First-Trimester Free T3 Levels Linked to Higher Odds of Neonatal Adverse Outcomes

Women whose blood tests in early pregnancy show elevated levels of free triiodothyronine, the active thyroid hormone often abbreviated FT3, appear to face substantially greater odds that their newborns will experience adverse outcomes, according to a retrospective case-control study published in BMC Pregnancy and Childbirth. The study, led by Xiaoyu Chen and colleagues, found that mothers in the highest quartile of first-trimester FT3 had more than five times the odds of a neonatal adverse outcome compared with those in the lowest quartile, even after adjusting for a broad panel of clinical and laboratory covariates.

The research team examined 378 mother-infant pairs in which the newborn experienced at least one prespecified clinician-assigned neonatal diagnosis or perinatal death during the birth hospitalization, and compared them with 419 controls randomly selected from eligible pairs without such outcomes. Controls were frequency-matched to cases on maternal age, categorized as under 35 versus 35 or older, and on parity, distinguishing nulliparous from multiparous women. All participants had undergone thyroid-function testing between 8 and 13 gestational weeks as part of routine early-pregnancy screening, and none had documented thyroid disease.

The composite neonatal adverse outcome encompassed a range of clinician-assigned diagnoses recorded during the birth hospitalization, along with perinatal death. Maternal FT3 concentrations were notably higher in the adverse-outcome group, with a median of 4.64 pmol/L compared with 4.23 pmol/L among controls, a difference that reached statistical significance at p < 0.001. To quantify the association across the full distribution of FT3 values, the investigators divided participants into quartiles and used the lowest quartile as the reference category in logistic regression models.

In the primary model, designated Model 2, the adjusted odds ratios for the composite outcome were 1.46 (95% confidence interval 0.94–2.26) for the second quartile, 2.44 (95% CI 1.58–3.77) for the third quartile, and 5.64 (95% CI 3.58–8.87) for the fourth quartile, relative to the first. The confidence intervals for the two highest quartiles excluded the null value, indicating statistically significant associations, while the second quartile did not reach conventional significance. The model adjusted for white blood cell count, platelet count, serum creatinine, uric acid, maternal age at delivery, maternal body mass index, gravidity, and parity, addressing potential confounding from inflammation, renal function, and baseline maternal characteristics.

Beyond the composite endpoint, higher FT3 quartiles were associated with several secondary neonatal outcomes after the researchers applied false-discovery-rate control to account for multiple comparisons. Restricted cubic splines were used to characterize the shape of the dose-response relationship across the FT3 range, and subgroup analyses explored whether the association varied across patient strata. The investigators also conducted a series of sensitivity analyses to probe the robustness of the finding under alternative assumptions and definitions.

Those sensitivity analyses included restricting the sample to women who tested negative for thyroid antibodies, limiting the analysis to term births, employing a focused major-morbidity outcome definition, excluding myocardial injury from the composite outcome, using an alternative reference category that combined the second and third quartiles, and adding supplementary adjustment for gestational diabetes mellitus, hypertensive disorders of pregnancy, thyroid-stimulating hormone, free thyroxine, thyroglobulin antibody, and thyroid peroxidase antibody. Across these variations, the associations observed for the third and fourth FT3 quartiles were generally retained, suggesting that the signal is not readily explained by thyroid autoimmunity, preterm delivery, or residual confounding from concurrent glycemic or hypertensive disorders.

Thyroid hormones play a central role in maternal physiological adaptation during pregnancy and in fetal development. While prior research has linked abnormalities in thyroid-stimulating hormone and free thyroxine to adverse pregnancy and neonatal outcomes, the relationship between first-trimester maternal FT3 and neonatal complications has remained insufficiently characterized. This study addresses that gap by focusing specifically on FT3 among women without documented thyroid disease, isolating a hormone that is often overlooked when screening focuses on TSH and FT4 alone.

The authors emphasize that these are observational findings from a retrospective, single-center design and do not establish causality. The case-control structure, while efficient for studying relatively uncommon outcomes, cannot rule out all forms of confounding or reverse causation, and the frequency-matching approach, though it balanced cases and controls on age and parity, does not eliminate selection biases inherent in retrospective sampling. The study also relied on clinician-assigned diagnoses rather than adjudicated research definitions for the composite outcome, a pragmatic choice that reflects real-world clinical documentation but may introduce classification variability.

Importantly, the researchers explicitly caution that their results do not support interventions aimed at lowering FT3 in pregnancy. The observed association between higher first-trimester FT3 and greater odds of neonatal adverse outcomes, particularly in the upper quartiles, requires confirmation in prospective studies before any clinical implications can be drawn. The findings nonetheless add to a growing body of evidence suggesting that thyroid hormone profiles beyond the conventional TSH and FT4 measures may carry meaningful information about fetal and neonatal risk, and they highlight a potential direction for future research into the endocrine determinants of perinatal health.

Subject of Research: The association between first-trimester maternal free triiodothyronine levels and neonatal adverse outcomes in a retrospective frequency-matched case-control study.

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

Article References: Chen, X., Fan, J., Li, L., Han, Z., Wang, J., Sun, W., Shao, Q., & Liu, Y. (2026). Association between first-trimester maternal free triiodothyronine levels and neonatal adverse outcomes: a retrospective frequency-matched case-control study. BMC Pregnancy and Childbirth. https://doi.org/10.1186/s12884-026-10169-2

Image Credits: AI Generated

DOI: 10.1186/s12884-026-10169-2

Keywords: free triiodothyronine, FT3, first trimester, neonatal adverse outcomes, case-control study, thyroid function, pregnancy, BMC Pregnancy and Childbirth, odds ratio, perinatal health, thyroid hormones, retrospective study