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Statistical design considerations applicable to clinical trials of iodine supplementation in pregnant women who may be mildly iodine deficient.

ABSTRACT: No large, randomized, placebo-controlled trial of iodine supplementation in pregnant women in a region of mild or moderate iodine deficiency has been completed in which a primary outcome measure was an assessment of the neurobehavioral development of the offspring at age ?2 y. In this article, I discuss considerations for the design of such a trial in a region of mild iodine deficiency, with a focus on statistical methods and approaches. Exposure and design issues include the ethics of using a placebo, the potential for overexposure to iodine, and the possibility of community randomization. The main scientific goal of the trial is important in determining the follow-up period. If the goal is to determine whether iodine supplementation during pregnancy improves neurobehavioral development in the offspring, then follow-up should continue until a reasonably reliable assessment can be conducted, which might be at age ?2 y. Once the timing of assessment is decided, the impact of potential loss to follow-up should be considered so that appropriate statistical methods can be incorporated into the design. The minimum sample size can be calculated by using a sample size formula that incorporates noncompliance and assumes that a certain proportion of study participants do not have any outcome observed. To have sufficient power to detect a reasonably modest difference in neurobehavioral development scores using an assessment tool with an SD of 15, a large number of participants (>500/group) is required. The minimum adequate number of participants may be even larger (>1300/group) depending on the magnitude of the difference in outcome between the supplementation and placebo groups, the estimated proportion of the iodine-supplementation group that fails to take the supplement, and the estimated proportion of pregnancies that do not produce outcome measurements.

SUBMITTER: Troendle JF

PROVIDER: S-EPMC5004499 | biostudies-other | 2016 Sep

REPOSITORIES: biostudies-other

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Statistical design considerations applicable to clinical trials of iodine supplementation in pregnant women who may be mildly iodine deficient.

Troendle James F JF

The American journal of clinical nutrition 20160817

No large, randomized, placebo-controlled trial of iodine supplementation in pregnant women in a region of mild or moderate iodine deficiency has been completed in which a primary outcome measure was an assessment of the neurobehavioral development of the offspring at age ≥2 y. In this article, I discuss considerations for the design of such a trial in a region of mild iodine deficiency, with a focus on statistical methods and approaches. Exposure and design issues include the ethics of using a p ...[more]

PMID: 27534639

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Project description:BackgroundWhereas the adverse effects of severe iodine deficiency during pregnancy are well documented, the effects of mild-to-moderate deficiency are not well established.ObjectivesWe aimed to explore whether iodine nutrition and timing of iodine supplement initiation are associated with thyroid function in pregnant and postpartum women.MethodsIn this cohort study, 137 pregnant women were enrolled and followed up at gestational weeks (GWs) 18 and 36, and 3 and 6 mo postpartum. Thyroid function tests [thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4)], urinary iodine and creatinine concentration (UIC:Cr), and iodine intake (including iodine supplement use) were measured at each time point. The associations between thyroid hormone concentrations and UIC:Cr, iodine intakes, and iodine supplement use were estimated using multiple generalized estimating equation models.ResultsThe median UIC at GW18 was 94 μg/L, indicating mild-to-moderate iodine deficiency. UIC:Cr (β; 95% CI) per 100 μg/g was negatively associated with fT3 (-0.191; -0.331, -0.051) and fT4 (-0.756; -1.372, -0.141) concentrations. Iodine intake (β; 95% CI) per 100 μg/d was positively associated with TSH (0.099; 0.022, 0.177), and negatively associated with fT3 (-0.084; -0.0141, -0.027) and fT4 (-0.390; -0.599, -0.182) concentrations. Compared with no use of supplement, those initiating an iodine-containing supplement prepregnancy and continuing through pregnancy had lower TSH (estimated means) (1.35 compared with 1.68 mIU/L, P = 0.021), and higher fT3 (4.48 compared with 4.28 pmol/L, P = 0.035) and fT4 (15.2 compared with 14.4 pmol/L, P = 0.024) concentrations.ConclusionsLower iodine availability during pregnancy and postpartum was associated with lower TSH, and higher fT3 and fT4 concentrations. The use of an iodine-containing supplement that was initiated prepregnancy and continuing through pregnancy was associated with lower TSH, and higher fT3 and fT4 concentrations, which may suggest improved thyroid function. These findings support the notion that optimization of iodine intake should start before pregnancy.This trial was registered at clinicaltrials.gov as NCT02610959.

Project description:BACKGROUND:Studies indicate that mild to moderate iodine deficiency in pregnancy may have a long-term negative impact on child neurodevelopment. These effects are likely mediated via changes in maternal thyroid function, since iodine is essential for the production of thyroid hormones. However, the impact of iodine availability on thyroid function during pregnancy and on thyroid function reference ranges are understudied. The aim of this study was to investigate the association between iodine intake and thyroid function during pregnancy. DESIGN:In a population-based pregnancy cohort including 2910 pregnant women participating in The Norwegian Mother and Child Cohort Study, we explored cross sectional associations of maternal iodine intake measured (1) by a food frequency questionnaire and (2) as iodine concentration in a spot urine sample, with plasma thyroid hormones and antibodies. RESULTS:Biological samples were collected in mean gestational week 18.5 (standard deviation 1.3) and diet was assessed in gestational week 22. Median iodine intake from food was 121??g/day (interquartile range 90, 160), and 40% reported use of iodine-containing supplements in pregnancy. Median urinary iodine concentration (UIC) was 59??g/L among those who did not use supplements and 98??g/L in the women reporting current use at the time of sampling, indicating mild to moderate iodine deficiency in both groups. Iodine intake as measured by the food frequency questionnaire was not associated with the outcome measures, while UIC was inversely associated with FT3 (p?=?0.002) and FT4 (p?<?0.001). Introduction of an iodine-containing supplement after gestational week 12 was associated with indications of lower thyroid hormone production (lower FT4, p?=?0.027, and nonsignificantly lower FT3, p?=?0.17). The 2.5th and 97.5th percentiles of TSH, FT4, and FT3 were not significantly different by groups defined by calculated iodine intake or by UIC. CONCLUSION:The results indicate that mild to moderate iodine deficiency affect thyroid function in pregnancy. However, the differences were small, suggesting that normal reference ranges can be determined based on data also from mildly iodine deficient populations, but this needs to be further studied. Introducing an iodine-containing supplement might temporarily inhibit thyroid hormone production and/or release.

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Statistical design considerations applicable to clinical trials of iodine supplementation in pregnant women who may be mildly iodine deficient.

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Statistical design considerations applicable to clinical trials of iodine supplementation in pregnant women who may be mildly iodine deficient.

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