Pre‐Operative Factors on Prognosis of Regenerative Endodontic Procedures: A Systematic Review and Meta‐Analysis

BACKGROUND: Although regenerative endodontics has advanced in recent years, the influence of pre-operative factors on treatment outcomes remains poorly understood. OBJECTIVE: To evaluate the effect of pre-operative factors-including age, gender, tooth type, aetiology of pulp necrosis, stage of root development, clinical signs/symptoms and periradicular status-on the treatment outcomes of regenerative endodontic procedures (REPs) in immature permanent teeth. METHODS: A literature search was conducted on six electronic databases and grey literature to identify studies investigating the effect of pre-operative factors on REP outcomes. The risk of bias was assessed using the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk-of-Bias 2 tool for randomised clinical trials (RCTs). Meta-analyses of proportions were conducted to estimate pooled rates for the outcomes 'clinical and radiographic healing', 'root development' and 'apical closure' across different pre-operative factors. Associations between these factors and treatment outcomes were assessed through meta-analyses of effect sizes. The certainty of evidence was evaluated using the GRADE approach. RESULTS: Twenty studies were included, comprising 13 observational studies and seven RCTs. Most studies presented a moderate to high risk of bias. The pooled success rate for clinical and radiographic healing exceeded 81% across all pre-operative factors. Moreover, root development was achieved in 52%-95% of cases, whereas complete apical closure ranged from 32% to 91%. No significant association was found between pre-operative factors and clinical and radiographic healing. It was found that teeth with pulp necrosis due to trauma presented 3.59 times higher relative risk of root development failure compared to those with necrosis due to anatomic anomaly (RR = 3.59, 95% CI 1.21-10.67, p = 0.02). Incisors presented 1.90 times higher relative risk of root development failure (RR = 1.90, 95% CI: 1.37-2.63, p < 0.01) and 1.98 times higher relative risk of incomplete apical closure (RR = 1.98, 95% CI: 1.34-3.13, p = 0.02) compared to premolars. The presence of an apical lesion increased the relative risk of root development failure by 2.55 times (RR = 2.55, 95% CI: 1.63-4.86, p = 0.01). The certainty of evidence was rated as very low. CONCLUSION: Pre-operative factors were not significantly associated with clinical and radiographic healing in REPs. However, trauma-related pulp necrosis, tooth type (incisors) and the presence of apical lesions were associated with an increased risk of root development failure. These findings should be interpreted with caution due to between-study heterogeneity, the moderate to high risk of bias and the very low certainty of the evidence.