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Context: Lower neurocognitive development scores at age 2 yr have been reported in association with euthyroid hypothyroxinemia during early pregnancy. Objective: The objective of this study was to further explore this association with euthyroid hypothyroxinemia during early pregnancy. Design: This was an observational, nested case-control study. Setting: The study was conducted at physician offices and prenatal clinics throughout Maine. Study Subjects: Between May 2004 and March 2006, TSH was measured in 5734 women in conjunction with second-trimester Down syndrome screening. After completion of pregnancy, free T4 was measured in stored second-trimester sera from euthyroid women (TSH 0.1–3.5 mIU/ml; n = 5560). Women with free T4 at the third centile or less (n = 99) were matched with women whose free T4 was at the 10th to the 90th centile (n = 99). Interventions: There were no interventions. Main Outcome Measure: Bayley Scales of Infant Development (BSID III) were administered to the 198 offspring at age 2 yr. Scores for cognitive, language, and motor development were compared between matched pairs of offspring from the two groups before and after correcting for relevant variables. Results: Unadjusted BSID-III scores (cognitive, language, and motor) were lower by about 3% at age 2 yr among offspring of 98 hypothyroxinemic women (cases), reaching borderline significance for cognitive and motor scores. After adjustment for gestational age, the child's age at testing, maternal weight, and education, all differences diminished and became nonsignificant. Scores less than 85 were more frequent among case children but did not reach statistical significance (P = 0.14). Conclusions: Isolated hypothyroxinemia during the second trimester is not associated with significantly lower BSID-III scores at age 2 yr, compared with scores for offspring of matched euthyroxinemic women.