Prenatal Iodine Supplementation and Early Childhood Neurodevelopment

Study Overview
=================
Brief Summary
-----------------
A randomized controlled trial to determine the effect of reducing iodine from vitamin and mineral supplements for pregnant women who have adequate iodine intakes (>165 μg/d from food alone) on cognitive development of children at 24 months of age.

Detailed Description
-----------------
It is known that severe iodine deficiency during pregnancy leads to profound intellectual disabilities in the child. Following results of a 2004 national survey of school-aged children showing that mild iodine deficiency had re-emerged in the south-eastern parts of Australia, the Australian government mandated the addition of iodine to salt used in bread making to increase population iodine intake. It is also recommended that all pregnant and lactating women take an additional iodine supplement containing 150 µg/d of iodine. Since this time, further evidence has emerged from cohort studies that children born to women with high iodine intake (as well as low iodine intake) have poorer neurodevelopmental scores, suggesting that more tailored supplementation may be a better strategy. Our PoppiE trial will determine if limiting iodine supplementation in women who already consume adequate iodine from food, improves cognitive scores in early childhood. A total of 754 pregnant women from around Australia who are ≤13 weeks of gestation will be enrolled and randomised to receive a standard prenatal vitamin and mineral supplement with a reduced amount of iodine (20 μg - intervention) or a standard prenatal vitamin and mineral supplement with 200 μg of iodine (control). The control supplement contains a level of iodine to match the amount in most commonly used vitamin and mineral supplements sold in Australia. Infant neurodevelopment at 24 months of age will be assessed using the Bayley-IV and conducted at participating centres or a location convenient to the family.

Official Title
-----------------
Prenatal Iodine Supplementation and Early Childhood Neurodevelopment

Conditions
-----------------
Pregnancy Related, Neurodevelopmental Disorders, Nutrition Disorder, Fetal

Intervention / Treatment
-----------------
* Combination Product: Low Iodine Supplement
* Combination Product: Standard Iodine Supplement


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Pregnant women ≤13 weeks of gestation. Consume greater than 165 µg/d of iodine from food alone based on our validated Iodine Specific Food Frequency Questionnaire (I-FFQ). English is main language spoken at home as child will need to understand and take instruction in English to participate in the neurodevelopmental assessment. Able to give informed consent. Exclusion Criteria: Known history of thyroid disease. Previous child diagnosed with thyroid dysfunction. Carrying a fetus with a known or suspected congenital abnormality.

Ages Eligible for Study
-----------------
Minimum Age: 16 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A multi-centre, randomised, controlled, clinician, researcher and participant blinded trial with two parallel groups. An independent statistician not otherwise involved in the study or data analysis will generate and keep the randomisation schedule. The computer-generated schedule will allocate women to intervention or control groups in the ratio of 1:1 using randomly permuted blocks of size 6 and 8, with stratification for state of enrolment. Randomisations will be performed by approved study staff via a secure web-based randomisation service.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Iodine Supplement<br>Iodine (potassium iodide) 20 μg Beta carotene (All trans-beta- carotene) 1500 μg; Vitamin E (dl-alphatocopheryl acetate) 13.5 mg AT; Vitamin D3 (cholecalciferol) 10 μg; Vitamin C (ascorbic acid granular) 60 mg; Niacinamide 18 mg; Pantothenic acid (calcium d- pantothenate) 6 mg; Vitamin B6 (DC pyridoxine hydrochloride) 1.9 mg; Vitamin B1 (thiamine mononitrate) 1.4 mg; Vitamin B2 (riboflavin) 1.4 mg; Biotin 30 μg; Vitamin B12 (methyl-cobalamin) 2.6 μg; Folic Acid 0.4 mg; Levomefolic acid 0.1 mg; Calcium (carbonate DC) 250 mg; Magnesium (oxide granular) 50 mg; Iron (ferrous fumarate) 20 mg; Zinc (oxide) 10 mg; Manganese (sulphate) 2 mg; Copper (sulphate) 1 mg; Selenium (rice chelate) 30 μg | Combination Product: Low Iodine Supplement<br>* Multivitamin and mineral supplement with reduced iodine<br>|
| Active Comparator: Standard Iodine Supplement<br>Iodine (potassium iodide) 200 μg Beta carotene (All trans-beta- carotene) 1500 μg; Vitamin E (dl-alphatocopheryl acetate) 13.5 mg AT; Vitamin D3 (cholecalciferol) 10 μg; Vitamin C (ascorbic acid granular) 60 mg; Niacinamide 18 mg; Pantothenic acid (calcium d- pantothenate) 6 mg; Vitamin B6 (DC pyridoxine hydrochloride) 1.9 mg; Vitamin B1 (thiamine mononitrate) 1.4 mg; Vitamin B2 (riboflavin) 1.4 mg; Biotin 30 μg; Vitamin B12 (methyl-cobalamin) 2.6 μg; Folic Acid 0.4 mg; Levomefolic acid 0.1 mg; Calcium (carbonate DC) 250 mg; Magnesium (oxide granular) 50 mg; Iron (ferrous fumarate) 20 mg; Zinc (oxide) 10 mg; Manganese (sulphate) 2 mg; Copper (sulphate) 1 mg; Selenium (rice chelate) 30 μg | Combination Product: Standard Iodine Supplement<br>* Multivitamin and mineral supplement with standard amount of iodine to match current leading brands of prenatal supplements<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Infant Developmental quotient (DQ) | The Bayley Scales of Infant and Toddler Development, 4th Edition Cognitive Scale score has a mean of 100 and standard deviation of 15, where higher scores indicate a better outcome. As the Bayley scales are age-standardized scales the exact minimum and maximum score depends on the exact age of the child at the time of the assessment, hence we have instead provided the mean and standard deviation (as is the norm when reporting standardized psychometric assessments). | 24 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Language development of infants using Bayley-IV | The Bayley Scales of Infant and Toddler Development, 4th Edition Language Scale score has a mean of 100 and standard deviation of 15, where higher scores indicate a better outcome. | 24 months of age | 
| Motor development of infants | The Bayley Scales of Infant and Toddler Development, 4th Edition Motor Scale score has a mean of 100 and standard deviation of 15, where higher scores indicate a better outcome. | 24 months of age | 
| Behavioral and emotional development | Behavioral and emotional development of infants using the Infant Toddler Social Emotional Assessment (ITSEA). The Infant-Toddler Social & Emotional Assessment scale has range of 0-100 where higher T scores indicate a worse outcome. | 24 months of age | 
| Health service utilization | Health service utilisation of children assessed through data linkage of the Medicare Benefits Schedule, Pharmaceutical Benefits Scheme to evaluate the cost effectiveness of the intervention. | 24 months of age | 
| Length of gestation | The gestational age in days at birth (or other event of interest) will be determined from the estimated date of delivery using the equation [280 - (estimated date of delivery - date of birth)]. | Birth | 
| Infant Birth Anthropometrics | Infant weight, length and head circumference will be analysed, using both the raw measurements and Z-scores for corresponding gestational age and sex, using means and standard deviations. | Birth | 
| Admission to special care baby unit (level 2 nursery). | Any admission to a special care baby unit or level 2 nursery up to 28 days post birth. | The neonatal period including birth to 28 days of age | 
| Thyroid stimulating hormone (TSH) level | Ascertained from Neonatal Screening Test | Within 5 days of birth | 
| Infant Anthropometrics | Average weight, height and head circumference measurements at 24 months of age will be converted to z-scores using WHO growth standards. For preterm infants, corrected age at the time of the measurement rather than chronological age will be used in deriving the z-scores. | 24 months of age | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Iodine, Supplementation