Casey Brian M, Thom Elizabeth A, Peaceman Alan M, Varner Michael W, Sorokin Yoram, Hirtz Deborah G, Reddy Uma M, Wapner Ronald J, Thorp John M, Saade George, Tita Alan T N, Rouse Dwight J, Sibai Baha, Iams Jay D, Mercer Brian M, Tolosa Jorge, Caritis Steve N, VanDorsten J Peter
From the University of Texas Southwestern Medical Center, Dallas (B.M.C.), the University of Texas Medical Branch, Galveston (G.S.), and the University of Texas Health Science Center at Houston, McGovern Medical School-Children's Memorial Hermann Hospital, Houston (B.S.) - all in Texas; George Washington University Biostatistics Center, Washington, DC (E.A.T.); Northwestern University, Chicago (A.M.P.); the University of Utah Health Sciences Center, Salt Lake City (M.W.V.); Wayne State University, Detroit (Y.S.); the National Institute of Neurological Disorders and Stroke (D.G.H.) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.M.R.), Bethesda, MD; Columbia University, New York (R.J.W.); the University of North Carolina at Chapel Hill, Chapel Hill (J.M.T.); the University of Alabama at Birmingham, Birmingham (A.T.N.T.); Brown University, Providence, RI (D.J.R.); Ohio State University, Columbus (J.D.I.), and MetroHealth Medical Center-Case Western Reserve University, Cleveland (B.M.M.) - both in Ohio; Oregon Health and Science University, Portland (J.T.); University of Pittsburgh, Pittsburgh (S.N.C.); and the Medical University of South Carolina, Charleston (J.P.V.).
N Engl J Med. 2017 Mar 2;376(9):815-825. doi: 10.1056/NEJMoa1606205.
Subclinical thyroid disease during pregnancy may be associated with adverse outcomes, including a lower-than-normal IQ in offspring. It is unknown whether levothyroxine treatment of women who are identified as having subclinical hypothyroidism or hypothyroxinemia during pregnancy improves cognitive function in their children.
We screened women with a singleton pregnancy before 20 weeks of gestation for subclinical hypothyroidism, defined as a thyrotropin level of 4.00 mU or more per liter and a normal free thyroxine (T) level (0.86 to 1.90 ng per deciliter [11 to 24 pmol per liter]), and for hypothyroxinemia, defined as a normal thyrotropin level (0.08 to 3.99 mU per liter) and a low free T level (<0.86 ng per deciliter). In separate trials for the two conditions, women were randomly assigned to receive levothyroxine or placebo. Thyroid function was assessed monthly, and the levothyroxine dose was adjusted to attain a normal thyrotropin or free T level (depending on the trial), with sham adjustments for placebo. Children underwent annual developmental and behavioral testing for 5 years. The primary outcome was the IQ score at 5 years of age (or at 3 years of age if the 5-year examination was missing) or death at an age of less than 3 years.
A total of 677 women with subclinical hypothyroidism underwent randomization at a mean of 16.7 weeks of gestation, and 526 with hypothyroxinemia at a mean of 17.8 weeks of gestation. In the subclinical hypothyroidism trial, the median IQ score of the children was 97 (95% confidence interval [CI], 94 to 99) in the levothyroxine group and 94 (95% CI, 92 to 96) in the placebo group (P=0.71). In the hypothyroxinemia trial, the median IQ score was 94 (95% CI, 91 to 95) in the levothyroxine group and 91 (95% CI, 89 to 93) in the placebo group (P=0.30). In each trial, IQ scores were missing for 4% of the children. There were no significant between-group differences in either trial in any other neurocognitive or pregnancy outcomes or in the incidence of adverse events, which was low in both groups.
Treatment for subclinical hypothyroidism or hypothyroxinemia beginning between 8 and 20 weeks of gestation did not result in significantly better cognitive outcomes in children through 5 years of age than no treatment for those conditions. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00388297 .).
孕期亚临床甲状腺疾病可能与不良结局相关，包括后代智商低于正常水平。目前尚不清楚孕期被诊断为亚临床甲状腺功能减退或低甲状腺素血症的女性接受左甲状腺素治疗是否能改善其子女的认知功能。
我们在妊娠20周前对单胎妊娠女性进行筛查，以确定亚临床甲状腺功能减退（定义为促甲状腺激素水平每升4.00 mU或更高且游离甲状腺素（T）水平正常（每分升0.86至1.90 ng [每升11至24 pmol]））和低甲状腺素血症（定义为促甲状腺激素水平正常（每升0.08至3.99 mU）且游离T水平低（<每分升0.86 ng））。在针对这两种情况的单独试验中，女性被随机分配接受左甲状腺素或安慰剂。每月评估甲状腺功能，并调整左甲状腺素剂量以达到正常促甲状腺激素或游离T水平（取决于试验），对安慰剂进行假调整。对儿童进行为期5年的年度发育和行为测试。主要结局是5岁时的智商得分（如果未进行5岁检查，则为3岁时的智商得分）或3岁以下死亡。
共有677例亚临床甲状腺功能减退女性在平均妊娠16.7周时进行了随机分组，526例低甲状腺素血症女性在平均妊娠17.8周时进行了随机分组。在亚临床甲状腺功能减退试验中，左甲状腺素组儿童的智商得分中位数为97（95%可信区间[CI]，94至99），安慰剂组为94（95%CI，92至96）（P = 0.71）。在低甲状腺素血症试验中，左甲状腺素组智商得分中位数为94（95%CI，91至95），安慰剂组为91（95%CI，89至93）（P = 0.30）。在每项试验中，4%的儿童智商得分缺失。在任何一项试验中，两组在任何其他神经认知或妊娠结局或不良事件发生率方面均无显著差异，两组不良事件发生率均较低。
妊娠8至20周开始治疗亚临床甲状腺功能减退或低甲状腺素血症，与不治疗相比，在5岁以下儿童中并未产生显著更好的认知结局。（由尤妮斯·肯尼迪·施莱佛国家儿童健康与人类发展研究所和国家神经疾病与中风研究所资助；ClinicalTrials.gov编号，NCT00388297。）
