Abstract: A total of 12 trials (11 randomized controlled trials and one quasi-randomized trial) of 563 people with HbSS, HbSC or HbSβthal, aged six to 35 years old, were included in the review; the majority of participants were African-American. Interventions ranged from a total of one hour to weekly sessions for eight weeks and the post-intervention assessments ranged from the end of the intervention period to 12 months after completion. The heterogeneity of the included trials, which encompasses setting, inclusion and exclusion criteria, interventional method and time of assessment, ranged from 'not important' to 'moderate to substantial' for different review outcomes. The overall risk of bias was low for selective reporting, unclear for random sequence generation, allocation concealment, blinding of participants and blinding of outcome assessment. Incomplete outcome reporting and blinding of personnel showed mixed bias representations. Patient knowledge was assessed by four trials (160 participants) with moderate to substantial heterogeneity. There was evidence that educational programs improved patient knowledge, standardised mean difference 0.87 points (95% confidence interval 0.28 to 1.45, moderate quality evidence), which improved further when a trial with high bias was removed in a sensitivity analysis. Caregiver knowledge, reported in a single trial of 20 families, also showed an improvement, standardised mean difference 0.52 points (95% confidence interval 0.03 to 1.00, moderate quality evidence). The effect on patient knowledge was sustained at longer follow-up periods, whereas the effect on caregiver knowledge was not sustained. There were two primary outcomes related to the effectiveness of educational programs on the recognition of signs and symptoms of disease-related morbidity. No comparative data were reported for patients or caregivers (or both) recognising signs and symptoms leading to self-management. Data from two trials were analysed for the utilization of health services and showed no evidence of an effect, mean difference 0.33 (95% confidence interval -0.57 to 1.23, moderate quality evidence). With regard to the review's secondary outcomes, depression showed a statistically significant decline in intervention groups, standardised mean difference -0.66 points (95% confidence interval -1.18, to -0.14, moderate quality evidence). Adherence to treatment was not assessed in any of the identified trials. No effects of interventions were seen on coping, family relationships or health-related quality of life of patients. The quality of evidence was low for positive coping and moderate for child knowledge, healthcare utilization and depression. This suggests that further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimates. This review identifies important positive effects of educational interventions on improving patient knowledge of sickle cell disease and depression. Effects on patients' knowledge were maintained for longer than for caregivers. The effect on knowledge was significant but small and whether it offers any clinical benefit is uncertain. Significant factors limiting these effects could be trials being under powered as well as attrition rates. Effects were not statistically significant in assessments of secondary outcomes, possibly due to the paucity of the number of trials and patients and caregivers. Trials showed moderate to high heterogeneity which might impact the results. To better study effects on outcomes, further controlled trials are needed with rigorous attention given to improve recruitment and retention and to decrease bias. Predetermined protocols using similar measurements should be used across multiple sites.

Plain-language summary: The review included 12 trials (563 people with HbSS, HbSC or HbSβthal aged six to 35 years). Participants were assigned randomly to either educational programs, no program and in some cases to a non-educational program, e.g. art therapy. Interventions ranged from a total of one hour to weekly sessions for eight weeks and post-intervention assessments ranged from the end of the intervention period to 12 months after completion. Educational programs and other interventions have resulted in improvements in patient knowledge or understanding of sickle cell disease, and a decrease in depression. Effects on patients' knowledge were maintained for longer than for caregivers. The effects are shown to be small but may result from the fact that most studies had very small numbers of participants and there was much variation between studies. The interventions studied showed no effect on patients' utilization of health services, relationships between families, caregiver or patient skills, coping or health-related quality of life of the patient. No comparative data were reported for patients or caregivers (or both) recognising signs and symptoms leading to self-management. No trials assessed the adherence to treatment. Trials varied in the interventions being studied as well as how the different outcomes were measured. The quality of evidence was low for the outcome positive coping and moderate for the outcomes child knowledge, healthcare utilization and depression. This suggests that further research is likely to have an important impact on our confidence in the effect of the treatment. Further research using randomized controlled trials with more people (including different populations) are needed to improve our understanding of which interventions are likely to be useful.