Anemia, Diarrhea, Iron
Conditions
Keywords
zinc, iron, interaction, diarrhea, delivery
Brief summary
With the long-term public health goal of developing an effective micronutrient supplementation program to improve child health by improving iron and zinc status and decreasing morbidity due to diarrhea in areas with high rates of childhood malnutrition, we seek to determine the most efficacious method of decreasing childhood morbidity and mortality due to diarrhea in toddlers by re-examining the issue of iron and zinc interaction and determining if this interaction can be minimized by separate administration of iron and zinc supplementation.
Detailed description
Iron supplementation is used in reducing anemia and improving hemoglobin status. Zinc supplementation is emerging as possibly an efficacious preventive measure in decreasing incidence of severe diarrhea. Previous studies have suggested interactions of zinc and iron when given together, reducing the effects of supplementation with both minerals. One study in Peru has shown a decrease in interaction effect with separate supplementation of iron and zinc in time when compared to iron administration alone or placebo; however, an evaluation of clinical outcomes and zinc or iron status when iron and zinc are administered separately compared to supplementation of zinc and iron together or each alone has not previously been done. This trial will assess the effect of iron and zinc supplementation given on alternate days compared with giving them together in a combined supplement. We propose a randomized, double blind, placebo-controlled community trial of children 6-23 months in Mirzapur, Bangladesh. We will recruit and enroll 1000 children 6-23 months old who are permanent residents of the selected villages. Each child will be randomly assigned to 1) daily alternating zinc and placebo 2) daily alternating iron/folic acid and placebo 3) daily alternating zinc/iron/folic acid and placebo 4) daily alternating zinc and iron/folic acid 5) daily placebo. Primary outcomes will include incidence of severe diarrhea, evaluated weekly for 6 months, hemoglobin, prevalence of anemia, and serum zinc. Analysis of the data will be done to compare the effect of separate iron and zinc supplementation as compared to combined iron and zinc supplementation as well as compared to iron, zinc, or placebo single supplementation. We will evaluate the difference in incidence rate of severe diarrhea, serum hemoglobin, percent anemia, and serum zinc. Since this will be a randomized, double-blind, placebo controlled trial, differences in effect will be most likely explained by the timing of supplement doses. If there is an improvement in clinical and biochemical outcomes, this would be consistent with a decreased interaction of absorption. If no difference is found, there may be another mechanism for the seeming interaction of iron and zinc besides that of mutually inhibitory absorption in the intestine.
Interventions
DIETARY_SUPPLEMENTiron and zinc combined
Children \>= 12 months received an average of 5mg zinc/day, 6.25 Iron/day, and 25IU folic acid/day. children\<12 received half that dose. This dose was alternated daily with placebo. Dissolvable doses were distributed in blister packs and reconstituted with a teaspoon of water. Doses were administered in the morning. For missed doses, the mother gave the child the next morning dose, and a second dose in the evening.
DIETARY_SUPPLEMENTiron and zinc on separate days
Children \>= 12 months received an average of 5mg zinc/day, alternating daily with 6.25 Iron/day, and 25IU folic acid/day. Children\<12 received half that dose. Dissolvable doses were distributed in blister packs and reconstituted with a teaspoon of water. Doses were administered in the morning. For missed doses, the mother gave the child the next morning dose, and a second dose in the evening.
DIETARY_SUPPLEMENTiron
Children \>= 12 months received an average 6.25 Iron/day, and 25IU folic acid/day. Children\<12 received half that dose. This dose was alternated daily with placebo. Dissolvable doses were distributed in blister packs and reconstituted with a teaspoon of water. Doses were administered in the morning. For missed doses, the mother gave the child the next morning dose, and a second dose in the evening.
DIETARY_SUPPLEMENTZinc
Children \>= 12 months received an average of 5mg zinc/day. Children\<12 received half that dose. This dose was alternated daily with placebo. Dissolvable doses were distributed in blister packs and reconstituted with a teaspoon of water. Doses were administered in the morning. For missed doses, the mother gave the child the next morning dose, and a second dose in the evening.
DIETARY_SUPPLEMENTplacebo
Children received daily placebo. Dissolvable doses were distributed in blister packs and reconstituted with a teaspoon of water. Doses were administered in the morning. For missed doses, the mother gave the child the next morning dose, and a second dose in the evening.
Sponsors
International Centre for Diarrhoeal Disease Research, Bangladesh
United States Agency for International Development (USAID)
Agency for Healthcare Research and Quality (AHRQ)
Johns Hopkins Bloomberg School of Public Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Months to 18 Months
Healthy volunteers
Yes
Inclusion criteria
* Children 6-18 months old * Permanent residents of the selected villages
Exclusion criteria
* Severe malnutrition requiring hospitalization (defined as weight for height \<-3 SD Z-score) * Severe anemia requiring treatment (hemoglobin \< 70 g/L) * Chronic illness that would impair feeding ability * Likely to move in next 6 months. * Fever greater than 38.5 * Regular iron supplementation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Diarrhea | 6 months | A diarrhea episode was defined as three or more loose, liquid, or watery stools for 2 consecutive days, separated in time from an earlier or subsequent episode by at least 2 consecutive diarrhea-free days. |
Secondary
| Measure | Time frame |
|---|---|
| Change in Hemoglobin | 6 months |
| Change in Zinc Status | 6 months |
| Percent Anemic | 6 months |
Countries
Bangladesh
Participant flow
Recruitment details
All 6-18 month old permanent residents of selected villages near Kumudini Hospital were enrolled from May 8, 2007-August 31, 2007.
Pre-assignment details
If one family had two eligible children, one was randomly selected for enrollment. Children with severe malnutrition (weight for height z-score -3 s.d.), severe anemia (hemoglobin \<70 g/l), chronic illnesses that would impair feeding ability, planned move during the study period, or active fever (\>38.5 C) were excluded from the study.
Participants by arm
| Arm | Count |
|---|---|
| Combined Iron and Zinc combined iron and zinc, alternating daily with placebo | 201 |
| Separate Iron and Zinc iron, alternating daily with zinc | 199 |
| Iron Alone iron, alternating daily with placebo | 201 |
| Zinc Alone zinc, alternating daily with placebo | 198 |
| Placebo placebo daily | 201 |
| Total | 1,000 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 0 | 0 | 0 | 0 | 2 |
| Overall Study | Lost to Follow-up | 7 | 8 | 8 | 5 | 4 |
| Overall Study | Protocol Violation | 1 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Separate Iron and Zinc | Iron Alone | Zinc Alone | Combined Iron and Zinc | Placebo | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 199 Participants | 201 Participants | 198 Participants | 201 Participants | 201 Participants | 1000 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 0.925 years STANDARD_DEVIATION 0.32 | 0.9 years STANDARD_DEVIATION 0.33 | 0.925 years STANDARD_DEVIATION 0.33 | 0.93 years STANDARD_DEVIATION 0.31 | 0.9 years STANDARD_DEVIATION 0.32 | 0.92 years STANDARD_DEVIATION 0.32 |
| Region of Enrollment Bangladesh | 199 participants | 201 participants | 198 participants | 201 participants | 201 participants | 1000 participants |
| Sex: Female, Male Female | 107 Participants | 93 Participants | 109 Participants | 87 Participants | 88 Participants | 484 Participants |
| Sex: Female, Male Male | 92 Participants | 108 Participants | 89 Participants | 114 Participants | 113 Participants | 516 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 201 | 2 / 199 | 0 / 201 | 4 / 198 | 4 / 201 |
| serious Total, serious adverse events | 11 / 201 | 8 / 199 | 17 / 201 | 10 / 198 | 22 / 201 |
Outcome results
Primary
Incidence of Diarrhea
A diarrhea episode was defined as three or more loose, liquid, or watery stools for 2 consecutive days, separated in time from an earlier or subsequent episode by at least 2 consecutive diarrhea-free days.
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combined Iron and Zinc | Incidence of Diarrhea | 201 episodes |
| Separate Iron and Zinc | Incidence of Diarrhea | 204 episodes |
| Iron Alone | Incidence of Diarrhea | 260 episodes |
| Zinc Alone | Incidence of Diarrhea | 224 episodes |
| Placebo | Incidence of Diarrhea | 235 episodes |
Secondary
Change in Hemoglobin
Time frame: 6 months
Secondary
Change in Zinc Status
Time frame: 6 months
Secondary
Percent Anemic
Time frame: 6 months