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. 2023 Aug 24;55(5):886–892. [Article in Chinese] doi: 10.19723/j.issn.1671-167X.2023.05.017

孕早期单纯甲状腺过氧化物酶抗体阳性与胎儿生长的关联

Association of maternal isolated thyroid peroxidase antibody positive in the first trimester with fetal growth

Jin-hui XU 1, Na HAN 2, Tao SU 2, Li-zi LIN 3, Yue-long JI 1, Shuang ZHOU 1, He-ling BAO 1, Zheng LIU 1, Shu-sheng LUO 1, Xiang-rong XU 1, Hai-jun WANG 1,*
PMCID: PMC10560913  PMID: 37807744

Abstract

Objective

To investigate the association of isolated thyroid peroxidase antibody (TPOAb) positive in the first trimester with fetal growth.

Methods

A total of 16 446 pregnant women were included in the birth cohort study, whose last menstrual period was between May 2016 and April 2019 and with singleton pregnancy. Maternal serum samples were collected when they firstly came for prenatal care in the first trimester. The pregnant women were consecutively seen and followed in the hospital and the information of pregnant women was extracted from the electronic medical information system. The pregnant women were divided into isolated TPOAb positive group (n=1 654) and euthyroid group (n=14 792). Three fetal ultrasound examinations were scheduled during the routine prenatal visits at the hospital and were performed by trained sonographers. All fetal growth indicators were quantified as gestational age- and gender- adjusted standard deviation score (Z-score) using the generalized additive models for location, scale and shape (GAMLSS). Fetal growth indicators included estimated fetal weight (EFW), abdominal circumference (AC), biparietal diameter (BPD), femur length (FL) and head circumference (HC). Fetal growth restriction (FGR) was defined as AC or EFW Z-score＜3rd centile based on clinical consensus. Generalized estimating equation (GEE) analysis was applied to assess the association of maternal isolated TPOAb positive with fetal growth. The generalized linear model was further used to analyze the association between isolated TPOAb positive and fetal growth indicator at different gestational ages when the fetal growth indicator was significantly associated with isolated TPOAb positive in the GEE mo-del.

Results

The median gestational age at three ultrasound measurements was 23.6 (23.3, 24.1), 30.3 (29.7, 30.9), 37.3 (37.0, 37.7) weeks, respectively. The BPD Z-score was higher in isolated TPOAb positive women, compared with the euthyroid pregnant women after adjustment (β=0.057, 95%CI: 0.014-0.100, P=0.009). The generalized linear model showed the BPD Z-score was higher in the isolated TPOAb positive women at the end of 21-25 weeks (β=0.052, 95%CI: 0.001-0.103, P=0.044), 29-32 weeks (β=0.055, 95%CI: 0.004-0.107, P=0.035) and 36-40 weeks (β=0.068, 95%CI: 0.011-0.125, P=0.020), compared with the euthyroid pregnant women. There was no difference in other fetal growth indicators (EFW, AC, FL and HC) and FGR between the isolated TPOAb positive and euthyroid pregnant women.

Conclusion

The BPD Z-score was slightly increased in the isolated TPOAb positive pregnant women in the first trimester, while other fetal growth indicators were not changed. The reproducibility and practical significance of this result need to be confirmed.

Keywords: Thyroid peroxidase antibody; Pregnancy trimester, first; Fetal development; Thyroid di-seases

甲状腺过氧化物酶(thyroid peroxidase，TPO)位于甲状腺上皮细胞的顶端细胞膜上，是参与甲状腺激素合成的关键酶。甲状腺过氧化物酶抗体(thyroid peroxidase antibody，TPOAb)是甲状腺特异性抗体，可通过细胞介导和抗体依赖的细胞毒作用引起甲状腺滤泡损伤，进而间接抑制甲状腺激素的合成[1-2]，在妊娠妇女中TPOAb阳性率为5. 1%~12.4%[3]。胎儿生长发育与孕妇甲状腺激素水平密切关联，孕早期甲状腺激素缺乏，即使轻微缺乏，也可能影响母亲和胎儿健康，导致流产、早产，影响胎儿出生体质量、神经认知发育等[4-7]。胎儿期是生长发育的关键期，胎儿生长又是一个动态过程。出生体质量是常用的反映胎儿生长发育的指标，但单一时点的指标不能完全反映胎儿生长情况[8]。随着产前超声测量技术的广泛应用，采用超声测量的胎儿生长指标与不良妊娠结局、出生后儿童期慢性非传染性疾病及神经智力发育等密切相关[9-12]。既往研究发现，妊娠期甲状腺激素水平及低甲状腺素血症影响胎儿生长发育指标[13-15]。但是，单纯TPOAb阳性是否影响采用超声测量的有关胎儿生长发育指标，即其是否影响胎儿生长发育，迄今仍缺乏详实资料。

本研究基于在北京市通州区妇幼保健院建立的出生队列，选取单纯TPOAb阳性和甲状腺功能正常的孕妇为研究对象，研究单纯TPOAb阳性与采用超声测量的有关胎儿生长发育指标的关联性，为孕早期单纯TPOAb阳性的诊治提供科学资料。

1. 资料与方法

1.1. 研究对象

本研究采用出生队列研究设计，选取末次月经在2016年5月至2019年4月且在北京市通州区妇幼保健院分娩的孕妇，数据来源于北京市通州区妇幼保健院的电子信息系统。研究对象纳入标准：单胎；首次甲状腺功能检查在孕早期(＜ 14周)；分娩孕周在28~42周；怀孕时年龄在18~49岁；早期建档、产前检查(甲状腺功能检查和超声检查)和分娩等资料完整；若同一妇女在本研究的研究时期内有多次妊娠记录，仅保留第一次妊娠记录。共有19 419名单胎孕妇符合入选条件。排除标准：胎儿出生缺陷(n=281)；通过辅助生殖技术受孕(n=83)；孕前诊断为高血压、心脏病、糖尿病、肾脏疾病、自身免疫性疾病等(n=79)；本人或其家庭中有甲状腺疾病史(n=50)；妊娠期间诊断为临床/亚临床甲状腺功能亢进、临床/亚临床甲状腺功能减退、低甲状腺素血症等其他甲状腺功能异常(n=2 350)；孕前服用左旋甲状腺素(levothyroxine，LT4)(n=8)；妊娠期间服用LT4(n=122)。最终纳入分析的孕妇为16 446名。本研究经北京大学生物医学伦理委员会批准(IRB00001052-20019)。

1.2. 常规临床资料收集

研究对象在孕早期建立围产档案时，由统一培训的医护人员完成研究对象常规资料的收集，包括研究对象的一般人口学资料(出生日期、教育水平、工作情况、孕前身高、体质量等)、生育史(孕产次、是否通过辅助生殖技术受孕、流产史等)、疾病史(个人和家族疾病史)和末次月经日期。

采用末次月经日期计算孕周，如果孕妇月经周期不规律，产科医生会进一步根据孕妇孕早期超声对末次月经日期进行核实，如果与孕妇自报的末次月经日期相差1周以上，则以超声检查报告的孕周为准。孕前体重指数(body mass index，BMI，单位为kg/m2)=孕前体质量/身高2。

1.3. 甲状腺功能检查及单纯TPOAb阳性诊断

1.3.1. 甲状腺功能检查

孕妇在第一次产检时，采取清晨空腹静脉血4 mL，分离血清，采用化学发光酶免疫法测定促甲状腺激素(thyroid stimulating hormone，TSH)、游离甲状腺素(free thyroxine，FT4)和TPOAb。测定仪器为雅培i2000(美国，伊利诺斯州)，试剂盒为雅培试剂，TSH、FT4和TPOAb的批次间和批次内变异系数差异≤10%。根据仪器厂商提供的参考范围，TPOAb水平大于5.6 IU/mL认为TPOAb阳性[16]。

1.3.2. 单纯TPOAb阳性诊断

采用2012年中国指南[17]推荐的TSH参考范围上限固定值2.5 mIU/L作为TSH参考范围上限，将TSH水平正常(0.03~ 2.5 mIU/L)、FT4水平正常(特异性参考范围：10.9~18.5 pmol/L)、TPOAb>5.6 IU/mL的孕妇作为单纯TPOAb阳性组；将TSH水平正常、FT4水平正常、TPOAb≤5.6 IU/mL的孕妇作为甲状腺功能正常组。

1.4. 研究指标

1.4.1. 结局指标

胎儿生长指标包括腹围(abdo-minal circumference，AC)、双顶径(biparietal diameter，BPD)、股骨长(femur length，FL)、头围(head circumference，HC)，由超声科医生在常规产前超声检查时按照统一方法测量得到，超声检查仪器为PHILIPSiU22彩色超声诊断仪。按照《孕前和孕期保健指南(2018)》[18]的推荐及医院超声检查孕周的分布范围，本研究分别选择孕21~25周、孕29~32周和孕36~40周作为三次超声检查的孕周范围。预测胎儿体质量(estimated fetal weight，EFW)采用Hadlock等[19]开发的公式计算获得：lgEFW= 1.326- 0.003 26 ×AC× FL+0.010 7×HC+0.043 8×AC+ 0.158×FL。胎儿生长是一个连续过程，胎儿生长指标的直接测量结果受胎龄的影响较大，结果之间的可比性差。为排除胎龄的影响，使不同胎龄的胎儿生长指标具有可比性，本研究将胎儿生长指标进行标准化处理，得到校正胎龄和性别的Z评分。标准化方法为基于位置、尺度、形状参数的广义加性模型(generalized additive methods for location, scale and shape，GAMLSS)[20]。根据胎儿生长受限(fetal growth restriction，FGR)的国际共识，本研究定义FGR为EFW或AC的Z评分小于人群第3百分位数[21]。

1.4.2. 协变量

依据既往文献中纳入的协变量及本研究收集资料的实际情况，将以下因素作为协变量：孕妇年龄(连续变量)、教育水平[低(高中及以下学历)、中(专科学历)、高(大学本科及以上学历)]、工作情况(有工作、无工作)、产次(初产妇、经产妇)、孕前BMI分类(按照中国人群营养状况标准对孕妇孕前BMI进行分类[22]，BMI＜18.5 kg/m2、BMI 18.5~23.9 kg/m2、BMI 24.0~27.9 kg/m2、BMI≥28.0 kg/m2分别归类为消瘦、正常、超重、肥胖)、甲状腺功能检查孕周(连续变量)。

1.5. 统计学分析

1.5.1. 描述性分析

研究对象基本特征中的连续变量(孕妇年龄、甲状腺功能检查孕周、TSH水平、FT4水平)均为非正态分布，采用中位数(第1四分位数，第3四分位数)进行描述，利用Wilcoxon秩和检验进行组间比较；对分类变量，采用例数(百分比)进行描述，利用卡方检验或Fisher确切概率法进行组间比较。

1.5.2. 关联分析

采用广义估计方程(generalized estimating equation，GEE)分析单纯TPOAb阳性与多次重复测量的胎儿生长指标(EFW、AC、BPD、FL和HC)Z评分及FGR的关联，由于孕妇的每次超声测量存在相关性，设定GEE的工作相关性矩阵为一阶自回归相关结构。当结局为胎儿生长指标Z评分时(连续变量结局)，选择GEE的连接函数为高斯分布(Gaussian distribution)，计算回归系数(β)及95%置信区间(confidence interval，CI)；当结局为FGR时(二分类变量结局)，选择GEE的连接函数为泊松分布(Poisson distribution)，计算相对危险度(relative risk，RR)和95% CI。本研究在简单模型中，仅分析单纯TPOAb阳性与胎儿生长之间的关联；在校正模型1中，校正孕妇年龄、教育水平、工作情况、产次、孕前BMI分类和甲状腺功能检查孕周，分析单纯TPOAb阳性与胎儿生长之间的关联。在校正模型2中，为排除不同TSH和FT4水平的影响，进一步校正孕妇TSH和FT4水平，分析单纯TPOAb阳性与胎儿生长之间的关联。对GEE分析中有统计学意义的关联结果，本研究进一步采用广义线性模型(generalized linear models，GLM)分析单纯TPOAb阳性与不同孕周的结局指标之间的关联。

1.5.3. 统计分析软件

采用R软件(4.0.3)进行统计分析。双侧检验P值＜ 0.05为差异具有统计学意义。

2. 结果

2.1. 描述性分析结果

本研究共纳入16 446名孕妇，单纯TPOAb阳性和甲状腺功能正常组之间孕妇年龄、教育水平差异均具有统计学意义(P均＜0.05)，在后面的关联分析中，把这些特征作为协变量进行校正。TSH水平、FT4水平的差异均具有统计学意义(P均＜0.05)，这与TPOAb阳性影响甲状腺功能有关，在模型中进一步校正。单纯TPOAb阳性和甲状腺功能正常组孕妇在工作情况、产次、孕前BMI分类、甲状腺功能检查孕周上的差异没有统计学意义(P均>0.05，表 1)。

表 1.

单纯TPOAb阳性孕妇与甲状腺功能正常孕妇的一般特征

Characteristics of isolated TPOAb positive and euthyroid pregnant women

Items Isolated TPOAb positive (n=1 654) Euthyroid(n=14 792) P value
Continuous variables were presented as median (1st quartile, 3rd quartile), and compared using Wilcoxon rank sum test. Categorical variables were presented as the frequency (percentage), and compared using the Chi-square test or Fisher exact test. TPOAb, thyroid peroxidase antibody; BMI, body mass index; TSH, thyroid stimulating hormone; FT4, free thyroxine.
Maternal age/years 29.6 (27.2, 32.6) 29.4 (27.1, 32.2) 0.021
Maternal education levels 0.005
    Low (high school and below) 232 (14.0) 2 299 (15.5)
    Middle (vocational college) 670 (40.5) 6 378 (43.1)
    High (university and above) 752 (45.5) 6 115 (41.3)
Current employment status 0.115
    Yes 1 479 (89.4) 13 027 (88.1)
    No 175 (10.6) 1 765 (11.9)
Parity 0.918
    Primipara 925 (55.9) 8 297 (56.1)
    Multipara 729 (44.1) 6 495 (43.9)
Pre-pregnancy BMI 0.637
    Underweight 165 (10.0) 1 443 (9.8)
    Normal weight 1 052 (63.6) 9 599 (64.9)
    Overweight 348 (21.0) 2 928 (19.8)
    Obesity 89 (5.4) 822 (5.6)
Gestational age at thyroid function testing/weeks 9.0 (8.0, 10.1) 9.0 (8.0, 10.3) 0.623
TSH/(mIU/L) 1.1 (0.7, 1.6) 0.9 (0.5, 1.3) ＜ 0.001
FT4/(pmol/L) 13.5 (12.5, 14.7) 13.6 (12.7, 14.8) ＜ 0.001
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本研究三次超声测量孕周中位数分别为23.6 (23.3，24.1)、30.3(29.7，30.9)和37.3(37.0，37.7) 周，甲状腺功能正常组和单纯TPOAb阳性组孕妇在不同孕周的超声测量胎儿生长情况见表 2。在孕21~25周、29~32周、36~40周，甲状腺功能正常组进行超声测量的孕妇分别有14 285(96.6%)、14 037(94.9%)和11 466(77.5%)名，FGR的比例分别为4.3%、3.8%和3.6%；单纯TPOAb阳性组进行超声测量的孕妇分别有1 606(97.1%)、1 569(94.9%)和1 273(77.0%)名，FGR的比例分别为3.9%、3.6%和4.1%。其他胎儿生长指标情况详见表 2。

表 2.

单纯TPOAb阳性孕妇与甲状腺功能正常孕妇在孕期的胎儿生长情况

Fetal growth parameters of isolated TPOAb positive and euthyroid pregnant women during pregnancy

Items 21-25 weeks 29-32 weeks 36-40 weeks
Euthyroid
(n=14 285)		 Isolated TPOAb positive
(n=1 606)		 Euthyroid
(n=14 037)		 Isolated TPOAb positive
(n=1 569)		 Euthyroid
(n=11 466)		 Isolated TPOAb positive
(n=1 273)
Fetal growth parameters (EFW, AC, BPD, FL, HC) were presented as x±s; Z-score was presented as x±s; FGR was presented as frequency (%). TPOAb, thyroid peroxidase antibody; EFW, estimated fetal weight; AC, abdominal circumference; BPD, biparietal diameter; FL, femur length; HC, head circumference; FGR, fetal growth restriction.
EFW/g 614.79±68.02 614.98±66.39 1529.19±181.38 1531.23±183.37 2935.17±305.42 2949.79±318.00
    Z-score -0.14±0.99 -0.13±0.98 0.00±0.99 0.00±0.99 -0.04±0.98 -0.01±1.00
AC/cm 19.07±0.92 19.08±0.92 26.11±1.27 26.14±1.28 33.04±1.54 33.10±1.59
    Z-score -0.02±0.98 0.00±0.99 -0.01±0.99 0.00±0.99 -0.03±0.98 0.00±1.00
BPD/cm 5.80±0.29 5.82±0.29 7.74±0.33 7.76±0.34 9.14±0.32 9.16±0.32
    Z-score -0.02±0.99 0.03±0.99 -0.01±0.99 0.05±1.00 -0.03±0.98 0.04±0.99
FL/cm 4.13±0.19 4.13±0.19 5.65±0.23 5.64±0.24 6.86±0.22 6.86±0.23
    Z-score -0.02±0.99 -0.03±0.98 0.00±0.99 -0.06±0.99 -0.02±0.98 -0.03±1.00
HC/cm 21.45±0.86 21.44±0.87 28.07±1.01 28.12±1.05 32.46±1.03 32.54±1.04
    Z-score -0.02±0.99 -0.01±0.99 -0.01±0.98 0.04±0.99 -0.03±0.98 0.04±0.99
FGR/% 607 (4.3) 62 (3.9) 535 (3.8) 57 (3.6) 407 (3.6) 52 (4.1)
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2.2. 关联分析结果

在校正模型1中，与甲状腺功能正常组相比，单纯TPOAb阳性组BPD的Z评分比甲状腺功能正常组高0.054(95%CI：0.011~0.097，P=0.013)，与其他胎儿生长结局指标的关联没有统计学意义(P均>0.05)。进一步校正TSH和FT4水平后，单纯TPOAb阳性组BPD的Z评分仍比甲状腺功能正常组高(β=0.057，95%CI：0.014~0.100，P=0.009，表 3)。

表 3.

单纯TPOAb阳性与胎儿生长的关联分析

Association of maternal isolated TPOAb positive with fetal growth

Items Adjust model 1 Adjusted model 2
β or RR (95%CI) P value β or RR (95%CI) P value
The adjusted model 1 was adjusted for maternal age, maternal educational level, current employment status, parity, pre-pregnancy body mass index (BMI) and gestational age of thyroid function testing. The adjusted model 2 was additionally adjusted for thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels. TPOAb, thyroid peroxidase antibody; EFW, estimate fetal weight; AC, abdominal circumference; BPD, biparietal diameter; FL, femur length; HC, head circumference; FGR, fetal growth restriction.
EFW 0.007 (-0.036, 0.049) 0.760 0.012 (-0.031, 0.055) 0.590
AC 0.016 (-0.025, 0.057) 0.451 0.020 (-0.022, 0.061) 0.349
BPD 0.054 (0.011, 0.097) 0.013 0.057 (0.014, 0.100) 0.009
FL -0.026 (-0.068, 0.016) 0.224 -0.020 (-0.062, 0.023) 0.358
HC 0.028 (-0.013, 0.070) 0.183 0.031 (-0.011, 0.073) 0.148
FGR 1.02 (0.85, 1.21) 0.862 1.01 (0.84, 1.21) 0.922
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在不同孕周分析单纯TPOAb阳性与BPD的Z评分的关联，在校正模型1中，单纯TPOAb阳性组在36~40周BPD的Z评分比甲状腺功能正常组高0.066(95%CI：0.010~0.123，P=0.022)，在21~25周和29~32周与甲状腺功能正常组BPD的Z评分差异没有统计学意义(P均>0.05)，但在数值上与甲状腺功能正常组相比有升高的趋势。进一步校正TSH和FT4水平后，单纯TPOAb阳性组BPD的Z评分在21~25周比甲状腺功能正常组高0.052(95%CI：0.001~0.103，P=0.044)，在29~32周比甲状腺功能正常组高0.055(95%CI：0.004~0.107，P=0.035)，在36~40周比甲状腺功能正常组高0.068(95%CI：0.011~0.125，P=0.020)，详见表 4。在模型2中，将得到的Z评分转化为实际值后，单纯TPOAb阳性组BPD在21~25周比甲状腺功能正常组高0.151 mm(95%CI：0.002~0.299)，在29~32周比甲状腺功能正常组高0.182 mm(95%CI：0.013~0.353)，在36~40周比甲状腺功能正常组高0.218 mm(95%CI：0.035~0.400)。

表 4.

单纯TPOAb阳性与不同孕周BPD的Z评分的关联分析

Association of maternal isolated TPOAb positive with BPD Z-score at different gestational weeks

Items Adjust model 1 Adjusted model 2
β (95%CI) P value β (95%CI) P value
The adjusted model 1 was adjusted for maternal age, maternal educational level, current employment status, parity, pre-pregnancy body mass index (BMI) and gestational age of thyroid function testing. The adjusted model 2 was additionally adjusted for thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels. TPOAb, thyroid peroxidase antibody; BPD, biparietal diameter.
21-25 weeks 0.049 (-0.001, 0.100) 0.056 0.052 (0.001, 0.103) 0.044
29-32 weeks 0.049 (-0.002, 0.100) 0.060 0.055 (0.004, 0.107) 0.035
36-40 weeks 0.066 (0.010, 0.123) 0.022 0.068 (0.011, 0.125) 0.020
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3. 讨论

本研究初步探讨了单纯TPOAb阳性与超声测量胎儿生长指标的关联，发现单纯TPOAb阳性孕妇的胎儿BPD的Z评分比甲状腺功能正常孕妇略有增加，且不受TSH和FT4水平的影响。本研究发现单纯TPOAb阳性组与甲状腺功能正常组相比BPD增加的效应值较低，但是在怀孕21~25周、29~32周、36~40周BPD的增加都有统计学意义，而且校正TSH、FT4水平和其他协变量后结果稳健。截至目前，未见胎儿BPD与后期生长发育的相关研究报道，尚不清楚本研究发现有统计学意义的差异相应的临床或公共卫生学意义。因HC与BPD高度相关，我们检索了HC相关研究，有一项前瞻性队列研究分析了低甲状腺素血症(FT4＜10th，TSH水平正常)与超声测量的胎儿HC的关联，发现在妊娠早期阶段(中位孕周为13.4周)低甲状腺素血症组孕妇胎儿的HC比甲状腺功能正常组高0.7 mm(90.3 mm vs. 89.6 mm，P=0.008)[15], 该研究结果提示，妊娠期甲状腺功能异常可能影响胎儿HC，但效应值较低。本研究发现单纯TPOAb阳性组HC的Z评分与甲状腺功能正常组相比在数值上有增加趋势，而且三次测量时HC与BPD均高度相关(相关系数大于0.70)，提示单纯TPOAb阳性也可能影响胎儿HC。总之，单纯TPOAb阳性对胎儿BPD和HC的影响尚需进一步研究证实。

有研究发现，孕妇在妊娠期间TPOAb阳性可能影响子代的神经智力发育。Generation R队列随访母子3 139对，在子代3岁时进行行为评估，发现妊娠期间TPOAb阳性孕妇的子代患儿童注意缺陷与多动障碍的风险增加(OR=1.77，95%CI：1. 15~2.72，P=0.01)[23]。一项巢式病例对照研究报道，单纯TPOAb阳性孕妇的子代在25~30个月龄时的智力发育指数比甲状腺功能正常孕妇的子代低10.65分(112.70分vs. 123.25分，P=0.001)、神经运动发育指数比甲状腺功能正常孕妇的子代低9.03分(110.64分vs. 119.67分，P=0.001)[24]。另外一项研究也发现TPOAb阳性孕妇的子代患自闭症的风险增加[25]。既往也有研究发现胎儿HC与子代神经智力发育密切相关[26-27]，如Generation R队列研究发现孕晚期HC上升增加儿童3月龄警觉性Z评分[27]。以上TPOAb阳性对子代神经智力发育影响的研究结果提示，妊娠期TPOAb阳性可能与胎儿脑发育异常有关，胎儿脑发育异常可能与超声测量的BPD或HC增加有关联，这些可能的关联尚有待研究。

单纯TPOAb阳性对胎儿生长的影响机制仍不清楚，既往研究提示单纯TPOAb阳性对胎儿生长的影响可能是通过对甲状腺激素的影响发挥作用[23]。人绒毛膜促性腺激素(human chorionic gonadotropin，hCG)是一种妊娠特异性激素，因其α亚单位与TSH相似，会直接刺激TSH受体，导致FT4水平升高，增多的甲状腺素会通过负反馈作用抑制TSH分泌，使血清TSH水平降低[28]。既往研究发现，TPOAb阳性会损伤甲状腺对hCG刺激作用的反应，在TPOAb阴性的孕妇中，hCG与FT4水平正相关，与TSH水平负相关；在TPOAb阳性的孕妇中，hCG与FT4和TSH的关联没有统计学意义[29]。单纯TPOAb阳性导致潜在免疫功能异常，虽然孕妇甲状腺激素水平未发生改变，但甲状腺本身已经受损，储备功能下降，后续可能影响甲状腺激素的分泌和供应，进而影响胎儿生长。目前，单纯TPOAb阳性对胎儿生长的机制研究较为缺乏，未来需进一步研究。

本研究采用重复测量数据分析孕早期单纯TPOAb阳性与胎儿生长指标的关联，相比于某一时点数据，能更全面地反映胎儿生长发育的连续过程。有研究报道碘营养状况会影响甲状腺功能和胎儿生长，碘不足组的胎儿生长指标和出生体质量均低于碘适宜组[30-31]，但由于北京市居民的碘营养水平适宜[32-33]，考虑到碘营养指标对本研究的影响可能较小，因此未将碘营养指标纳入本研究的分析中。此外，孕早期单纯TPOAb阳性孕妇的胎儿BPD的Z评分仅略有增加，其是否仅为统计差异有待证实，其实际意义仍有待明确，其发生机制也有待阐释。

Funding Statement

国家自然科学基金(92046019、81973053)

Supported by the National Natural Science Foundation of China (92046019, 81973053)

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