Prenatal iodine supplementation and early childhood neurodevelopment: the PoppiE trial – study protocol for a multicentre randomised controlled trial

{"Background": "Iodine is essential for fetal brain development, and severe deficiency is the most common preventable cause of intellectual disability globally. After mild-to-moderate iodine deficiency re-emerged in parts of Australia, the government mandated iodine fortification of bread and recommended pregnant women take 150 \u00b5g/day iodine supplements. However, recent cohort studies suggest that both low and high iodine intake during pregnancy may be associated with poorer child neurodevelopmental outcomes. A 2018 cohort study of 800 mother\u2013infant pairs found that maternal iodine intake in the lowest and highest quartiles was associated with lower cognitive and language scores and higher odds of cognitive delay compared with the second quartile, with inflection points around 185 \u00b5g/day (lower) and 350 \u00b5g/day (upper). Australia is one of few countries with combined iodine fortification and supplementation policies, and many prenatal supplements provide 200\u2013220 \u00b5g/day iodine\u2014above the recommended 150 \u00b5g/day. The only adequately powered RCT of iodine supplementation in pregnancy (conducted in India and Thailand, areas with mild-to-moderate deficiency) found no differences in neurodevelopment at 5\u20136 years. The PoppiE trial is designed to address the evidence gap in iodine-sufficient populations.", "Methods": "The PoppiE trial is a multicentre, randomised, controlled, clinician-researcher-participant blinded trial with two parallel groups, conducted across seven Australian locations using a hybrid decentralised model. A total of 754 women (377 per group) aged \u226516 years, \u226413 weeks' gestation, with iodine intake \u2265165 \u00b5g/day from food (assessed by validated Iodine Specific Food Frequency Questionnaire) are being randomised to receive either a low-iodine (20 \u00b5g/day) prenatal multivitamin and mineral supplement (intervention) or an identical supplement containing 200 \u00b5g/day iodine (control), taken daily from enrolment until delivery. The primary outcome is the developmental quotient at 24 months assessed with the Cognitive Scale of the Bayley Scales of Infant Development, fourth edition (Bayley-IV). Secondary outcomes include language and motor scores from Bayley-IV, behavioural/emotional development (Infant Toddler Social Emotional Assessment), infant health outcomes (gestation length, birth weight/length/head circumference, NICU admission, feeding, growth at 24 months), maternal outcomes (pregnancy complications, mode of delivery), and health service utilisation via MBS/PBS data linkage. Adherence is monitored via SMS, email, and telephone contacts at multiple timepoints. A mid-pregnancy urine sample is collected for urinary iodine concentration. Randomisation uses computer-generated permuted blocks with varying sizes, stratified by enrolment location, performed via REDCap. The sample size of 297 per group provides 90% power to detect a 4-point mean difference in Bayley-IV Cognitive Scale (SD=15, two-tailed \u03b1=0.05), with allowance for 6% perinatal losses and 15% loss to follow-up. Analysis will be intention-to-treat using linear regression with adjustment for enrolment location and generalised estimating equations for multiple births. Missing data will be addressed by multiple imputation. Enrolment began January 2021 and is expected to complete by October 2023; 24-month assessments run from July 2023 to September 2026.", "Key Results": "As of 23 December 2022, 500 participants had been randomised. No outcome data are yet available as the trial is ongoing. The protocol describes planned analyses but reports no results.", "Clinical Implications": "If the trial shows that limiting iodine supplementation in women with adequate dietary intake improves child cognitive development, this would necessitate rapid changes to universal supplementation recommendations for pregnant women in iodine-sufficient populations. If no differences are found, this would provide reassurance that current policies are not harmful. The trial addresses a critical public health question: whether a 'one-size-fits-all' approach to prenatal iodine supplementation should be replaced by targeted supplementation based on individual dietary iodine intake. Given the narrow margin between deficiency and excess suggested by observational data, the results will have direct implications for clinical guidelines in Australia and other iodine-sufficient countries with combined fortification and supplementation policies."}