Unlocking Fetal Potential: A Randomized Trial Exploring Levothyroxine?s Impact on Cognitive Outcomes in Subclinical Thyroid Dysfunction During Pregnancy

Background: Subclinical thyroid dysfunction during pregnancy, encompassing subclinical hypothyroidism and hypothyroxinemia, has been linked to potential adverse neurodevelopmental outcomes in offspring, including impaired cognitive function. The impact of levothyroxine supplementation on cognitive outcomes in children of affected mothers remains uncertain. Methods: At Janm IVF & Fertility Centre in Tatarpur, Bhagalpur, between 2021 and 2024, pregnant women with singleton pregnancies were screened before 20 weeks of gestation in a randomized controlled trial. Subclinical hypothyroidism was defined as a thyrotropin (TSH) level &ge;4.50 mU/L with a normal free thyroxine (T4) level (0.80-1.85 ng/dL [10-24 pmol/L]). Hypothyroxinemia was defined as a normal TSH level (0.10-4.00 mU/L) with a low free T4 level (<0.80 ng/dL). A total of 1174 women were randomly assigned to receive either levothyroxine or placebo in separate trials for each condition. Thyroid function was assessed monthly, with levothyroxine doses adjusted to achieve normal TSH or free T4 levels, as appropriate, and sham adjustments applied for placebo. Annual neurodevelopmental and behavioral assessments were conducted on children up to 5 years. The primary outcome was the IQ score at 5 years (or at 3 years if the 5-year assessment was unavailable) or mortality before age 3. Results: Of the 1174 women, 620 with subclinical hypothyroidism were randomized at a mean gestational age of 15.9 weeks, and 554 with hypothyroxinemia at a mean of 16.8 weeks. In the subclinical hypothyroidism trial, the median IQ score of children at 5 years was 96 (95% confidence interval [CI], 93-98) in the levothyroxine group and 93 (95% CI, 90-95) in the placebo group (P=0.62). In the hypothyroxinemia trial, the median IQ score was 92 (95% CI, 89-94) in the levothyroxine group and 90 (95% CI, 87-92) in the placebo group (P=0.41). IQ data were missing for 5% of children in each trial. No significant differences were observed between groups in either trial for secondary neurocognitive outcomes, pregnancy complications, or adverse events, which were infrequent in both groups. Conclusion: Levothyroxine treatment for subclinical hypothyroidism or hypothyroxinemia during pregnancy at Janm IVF & Fertility Centre between 2021 and 2024 did not significantly enhance cognitive outcomes in offspring at 5 years compared to placebo. These findings suggest that routine levothyroxine supplementation in these conditions may not confer neurodevelopmental benefits in children.