早产(PTD)是婴儿死亡的主要原因。越来越多的证据表明,甲状腺功能障碍可能与PTD的风险增加有关,但连续谱母体游离甲状腺素(FT4)与PTD之间的剂量依赖性关联仍未明确.本研究旨在使用基于机器学习的模型进一步研究这种关系。
2014年1月至2018年12月在上海进行了基于医院的队列研究。中国。包括分娩单胎活产并具有妊娠早期甲状腺功能数据的孕妇。应用带有惩罚三次回归样条的广义加性模型来探索母体FT4与PTD风险以及PTD亚型之间的非线性关联。进一步应用事件发生时间法和多变量Cox比例风险模型分析异常高和低的母体FT4浓度与PTD发生时间的关联。
最终分析共纳入了65,565例单胎妊娠,有完整的医疗记录,并且在妊娠前没有已知的甲状腺疾病。孕早期的母体FT4与PTD之间存在U型剂量依赖性关系(p<0.001)。与母体FT4的正常范围相比,低母体FT4(<11.7pmol/L;调整后的风险比[HR]1.34,95%CI[1.13-1.59])和高母体FT4(>19.7pmol/L;HR1.41,95%CI[1.13-1.76])的PTD风险均增加。孤立性低甲状腺素血症和PTD之间的关联主要与自发性PTD相关(HR1.33,95%CI[1.11-1.59]),而与正常甲状腺女性相比,明显的甲状腺功能亢进可能归因于医源性PTD(HR1.51,95%CI[1.18-1.92])。此外,中介分析发现,在明显的甲状腺功能亢进与医源性PTD风险之间的关联中,估计有11.80%是通过妊娠期高血压疾病的发生介导的(p<0.001).
我们首次揭示了母体FT4和PTD之间的U型关联,超出母体甲状腺功能检查异常的临床定义。我们的研究结果为需要建立孕妇FT4浓度的最佳范围以预防妊娠不良结局提供了见解。
Preterm delivery (PTD) is the primary cause of mortality in infants. Mounting evidence indicates that thyroid dysfunction might be associated with an increased risk of PTD, but the dose-dependent association between the continuous spectrum maternal free thyroxine (FT4) and PTD is still not well-defined. This study aimed to further investigate this relationship using a machine learning-based model.
A hospital-based cohort study was conducted from January 2014 to December 2018 in Shanghai,
China. Pregnant women who delivered singleton live births and had first-trimester thyroid function data available were included. The generalized additive models with penalized cubic regression spline were applied to explore the non-linear association between maternal FT4 and risk of PTD and also subtypes of PTD. The time-to-event method and multivariable Cox proportional hazard model were further applied to analyze the association of abnormally high and low maternal FT4 concentrations with the timing of PTD.
A total of 65,565 singleton pregnancies with completed medical records and no known thyroid disease before pregnancy were included for final analyses. There was a U-shaped dose-dependent relationship between maternal FT4 in the first trimester and PTD (p <0.001). Compared with the normal range of maternal FT4, increased risk of PTD was identified in both low maternal FT4 (<11.7 pmol/L; adjusted hazard ratio [HR] 1.34, 95% CI [1.13-1.59]) and high maternal FT4 (>19.7 pmol/L; HR 1.41, 95% CI [1.13-1.76]). The association between isolated hypothyroxinemia and PTD was mainly associated with spontaneous PTD (HR 1.33, 95% CI [1.11-1.59]) while overt hyperthyroidism may be attributable to iatrogenic PTD (HR 1.51, 95% CI [1.18-1.92]) when compared with euthyroid women. Additionally, mediation analysis identified that an estimated 11.80% of the association between overt hyperthyroidism and iatrogenic PTD risk was mediated via the occurrence of hypertensive disorders in pregnancy (p <0.001).
We revealed a U-shaped association between maternal FT4 and PTD for the first time, exceeding the clinical definition of maternal thyroid function test abnormalities. Our findings provide insights towards the need to establish optimal range of maternal FT4 concentrations for preventing adverse outcomes in pregnancy.