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.

Effect of gestational diabetes mellitus on maternal thyroid function and body mass index

“…In accordance with the present results, previous reports demonstrated an associations between GDM and decreased thyroid hormones, increased anti-thyroid autoantibodies and higher BMI 1,15,[22][23][24] . The associations between FT4, maternal weight, and GDM were recently investigated by Haddow and his group in more than 9000 singleton, euthyroid women in the FaSTER (First and Second Trimester Evaluation of Risk) trial 2 .…”

“…An earlier report documented an inverse association between maternal weight and FT4 in the second trimester 2 . In a subsequent separate report on the same cohort, FT4 odds ratio for GDM was significant in the second (1.89), but not in the first (1.11) trimester 1 . Comparable findings were shown by Cleary-Goldman et al, when they demonstrated 1.7 odds ratio of hypothyroxinemia in GDM patients during the second trimester 24 .…”

“…Abnormal thyroid function and glucose tolerance have been both reported during pregnancy [1][2][3] . It was hypothesized that thyroid hormones gradually increase during the first trimester, but decrease gradually over the rest of pregnancy [4][5][6] .…”

Higher thyroid‐stimulating hormone levels in the first trimester are associated with gestational diabetes in a Chinese population

“…There were also limitations to our study. First, we were unable to measure free T 4 , thyroid-peroxidase antibodies or other thyroid hormones and autoantibodies associated with autoimmune thyroiditis levels that are known to be related to Type 2 diabetes and GDM [17,30]. Second, the International Association of Diabetes and Pregnancy Study Group recommend a one-step procedure to screen and diagnose GDM, but our three-tier antenatal care system performs a two-step procedure, thus some GDM cases may have been missed due to exclusion during the two-step procedure.…”

High levels of maternal total tri-iodothyronine, and low levels of fetal free L-thyroxine and total tri-iodothyronine, are associated with altered deiodinase expression and activity in placenta with gestational diabetes mellitus

“…GDM is characterized by abnormal maternal D-glucose metabolism and altered insulin signaling in feto-placental circulation [2]. It has been described that a decrease in maternal Free L-Thyroxine (FT 4 ) levels during the first trimester of pregnancy could also increase GDM risk [3][4][5]. Several studies relate alterations in Thyroid Hormones (TH) levels with GDM, but their results are controversial.…”