Department of Internal Medicine, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
Academic Center for Thyroid Diseases, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands.
J Clin Endocrinol Metab. 2024 Oct 15;109(11):e2151-e2158. doi: 10.1210/clinem/dgae528.
Establishing local trimester-specific reference intervals for gestational TSH and free T4 (FT4) is often not feasible, necessitating alternative strategies. We aimed to systematically quantify the diagnostic performance of standardized modifications of center-specific nonpregnancy reference intervals as compared to trimester-specific reference intervals.
We included prospective cohorts participating in the Consortium on Thyroid and Pregnancy. After relevant exclusions, reference intervals were calculated per cohort in thyroperoxidase antibody-negative women. Modifications to the nonpregnancy reference intervals included an absolute modification (per .1 mU/L TSH or 1 pmol/L free T4), relative modification (in steps of 5%) and fixed limits (upper TSH limit between 3.0 and 4.5 mU/L and lower FT4 limit 5-15 pmol/L). We compared (sub)clinical hypothyroidism prevalence, sensitivity, and positive predictive value (PPV) of these methodologies with population-based trimester-specific reference intervals.
The final study population comprised 52 496 participants in 18 cohorts. Optimal modifications of standard reference intervals to diagnose gestational overt hypothyroidism were -5% for the upper limit of TSH and +5% for the lower limit of FT4 (sensitivity, .70, CI, 0.47-0.86; PPV, 0.64, CI, 0.54-0.74). For subclinical hypothyroidism, these were -20% for the upper limit of TSH and -15% for the lower limit of FT4 (sensitivity, 0.91; CI, 0.67-0.98; PPV, 0.71, CI, 0.58-0.80). Absolute and fixed modifications yielded similar results. CIs were wide, limiting generalizability.
We could not identify modifications of nonpregnancy TSH and FT4 reference intervals that would enable centers to adequately approximate trimester-specific reference intervals. Future efforts should be turned toward studying the meaningfulness of trimester-specific reference intervals and risk-based decision limits.
建立适用于妊娠期 TSH 和游离 T4（FT4）的本地特定孕期参考区间通常是不可行的，因此需要采用替代策略。我们旨在系统地量化标准化修改中心特定非妊娠参考区间与特定孕期参考区间相比的诊断性能。
我们纳入了参加甲状腺与妊娠联盟的前瞻性队列研究。排除相关因素后，在甲状腺过氧化物酶抗体阴性的女性中，按每个队列计算参考区间。非妊娠参考区间的修改包括绝对值修改（每 TSH 增加或减少 0.1mU/L 或 FT4 增加或减少 1pmol/L）、相对值修改（每增加或减少 5%）和固定限制（上界 TSH 范围在 3.0 至 4.5mU/L 之间，下界 FT4 范围在 5-15pmol/L 之间）。我们将这些方法与基于人群的特定孕期参考区间的亚临床甲状腺功能减退症患病率、敏感性和阳性预测值（PPV）进行了比较。
最终研究人群包括来自 18 个队列的 52496 名参与者。诊断妊娠显性甲状腺功能减退症的最佳标准参考区间修改值为 TSH 上限减少 5%，FT4 下限增加 5%（敏感性为 0.70，CI 为 0.47-0.86；PPV 为 0.64，CI 为 0.54-0.74）。对于亚临床甲状腺功能减退症，TSH 上限减少 20%，FT4 下限减少 15%（敏感性为 0.91，CI 为 0.67-0.98；PPV 为 0.71，CI 为 0.58-0.80）。绝对值和固定值修改得到了相似的结果。置信区间较宽，限制了其普遍性。
我们无法确定修改非妊娠 TSH 和 FT4 参考区间的方法，以使各中心能够充分接近特定孕期参考区间。未来的研究应致力于研究特定孕期参考区间的意义和基于风险的决策界限。
