Hematopoietic stem cell transplantation (HSCT) is a crucial component in the treatment of various malignant and non-malignant hematological disorders. Among pediatric patients, hematologic malignancies, such as leukemia, are some of the most common types of cancer. However, conditioning regimens administered before HSCT often lead to acute or chronic side effects [1, 2].

The conditioning regimen is tailored to the patient's hematological diagnosis, age, and overall medical status. The primary aim is to eliminate abnormal cells and suppress the immune system to prevent host-versus-graft immune rejection. This regimen is cytotoxic and induces a transient period of neutropenia following stem cell engraftment, typically lasting 2 to 4 weeks. During this phase, patients experience immunosuppression, making them more vulnerable to infections. The toxicity of the conditioning agents can damage normal mucosal and skin barriers, allowing endogenous bacteria to invade [3, 4]. This side effect increases the risk of infectious complications and poor clinical outcomes [5].

The oral cavity is a key target site for drug toxicity and bacterial invasion, often resulting in a range of adverse effects, such as oral mucositis (OM), reduced salivary secretion, xerostomia, altered taste perception, oral infections, and frequently associated oral pain. These complications can affect the patient’s ability to eat, thereby negatively affecting nutritional status and medication adherence [6, 7].

As a result, there is broad consensus among researchers on the necessity of assessing oral health and providing appropriate dental interventions before initiating HSCT. Additionally, the approach to dental treatment in pediatric patients differs significantly from that in adults [8, 9]. Despite these concerns, studies focusing on the diagnosis and management of oral diseases in pediatric patients undergoing HSCT and their impact on the transplantation process are scarce. A prospective multicenter study focused on pediatric recipients of HSCT in the neutropenic phase concerning oral complications, timing, severity, and patient experience. However, the number of cases in that study was relatively small and the pre-transplant oral examination data were incomplete. Moreover, it focused only on the observation of a single disease-oral mucositis and lacked analysis of other common oral diseases such as caries or pulp and periapical diseases in children, as well as the specific conditions of deciduous tooth retention, loosening, and eruption gingivitis [10]. Therefore, in our retrospective and hospital-based study, with adequate sample size, we aimed to determine the prevalence and severity of various oral diseases and their impact on HSCT outcomes. Our study is the first to conduct detailed age-based group statistics and analyses of children with hematological diseases at different dentition stages (deciduous dentition, mixed dentition, and permanent dentition). Our research starts from the perspective of dentists' concerns and covers most of oral diseases in children undergoing HSCT and comprehensively and statistically analyze the prevalence rates of these diseases and the risks during transplantation, filling the gap in this area of research.

In this retrospective study, we reviewed pediatric patients who underwent pre-transplant oral examinations at the Department of Stomatology, Peking University People's Hospital, between 2020 and 2022. Here, all patients undergoing HSCT are required to undergo a pre-transplant oral examination, which was jointly completed by three doctors(Xuan Gao, Shengnan Zhao, Shuting Wang) at the Department of Stomatology.

Medical records, including pretransplant oral examination and inpatient transplantation records, were reviewed to collect information (sex, age, disease, etc.) from the electronic medical record system. Pretransplant oral examination details, imaging data, and treatment information of the same patient were collected from the electronic medical record system by two dentists (Xuan Gao, Shengnan Zhao). Data such as the number of days from the initial dental visit to transplantation, hematological test results (white blood cell count, neutrophil count, and platelet count) at the time of oral examination and transplantation, number of fever days, and oral complications were recorded by one dentist (Shuting Wang).

Inclusion Criteria: patients under 18 years of age.

Exclusion Criteria: 1) patients who had not undergone HSCT by January 2023 due to autologous or donor-related reasons, 2) non-hematologic disease.

The study divided pediatric HSCT patients into two groups based on age: the children group (below 8 years old) and the adolescent group (8 years and older).

Before transplantation, the patient was diagnosed with dental pulp diseases, dental caries, pulpitis, periapical diseases, gingivitis, etc. During the transplantation, the patient was diagnosed with odontogenic complications and oral mucositis.

Prevalence is used for various oral diseases before transplantation. Incidence is used for OM during transplantation.

Diagnostic criteria of oral diseases are shown in (Table 1).

All figures were generated with the R software (http://www.R-project.org; Version 4.2.1). The criteria of statistical significance was set as a p-value < 0.05 or adjust p-value < 0.05. For continuous variables, the normality of the data was checked using a histogram and Kolmogorov-Smirnov Lillefors tests. P > 0.05 indicates the data follows a normal distribution. For normally distributed data, t-tests were employed, while for non - normally distributed data, such as age, time interval and transplantation days, the Mann-Whitney U test was used. Chi-square test or Fisher's exact test was used to analyze the categorical variables. When the sample size was small (e.g., n < 40) or the expected frequency of any cell was less than 5, such as in the Impacted teeth group (Table 2 and Table 3), Fisher’s exact test was applied. To better explain the risk factors for OM, multivariate logistic regression was performed to confirm the potential risk of gingivitis in patients with OM. Age, gender, hematologic disease, stem cell source, gingivitis and impacted teeth were selected for the multivariate logistic regression analysis based on univariate analysis results.

This retrospective study was reviewed and approved by the Ethics Committee of Peking University People's Hospital (approval no. 2023PHE037-001), dated February 27, 2023, and complied with the Declaration of Helsinki. The requirement for informed consent was waived due to the retrospective nature of the study.

A total of 168 valid medical records were collected for the study: 119 males and 49 females with an average age of 10.49 years. All the patients underwent allogeneic stem cell transplantation. The average hospitalization duration for pediatric HSCT patients was 33.01 days. Of the 168 patients, 110 (65.48%) experienced infectious fever, with an average of 3.34 days of fever. During the transplantation process, 89 patients (52.98%) had abnormal oral microbiota, and 85 patients (50.60%) developed acute graft-versus-host disease (GVHD). More than 50% of OM cases occurred between 5–8 days after stem cell infusion, with a peak incidence observed at 6 days (40 cases, 56.34%) after cell infusion. The general patient conditions are summarized in Table 2.It was found that, the adolescent group had a significantly shorter time between the initial dental examination and beginning date of transplantation and higher occurrence of OM, but no significant differences were observed between the two groups in terms of gender, hematologic disease, etc.

A comparison of the factors related to OM during transplantation in pediatric patients with hematological diseases is shown in Table 3. Chi-square tests showed that the proportions of children with gingivitis was significantly higher in the OM group than that in the non-OM group, suggesting that gingivitis may be risk factor for OM during transplantation. On the other hand, the proportions of children with impacted teeth was significantly lower in the OM group than that in the non-OM group. Significant differences were also observed between the two groups in terms of gender, age, hematologic disease and stem cell source. However, the results of multivariate logistic regression (Table 4) showed that gender, hematologic disease and impacted teeth actually had no impact on OM. Age, stem cell source and gingivitis had a significant impact on OM. Due to the small number, after removing the Peripheral + Cord blood group and establishing an adjusted stem cell source grouping, we found that stem cell source had no impact on the occurrence of OM. We used Variance Inflation Factor (VIF) to test for multicollinearity. The VIF values for gender, age, hematologic disease, stem cell source, gingivitis and impacted teeth were 1.053,1.087, 1.235, 1.236,10140 and 1.02464, respectively, indicated that the correlation between the independent variables is weak.

Among the 168 pediatric HSCT patients, 129 (76.79%) were found to have one or more oral diseases during the pre-transplant oral examination. The prevalence of oral diseases, from highest to lowest, was as follows: Dental pulp disease in 82 cases (48.81%), gingivitis in 60 cases (35.71%), loose deciduous teeth in 22 cases (13.10%), erupting teeth in 15 cases (8.93%)and impacted teeth in 6 cases(3.57%-all in adolescent group).As shown in Table 2, adolescents had a significantly higher prevalence of gingivitis compared to children under 8 years of age.

Although the prevalence of oral diseases was high before transplantation, the rate of oral treatment within one year was relatively low, with only 22 patients (13.10%) receiving treatment. Pre-transplant oral treatment was administered to 10 patients(one patient may receive several different treatments simultaneously). Of these, 7 patients underwent extraction of loose deciduous teeth, including 2 due to apical periodontitis, 2 due to pulpitis, and 3 with grade II/Ⅲ mobility. Additionally, 4 patients received resin fillings for deciduous dental caries, and 1 patient had a reshaped fractured root. None of the treated patients developed odontogenic complications during the transplantation. Two children experienced odontogenic complications during the transplantation. One child developed gingival swelling and pain, whereas the other child, with deciduous dentition and younger age, experienced two oral-related infections. The detailed conditions are listed in Table 5.

Our previous studies focused primarily on the impact of oral diseases on adult patients undergoing HSCT, highlighting the importance of managing periodontal disease and impacted third molars prior to HSCT [18, 19]. However, there are significant differences between oral diseases in pediatric and adult populations, as well as differences in treatment protocols. Moreover, studies on the effects of oral diseases on pediatric HSCT outcomes are rare. In this study, we compared the general characteristics of 168 pediatric patients undergoing HSCT by different age groups. The adolescent group had a significantly shorter time between the initial dental examination and beginning date of transplantation, indicating that advancing age may reduce the waiting time prior to transplantation.

OM is a major complication associated with allogeneic HSCT and its negative effects include pain, impaired eating and nutrition, increased use of pain medications, extended hospital stays, and increased risk of systemic infections [10]. Several studies of pediatric patients undergoing HSCT have reported high OM rates during transplantation. In a previous study, 73.5% of 49 pediatric patients had OM [20]. Another study found 59.2% OM in patients aged < 9months and 87.8% in those aged > 9months [21]. A third study reported an OM incidence rate of 41%, which was lower in patients with cancer [22].

In our study, 42.26% of pediatric patients who underwent HSCT developed OM, a rate that is similar to previous studies. Our results showed that the children in the OM group were significantly older than those in the non-OM group. This finding has not been reported in prior studies. Furthermore, studies on the impact of oral diseases on OM incidence in pediatric HSCT patients are scarce, but we found that the incidence of gingivitis was significantly higher in the OM group, suggesting that oral hygiene status and gingivitis may be risk factors for OM during transplantation. We speculate that the reason may be due to the elder children are in the mixed dentition period which leads to an increase in plaque retention areas and difficulties in oral care. Additionally, during adolescence, the increased incidence of pubertal gingivitis may also contribute to the higher incidence of OM. Further validation is required in prospective, large sample studies.

In our study, 76.79% of the pediatric HSCT patients were found to have oral diseases during pre-transplant oral examinations. This high rate of oral disease is consistent with the findings of a retrospective study of 30 children with malignant hematological diseases, where 63.3% of the patients were diagnosed with one or more oral pathologies before HSCT [23].

According to the results of China's Fourth National Oral Health Survey [24], In children aged 3–5 years, the caries prevalence was 63.11%. In addition, the rate of dental treatment remains low. Our study shows that the prevalence of caries and dental treatment rates in pediatric patients who have undergone HSCT are similar to those in the general population of children in China.

Gingivitis is also common among pediatric patients who have undergone HSCT. One study reported a gingivitis rate of approximately 36.7%, which included simple and eruption-related gingivitis. However, no cases of dental infections caused by gingivitis have been reported [23]. Our results showed that the prevalence of gingivitis was 35.71% and increased with age. Gingivitis might be influenced by puberty-related changes and malocclusion, which can negatively affect periodontal health. However, this trend needs to be confirmed in future studies with larger sample sizes.

In our study, only two pediatric patients experienced odontogenic infections during the transplantation process. The first case involved bilateral mandibular gingival swelling that was managed with local hygiene care without fever or antibiotics. This indicates that infections caused by gingivitis and tooth pain in pediatric patients after HSCT may carry a relatively low risk of developing severe infections. Such infections can generally be controlled by improving oral hygiene and increasing the use of antibiotics. However, the second patient had recurrent oral infections, including acute parotitis and facial cellulitis, and was treated with escalating antibiotics over an extended period. Research shows that Viral mumps and juvenile recurrent parotitis (JRP) are the two most common causes of parotitis in children. Acute sialadenitis typically presents with swelling, pain, fever, and erythema of the affected gland [25]. In patients (HSCT) patients, weakened immune function may increase the incidence of parotitis, which can lead to worsening infections, dissemination, and even life-threatening conditions. One report described a rare case of purulent sialadenitis caused by the opportunistic pathogen Burkholderia cepacia following transplantation [26]. Another case described a 19-year-old male with parotitis that led to fatal meningoencephalitis after HSCT[27]. Although severe infections and their outcomes are rare, they can occur in vulnerable populations undergoing HSCT.

Therefore, pediatric patients undergoing HSCT should be closely monitored for the risk of parotitis. Hematologists should collaborate with dentists to enable early diagnosis and intervention, control infections, and prevent adverse outcomes.

There is limited research on pretransplant oral treatment protocols for pediatric HSCT patients, and there are varying opinions on how to manage different oral diseases. Debate exists over the management of loose primary teeth, with De Fonseca advocating natural exfoliation for teeth without inflammation [8], while others propose extraction because of the risk of infection and chewing pain [9, 23]. Some recommend extracting teeth 2–3 weeks before HSCT to allow mucosal healing [28].

In addition, pediatric HSCT patients face debates over pulpitis and apical periodontitis treatments, such as vital pulp therapy and apexification. Some studies [8, 28] recommend extraction due to potential infection from failed root canals, while others [29, 30, 31] advise against extraction near the transplantation due to complications. One study [23] showed the safety of root canal treatments in four children undergoing HSCT.

In our study, only 10 patients received oral treatment before transplantation. None of the treated patients developed dental infections during the transplantation process, and no infections were observed in patients with untreated carious teeth, pulpitis, or apical periodontitis, or in those who did not have loose primary teeth extracted.

Based on the dental infections during transplantation in our study and oral treatment protocols, we propose a conservative oral management protocol for pediatric HSCT patients.:

2Erupting teeth with gingivitis should undergo oral hygiene treatment with the local removal of the causative factors.

Due to its retrospective nature, this study relied on medical record data, which may have resulted in incomplete or biased information. Without systematic dental evaluations by a bedside dentist during HSCT, mild oral complications may have been overlooked, potentially leading to an underestimation of the true incidence of oral mucositis or odontogenic infections. The relevance of oral diseases and complications during transplantation may have been overlooked. Dentist-hematologist consultations and dental bedside examinations need to be improved to ensure accurate oral records during transplantation. Additionally, the lack of OM grading in medical records during transplantation leads to an inability to classify the severity of mucositis. A structured OM and gingivitis grading protocol will be implemented in future prospective work according to the grading of OM (WHO) and gingivitis grading (2017 WORLD WORKSHOP).

Being a single-center study, although we were able to collect adequate data in a short period of time, the data source is limited to the Chinese hematological disease population who visited our hospital. Considering these limitations, a long-term multicenter prospective study should be conducted to assess the impact of pre- and in-transplant oral care on post-transplant oral health.

We evaluated the distribution of oral diseases in pediatric patients with hematological disorders before HSCT and their potential impact on the transplantation process. The results showed that 71 patients (42.26%) developed OM during transplantation. Oral disease prevalence was high among pediatric HSCT patients, and despite a low rate of treatment for oral diseases, the incidence of odontogenic complications during transplantation was low; only two patients developed complications that did not hinder the transplant process. We propose a conservative oral management protocol for pediatric patients undergoing HSCT.