Assessing the adherence and acceptability to iron and folic acid compared with multiple micronutrient supplements during pregnancy: a cluster-randomized noninferiority trial in Cambodia

BACKGROUND: The Cambodian Ministry of Health is exploring transitioning from iron and folic acid (IFA) to multiple micronutrient supplements (MMS) during pregnancy and is seeking rigorous evidence to inform this policy change. OBJECTIVE: Our objective was to assess the adherence and acceptability of MMS versus IFA supplementation during pregnancy. METHODS: We conducted an open-label cluster-randomized non-inferiority trial across 48 health centers in Cambodia. A total of 1,546 healthy pregnant individuals (18-45 years) were recruited at their first antenatal care (ANC) visit (<14 weeks' gestation) and randomized to one of three arms at the health center level: 1) IFA for 90 days (IFA-90, n=515), the current standard of care; 2) MMS for 180 days via one 180-tablet bottle (MMS-180, n=516); or 3) MMS for 180 days via two 90-tablet bottles (MMS-90, n=515). Our primary outcome was the non-inferiority of adherence rates of MMS-180 compared to IFA-90, assessed by tablet counts and compared against a pre-defined non-inferiority margin of 15%. Mixed-effects linear regression models were used to estimate the mean difference (95% CI) in adherence rates. Our secondary outcomes included the mean difference in ANC attendance between the MMS groups and the acceptability of MMS across six domains. RESULTS: Overall, 88% of participants completed the trial, with high mean adherence rates across arms (91% for IFA-90, 95% for MMS-180, and 95% for MMS-90). The adjusted mean (95% CI) difference in adherence rates between MMS-180 and IFA-90 groups was 3.9% (1.7, 6.2). The adjusted mean (95% CI) difference in ANC visits for MMS-180 and MMS-90 groups was 0.0 (-0.1, 0.2) visits. The acceptability of MMS was positive (90-100% 'agreement' across six domains). CONCLUSIONS: Both IFA and MMS were highly acceptable, yet adherence to MMS was superior to IFA. These findings support the transition from IFA to MMS in Cambodia. TRIAL REGISTRATION: Clinicaltrials.gov (NCT05867836).