Free Thyroxine During Early Pregnancy and Risk for Gestational Diabetes

Abstract

Several studies have now reported associations between gestational diabetes mellitus (GDM) and low free thyroxine (fT4) during the second and third trimesters, but not in the first trimester. The present study further examines relationships between low fT4, maternal weight, and GDM among women in the FaSTER (First and Second Trimester Evaluation of Risk) trial, in an effort to determine the extent to which thyroid hormones might contribute to causality. The FaSTER cohort includes 9351 singleton, euthyroid women; 272 of these women were subsequently classified as having GDM. Thyrotropin (TSH), fT4, and thyroid antibodies were measured at 11-14 weeks' gestation (first trimester) and 15-18.9 weeks' gestation (second trimester). An earlier report of this cohort documented an inverse relationship between fT4 in the second trimester and maternal weight. In the current analysis, women with GDM were significantly older (32 vs. 28 years) and weighed more (75 vs. 64.5 kg). Maternal weight and age (but not TSH) were significantly associated univariately with fT4 (dependent variable), in the order listed. Second trimester fT4 odds ratios (OR) for GDM were 2.06 [95% CI 1.37-3.09] (unadjusted); and 1.89 [95% CI 1.26-2.84] (adjusted). First trimester odds ratios were not significant: OR 1.45 [95%CI 0.97-2.16] (unadjusted) and 1.11 [95% CI 0.74-1.62] (adjusted). The second trimester fT4/GDM relationship thus appeared to strengthen as gestation progressed. In FaSTER, high maternal weight was associated with both low fT4 and a higher GDM rate in the second trimester. Peripheral deiodinase activity is known to increase with high caloric intake (represented by high weight). We speculate that weight-related low fT4 (the metabolically inactive prohormone) is a marker for deiodinase activity, serving as a substrate for conversion of fT4 to free triiodothyronine (fT3), the active hormone responsible for glucose-related metabolic activity.

Fig 1. Relationships between gestational diabetes (GDM) and age (Fig 1A), weight (Fig 1B), free thyroxine (fT4) (Fig 1C), and thyrotropin (TSH) (Fig 1D).

Open circles represent percents of GDM cases at each decile of the variable shown on the X-axis. Solid lines indicate unadjusted slopes of the respective relationships; p-values indicate slope significance. The dotted line in Fig 1C shows the slope of the fT4/GDM relationship, after adjustment for age, weight, and TSH.

Fig 2. Second trimester relationships between free thyroxine (fT4), maternal weight, and gestational diabetes in the FaSTER trial.

A to E Indicates that there is an inverse relationship between maternal weight and fT4 [13, 14, 21]; E to B Indicates that lower fT4 is associated with a higher GDM rate [7]; A to B Indicates that higher weight is associated with higher GDM rate.

Fig 3. Schematic diagram depicting how caloric intake and deiodinase activity fit into relationships shown in Fig 2.

Higher caloric intake (C) reflects higher weight (A) and induces higher deiodinase activity (D) [32, 34]. Lower fT4 (E) and higher T3/T4 ratios (F) occur as a consequence of higher deiodinase activity and are associated with both insulin resistance (G) [24, 25] and gestational diabetes (B).