Prenatal Iodine Supplementation and Early Childhood Neurodevelopment (PoppiE)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Pregnancy Related; Neurodevelopmental Disorders; Nutrition Disorder, Fetal
• Intervention / Treatment: Combination product: Low Iodine Supplement; Combination product: Standard Iodine Supplement

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.

• Study Type: Interventional
• Enrollment (Actual): 794
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Karen P Best, PhD; Phone Number: +61434243404; Email: karen.best@sahmri.com
• Study Contact Backup: Name: Tim Green, PhD; Email: tim.green@sahmri.com

Study Locations

• Australia
  • South Australia
    • North Adelaide, South Australia, Australia, 5081
      • South Australian Health and Medical Research Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Low Iodine Supplement; 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; Multivitamin and mineral supplement with reduced iodine
Active Comparator: Standard Iodine Supplement; 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; Multivitamin and mineral supplement with standard amount of iodine to match current leading brands of prenatal supplements

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants with pre-eclampsia	Clinical diagnosis of pre-eclampsia as recorded in the participants handheld record.	At any time throughout current pregnancy
Proportion of participants with induction of labour and reason for induction.	As recorded in the participants handheld record.	Delivery
Proportion of participants with postpartum hemorrhage	Clinical diagnosis of postpartum hemorrhage as recorded in the participants handheld record.	Within 24 hours of delivery of the infant
Proportion of participants with gestational diabetes	Clinical diagnosis of gestational diabetes as recorded in the participants handheld record.	At any time throughout current pregnancy
Proportion of participants with induced labour	As recorded in the participants handheld record.	Delivery
Proportion of participants with vaginal delivery	Vaginal or caesarean delivery	Delivery
Proportion of Maternal Adverse Events per group	Side effects and tolerability of supplements will be assessed through routine data collection.	From the date of randomization until delivery of the infant (up to 40 weeks)
Proportion of Maternal Serious Adverse Events per group	Maternal admissions to intensive care during the intervention period. Maternal death in the intervention period.	From the date of randomization until the date of delivery (up to 40 weeks)
Proportion of Fetal/Infant Serious Adverse Events	Fetal Mortality (after randomisation and prior to birth) including; miscarriage/terminations (pregnancy loss <20 weeks of gestation); stillbirth (intrauterine fetal death ≥20 weeks of gestation). Infant Mortality including; neonatal death (death of a live born infant in the first 28 days of life); infant death (death of an infant after the first 28 days of life). Major congenital anomalies.	From the date of randomization until the infant is 24 months of age (up to 144 weeks)
Economic Evaluation	A within-trial cost-effectiveness analysis will be conducted comparing costs and outcomes of the trial arms. The analysis will take into account a range of cost items including cost of interventions (i.e., dietary supplements) and cost of eligibility screening. Medicare data and data held by the State departments of health will be used to estimate direct health care costs associated with the management of poor developmental health outcomes over the study period including pharmaceuticals, out of hospital services (e.g., doctor visits), and hospital services (including emergency department presentations).	From the date of randomization until the infant is 24 months of age (up to 144 weeks)
Urinary Iodine Concentration	At baseline, median iodine concentration by state will be determined to confirm state differences in iodine status that have been previously identified and to determine balance between the two treatment groups. At 28 weeks we will examine median UIC by treatment group to assess group compliance and the success of the intervention.	At baseline (enrolment <13 weeks of gestation) and mid-pregnancy (28 weeks of gestation)

Collaborators and Investigators

• Sponsor: South Australian Health and Medical Research Institute
• Collaborators: Women's and Children's Hospital, Australia; Flinders Medical Centre; Royal North Shore Hospital; Mater Mothers' Hospital; The Royal Women's Hospital
• Investigators: Principal Investigator: Karen P Best, PhD, South Australian Health and Medical Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): January 18, 2021
• Primary Completion (Estimated): May 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: September 30, 2020
• First Submitted That Met QC Criteria: October 7, 2020
• First Posted (Actual): October 14, 2020

Study Record Updates

• Last Update Posted (Actual): April 3, 2024
• Last Update Submitted That Met QC Criteria: April 1, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Keywords: Iodine; Supplementation
• Additional Relevant MeSH Terms: Mental Disorders; Malnutrition; Fetal Diseases; Pregnancy Complications; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Nutrition Disorders; Neurodevelopmental Disorders; Fetal Nutrition Disorders; Physiological Effects of Drugs; Anti-Infective Agents, Local; Anti-Infective Agents; Trace Elements; Micronutrients; Iodine; Cadexomer iodine
• Other Study ID Numbers: PoppiE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Access to study data may be granted, upon review and approval of the HREC, trial steering committee and in accordance with SAHMRI W&K 'Guidelines and Agreement for the use of materials in an ancillary study associated with original clinical trials or cohort studies.
• IPD Sharing Time Frame: Following final data analysis and primary publication
• IPD Sharing Access Criteria: Access to study data may be granted, upon review and approval of the HREC, trial steering committee and in accordance with SAHMRI W&K 'Guidelines and Agreement for the use of materials in an ancillary study associated with original clinical trials or cohort studies.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No