Association between first-trimester maternal free triiodothyronine levels and neonatal adverse outcomes: a retrospective frequency-matched case-control study

Thyroid hormones, particularly free triiodothyronine (free T3), support maternal adaptation and fetal development in pregnancy. Although abnormalities in thyroid-stimulating hormone and free thyroxine have been associated with adverse outcomes, the association between first-trimester maternal FT3 and neonatal adverse outcomes remains insufficiently characterized. We examined this association among women without documented thyroid disease. We conducted a single-center retrospective, frequency-matched case-control study including all 378 eligible cases with neonatal adverse outcomes and 419 controls randomly selected within matching strata from eligible mother-infant pairs without neonatal adverse outcomes. Controls were frequency-matched to cases on maternal age (< 35 vs. ≥ 35 years) and parity (nulliparous vs. multiparous). Thyroid-function testing at 8–13 gestational weeks was part of routine early-pregnancy screening. The composite neonatal adverse outcome was defined as at least one prespecified clinician-assigned neonatal diagnosis or perinatal death during the birth hospitalization. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs) across FT3 quartiles, with Q1 as the reference. The primary Model 2 adjusted for white blood cell count, platelet count, serum creatinine, uric acid, maternal age at delivery, maternal BMI, gravidity, and parity. Restricted cubic splines, subgroup analyses, false-discovery-rate adjustment of secondary outcomes, and sensitivity analyses addressing thyroid autoimmunity, term births, outcome definition, myocardial injury, reference category, and supplementary covariate adjustment were also performed. Maternal FT3 was higher in the neonatal adverse outcome group than in the group without a neonatal adverse outcome (median, 4.64 vs. 4.23 pmol/L; p < 0.001). In the primary Model 2, compared with Q1, the adjusted ORs for the composite outcome were 1.46 (95% CI 0.94–2.26; p = 0.092) for Q2, 2.44 (95% CI 1.58–3.77; p < 0.001) for Q3, and 5.64 (95% CI 3.58–8.87; p < 0.001) for Q4. Higher FT3 quartiles were also associated with several secondary neonatal outcomes after false-discovery-rate control. The associations for Q3 and Q4 were generally retained in sensitivity analyses, including restriction to antibody-negative women and term births, use of a focused major-morbidity outcome, exclusion of myocardial injury from the composite, an alternative Q2-Q3 reference category, and supplementary adjustment for gestational diabetes mellitus, hypertensive disorders of pregnancy, TSH, FT4, TgAb, and TPOAb. Higher first-trimester maternal FT3 was associated with greater odds of neonatal adverse outcomes, particularly in the upper FT3 quartiles. These observational findings do not establish causality or support interventions to lower FT3 and require confirmation in prospective studies. Not applicable (retrospective casecontrol study).