Reference Intervals of Thyroid Function During Pregnancy: Self-Sequential Longitudinal Study Versus Cross-Sectional Study

Background: A self-sequential longitudinal reference interval may be expected to minimize the inter-individual variation of thyroid function. Comparison between the self-sequential longitudinal reference interval (SLRI) and cross-sectional reference interval (CSRI) in pregnancy has not been well investigated. The objectives of this study were to establish a stringent SLRI of thyroid function in pregnant women and to compare it with the conventional CSRI. Methods: Three cohorts were enrolled: group 1, pregnant women for an SLRI (n=99); group 2, pregnant women for a CSRI (n=1318); group 3, non-pregnant control women (NC) as a control group (n=301) according to the criteria of the National Academy of Clinical Biochemistry. Thyrotropin (TSH), total thyroxine (TT4), free thyroxine (fT4), total triiodothyronine (TT3), free triiodothyronine (fT3), serum ferritin (SF), and urine iodine concentration (UIC) were measured in the three groups. Results: Compared with CSRI, the reference interval of the SLRI group had narrower reference intervals of fT4 in the first and second trimesters (p<0.05). The median of TSH was at a low level during the first trimester, and then gradually elevated in the second and third trimesters. The median of fT4 persistently decreased from 12 weeks, and did not return to the level of the NC group until 12 months postpartum. The TT4 increased to 131.4nmol/L at gestational week 8, and reached a peak (170.0nmol/L) at gestational week 12. In the first trimester, the prevalence of hypothyroxinemia was 9.1%, 4.0%, and 2.0% with a fT4 value below the 10th, 5th, and 2.5th percentile, respectively. In contrast, 29.3% of TT4 values were below the lower non-pregnancy reference limit multiplied by 1.5. Conclusions: No significant difference was found between a SLRI and a CSRI, even in a stringent self-sequential longitudinal reference interval of thyroid function in pregnant women. In addition, the limit of TT4 below the non-pregnant level multiplied by a factor 1.5 is not appropriate for diagnosing hypothyroxinemia in the first trimester.