Addressing Anemia Among Adolescents in Zanzibar with School-Based Supplementation of Once Weekly Iron-Folic Acid or Daily Multiple Micronutrients: A Cluster-Randomized Trial

Background: Adolescent anemia is prevalent in low- and middle- income countries but has not been addressed. Supplementation with iron and folic acid (IFA) is recommended by the World Health Organization (WHO); however, evidence of effectiveness in adolescent is lacking. Given multiple micronutrient deficiencies co-exist, multiple micronutrient supplements (MMS) may be better suited to address anemia. We investigated the effectiveness of school-based supplementation of IFA or MMS in addressing anemia among secondary schools adolescents in Zanzibar, Tanzania. Methods: This was a non-masked three-arm cluster-randomized trial in which 42 schools were randomized to weekly IFA, daily MMS, or control (standard nutrition curriculum). Secondary students aged 10-17 years were supplemented for two 17-week periods between May-October, in 2022 and 2023. Hemoglobin was evaluated during four surveys conducted before and after each supplementation round. We used multi-level mixed effects models to estimate associations between study arm and anemia, categorized by WHO cut points as none, mild, moderate, or severe. The trial is registered with ClinicalTrials.gov: NCT05104554 and is complete. Findings: At baseline, 2,480 students were enrolled and 53·3% had anemia, with similar prevalence across all arms. Participants in the MMS arm had 37% lower risk of moderate or severe anemia at final endline, compared to those in the control arm (RR=0·63; 95% CI: 0·41, 0·99). No differences were observed in prevalence of anemia in the IFA group compared to the control group. Effects were modified by sex (p for interaction=0·004), with MMS males experiencing 73% lower risk of moderate or severe anemia compared to controls (RR=0·27; 95% CI: 0·12, 0·61), while for females the effect was smaller (RR=0·69; 95% CI: 0·44,1·08). Interpretation: School-based supplementation with MMS may be effective in addressing anemia among adolescents; however, the specific context and appropriate complementary interventions must be considered. Trial Registration: The trial is registered with ClinicalTrials.gov: NCT05104554 on October 21, 2021. Funding: This study was supported by an anonymous donor. Declaration of Interest: All authors declare no conflicts of interest. Ethical Approval: Approval for this study was obtained from the Ethical Review Board of Zanzibar Health Research Institute ZAHREC/03/AUG/2021/19 and the Harvard TH Chan School of Public Health Institutional Review Board (IRB20-1108). Parents provided informed consent for their adolescent children to participate in the study, and adolescents provided their assent.