In Ethiopia, one in five mothers suffers from postpartum depression, which needs to be prevented through interventions. According to the World Health Organization, maternal healthcare providers have a unique opportunity to provide psychosocial interventions to prevent the damaging effects of perinatal depression. Hence, this study assessed the effectiveness of prenatal group-based psycho-education in preventing postpartum depression (PPD) in primary healthcare units. We conducted a two-arm cluster-randomized controlled trial, enrolling 550 pregnant women at 12-20 weeks of gestation with a normal score (0-4) and a mild score (5-9) on the Patient Health Questionnaire-9 (PHQ-9). The study utilized simple randomization techniques to assign clusters between arms in a 1:1 ratio. The data was collected through face-to-face interviews conducted at 12-20 weeks of gestation and 6 weeks postpartum. The intervention group received usual care plus five prenatal group-based psycho-education (PGBPE) classes, while the control group received only usual care. The PPD status between arms was compared using the chi-square test of association. A mixed-effects multilevel logistic regression model was also used to examine the predictors of the outcome variables. The overall response rate at the end line was 92.9%. Thus, compared to that in controls, the PPD in the intervention clusters was considerably lower (20 (7.6%) vs. 74 (28.9%)), P = 0.001)/65% (AOR = 0.35, 95% CI = 0.13-0.99), although no difference was detected at baseline. Social support (AOR = 0.04, 95% CI = 0.01-0.15), partner emotional support (AOR = 0.24, 95% CI = 0.12-0.51), PPD literacy (AOR = 0.25, 95% CI = 0.11-0.62), and self-esteem (AOR = 0.22, 95% CI = 0.11-0.47) were more likely to protect mothers from PPD. On the contrary, domestic work (AOR = 9.75, 95% CI = 3.37-28.16), neonates with complications (AOR = 5.79, 95% CI = 2.04-16.45), and unhealthy coping (AOR = 2.39, 95% CI = 1.06-5.42) exposed mothers to PPD. The implementation of a PGBPE in primary healthcare units (PHCUs) was effective at preventing PPD. Therefore, this intervention method has to be promoted and used in PHCUs to prevent PPD. [Pan African Clinical Trial Registry], identifier [PACTR 202203616584913].
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