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1 ORIGINAL ARTICLE Endocrine Care Assessment of Thyroid Function During First- Trimester Pregnancy: What Is the Rational Upper Limit of Serum TSH During the First Trimester in Chinese Pregnant Women? Chenyan Li, Zhongyan Shan, Jinyuan Mao, Weiwei Wang, Xiaochen Xie, Weiwei Zhou, Chenyang Li, Bin Xu, Lihua Bi, Tao Meng, Jianling Du, Shaowei Zhang, Zhengnan Gao, Xiaomei Zhang, Liu Yang, Chenling Fan, and Weiping Teng The Endocrine Institute and The Liaoning Provincial Key Laboratory of Endocrine Diseases (ChenyanL., Z.S., J.M., W.W., X.X., C.F., W.T.), Department of Endocrinology and Metabolism, The First Hospital of China Medical University, Shenyang, China; Shenyang Women s and Children s Hospital (W.Z., ChenyangL.), Shenyang, China; Departments of Obstetrics and Gynecology (B.X.) and Endocrinology (S.Z.), No. 202 Hospital of People s Liberation Army, Shenyang, China; Dalian Obstetrics and Gynecology Hospital (L.B.), Dalian, China; Department of Obstetrics and Gynecology (T.M.), The First Hospital of China Medical University, Shenyang, China; Department of Endocrinology (J.D.), The First Affiliated Hospital of Dalian Medical University, Dalian, China; Department of Endocrinology (Z.G.), Dalian Municipal Central Hospital Affiliated of Dalian Medical University, Dalian, China; Department of Endocrinology (X.Z.), The First Hospital of Dandong, Dandong, China; and Shenyang Women and Children Health Care Center (L.Y.), Shenyang, China Context: Guidelines of the American Thyroid Association (ATA) proposed that the upper limit of the TSH reference range should be 2.5 miu/l in first trimester, but the reported ranges in China are significantly higher. Objective: Our objective was to establish a rational reference range of serum TSH for diagnosis of subclinical hypothyroidism in the first trimester of pregnant women in China. Design: We screened 4800 pregnant women in the first trimester and 2000 women who planned to become pregnant and evaluated 535 pregnant women in follow-up visits during the second and third trimester. Results: Median concentrations of serum TSH decreased significantly from the seventh week of gestation. The median of TSH from 4 to 6 weeks was significantly higher than from 7 to 12 weeks (2.15 [ ] miu/l vs 1.47 [ ] miu/l, P.001); however, there was no significant difference compared with nonpregnant women (2.07 [ ] miu/l; P.784). The median of free T 4 was not significantly altered in the first trimester. The prevalence of subclinical hypothyroidism in the 4800 pregnant women was 27.8% on the diagnostic criteria of TSH 2.5 miu/l and 4.0% using the reference interval derived by our laboratory ( miu/l).additionally, of 118 pregnant women who had serum TSH 2.5 miu/l in the first trimester, only 30.0% and 20.3% of them at the 20th and 30th week of gestation had TSH 3.0 miu/l. Conclusions: The reference range for nonpregnant women can be used for the assessment of pregnant women at 4 to 6 weeks of gestation. The upper limit of serum TSH in the first trimester was much higher than 2.5 miu/l in Chinese pregnant women. (J Clin Endocrinol Metab 99: 73 79, 2014) ISSN Print X ISSN Online Printed in U.S.A. Copyright 2014 by The Endocrine Society Received March 18, Accepted November 6, First Published Online November 25, 2013 Abbreviations: BMI, body mass index; FT 4, free T 4 ; HCG, human chorionic gonadotropin; MUI, median of urine iodine; SCH, subclinical hypothyroidism; TgAb, thyroglobulin antibody; TPOAb, thyroid-peroxidase antibody. doi: /jc J Clin Endocrinol Metab, January 2014, 99(1):73 79 jcem.endojournals.org 73

2 74 Li et al Thyroid Function During First-Trimester Pregnancy J Clin Endocrinol Metab, January 2014, 99(1):73 79 Subclinical hypothyroidism (SCH) is one of the major thyroid disorders during pregnancy, present in 2% to 3% of pregnant women (1). SCH is associated with an increased risk of adverse pregnancy complications and possibly with an increased risk of neurocognitive deficits in the developing fetus. Because of a lack of specific clinical symptoms, SCH has to be defined by serum TSH concentration. Thus, the reference range of TSH is critical for diagnosis and treatment. The levels of TSH are markedly influenced by the pregnancy-related changes during the first trimester. Therefore, in 2011, the guidelines of the American Thyroid Association (ATA) proposed that Trimester-specific reference ranges for TSH, as defined in populations with optimal iodine intake, should be applied. If trimester-specific reference ranges for TSH are not available in the laboratory, the following reference ranges are recommended: first trimester miu/l; second trimester miu/l; third trimester miu/l (1). The upper limit of 2.5 miu/l for serum TSH has become internationally accepted. However, in recent years, reference intervals of serum TSH reported for pregnant women in China have been found to be significantly higher than that of Europe and the United States (2 15). In China, which is still a developing country, most doctors prefer a one-size fits all criterion for defining SCH proposed by ATA. For that purpose, in June 2012, we started a large-scale populationbased study focusing on subclinical hypothyroid in early pregnancy (SHEP) in 3 cities of Liaoning Province in China. We have enrolled 4800 pregnant women (average 6.8 gestational weeks) and 2000 women who planned to be pregnant. In this preliminary report, we analyzed the TSH levels in each gestational week during the first trimester. We discuss the rationale in defining 2.5 miu/l as the upper limit of the serum TSH reference range. We aimed to establish a proper reference range of serum TSH to define SCH in the first trimester in Chinese women. Subjects and Methods Subjects The Subclinical Hypothyroid in Early Pregnancy study started in 3 cities of Liaoning Province in China in June Nineteen hospitals participated in this study, including the Department of Obstetrics and Gynecology and the Department of Endocrinology. Recruitment criteria included residing in the city for more than 10 years, age 19 to 40 years old, and planning to become pregnant or having a singleton pregnancy at 4 to 12 weeks of gestation. Exclusion criteria applied to multiple pregnancies, patients with thyroid disease history or any other chronic diseases, and patients on oral contraceptive regimens or any medical regimen that may affect thyroid function, such as glucocorticoids, dopamine, or antiepileptic drugs. Selection of the reference population was in light of Guideline 22 of the National Academy of Clinical Biochemistry (16), and patients with a family or personal history of thyroid dysfunction, visible or palpable goiter, medications (except for vitamins), and detectable thyroid autoantibodies were excluded. A total of 6800 women participated in this study (age years), including 4800 pregnant women and 2000 women of reproductive age. In addition, 3741 pregnant women and 1410 women of reproductive age were selected as reference populations. The sample of each gestational week was different, ranging from 128 to 763. To avoid statistical biases produced by sample size, age, body mass index (BMI), we used the smallest sample size among the groups (that is 128 in the group of gestational weeks) as the point of reference to select reference women in each gestational week with age 1 year and BMI 1 kg/m 2 (1:1 paired) and nonpregnant women (5:1 paired). Of the 3741 pregnant women, follow-up visits were done for 535 pregnant women at weeks 20 and 30 of gestation. Of these 535 pregnant women, we lost contact with 45, and 34 pregnancies ended in miscarriage. Thus, 456 women completed the study with a follow-up rate of 85%. All subjects were asked to complete a questionnaire, and their serum TSH, free T 4 (FT 4 ), thyroid-peroxidase antibody (TPOAb), thyroglobulin antibody (TgAb), and human chorionic gonadotropin (HCG) were measured, as well as iodine in the urine. Methods All subjects signed consent forms to participate in the study. Samples of spot urine and blood were obtained from each participant in the morning after an overnight fast. All specimens were frozen at 20 C until shipment and assayed as soon as possible. Serum TSH, FT 4, TPOAb, TgAb, and HCG were measured in all participants using the electrochemiluminescence immunoassay with Cobas Elesys 601 (Roche Diagnostics). The functional sensitivity of serum TSH was miu/l. The intra-assay coefficients of variation of serum TSH, FT 4, TPOAb, TgAb, and HCG were 1.57% to 4.12%, 2.24% to 6.33%, 2.42% to 5.63%, 1.3% to 4.9%, and 1.7% to 2.8%, respectively. The interassay coefficients of variation were 1.26% to 5.76%, 4.53% to 8.23%, 5.23% to 8.16%, 2.1%% to 6.9%, and 3.3% to 7.4%, respectively. The laboratory reference ranges of TSH were 0.27 to 4.2 miu/l, FT 4 12 to 22 pmol/l, TPOAb 0 to 34 IU/mL, and TgAb 0 to 115 IU/mL. The reference range for HCG varied with each week of pregnancy, with the highest levels being at 9 weeks of gestation as measured with Roche kits. Urinary iodine concentration was determined in all participants by the ammonium persulfate method based on the Sandell-Kolthoff reaction.the intra- and interassay coefficients of variation for urinary iodine concentration were 3% to 4% and 4% to 6% at 66 g/l and 2% to 5% and 3% to 6% at 230 g/l, respectively. Statistical analysis For TSH and FT 4 analyses, the medians and 2.5th and 97.5 th percentiles were defined for all reference women. The Kolmogorov-Smirnov method was used to test normality of the data distribution. In comparisons between the study groups, normally distributed variables such as age and BMI were assessed using one-way ANOVA followed by Bonferroni correction in paired comparisons. Serum TSH, FT 4, and HCG levels and urinary iodine concentrations failed the normality test; therefore, these

3 doi: /jc jcem.endojournals.org 75 Table 1. Serum Levels of TSH, FT 4, HCG in the Reference Population at Different Gestational Weeks a HCG, IU/mL TSH, miu/l FT 4, pmol/l Week of Gestation n Median P Value 2.5th 50th 97.5th P Value 2.5th 50th 97.5th P Value b b b b b b a The P values represent the median level of this group compared with the upper group. b P variables were assessed using Kruskal-Wallis one-way ANOVA on ranks in groups, and pairwise comparisons were performed using Mann-Whitney rank sum test. Spearman s rank correlation was used to examine the correlation between TSH and HCG, FT 4, and HCG. A significance level of.0018 was considered significant for multiple comparisons between 8 groups in Table 1 and a significance level of.008 was considered significant for multiple comparisons between 4 groups in Table 2. A P value of.05 was used for all other statistical testing. All statistical analyses were performed with SPSS version 17.0 software. Ethics committee approval The experimental procedure described here was approved by the Ethics Committee of China Medical University and is congruent with the Declaration of Helsinki. Informed consent was obtained from every patient. Results Iodine status The mean age of the reference pregnant women was 28.2 (range 19 37) years, the mean gestational week was 7.4 (range 4 12) weeks, and the median of urine iodine (MUI) was g/l. In nonpregnant reference women, the mean age was 28.8 (range 19 37) years, and the MUI was g/l. According to the MUI level measured in 101 schoolchildren (which was g/l), the region was classified as having adequate iodine status. Serum levels of TSH, FT 4, and HCG Between the gestational week groups, there was no statistically significant difference in age or BMI. Table 1 shows the reference range of serum TSH and FT 4 and the median value of HCG, TSH, and FT 4 week by week during the first trimester in pregnant women. Median (50th percentile) concentrations of serum TSH decreased significantly from the seventh week of pregnancy (2.01 miu/l [median level of TSH in the sixth week of gestation] vs 1.58 miu/l [median level of TSH in the seventh week of gestation], P.001), reaching a nadir 1.10 miu/l between gestational weeks 10 and 11, and then increasing from that point on. At 4 weeks of gestation, serum HCG levels rose significantly until 9 to 11 weeks, where it reached a plateau and then began to decline. The correlation between TSH and HCG was found to be statistically significant but explains 20% of the variation (r 0.45, r , P.001). We did not find significant changes in serum FT 4 in the first trimester and found no significant correlations between FT 4 and HCG (r 0.06, r , P.072). The distribution of TSH in different subgroups is depicted in Figure 1. The median level of TSH during 7 to 12 weeks of gestation was significantly lower than that of 4 to 6 weeks of gestation (1.47 vs 2.15 miu/l, P.001), and the median TSH level during 4 to 6 gestational weeks was comparable to the values measured in nonpregnant women (2.15 vs 2.07 miu/l, P.784). The TSH reference intervals for nonpregnant women, pregnant women at 4 to 6 weeks of gestation, pregnant women at 7 to 12 weeks of Figure 1. The distribution of TSH in different subgroups. Compared with pregnant women during 7 to 12 gestational weeks, the distribution of TSH at 4 to 6 gestational weeks moves to the right significantly and almost coincides with nonpregnant women.

4 76 Li et al Thyroid Function During First-Trimester Pregnancy J Clin Endocrinol Metab, January 2014, 99(1):73 79 Table 2. Serum Levels of TSH and FT 4 in Reference Subpopulation a TSH, miu/l FT 4, pmol/l Population n 2.5th 50th 97.5th P Value 2.5th 50th 97.5th P Value Nonpregnant Pregnant 4 6 wk b 7 12 wk b wk b a The P values represent the median level of this group compared with the upper group. b P.008. gestation, and pregnant women at 4 to 12 weeks of gestation were 0.69 to 5.64 miu/l, 0.56 to 5.31 miu/l, 0.10 to 4.34 miu/l and 0.14 to 4.87 miu/l, respectively. Median concentrations of serum FT 4 increased significantly at the 4 to 6 gestational weeks compared with nonpregnant women (median vs pmol/l, P.001), but there was no difference between 4 to 6 gestational weeks and 7 to 12 gestational weeks (median: vs pmol/l, P.651) (Table 2). In the 3741 reference pregnant women, we analyzed the relationship between TSH and FT 4.FT 4 was relatively constant with the median at 15 to 16 pmol/l with a TSH level of 0.8 to 4.8 miu/l. When FT 4 began to decline significantly, serum TSH levels were close to 4.8 miu/l (Figure 2). Prevalence of SCH Results of the screening for SCH in 4800 pregnant women according to the criteria of the ATA (TSH 2.5 miu/l) and pregnancy-specific reference ranges (4 6 gestational weeks, 7 12 gestational weeks, and 4 12 gestational weeks) are shown in Table 3. Using the ATA criteria, ie, TSH 2.5 miu/l, the prevalence of SCH was 36.6% in pregnant women at 4 to 6 gestational weeks, Figure 2. Relationship between TSH and FT 4. When the TSH levels were 0.8 to 4.8 miu/l, FT 4 was relatively constant and the median was 15 to 16 pmol/l. When serum TSH levels were above 4.8 miu/l, FT 4 began to decline significantly. 22.4% in pregnant women at 7 to 12 gestational weeks, and 27.8% in pregnant women at 4 to 12 gestational weeks. Using the ATA criteria, the prevalence of SCH was much higher than that using the serum TSH-specific reference ranges, which were 3.8%, 4.0%, and 4.0%. If the criteria for pregnant women at 7 to 12 gestational weeks were applied to women at 4 to 6 weeks of gestation, the prevalence of SCH rose to 9.3%. Conversely, if the TSH reference range for 4 to 6 gestational weeks was applied to pregnant women at 7 to 12 gestational weeks, the prevalence of SCH decreased to 2.1%. Concordance of SCH diagnosis in T 2 and T 3 Follow-up visits were performed with 456 women at 20 and 30 weeks of gestation. Of these women, 118 had TSH 2.5 miu/l in the first trimester. According to the SCH criteria of TSH 3.0 miu/l proposed by ATA, only 34 (30.0%) at the second trimester and 24 (20.3%) at the third trimester had been confirmed to be SCH. Discussion In 2011, the ATA proposed trimester-specific reference ranges for TSH to define SCH, and these guidelines have been accepted internationally. However, the reference range of the first trimester given by ATA guidelines was mostly derived from the cohorts at 9 to 12 weeks of gestation (1). On the other hand, in China, many pregnant women visit clinics before 8 weeks of gestation for prenatal care. Some even obtain prenatal care before 6 weeks of gestation. Moreover, many experts agree that early treatment can improve the outcome and success of a pregnancy. Therefore, assessment of thyroid function during early pregnancy becomes imperative to physicians in endocrinology, obstetrics, and gynecology. Results of the present study showed that median serum TSH levels decreased significantly from the seventh gestational week. This phenomenon was also reported by Männistö and colleagues (8), although their study did not

5 doi: /jc jcem.endojournals.org 77 Table 3. Prevalence of SCH With Different Diagnostic Prevalence of SCH, n (%) Weeks of Gestation Sample, n ATA analyze whether the change was statistically significant. The change in TSH level during the first trimester might happen due to the role of HCG. In our population, the correlation between HCG and TSH levels at 4 to 12 weeks was found to be statistically significant. However, that is a weak association, and we found TSH levels were suppressed at high HCG levels (Table 1), which is very similar to what has been reported in other studies (17, 18). The median levels of serum TSH during gestational weeks 7 to 12 (1.47 miu/l) were significantly lower than that of gestational weeks 4 to 6 (2.15 miu/l), and the latter did not significantly differ from nonpregnant women (2.07 miu/l). Thus, we propose that the pregnancy-specific reference range in first trimester is suitable for weeks 7 to 12 of gestation. If the reference range for TSH at 4 to 6 weeks of gestation was not available in the laboratory, we could use the reference range of nonpregnant women. When establishing the reference range at 7 to 12 weeks of gestation, pregnant women before the seventh gestational week should be excluded from this analysis. Otherwise, the reference range would increase. Although many firsttrimester TSH reference ranges were reported worldwide, the majority of these reference ranges were derived from a gestational age of 7 to 12 weeks. We report here, for the first time, that the TSH reference intervals in the first trimester should be divided into two, 4 to 6 weeks and 7 to 12 weeks. However, it should reinforce the point that, using the nonpregnant reference range at the beginning of pregnancy, especially at 7 to 12 weeks gestation, may delay the initiation of levothyroxine treatment, so that a certain number of patients may run the risk of being left untreated. If using the diagnosis of SCH in women of 4 to 6 gestational weeks with TSH reference range at 7 to 12 weeks of gestation, the rate of misdiagnosis was 5.5%. Therefore, it is necessary to choose the reference range of TSH corresponding to the gestational week in the first trimester. Reference intervals of TSH in the present study were 0.14 to 4.87 miu/l during the first trimester, being 0.10 to 4.34 miu/l during 7 to 12 weeks of gestation. These values are significantly higher than those reported in Europe and the United States ( miu/l) (7 15). The 4 6 wk 7 12 wk 4 12 wk Roche criteria (36.6) 70 (3.8) 170 (9.3) 104 (5.7) 185 (10.2) (22.4) 63 (2.1) 119 (4.0) 86 (2.9) 137 (4.6) (27.8) 133 (2.8) 289 (6.0) 190 (4.0) 322 (6.7) a First trimester criteria were as follows: for ATA, TSH 2.5 miu/l; 4 to 6 gestational weeks, 0.56 to 5.31 miu/l; 7 to 12 gestational weeks, 0.10 to 4.34 miu/l; 4 to 12 gestational weeks, 0.14 to 4.87 miu/l; Roche, TSH 0.27 to 4.2 miu/l. values reported here are actually nearer to the values reported in India ( miu/l) (19) and Spain ( ) (20) but lower than that of the United Arab Emirates ( miu/l) (21). If we followed the ATA criteria for SCH (TSH 2.5 miu/l), the prevalence of SCH in our study would be 36.6% in women at a gestation of 4 to 6 weeks, 22.4% in those at a gestation of 7 to 12 weeks, and 27.8% in those at a gestation of 4 to 12 weeks, which are similar to results from a large national sample of pregnant women screened in the United States (22). The results indicate that, using the trimester reference range recommended by the ATA, African American pregnant women have the lowest rate of gestational hypothyroidism (19.2%), whereas Asian women have the highest rate (27.7%).The prevalence would be much higher than that reported previously, which was 3% to 5% in the general population (23) and 5.3% in pregnant women at 8 weeks of gestation (24). If we used 2.5 miu/l as the upper limit of TSH in the first trimester in Chinese women, 27.8% of women required treatment with levothyroxine due to SCH, whereas the actual prevalence rate was only 4%. According to the ATA criteria for SCH in the second and third trimester (TSH 3.0 miu/l), of the 118 pregnant women who had serum TSH 2.5 miu/l in the first trimester, we found that only 30.0% of them had TSH 3.0 miu/l at the 20th gestational week and 20.3% of them had TSH 3.0 miu/l at the 30th gestational week. These data indicated that the concordance rates of SCH in the second trimester and third trimester were less than 30%. Why was the upper limit of the TSH reference range significantly higher than 2.5 miu/l in Chinese pregnant women? We probably can find the answer from a sectional study of 10 cities in China conducted by our group recently (25 27). In these studies, we discovered that the serum TSH levels in the Chinese population were notably higher than those previously reported, and the same was true in pregnant women. Recently, numerous studies have been conducted investigating the TSH reference range of pregnant women in the first trimester in China. These studies all reported an upper TSH limit of more than 3.6 miu/l (3 6). These findings, however, may be related

6 78 Li et al Thyroid Function During First-Trimester Pregnancy J Clin Endocrinol Metab, January 2014, 99(1):73 79 to long-term iodine fortification and aggravated thyroid autoimmunity. It has been found that SCH is associated with adverse pregnancy outcomes and neurocognitive deficits in the developing fetus due to the lack of thyroid hormone availability. The present study demonstrated that when serum FT 4 began to decline significantly, TSH levels were close to 4.8 miu/l. FT 4 was constant when TSH levels fell between 2.5 and 4.8 miu/l. Lazarus and colleagues (28) reported the results of a randomized trial of thyroid-function screening study involving pregnant women in the United Kingdom and Italy. Antenatal screening at gestational weeks 11 to 14 and maternal treatment for hypothyroidism did not result in improved cognitive function in children at 3 years of age. One possible explanation for the lack of benefits from levothyroxine therapy is that the women in the study had milder hypothyroidism than the control group (29, 30). In this study, the upper limit of TSH was 3.8 miu/l in the United Kingdom and 3.1 miu/l in Italy. Those values were higher than 2.5 miu/l but lower than our reference upper limit. Our group analyzed the relationship between the levels of TSH in pregnant women and their children s intelligence. The results indicated the children of pregnant women with TSH 3.93 miu/l had lower mental development index (MDI) and psychomotor developmental index (PDI). However, those of women with TSH 2.5 miu/l to 3.93 miu/l had similar MDI and PDI to those of controls. These results suggested that the elevation of TSH in pregnant women was associated with damage to their children s intelligence. The cutoff value of TSH in pregnant women should be the upper limit of the gestation-specific reference interval rather than 2.5 miu/l (31). Casey et al (32) reported pregnancies in women with SCH were 3 and times more likely to be complicated by placental abruption and preterm birth, respectively. Benhadi and colleagues (33) found the risk of child loss increased with higher levels of maternal TSH. However, there are no data indicating that TSH levels between 2.5 and 5.0 miu/l could increase risk of placental abruption or preterm birth. The results indicating that TSH levels between 2.5 and 5.0 miu/l could increase the risk of miscarriage when thyroid antibodies were not present are inconsistent (34, 35). In 478 followed-up women of the present study, TSH levels at 2.5 to 4.87 miu/l before 12 weeks of gestation did not elevate the risk of miscarriage significantly (for TSH of miu/l, miscarriage occurred in 7 of 103 [6.8%]; for TSH of miu/l, miscarriage occurred in 23 of 358 [6.4%]; P.463). Although in these studies, gestationspecific reference intervals of TSH were used constantly rather than 2.5 miu/l. However, we need to be aware that in addition to maternal thyroid function contributing to these deficits, other factors such as the age of the mother, lack of perinatal care, and diet should be considered. In conclusion, we found that the upper limit of serum TSH reference in the first trimester was much higher than 2.5 miu/l in Chinese pregnant women. This observation led us to demonstrate, for the first time, that 2 reference ranges should be established in the first trimester for assessment of thyroid function: 4 to 6 weeks and 7 to 12 weeks of gestation. For early pregnant women, the reference range should be chosen corresponding to the gestational week. The reference range for nonpregnant women can be used for assessment of pregnant women during the 4 to 6 gestational weeks. Acknowledgments We gratefully acknowledge the invaluable contribution of doctors from the Gynecology and Obstetrics clinics in the 13 hospitals and 6 prenatal clinics in Liaoning Province and are indebted to the residents who participated in this study. Address all correspondence and requests for reprints to: Weiping Teng, MD, or Zhongyan Shan, MD, PhD, The Endocrine Institute and The Liaoning Provincial Key Laboratory of Endocrine Diseases, Department of Endocrinology and Metabolism, The First Hospital of China Medical University, Shenyang, Liaoning, , PR China. twp@vip.163.com or shanzhongyan@medmail.com.cn. This study was supported by the 973 Science and Technology Research Foundation, Ministry of Science and Technology in China (Grant 2011CB512112); the Chinese National Natural Science Foundation (Grant ); Health and Medicine Research Foundation, Ministry of Health in China (Grant ); and Research Foundation, Department of Science and Technology, Liaoning Province government, China (Grant ). Disclosure Summary: The authors have no potential conflict of interest to declare. References 1. Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid. 2011;21: Panesar NS, Li CY, Rogers MS. Reference intervals for thyroid hormones in pregnant Chinese women. Ann Clin Biochem. 2001;38: Li J, Teng WP, Shan ZY, et al. GestationaI month-specific reference ranges for TSH and thyroxine in Han nationality women in iodine sufficient area of China. 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