Non-anemic Iron Deficiency
Conditions
Keywords
child development, screening, Non-anemic iron deficiency, primary care pediatrics, prevention and health promotion
Brief summary
The pre-school years are critical years for children to acquire early learning skills such as language, fine motor and social skills; this is termed early child development. Primary care doctors (family doctors and pediatricians) are in a unique position to identify children with health or developmental problems. Screening is the process of testing healthy people for the earliest signs of health problems, followed by treatment, with the expectation that screening will improve the health of those screened. The focus of this research is screening young children for the earliest signs of iron deficiency (low blood iron levels) followed by treatment with oral iron. Previous research has shown that children with later stages of iron deficiency have serious delays in their development. Some research has shown that these delays may persist into young adulthood often with a significant reduction in intelligence. Early stages of iron deficiency may be difficult for parents or doctors to detect, and a blood test is usually needed. However, Canadian guidelines do not recommend screening all children for iron deficiency, because there is not enough good quality research to prove that screening is effective. In this study, the investigators will ask parents to allow their child between the ages of 1 to 3 years to have a blood test for iron levels. If the blood level is low, the child will be randomly assigned to receive either oral iron liquid for 4 months plus diet counseling, or a placebo liquid plus diet counseling. A psychologist will measure each child's early learning ability before and after the treatment. If this approach to screening children's blood iron levels followed by treatment improves children's development, parents and doctors may consider that routine blood screening tests are justified. Overall, this research is an important step to improving the ways in which primary care doctors can ensure that children have the best start to life-long health and achievement.
Interventions
DIETARY_SUPPLEMENTFerrous Sulfate
6 mg elemental iron/kg/day (0.4 ml/kg/day) in 2 or 3 divided doses (at the discretion of prescribing study doctor) for four months plus dietary counseling
DIETARY_SUPPLEMENTPlacebo
0.4 ml/kg/day in 2 or 3 divided doses (at the discretion of prescribing study doctor) for four months plus dietary counseling
BEHAVIORALDietary counseling
Dietary counseling will include written recommendations regarding maximum daily cow's milk intake, varied solid food intake including high iron containing foods, and avoidance of foods which reduce iron absorption.
Sponsors
Canadian Institutes of Health Research (CIHR)
Mead Johnson Nutrition
Mount Sinai Hospital, Canada
Unity Health Toronto
The Hospital for Sick Children
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
The research pharmacy prepared ferrous sulfate and placebo in bottles of similar appearance and weight. The placebo was developed by the research pharmacy, was similar in color and consistency to the active agent, and had a distinctive taste. Individuals masked to group allocation throughout the study included parents, attending physicians, research assistants, study personnel conducting outcome assessments, data analysts, and investigators. The biostatistician was unmasked after completion of data collection and locking of the database. The principal investigator was unmasked after the analysis.
Eligibility
Sex/Gender
ALL
Age
12 Months to 40 Months
Healthy volunteers
Yes
Inclusion criteria
* Age between 12 and 40 months attending any well child visit * Informed parental consent
Exclusion criteria
* developmental disorder * genetic, chromosomal or syndromic condition * chronic medical condition (with the exception of asthma and allergies) * chronic anemia, iron deficiency, or recent oral iron supplementation or treatment * prematurity, with a gestational age of less than 35 weeks * low birth weight less than 2,500 g; * attending the office for an acute illness, such as a viral illness, or other health concern other than for a well-child assessment * any contraindications to receiving elemental iron * the use of any natural health product containing the same medicinal ingredient(s) as the investigational product * English is not spoken to the child in the home or in a child care setting * CRP level ≥10 mg/L
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Early Learning Composite (ELC) From the Mullen Scales of Early Learning | Baseline and 4 months after enrollment | ELC is a measure of infant cognition (similar to IQ). In populations, infants have a mean score of 100 points and standard deviation of 15 points. A higher score indicates higher cognitive ability. Four cognitive skills are summarized into an Early Learning Composite score - Fine Motor, Visual Reception, Receptive Language, and Expressive Language. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Serum Ferritin | 4 months after enrollment | Blood samples analyzed for serum ferritin |
Countries
Canada
Participant flow
Recruitment details
Healthy children were enrolled while attending a scheduled health supervision visit at 1 of 8 primary care practices participating in a primary care research network called TARGet Kids! in Toronto, Canada. Enrollment began on June 15, 2012, and data collection was completed on November 9, 2018.
Pre-assignment details
220 children were assessed for eligibility. Based on each child's baseline blood tests (hemoglobin and ferritin), children with nonanemic iron deficiency (NAID) were eligible for the randomized trial; and children with iron deficiency anemia (IDA) and iron sufficiency (IS) were eligible for the open label study (not randomized). Therefore, 60 children were eligible for the randomized arms; 67 children were eligible for the open label study (not randomized). The total enrolled was 127 children.
Participants by arm
| Arm | Count |
|---|---|
| NAID - Iron Plus Diet Advice From the screening cohort, children with NAID (nonanemic iron deficiency) were invited to participate in an RCT. This group was randomized to receive Ferrous Sulfate 6 mg elemental iron/kg/day in 2 divided doses for four months plus diet advice | 31 |
| NAID - Placebo Plus Diet Advice From the screening cohort, children with NAID (nonanemic iron deficiency) were invited to participate in an RCT. This group was randomized to receive Placebo in 2 divided doses for four months plus diet advice | 29 |
| IS - Iron Sufficient From the screening cohort, a random sample of children with Iron Sufficiency were invited to participate in a prospective observational arm. They received diet advice only. | 30 |
| IDA - Iron Deficiency Anemia From the screening cohort, children with Iron Deficiency Anemia (IDA) were invited to participate in a prospective observational arm. They received usual care, including Ferrous Sulfate 6 mg elemental iron/kg/day in 2 divided doses for four months plus diet advice. | 37 |
| Total | 127 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| 12 months | Lost to Follow-up | 7 | 8 | 5 | 3 |
| 4 months | Lost to Follow-up | 3 | 2 | 1 | 5 |
Baseline characteristics
| Characteristic | NAID - Iron Plus Diet Advice | NAID - Placebo Plus Diet Advice | IS - Iron Sufficient | IDA - Iron Deficiency Anemia | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 31 Participants | 29 Participants | 30 Participants | 37 Participants | 127 Participants |
| Age, Categorical >=65 years | 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 |
| Age, Continuous | 24.0 months STANDARD_DEVIATION 8.1 | 24.5 months STANDARD_DEVIATION 6.6 | 27.97 months STANDARD_DEVIATION 8.7 | 20.32 months STANDARD_DEVIATION 6.13 | 23.97 months STANDARD_DEVIATION 7.32 |
| Early Learning Composite (ELC) | 108.7 points STANDARD_DEVIATION 15.2 | 109.2 points STANDARD_DEVIATION 14.9 | 106.33 points STANDARD_DEVIATION 10.55 | 103.73 points STANDARD_DEVIATION 12.82 | 106.81 points STANDARD_DEVIATION 13.26 |
| Race/Ethnicity, Customized Maternal Ethnicity Other | 17 Participants | 8 Participants | 10 Participants | 18 Participants | 53 Participants |
| Race/Ethnicity, Customized Maternal Ethnicity other European | 14 Participants | 21 Participants | 20 Participants | 19 Participants | 74 Participants |
| Region of Enrollment Canada | 31 participants | 29 participants | 30 participants | 37 participants | 127 participants |
| Serum Ferritin | 9.7 ug/L STANDARD_DEVIATION 2.3 | 10.1 ug/L STANDARD_DEVIATION 2.5 | 26.63 ug/L STANDARD_DEVIATION 10.84 | 7.14 ug/L STANDARD_DEVIATION 3.22 | 13.04 ug/L STANDARD_DEVIATION 4.63 |
| Sex: Female, Male Female | 13 Participants | 17 Participants | 15 Participants | 19 Participants | 64 Participants |
| Sex: Female, Male Male | 18 Participants | 12 Participants | 15 Participants | 18 Participants | 63 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 28 | 0 / 27 | 0 / 29 | 0 / 32 |
| other Total, other adverse events | 16 / 28 | 7 / 27 | 0 / 29 | 16 / 32 |
| serious Total, serious adverse events | 0 / 28 | 0 / 27 | 0 / 29 | 0 / 32 |
Outcome results
Primary
Early Learning Composite (ELC) From the Mullen Scales of Early Learning
ELC is a measure of infant cognition (similar to IQ). In populations, infants have a mean score of 100 points and standard deviation of 15 points. A higher score indicates higher cognitive ability. Four cognitive skills are summarized into an Early Learning Composite score - Fine Motor, Visual Reception, Receptive Language, and Expressive Language.
Time frame: Baseline and 4 months after enrollment
Population: ELC 4 months after enrollment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NAID - ferrous sulfate plus diet advice | Early Learning Composite (ELC) From the Mullen Scales of Early Learning | 113.0 units on a scale | Standard Deviation 19.3 |
| NAID - placebo plus diet advice | Early Learning Composite (ELC) From the Mullen Scales of Early Learning | 113.5 units on a scale | Standard Deviation 12.6 |
| Iron sufficient | Early Learning Composite (ELC) From the Mullen Scales of Early Learning | 110.48 units on a scale | Standard Deviation 10.16 |
| Iron deficiency anemia | Early Learning Composite (ELC) From the Mullen Scales of Early Learning | 107.94 units on a scale | Standard Deviation 13.69 |
Secondary
Serum Ferritin
Blood samples analyzed for serum ferritin
Time frame: 4 months after enrollment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| NAID - ferrous sulfate plus diet advice | Serum Ferritin | 37.8 ug/L | Standard Deviation 30.8 |
| NAID - placebo plus diet advice | Serum Ferritin | 20.4 ug/L | Standard Deviation 11.2 |
| Iron sufficient | Serum Ferritin | 27.13 ug/L | Standard Deviation 9.06 |
| Iron deficiency anemia | Serum Ferritin | 57.55 ug/L | Standard Deviation 40.44 |