孕五周hcg1316ml正常吗(孕五周hcg13000)

翻译：何丽珊 厦门理工学院

审校：郑剑兰 厦门大学附属成功医院（陆军第73集团军医院）

接上文：

应用什么药物治疗临床甲减，妊娠期如何管理和调整？

临床甲减孕妇应接受适量的甲状腺激素替代治疗，以尽量减少不良结局的风险。对于妊娠期临床甲减的治疗，美国甲状腺协会和美国临床内分泌学家协会推荐T4替代疗法，左旋甲状腺素，剂量从1-2μg/kg/d开始或约100μg/d[3,30]。行甲状腺切除术或放射性碘治疗后无甲状腺功能的孕妇可能需要更高的剂量。妊娠期应避免使用含T3的甲状腺激素制剂（例如干甲状腺片或合成T3），因为与T4相比，这些制剂中高浓度的T3会导致母亲T3的超生理水平和T4的低水平。母亲T4对胎儿中枢神经系统发育至关重要[3]。

与甲亢孕妇不同，甲减孕妇的治疗是通过检测TSH水平来评估的而不是FT4。应检测接受甲减治疗孕妇的TSH水平，并相应调整左旋甲状腺素的剂量，使TSH目标在参考值下限和2.5mU/L之间。调整药物时，通常每4-6周评估一次TSH[3,46]。

妊娠后母亲对T4的需求量增加, 约1/3的女性需补充甲状腺激素[51,52]。这种需求的增加与雌激素分泌的增加有关[53]。对于产前检查前就接受甲减治疗的女性，可以考虑在妊娠确认时用比原来增加25%的T4替代治疗。

妊娠期甲状腺自身抗体的筛查或检测是否有作用？

已提出检测临床和亚临床甲状腺功能障碍的抗甲状腺抗体。高达20%的育龄女性发现甲状腺过氧化物酶抗体（TPOAb）和甲状腺球蛋白抗体（TgAb）[54]。TPOA阳性的女性患甲状腺疾病和产后甲状腺炎的风险增加[55]。然而，大多数这些抗体阳性的人的甲状腺功能正常。

不建议对甲状腺功能正常（如无甲状腺疾病史和甲状腺功能检测结果正常）的女性常规检测TPOAb，因为单独使用甲状腺激素治疗TPOAb并不能改善妊娠结局。一项包括47045名孕妇的患者数据系统分析中，纠正亚临床甲减后，TPOAb水平仍与早产显著相关[43]。然而，在随后的两项试验中，与未治疗或使用安慰剂相比，左旋甲状腺素治疗并未降低TPOAb阳性的甲状腺功能正常女性的早产率或改善其他结局[56,57]。同样，2017年母胎医学网的甲状腺素治疗妊娠期亚临床甲减或甲状腺素血症的随机试验中，TPOAb水平与治疗组之间没有相互影响，用左旋甲状腺素治疗的女性中，其后代的神经认知发育或妊娠结局没有差异[41]。

在弥漫性毒性甲状腺肿Graves病的女性中检测甲状腺抗体，包括甲状腺受体抗体（TRAb）和甲状腺刺激性免疫球蛋白（TGI），可以确定那些为甲亢风险高的胎儿或新生儿[3]。这些抗体的检测可能会导致胎儿检测增加，并通过超声或产前胎儿检测连续评估生长。一些临床医生可能会根据抗体状态来指导甲亢女性的胎儿评估频率，而另一些临床医生则会选择不管抗体状态的连续评估。因此，检测可能不会影响管理，也没有这些抗体需常规评估的强有力证据。如果是妊娠期甲亢，咨询母胎医学专科医生可能有助于制定检测和管理计划。

妊娠剧吐时甲状腺功能会发生什么变化，是否应常规进行甲状腺功能检查？

3-11%的妊娠早期女性可观察到甲亢的短暂生化特征[58,59]。许多妊娠剧吐女性血清T4水平异常高，TSH水平低。在2014年对妊娠剧吐标志物的系统评价中，已发表的34项甲状腺功能分析研究中，三分之二的结果显示，与无剧吐症状的女性相比，有症状女性的TSH水平降低或FT4水平升高[60]。这些甲状腺功能异常是由高浓度人绒毛膜促性腺激素（hCG）刺激TSH受体所致。

这种生理性甲亢，也称为妊娠短暂性甲亢，可能与多胎妊娠或葡萄胎有关。妊娠短暂性甲亢的女性很少有症状，用硫代酰胺类药物治疗没有被证明是有益的[30]，因此不建议使用。此外，妊娠短暂性甲亢与妊娠不良结局无关[59]。妊娠剧吐和甲状腺功能检查结果异常女性的期待疗法通常会导致妊娠早期后血清FT4水平降低，且hCG水平降低。然而，在FT4恢复正常水平后，TSH水平可能会持续抑制数周[37]。因此，除非有临床甲亢的其他征象，否则不建议对妊娠剧吐患者进行甲状腺功能检测。

如何诊断和治疗妊娠期甲状腺危象和甲状腺毒性心力衰竭？

甲状腺危象和甲状腺毒性心力衰竭是罕见、急性和危及生命的妊娠期疾病。妊娠期甲状腺危象会带来母亲心力衰竭的高风险[61]。甲状腺危象是由过量甲状腺激素引起的高代谢状态。临床诊断为严重甲状腺毒症伴有全身失代偿[4]。临床评分系统，例如Burch-Wartofsky点量表，可用于确诊并评估疾病的严重程度。甲状腺危象在临床上通常表现为以下体征和症群：发热，心动过速，心律失常和中枢神经系统功能障碍[4]。

T4过量的心肌效应导致心肌病诱发心力衰竭和肺动脉高压在妊娠期比甲状腺危象更常见，并已在9%甲亢失控的孕妇中发现[61]。失代偿通常由子痫前期，贫血，败血症或这些病症综合引起。T4诱发的心肌病和肺动脉高压通常是可逆的[61-63]。

如果怀疑甲状腺危象或甲状腺毒性心力衰竭，应检测血清T4，TT3和TSH水平以确诊，但在结果出来之前不应停止治疗。妊娠期甲状腺危象和甲状腺毒性心力衰竭的治疗相似，应在重症监护区管理，即包含在待产和分娩室内的特殊护理部门（方框1）。

在治疗甲状腺危象的同时，还应治疗可知的根本病因（如感染，创伤）。同样重要的是要注意，甲状腺危象急性发作中即使胎儿状况不好，但随着母亲状况的稳定，这种状况可能会改善。一般来说，避免在甲状腺危象时分娩是明智的。

如何评估胎儿的甲状腺功能？

无论母亲目前的甲状腺状况如何，母亲甲亢病史可导致胎儿甲状腺毒症。因此，在母亲甲亢并发胎儿水肿，生长受限，胎儿甲状腺肿或持续性胎儿心动过速时，应考虑诊断胎儿甲状腺毒症[64]。如果怀疑胎儿患甲状腺毒症，建议咨询母胎医学专科医生[64]。不建议通过超声或脐带血采样常规评估胎儿甲状腺功能[65,66]。脐带血采样仅应极少数情况下使用，即基于超声和产前检查的无创胎儿评估无法合理排除胎儿甲状腺疾病的诊断时[3,47]。

如何评估妊娠期甲状腺结节或甲状腺癌？

甲状腺结节见于1-2%的育龄女性，患病率随年龄增长而增加[37]。妊娠期甲状腺结节的处理取决于风险分层，其中包括胎龄和肿块大小等因素。因此，甲状腺结节的孕妇应具有完整的病史和体格检查，血清TSH检测和颈部超声检查。超声检查能可靠地发现大于0.5厘米的结节。约90-95%的孤立性甲状腺结节是良性的[67,68]。恶性肿瘤的超声特征包括低回声，边缘不规则和微钙化[69]。当这三个特征都存在时，恶性肿瘤的风险超过70%[3]。如果超声怀疑是恶性肿瘤，可用细针穿刺进行组织学检查，包括肿瘤标志物和免疫染色以评估恶性程度[67,70]。不建议在妊娠期进行放射性碘扫描，因为具有与胎儿照射有关的理论风险。但如果在妊娠12周前无意中服用了放射性碘，美国甲状腺协会指出，胎儿甲状腺直到妊娠约12周才变得功能活跃，似乎不存在损害的风险[3]。

妊娠期甲状腺癌的评估涉及综合学科研究方法。大多数甲状腺癌分化良好，并且病程缓慢。甲状腺癌是遗传性家族性癌症综合征一部分的可能性不大，但应予以考虑。当在妊娠早期或中期诊断出甲状腺恶性肿瘤时，可以在妊娠晚期前进行甲状腺切除术，但由于担心甲状旁腺的误切，常常会选择将手术至延迟分娩后。对于没有侵袭性甲状腺癌证据的女性或妊娠晚期诊断为甲状腺癌的女性，手术治疗可推迟到产后立即进行[3,69]。

如何诊断和治疗产后甲状腺炎？

产后甲状腺炎定义为分娩后12个月内的甲状腺功能障碍，其中包括甲亢，甲减或两者同时的临床证据。约5-10%的女性在分娩后的第一年发现短暂性自身免疫性甲状腺炎[55,71]。产后甲状腺炎倾向在妊娠前可意料，且与甲状腺自身抗体血清水平升高直接相关[55]。在临床实践中，产后甲状腺炎很少被诊断出来，因为它通常在分娩后数月出现模糊且非特异性症状[72]。

产后甲状腺炎的临床表现各异。传统上，两个公认的临床阶段可能会连续发展。新出现的TSH和FT4异常水平证实了任一阶段的诊断。典型的，第一阶段的特征是破坏性甲状腺毒症，症状是由腺体破坏甲状腺激素过度释放引起的。起病突然，通常发现一个小的无痛性甲状腺肿。产后甲状腺炎可能引起甲亢症状，包括疲劳，烦躁，体重减轻，心悸或不耐热[73]。这种甲状腺毒性阶段通常仅持续几个月，受影响的女性常只有轻微症状。用硫代酰胺类药物治疗常是无效的，但如果症状太重，β受体阻断剂可能会有所帮助。通常的第二阶段是产后4至8个月出现临床甲减，常见甲状腺肿大，以及疲劳，便秘或抑郁症的甲减症状[73]。产后抑郁症的情况与任何新的抑郁症诊断一样，筛查TSH以排除甲状腺功能障碍的诊断是合理的[74]。

大多数产后甲状腺炎女性的病情会自行缓解。然而，约三分之一的产后甲状腺炎患者最终会发展为永久性，每年临床甲减的发病率为3.6%[71,73,75-77]。这些病例应与合适的专家合作管理，美国甲状腺协会建议定期甲状腺检测以评估临床甲减[3]。有甲状腺自身抗体的，特别是抗体滴度较高的女性，产后甲状腺炎的风险和发生永久性甲减的风险增加。

建议摘要

以下建议基于良好一致的科学证据（A级）：

不建议对妊娠期甲状腺疾病进行普遍筛查，因为尚未证明对母亲亚临床甲减的鉴别和治疗可改善妊娠结局和后代的神经认知功能。

如果有必要，评估甲状腺状态的一线筛查应是检测TSH水平。

应检测接受甲减治疗孕妇的TSH水平，并相应调整左旋甲状腺素的剂量，使目标TSH水平介于参考值下限至2.5mU/L之间。调整药物治疗时，通常每4-6周评估一次促甲状腺激素。

患临床甲减的孕妇应接受适量的甲状腺激素替代治疗，以将不良结局的风险降至最低。

应检测正在接受甲亢治疗孕妇的FT4水平，并相应调整抗甲状腺药物（硫代酰胺）的剂量，使FT4达到正常妊娠参考值上限。在同时也有T3甲状腺毒症的女性中，应检测TT3，目标水平在正常妊娠参考值上限。

临床甲亢孕妇应使用抗甲状腺药物（硫代酰胺）治疗。

以下建议基于有限或不一致的科学证据（B级）：

PTU或MMI ，均为硫代酰胺，可用于治疗临床甲亢孕妇。药物的选择取决于妊娠阶段，对以前治疗的反应，以及甲状腺毒症主要是T4或T3。

以下建议主要基于共识和专家意见（C级）：

有甲状腺疾病、I型糖尿病、临床怀疑甲状腺疾病或家族史的女性应进行甲状腺功能检测。

除非有临床甲亢症状，否则不建议对妊娠剧吐患者进行甲状腺功能检测。

专家简介

郑剑兰，主任医师，教授，研究生导师

厦门大学附属成功医院、陆军第73集团军医院暨全军计划生育优生优育技术指导中心妇儿科主任，全军妇产科专业委员及产科学组秘书长，南京军区妇产科副主任委员，英国帝国理工大学母婴研究中心签约学者，全球健康中心及美国辛辛那提大学交流学者，中华医学会围产医学分会委员，中国医师协会母胎医学分会委员，中国对外交流促进会妇产科分会委员，中国妇幼保健协会高危妊娠常务委员，中国研究型医院学会孕产期母儿心脏病专业委员会常务委员，福建省围产医学分会委员、优生优育及妇幼保健协会盆底委员会常务委员、骨质疏松及骨矿盐学会委员，厦门市围产医学分会候任主任委员、妇产科副主任委员、产科质控中心副主任，SCI期刊《ANZJOG》 及《JOGR》审稿专家。

妇产科临床工作30多年，擅长妇科腔镜及产科危急重症抢救，近年来主要从事围产医学研究。主编专著2部；发表SCI及国内核心期刊论著20余篇；主持国家自然科学基金面上项目，省市及军队科研项目10项；引进Bakri产后止血球囊和CRB促宫颈成熟及引产球囊；发明Zheng子宫压迫缝合术，第一完成人获国家专利3项，并获军队和福建省、厦门市医疗成果及科技进步奖9项，享受军队一类科技人才岗位津贴，是军队334工程拔尖人才和厦门大学科技创新人才，多次荣立军队二等功及三等功。

参考文献：

1. Vannucchi G, Covelli D, Vigo B, Perrino M, Mondina L, Fugazzola L. Thyroid volume and serum calcitonin changes during pregnancy. J Endocrinol Invest 2017;40: 727–32. (Level II-3)

2. Huang SA. Physiology and pathophysiology of type 3 deiodinase in humans. Thyroid 2005;15:875–81. (Level III)

3. Alexander EK, Pearce EN, Brent GA, Brown RS, Chen H, Dosiou C, et al. 2017 guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum [published erratum appears in Thyroid 2017;27:1212]. Thyroid 2017;27:315–89. (Level III)

4. Ross DS, Burch HB, Cooper DS, Greenlee MC, Laurberg P, Maia AL, et al. 2016 American Thyroid Association guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis [published erratum appears in Thyroid 2017;27:1462]. Thyroid 2016;26:1343– 421. (Level III)

5. Bernal J. Thyroid hormone receptors in brain development and function. Nat Clin Pract Endocrinol Metab 2007;3: 249–59. (Level III)

6. Calvo RM, Jauniaux E, Gulbis B, Asunción M, Gervy C, Contempré B, et al. Fetal tissues are exposed to biologically relevant free thyroxine concentrations during early phases of development. J Clin Endocrinol Metab 2002; 87:1768–77. (Level III)

7. Korevaar TI, Muetzel R, Medici M, Chaker L, Jaddoe VW, de Rijke YB, et al. Association of maternal thyroid function during early pregnancy with offspring IQ and brain morphology in childhood: a population-based prospective cohort study. Lancet Diabetes Endocrinol 2016;4:35–43. (Level II-2)

8. Thorpe-Beeston J, Nicolaides KH, Snijders RJ, Felton CV, McGregor AM. Thyroid function in small for gestational age fetuses. Obstet Gynecol 1991;77:701–6. (Level II-3)

9. Ecker JL, Musci TJ. Thyroid function and disease in pregnancy. Curr Probl Obstet Gynecol Fertil 2000;23:109–22. (Level III)

10. Dong AC, Stagnaro-Green A. Differences in diagnostic criteria mask the true prevalence of thyroid disease in pregnancy: a systematic review and meta-analysis. Thyroid 2019;29:278–89. (Systematic Review and Meta-Analysis)

11. Davis LE, Lucas MJ, Hankins GD, Roark ML, Cunningham FG. Thyrotoxicosis complicating pregnancy. Obstet Gynecol 1989;160:63–70. (Level III)

12. Millar LK, Wing DA, Leung AS, Koonings PP, Montoro MN, Mestman JH. Low birth weight and preeclampsia in pregnancies complicated by hyperthyroidism. Obstet Gynecol 1994;84:946–9. (Level II-2)

13. Krassas GE, Poppe K, Glinoer D. Thyroid function and human reproductive health. Endocr Rev 2010;31:702–55. (Level III)

14. Pearce EN. Management of thyrotoxicosis: preconception, pregnancy, and the postpartum period. Endocr Pract 2019; 25:62–8. (Level III)

15. Uenaka M, Tanimura K, Tairaku S, Morioka I, Ebina Y, Yamada H. Risk factors for neonatal thyroid dysfunction in pregnancies complicated by Graves’ disease. Eur J Obstet Gynecol Reprod Biol 2014;177:89–93. (Level III)

16. Aggarawal N, Suri V, Singla R, Chopra S, Sikka P, Shah VN, et al. Pregnancy outcome in hyperthyroidism: a case control study. Gynecol Obstet Invest 2014;77:94–9. (Level II-2)

17. Sheehan PM, Nankervis A, Araujo Júnior E, Da SC. Maternal thyroid disease and preterm birth: systematic review and meta-analysis. J Clin Endocrinol Metab 2015;100: 4325–31. (Systematic Review and Meta-Analysis)

18. Matsuura N, Harada S, Ohyama Y, Shibayama K, Fukushi M, Ishikawa N, et al. The mechanisms of transient hypothyroxinemia in infants born to mothers with Graves’ disease. Pediatr Res 1997;42:214–8. (Level III)

19. McKenzie JM, Zakarija M. Fetal and neonatal hyperthyroidism and hypothyroidism due to maternal TSH receptor antibodies. Thyroid 1992;2:155–9. (Level III)

20. Weetman AP. Graves’ disease. N Engl J Med 2000;343: 1236–48. (Level III)

21. van der Kaay DC, Wasserman JD, Palmert MR. Management of neonates born to mothers with Graves’ disease. Pediatrics 2016;137:e20151878. (Level III)

22. Casey BM, Dashe JS, Wells CE, McIntire DD, Leveno KJ, Cunningham FG. Subclinical hyperthyroidism and pregnancy outcomes. Obstet Gynecol 2006;107:337–41. (Level II-2)

23. Diéguez M, Herrero A, Avello N, Suárez P, Delgado E, Menéndez E. Prevalence of thyroid dysfunction in women in early pregnancy: does it increase with maternal age? Clin Endocrinol (Oxf) 2016;84:121–6. (Level II-3)

24. Surks MI, Ortiz E, Daniels GH, Sawin CT, Col NF, Cobin RH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004; 291:228–38. (Level III)

25. Tudela CM, Casey BM, McIntire DD, Cunningham FG. Relationship of subclinical thyroid disease to the incidence of gestational diabetes. Obstet Gynecol 2012;119:983–8. (Level II-3)

26. Wilson KL, Casey BM, McIntire DD, Halvorson LM, Cunningham FG. Subclinical thyroid disease and the incidence of hypertension in pregnancy. Obstet Gynecol 2012;119: 315–20. (Level II-3)

27. Institute of Medicine. Dietary reference intakes: the essential guide to nutrient requirements. Washington, DC: National Academies Press; 2006. Available at: https:// www.nap.edu/catalog/11537/dietary-reference-intakes-theessential-guide-to-nutrient-requirements. Retrieved January 10, 2020. (Level III)

28. Harding KB, Peña‐Rosas JP, Webster AC, Yap CM, Payne BA, Ota E, et al. Iodine supplementation for women during the preconception, pregnancy and postpartum period. Cochrane Database of Systematic Reviews 2017, Issue 3. Art. No.: CD011761. DOI: 10.1002/14651858.CD011761. pub2. (Systematic Review and Meta-Analysis)

29. Pearce EN, Lazarus JH, Moreno-Reyes R, Zimmermann MB. Consequences of iodine deficiency and excess in pregnant women: an overview of current knowns and unknowns. Am J Clin Nutr 2016;104(suppl 3):918S–23S. (Level III)

30. Casey BM, Leveno KJ. Thyroid disease in pregnancy. Obstet Gynecol 2006;108:1283–92. (Level III)

31. Yazbeck CF, Sullivan SD. Thyroid disorders during pregnancy. Med Clin North Am 2012;96:235–56. (Level III)

32. Abalovich M, Gutierrez S, Alcaraz G, Maccallini G, Garcia A, Levalle O. Overt and subclinical hypothyroidism complicating pregnancy. Thyroid 2002;12:63–8. (Level III)

33. Bryant SN, Nelson DB, McIntire DD, Casey BM, Cunningham FG. An analysis of population-based prenatal screening for overt hypothyroidism. Obstet Gynecol 2015;213:565.e1–6. (Level II-2)

34. Brown RS, Bellisario RL, Botero D, Fournier L, Abrams CA, Cowger ML, et al. Incidence of transient congenital hypothyroidism due to maternal thyrotropin receptorblocking antibodies in over one million babies. J Clin Endocrinol Metab 1996;81:1147–51. (Level II-3)

35. Casey BM, Dashe JS, Wells CE, McIntire DD, Byrd W, Leveno KJ, et al. Subclinical hypothyroidism and pregnancy outcomes. Obstet Gynecol 2005;105:239–45. (Level II-2)

36. Cleary-Goldman J, Malone FD, Lambert-Messerlian G, Sullivan L, Canick J, Porter TF, et al. Maternal thyroid hypofunction and pregnancy outcome. Obstet Gynecol 2008;112:85–92. (Level II-3)

37. Fitzpatrick DL, Russell MA. Diagnosis and management of thyroid disease in pregnancy. Obstet Gynecol Clin North Am 2010;37:173–93. (Level III)

38. Haddow JE, Palomaki GE, Allan WC, Williams JR, Knight GJ, Gagnon J, et al. Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. N Engl J Med 1999;341:549–55. (Level II-2)

39. Pop VJ, Kuijpens JL, van Baar AL, Verkerk G, van Son MM, de Vijlder JJ, et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 1999;50:149–55. (Level II-3)

40. Lazarus JH, Bestwick JP, Channon S, Paradice R, Maina A, Rees R, et al. Antenatal thyroid screening and childhood cognitive function [published erratum appears in N Engl J Med 2012;366:1650]. N Engl J Med 2012;366:493–501. (Level I)

41. Casey BM, Thom EA, Peaceman AM, Varner MW, Sorokin Y, Hirtz DG, et al. Treatment of subclinical hypothyroidism or hypothyroxinemia in pregnancy. Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal–Fetal Medicine Units Network. N Engl J Med 2017;376:815–25. (Level I)

42. Hales C, Taylor PN, Channon S, Paradice R, McEwan K, Zhang L, et al. Controlled antenatal thyroid screening II: effect of treating maternal suboptimal thyroid function on child cognition. J Clin Endocrinol Metab 2018;103:1583– 91. (Level II-2)

43. Korevaar TI, Derakhshan A, Taylor PN, Meima M, Chen L, Bliddal S, et al. Association of thyroid function test abnormalities and thyroid autoimmunity with preterm birth: a systematic review and meta-analysis. Consortium on Thyroid and Pregnancy—Study Group on Preterm Birth [published erratum appears in JAMA 2019;322:1718]. JAMA 2019;322:632–41. (Systematic Review and MetaAnalysis)

44. Casey BM, Dashe JS, Spong CY, McIntire DD, Leveno KJ, Cunningham GF. Perinatal significance of isolated maternal hypothyroxinemia identified in the first half of pregnancy. Obstet Gynecol 2007;109:1129–35. (Level II3)

45. Cappola AR, Casey BM. Thyroid function test abnormalities during pregnancy. JAMA 2019;322:617–9. (Level III)

46. Fister P, Gaberscek S, Zaletel K, Krhin B, Gersak K, Hojker S. Thyroid volume changes during pregnancy and after delivery in an iodine-sufficient Republic of Slovenia. Eur J Obstet Gynecol Reprod Biol 2009;145:45–8. (Level III)

47. De Groot L, Abalovich M, Alexander EK, Amino N, Barbour L, Cobin RH, et al. Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2012;97:2543–65. (Level III)

48. Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. American Association of Clinical Endocrinologists and American Thyroid Association Taskforce on Hypothyroidism in Adults [published errata appear in Thyroid 2013;23:251; Thyroid 2013;23:129]. Thyroid 2012;22:1200–35. (Level III)

49. Yoshihara A, Noh J, Yamaguchi T, Ohye H, Sato S, Sekiya K, et al. Treatment of Graves’ disease with antithyroid drugs in the first trimester of pregnancy and the prevalence of congenital malformation. J Clin Endocrinol Metab 2012; 97:2396–403. (Level II-3)

50. Brent GA. Clinical practice. Graves’ disease. N Engl J Med 2008;358:2594–605. (Level III)

51. Abalovich M, Alcaraz G, Kleiman-Rubinsztein J, Pavlove MM, Cornelio C, Levalle O, et al. The relationship of preconception thyrotropin levels to requirements for increasing the levothyroxine dose during pregnancy in women with primary hypothyroidism. Thyroid 2010;20:1175–8. (Level III)

52. Alexander EK, Marqusee E, Lawrence J, Jarolim P, Fischer GA, Larsen PR. Timing and magnitude of increases in levothyroxine requirements during pregnancy in women with hypothyroidism. N Engl J Med 2004;351:241–9. (Level III)

53. Arafah BM. Increased need for thyroxine in women with hypothyroidism during estrogen therapy. N Engl J Med 2001;344:1743–9. (Level II-3)

54. Thangaratinam S, Tan A, Knox E, Kilby MD, Franklyn J, Coomarasamy A. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ 2011;342:d2616. (Systematic Review and Meta-Analysis)

55. Stagnaro-Green A, Pearce E. Thyroid disorders in pregnancy. Nat Rev Endocrinol 2012;8:650–8. (Level III)

56. Wang H, Gao H, Chi H, Zeng L, Xiao W, Wang Y, et al. Effect of levothyroxine on miscarriage among women with normal thyroid function and thyroid autoimmunity undergoing in vitro fertilization and embryo transfer: a randomized clinical trial. JAMA 2017;318:2190–8. (Level I)

57. Dhillon-Smith R, Middleton LJ, Sunner KK, Cheed V, Baker K, Farrell-Carver S, et al. Levothyroxine in women with thyroid peroxidase antibodies before conception. N Engl J Med 2019;380:1316–25. (Level I) 58. Yeo CP, Khoo DH, Eng PH, Tan HK, Yo SL, Jacob E. Prevalence of gestational thyrotoxicosis in Asian women evaluated in the 8th to 14th weeks of pregnancy: correlations with total and free beta human chorionic gonadotrophin. Clin Endocrinol (Oxf) 2001;55:391–8. (Level II-3)

59. Kinomoto-Kondo S, Umehara N, Sato S, Ogawa K, Fujiwara T, Arata N, et al. The effects of gestational transient thyrotoxicosis on the perinatal outcomes: a case–control study. Arch Gynecol Obstet 2017;295:87–93. (Level II-2)

60. Niemeijer MN, Grooten IJ, Vos N, Bais JM, van der Post JA, Mol BW, et al. Diagnostic markers for hyperemesis gravidarum: a systematic review and metaanalysis. Obstet Gynecol 2014;211:150.e1–15. (Systematic Review and Meta-Analysis)

61. Sheffield JS, Cunningham FG. Thyrotoxicosis and heart failure that complicate pregnancy. Obstet Gynecol 2004; 190:211–7. (Level III)

62. Siu C, Zhang X, Yung C, Kung AW, Lau C, Tse H. Hemodynamic changes in hyperthyroidism-related pulmonary hypertension: a prospective echocardiographic study. J Clin Endocrinol Metab 2007;92:1736–42. (Level II-3)

63. Vydt T, Verhelst J, De Keulenaer G. Cardiomyopathy and thyrotoxicosis: tachycardiomyopathy or thyrotoxic cardiomyopathy? Acta Cardiol 2006;61:115–7. (Level III)

64. Brand F, Liégeois P, Langer B. One case of fetal and neonatal variable thyroid dysfunction in the context of Graves’ disease. Fetal Diagn Ther 2005;20:12–5. (Level III)

65. Cohen O, Pinhas-Hamiel O, Sivan E, Dolitski M, Lipitz S, Achiron R. Serial in utero ultrasonographic measurements of the fetal thyroid: a new complementary tool in the management of maternal hyperthyroidism in pregnancy. Prenat Diagn 2003;23:740–2. (Level III)

66. Luton D, Le Gac I, Vuillard E, Castanet M, Guibourdenche J, Noel M, et al. Management of Graves’ disease during pregnancy: the key role of fetal thyroid gland monitoring. J Clin Endocrinol Metab 2005;90:6093–8. (Level III)

67. Hegedüs L. Clinical practice. The thyroid nodule. N Engl J Med 2004;351:1764–71. (Level III)

68. Kwong N, Medici M, Angell TE, Liu X, Marqusee E, Cibas ES, et al. The influence of patient age on thyroid nodule formation, multinodularity, and thyroid cancer risk. J Clin Endocrinol Metab 2015;100:4434–40. (Level II-2)

69. Gharib H, Papini E, Garber JR, Duick DS, Harrell RM, Hegedüs L, et al. American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules —2016 update. Endocr Pract 2016;22:622–39. (Level III)

70. Bartolazzi A, Gasbarri A, Papotti M, Bussolati G, Lucante T, Khan A, et al. Application of an immunodiagnostic method for improving preoperative diagnosis of nodular thyroid lesions. Thyroid Cancer Study Group. Lancet 2001;357:1644–50. (Level II-3)

71. Nathan N, Sullivan SD. Thyroid disorders during pregnancy. Endocrinol Metab Clin North Am 2014;43:573– 97. (Level III)

72. Stagnaro-Green A, Glinoer D. Thyroid autoimmunity and the risk of miscarriage. Best Pract Res Clin Endocrinol Metab 2004;18:167–81. (Level III)

73. Muller AF, Drexhage HA, Berghout A. Postpartum thyroiditis and autoimmune thyroiditis in women of childbearing age: recent insights and consequences for antenatal and postnatal care. Endocr Rev 2001;22:605– 30. (Level II-3)

74. Bergink V, Pop VJ, Nielsen PR, Agerbo E, Munk-Olsen T, Liu X. Comorbidity of autoimmune thyroid disorders and psychiatric disorders during the postpartum period: a Danish nationwide register-based cohort study. Psychol Med 2018;48:1291–8. (Level II-2)

75. Cunningham FG, Leveno KJ, Bloom SL, Dashe JS, Hoffman BL, Casey BM, et al, editors. Williams obstetrics. 25th ed. New York, NY: McGraw-Hill Education; 2018. (Level III)

76. Lucas A, Pizarro E, Granada ML, Salinas I, Roca J, Sanmartí A. Postpartum thyroiditis: long-term follow-up. Thyroid 2005;15:1177–81. (Level III)

77. Premawardhana LD, Parkes AB, Ammari F, John R, Darke C, Adams H, et al. Postpartum thyroiditis and long-term thyroid status: prognostic influence of thyroid peroxidase antibodies and ultrasound echogenicity. J Clin Endocrinol Metab 2000;85:71–5. (Level II-3)