Effects of therapeutic zinc supplementation for diarrhea and two preventive zinc supplementation regimens on the incidence and duration of diarrhea and acute respiratory tract infections in rural Laotian children: A randomized controlled trial

Abstract

Background: Diarrhea and respiratory tract infections are leading causes of childhood morbidity and mortality. This individually randomized, double-blind placebo-controlled trial was designed to evaluate the effects of different zinc supplementation regimens on the incidence and duration of diarrhea and acute lower (ALRI) and upper (AURI) respiratory tract infections among rural Laotian children. The study included 3407 children, 6-23 months at enrollment.

Methods: Children were randomized to one of four study groups: therapeutic zinc supplements for diarrhea treatment (20 mg/d for 10 days with each episode; TZ), daily preventive zinc tablets (7 mg/d; PZ), daily multiple micronutrient powder (10 mg/d zinc, 6 mg/d iron and 13 other micronutrients; MNP), or daily placebo powder for 9 months. Incidence and duration of diarrhea (≥3 liquid stools/24 hours), ALRI (persistent cough with wheezing, stridor or chest in-drawing) and AURI (purulent nasal discharge with cough) were assessed by parental report during weekly home visits and analyzed using negative binomial models.

Results: Baseline mean age was 14.2 ± 5.1 months, and 71% had low plasma zinc (<65 μg/dL). Overall diarrhea incidence (0.61 ± 0.01 episodes/100 days at risk) and duration (2.12 ± 0.03 days/episode) did not differ by study group. Age modified the impact of the interventions on diarrhea incidence (P = 0.06) and duration (P = 0.01). In children >18 months, TZ reduced diarrhea incidence by 24% vs MNP (P = 0.035), and 36% vs Control (P = 0.004), but there was no difference with PZ. This patterned remained when analyses were restricted to diarrhea episode occurring after the first treatment with TZ. Also, in children >18 months, TZ reduced diarrhea duration by 15% vs PZ (P = 0.03), and 16% vs Control (P = 0.03), but there was no difference with MNP. There were no overall effects of study group on incidence of ALRI (overall mean 0.005 ± 0.001 episodes/100 days, P = 0.14) or AURI (overall mean 0.09 ± 0.01 episodes/100 days, P = 0.72).

Conclusions: There was no overall impact of TZ, PZ or MNP on diarrhea, ALRI and AURI. However, in children >18 months, TZ significantly reduced both the duration of diarrhea episodes and the incidence of future diarrhea episodes compared with placebo.

Trial registration: ClinicalTrials.gov: NCT02428647.

Figure 1

Flow diagram of study participant randomization and inclusion into data analyses. MNP – Micronutrient powder, PZ – preventive zinc, TZ – therapeutic zinc.

Figure 2

Modifying effect of child age on the responses to therapeutic zinc supplementation for diarrhea, daily preventive zinc supplementation, daily MNP and placebo on diarrhea incidence and duration among young Laotian children. TZ – therapeutic zinc, PZ – preventive zinc, MNP – micronutrient powder. All values adjusted for age, sex, and district. Values with different superscripts are significantly different (P < 0.01).