which created a hypoxic situation, causing tissue infarction.

Andrews et a1.,'* using a sample of22 patients with SCA in 1983, observed that 22.7% of these patients showed evidence of radiographic change associated with the orofacial region, but none of them reported oral complaints or symptoms at the time of the examination. Of these changes, 38.1 % were associated with the periapical region of the teeth. The authors concluded that necrosis of the pulp can occur without the patient being aware of it in the absence of trauma, caries, or dental treatment. In addition, they suggest that pulpal necrosis may occur in patients with SCA as a result of some compromise in the pulpal microcirculation. The results of the pain, histological, and pulpal studies suggest that the teeth of patients with SCA may be at increased risk of periapical infection and pathologic change.

Patients with SCD may also be at increased risk of depression. An early study in 198813 of 89 patients with SCD found that these patients have significant distress in the areas of employment, finances, sleeping, eating, and the performance of daily activities. In addition, a lack of assertiveness in social relationships was found, causing the authors to suggest that depression may be a common problem among sickle cell patients. A study of pain-coping strategies in children and adolescents with SCD in 199114 found that children high on negative thinking and passive adherence were less active, required more health care services, and were more distressed during painful episodes. Children high on coping attempts were more active and required less frequent health care treatment.

A study in 1998 of adolescents with SCD15 in Arkansas found that while they had posit ive social and family relationships, they expressed concerns about self-confidence and being a burden on their families. More recently, in 1999, Schaeffer et al.'" found that patients with SCD who reported more painful episodes were more likely to report depressive symptoms, and that gender and family income were positively and significantly associated with depressive symptomatology.

Since many antidepressant medications can cause xerostomia and increase the incidence of dental disease, ~ t u d i e s ' ~ ~ ~ * have found an association between depression and higher rates of dental canes. A higher incidence of oral infection, including candidiasis and periodontal disease, is also observed in depressed patients." In 1999, a study2" of 780 adults found a significant relationship

100

80 0 Missing Filled

W Decayed DMFS 60

40

20

0 6 . 1 9 ~ 0 2 0 - 2 Q y O M - S B y a 7 5 - 9 2 y O

I Age group Cases precede controls in each age group

Figure 1. The component DMFS (Decayed, Missing, Filled Surfaces) score for SCA cases and non-SCA controls. Cases precede controls within each age group.

0.9

0.3 0.2 0.1

6-19yO 20-29yO 30.59~0 75.92~0

Age group

Figure 2. The score for unmet treatment need, the D/D+F ratio, for SCA cases and non-SCA controls.

Number Teeth

10 9 Cases Controls i

6-19yO 20-29yO 30.59~0 75.92~0

Age group

Figure 3. The total number of permanent teeth for SCA cases and non-SCA controls.

between abundant lactobacillus growth and a high rate of depressive symptoms, even after adjustment for measured

72 Laurence eta/.

Table 1. Characteristics of Persons with Sickle Cell Anemia and Their Controls.

SCA Cases (ksd) Controls (ksd) % Higher n = 35 n = 140 in Cases p Value

Mean age (yrs) 30.4 (19.4) 30.4 (19.0) % Male 34.0 40.0

D of DMFS 6.0 (7.7) 5.0 (6.0) 20.0 0.43 DMFS 33.0 (32.3) 26.2 (27.7) 26.0 0.21

M of DMFS 19.5 (30.7) 13.8 (26.6) 40.7 0.28 F of DMFS 7.6 ( 8.9) 7.3 ( 8.6) 3.5 0.88

DMFT 12.0 ( 8.3) 9.9 (6.9) 21.2 0.1 2 DiD+F 0.56 ( 0.4) 0.45 ( 0.4) 24.4 0.15

# Permanent Teeth 23.4 (6.4) 24.2 (6.4) 0.51

= 3.4% higher in controls.

Table 2. Component DMFS Score Stratified by Age Group, Sickle Cell Anemia, and Controls.

Age group 6-1 9 yrs 10 cases, 38 controls

D M F DMFS

Age group 20-29 yrs 10 cases, 43 controls

D M F DMF S

Age group 30-59 yrs 13 cases, 51 controls

D M F DMFS

Age group 75-92 yrs 2 cases, 8 controls

D M F DMFS

Cases (ksd) Controls (ksd) p Value ( i sd)

2.6 ( 3.6) 3.3 (4.7) 0.68

7.3 ( 8.8) 7.2 ( 8.1 I 0.98

2.2 ( 3.0) 1.5 ( 3.8) 0.6 2.5 (6.1) 2.4 ( 4.4) 0.96

7.8 ( 9.8) 6.5 (6.1) 0.59 6.9 ( 8.9) 4.8 ( 8.5) 0.49 11.2 ( 9.5) 7.0 ( 7.0) 0.12 25.9 (1 9.9) 18.3 ( 1 4.2) 0.17

7.5 (8.1) 5.6 ( 6.6) 0.4 31.1 (31.2) 22.4 (28.0) 0.33 8.5 ( 9.0) 1 1 . 1 (9.7) 0.37

47.0 (28.5) 39.1 (26.7) 0.35

4.0 ( 5.7) 1.5 ( 2.3) 0.32 93.0 (49.5) 66.1 (54.6) 0.55 9.5 (1 3.4) 8.5 (1 3.7) 0.93

106.5 (30.4) 76.1 (46.9) 0.42

confounders, including drugs known to reduce the lactobacillus count by reducing salivary flow. A high lactobacillus count indicates the presence of risk factors for the development of caries. The authors2’ concluded that the association suggests that depressed subjects are at an increased risk of caries and other dental diseases. The association of SCD with depression is more reason, in addition to the pain and histological studies, to believe that the teeth of patients with SCA are at increased risk for pathologic change.

Two s t ~ d i e s ~ ~ , ~ ~ specifically looked at dental decay and its

Spec Care Dentist 22(2) 2002

relationship to SCD. In 1986, Okafor et ~ 1 . 2 ~ used a retrospective approach to evaluate oral and dental complications in a study of 37 consecutive patients with SCA, aged 14 to 33 years, matched to 24 non-sickle controls for age and sex in a hospital in Nigeria. The study found increased evidence of overjet and overbite and a reduced prevalence of dental decay among individuals with SCA. However, the article neither describes how dental caries was measured nor presents any statistical comparisons. In 1998, in a more methodologically rigorous study, O’Rourke and Hawley? while primarily looking at orofacial and dental pain among 51 patients with SCD in Jamaica, compared rates of dental decay between persons with sickle cell anemia and an equal number of non-sickle-cell controls. (The subjects ranged in age kom 13 to 45 yrs.) No difference was found in the severity or prevalence of caries between the groups.

METHODS This study used a retrospective cohort to determine whether individuals with SCA had a higher DMFS index than those without the disease. In this study, all subjects were recruited from Howard University’s College of Dentistry (HUCD). Frequency matching was performed with a four-to-one ratio of non-SCD controls to persons with SCA at enrollment by age and race. We selected the persons with SCA by searching through all available records of patients who were treated at HUCD between 1983 and 1999, and 38 individuals with SCA based on self-report by the medical history were identified. Anyone giving a history of SCA, SCD, or sickle cell trait was excluded as a potential non-SCA control.

The caries rates were ascertained from clinical examination (visual-tactile criteria) and full-mouth radiographs recorded at the time of the patients’ initial presentation to the dental clinic. The number of decayed, missing, and filled surfaces (DMFS) for each tooth was recorded by the principal investigator on a DMFSiOPSCAN data card. For the final analysis of DMFS on permanent teeth, the three children with SCA aged five and under and their controls were eliminated from the study.

Two-sample comparisons of continuous data were

Spec Care Dentist 22(2) 2002 Sickle Cell Anemia and Dental Caries: An Update 73

conducted by t tests. This was deemed appropriate, since the data did not differ significantly from normality. A two-sided alpha level of 0.05 was used to assess statistical significance. Because this study was a retrospective search of existing records, there were no data to allow for testing of the validity or reliability of the faculty in diagnosing dental caries. All calculations were performed by means of the SPSS (Statistical Package for the Social Sciences) data analysis software package.

RESULTS Table 1 shows a summary of the data for the persons with SCA and their non-SCA controls. Both groups had a mean age of 30.4 yrs, and 34% of the persons with SCA were males as compared with 40% of the controls. The mean DMFS score for persons with SCA was 33.0 * 32.3, while that for the controls was 26.2 + 27.7, a difference of 26%, which was not statistically significant. The mean scores for filled surfaces were similar for persons with SCA and the controls, with values of 7.6 k 8.9 and 7.3 f 8.6, respectively. The numbers of decayed surfaces were also similar, 6.0 + 7.7 for persons with SCA and 5.0 f 6.0 for the controls. The most notable difference was observed for the number of missing surfaces, with a value of 19.5 k 30.7 for the persons with SCA and 13.8 k 26.6 for the controls, a difference of 40.7%. The D/D+F ratio, which is a measure of untreated decay, was 56% for SCA and 45% for the controls, and was 24.4% higher in the persons with SCA . The DMFT score, where T stands for a tooth as opposed to surfaces, measures tooth count instead of tooth surfaces. The DMFT was 21.2% higher for persons with SCA than for the controls, 12.0 f 8.3 vs. 9.9 * 6.9, respectively. Last, Table 1 shows that the mean total numbers of permanent teeth were similar for persons with SCA and the controls, 23.4 * 6.4 and 24.2 + 6.4.

Fig. 1 shows the component DMFS score for persons with SCA and non-SCA controls when stratified by age group. A trend of an increasingly larger M component becomes apparent. In the 20-29 age group, persons with SCA were 60% higher for tilled surfaces, 11.2 * 9.5 for persons with SCA us. 7.0 + 7.0 for the controls. The scores for missing surfaces in the 20- to 29-year-olds show persons with SCA being 44% higher, with values of 6.9 k 8.9 and 4.8 + 8.5 for persons with SCA and controls, respectively. For the 30-59 age group, the scores for the filled and decayed surfaces are similar for persons with SCA and the controls, but the missing surfaces continue to show a marked difference (39%), 3 1.1 * 3 1.2 for persons with SCA and 22.4 f 28.0 for controls.

While this large difference is also apparent in the 75-92 age category, with SCA having a score of 93.0 h 49.5 for missing surfaces and controls having a value of 66.1 f 54.6, a difference of 40.7%, these data should be interpreted with caution, since there were only two cases and eight controls in this category.

Table 2 summarizes the component DMFS score when stratified by age group. It shows the results from Fig. 1 in detail, including the number of subjects in each stratum. Fig. 2 shows the D/D+F ratio, a measure of unmet treatment need, stratified by age group. The results show that the D/D+F ratio is consistently higher for persons with SCA in ail age categories except ages 20-29, and the apparent trend is a decrease in the D/D+F ratio for both persons with SCA and the controls as age increases. Last, Fig. 3 shows the total number of permanent teeth for persons with SCA and controls stratified by age group.

The important trend is that persons with SCA have slightly fewer teeth within each age group, a finding consistent with parallel increases in the M coniponent of the DMFS index.

DISCUSSION The results from this study suggest that patients with SCA may have an increased susceptibility to dental caries or periodontal disease and could possibly have different treatment pathways once caries is detected. The difference in the DMFS score between persons with SCA and the controls is almost negligible for 6- to 19-year-olds, notable for those aged 20-29 and 30-59, and largest for those in the age group from 75-92 years. The missing component of the DMFS score is larger for persons with SCA than for the controls for all age groups, the difference progressively increasing from 0.6 M surfaces to 2.1 M surfaces to 8.7 M surfaces and finally to 26.9 M surfaces as the age group goes from 6- 19 to 75-92, respectively. The filled and decayed components of the DMFS score do not exhibit such large increases.

The overall difference for all subjects between the numbers of missing surfaces for the persons with SCA and the controls was 40.7% (5.6 M surfaces), which, although not statistically significant because of the small sample size, is of sufficient size to be clinically relevant. Although the D/D+F ratio was 24.4% higher in persons with SCA, this may not indicate that they were treated less often once they had decay, but rather that they were more often ‘treated’ with an extraction rather than a restoration. As the D or F component goes to the M category, a smaller denominator results, so the D/D+F ratio becomes larger for the persons with SCA. In fact, given the much higher M component, this could indicate that once decay occurred, patients with SCA were less likely to get a restoration, i e . , the decay is either left alone (leading to the slightly higher D component) or the affected tooth is eventually extracted (leading to the higher M Component). Another plausible pathway is that an increased incidence of pulpal necrosis, if untreated, could lead to an increased incidence of periapical disease and possibly result in tooth loss, resulting in a higher M component.

The fact that both the mean ages and the distributions of persons with SCA cases and non-SCA controls by age group were similar suggests that matching on age was successful, reducing the potential for residual confounding by age. In addition, the use of persons with SCA cases and non-SCA controls from the same patient base means that factors which have the potential to act as confounders, such as socioeconomic status, are likely to be similar between the two groups.

The main limitation of this study is the small sample size used, an inherent problem in a pilot study. This limits the internal and external validity of this study and increases the likelihood that the differences observed could be due to chance. In addition, there were very little demographic data available for persons with SCA and non-SCA controls, so we could not properly address the roles of potential confounders such as income in this study. We were also not able to assess the presence of depressive symptoms among the study subjects, so its role in any possible caries pathway could not be examined.

Presently, it is estimated that there is an 85% chance that infants with SCA will survive to age 20.23 This is a vast improvement from 20 years ago, when about 50% of patients with SCA were expected to die before the age of 20.(‘ For the older exposed individuals, a survival bias may have been introduced

74 Laurence eta/. Spec Care Dentist 22(2) 2002

where these people may be healthier and not representative of most people with SCA, and the differences between the persons with SCA and non-SCA controls may actually be larger than those found in this study. Another possibility is that patients who are selected from dental school records may have more dental disease than those who do not actively seek treatment, and the results of the study may be more applicable to those individuals with higher rates of caries in the general population. The potential for misclassification also exists, since case identification was based on medical history, and it was not possible to confirm case status by means of hemoglobin electrophoresis. Some healthy SCA controls or sickle cell traits may have incorrectly classified themselves as persons with SCA. Conversely, some persons with SCA may not have been aware of their status, since diagnosis of SCA was largely symptomatic prior to the adoption of neonatal screening, and some older individuals with mild symptoms may not be aware that they have the disease.

A major limitation of the DMFS index is that while DMFS scores are usually used to represent an individual’s caries experience, they can overestimate the prevalence or incidence of disease. Teeth missing due to factors other than dental decay, such as trauma or periodontal disease, should be excluded from the DMFT or DMFS. As a result, the DMFS or DMFT index is more useful in children than adults, because adults are more likely to have permanent teeth or surfaces missing due to reasons other than dental caries.24 This limitation is particularly relevant to our study, where the largest differences were observed in the older age groups, and leaves open the possibility that periodontal disease significantly contributed to the increased M.

CONCLUSIONS The results from this study suggest that patients with sickle cell anemia are more likely to have higher average DMFS scores that may be the result of several possible pathways, including an increased incidence of dental caries, periodontal disease, or tooth loss as a result of untreated pulpal necrosis. Previous studies, as discussed in the introduction, suggest the increased likelihood of these pathways. Future studies should be conducted on a larger scale to verify these findings and to continue this line of investigation. The results in Table 1 and Table 2 provide a basis for the power or sample size calculations necessary in planning such large-scale studies. Additionally, fbture studies should also be conducted to determine the relative contribution that providers, as compared with patients, make in the dental caries treatment decision pathways for patients with SCA.

ACKNOWLEDGMENT This study is supported by NIDCR Grant #T32 DE07255.

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