 編者按：甲狀腺功能亢進(jìn)癥（簡(jiǎn)稱“甲亢”）好發(fā)于育齡期女性，妊娠期甲亢可導(dǎo)致多種妊娠不良結(jié)局和母嬰并發(fā)癥,。因此,，妊娠期甲亢相關(guān)的診斷和治療一直是大家高度重視的問(wèn)題。正值一年一度的國(guó)際甲狀腺知識(shí)宣傳周,，《國(guó)際糖尿病》特別邀請(qǐng)中國(guó)醫(yī)科大學(xué)附屬第一醫(yī)院,、中國(guó)醫(yī)科大學(xué)內(nèi)分泌研究所、遼寧省內(nèi)分泌疾病重點(diǎn)實(shí)驗(yàn)室李靜教授結(jié)合近幾年相關(guān)研究報(bào)道,，圍繞妊娠期甲亢的診斷,、治療及備孕期管理各方面進(jìn)行精彩的報(bào)告。  妊娠期甲亢的診斷 妊娠期甲亢最常見的病因包括妊娠期一過(guò)性甲狀腺毒癥（GTT）和妊娠期Graves病甲亢,，兩者懷孕期間的患病率分別為3%[1]和0.2%[2],。不同病因所致妊娠期甲亢的病程不同，治療選擇也不同,，因此盡快明確妊娠期甲亢的病因至關(guān)重要[3],。GTT和妊娠期Graves病甲亢的實(shí)驗(yàn)室檢查均表現(xiàn)為血清促甲狀腺激素（TSH）水平下降和甲狀腺激素水平上升。GTT一般發(fā)生在孕早期，由孕母血清hCG水平升高所致,，GTT會(huì)自發(fā)痊愈[4],。而妊娠期Graves病甲亢是由促甲狀腺激素受體抗體（TRAb）升高所致的自身免疫性疾病。由于相較于T3,，Graves患者更傾向于生成T4[5],，因此Graves患者血清總T3/T4往往會(huì)升高，一般大于20:1[6],；與之相反,，GTT患者血清T3水平通常高于T4水平，GTT患者總T3/T4一般小于20:1[6],。TRAb可以分為刺激性（TSAb）,、中性和阻斷性抗體（TBAb）。以TSAb升高為主時(shí)導(dǎo)致甲亢,，可稱為經(jīng)典型Graves?。?/span>極小部分以TBAb升高為主,，可導(dǎo)致甲減和甲功波動(dòng),，可稱為非經(jīng)典型Graves病。兩者雖然均會(huì)導(dǎo)致TRAb升高,，但疾病的轉(zhuǎn)歸不同,，治療方法也截然相反。由于妊娠會(huì)改變?cè)心傅拿庖郀顟B(tài),，可能會(huì)發(fā)生TSAb和TBAb之間的亞型轉(zhuǎn)換[7],。TBAb極易通過(guò)胎盤導(dǎo)致胎兒甲減，因此妊娠期間應(yīng)及時(shí)篩查并發(fā)現(xiàn)高表達(dá)TBAb者,，必要時(shí)給予充足的LT4治療,，應(yīng)注意其胎兒神經(jīng)發(fā)育可能存在不可逆的損害[8]。盡管傳統(tǒng)免疫分析法測(cè)定TRAb具有較高的敏感性和特異性,，然而其并不能區(qū)分抗體類型[9],。通過(guò)生物學(xué)測(cè)定技術(shù)可以來(lái)區(qū)分不同類型的TRAb的含量[10]，但由于其測(cè)量手段復(fù)雜,，價(jià)格昂貴,，不建議將其作為妊娠期Graves病患者的普遍檢查手段。但建議有自身免疫性甲狀腺疾病病史,、有放射性碘（RAI）治療和甲狀腺切除術(shù)治療史[11],、典型Graves病自發(fā)進(jìn)化為甲減的患者[12]、既往或目前的免疫重建治療后繼發(fā)自身免疫性甲狀腺功能障礙以及Graves病甲亢持續(xù)阻斷替代治療超過(guò)18個(gè)月者[7],，應(yīng)在確認(rèn)妊娠時(shí)篩查TRAb的類型,。 妊娠期甲亢的治療 01 妊娠期甲亢的治療 02 妊娠期Graves病甲亢患者治療方法的選擇 03 嚴(yán)格控制妊娠期ATDS的使用劑量 Graves甲亢患者備孕期管理 為避免ATDs和孕期甲亢對(duì)母嬰造成不良影響,，被診斷為Graves病的育齡期女性應(yīng)在甲狀腺功能正常后再妊娠。如果患者不想在孕期使用ATDs,，可以在孕前采取甲狀腺切除術(shù)或RAI消融術(shù)等根治手段,。需要注意的是，RAI消融術(shù)后應(yīng)推遲6個(gè)月妊娠,，以最大限度地減少輻射的潛在不良影響[27],。對(duì)于選擇ATDs治療的婦女，主要有以下幾個(gè)策略：第一種是在懷孕前,，尤其是備孕前三個(gè)月由MMI轉(zhuǎn)換為PTU治療[28],，以避免孕早期暴露于MMI對(duì)母胎造成的不良影響，但這會(huì)增加PTU對(duì)孕母所致的不良影響,；第二種是在發(fā)現(xiàn)妊娠后馬上從MMI轉(zhuǎn)換為PTU[17]，這種方法降低了PTU相關(guān)肝毒性的風(fēng)險(xiǎn),，但由于很多婦女不能在孕早期及時(shí)發(fā)現(xiàn)妊娠,，這會(huì)增加孕早期胎兒暴露于MMI和由PTU轉(zhuǎn)換為MMI所造成的先天性畸形的患病率和嚴(yán)重程度[22]。對(duì)于哪種策略更佳,，仍需進(jìn)一步的研究來(lái)闡明,。最后，少部分患者可在確認(rèn)妊娠后停止ATDs治療,，該策略僅適用于滿足以下條件的女性：ATDs劑量低（MMI低于5~10mg/day,，PTU低于100~200mg/day）,、ATDs治療>6個(gè)月無(wú)、Graves眼病,、TRAb陰性或者弱陽(yáng)性[17],。此類患者妊娠期間需密切監(jiān)測(cè)甲狀腺功能，確定甲亢沒(méi)有在妊娠中期之前復(fù)發(fā),。 結(jié)語(yǔ) 總之,，目前關(guān)于妊娠期甲亢的病因鑒別較為重要。GTT通常不需ATDs治療,，而Graves病甲亢需要根據(jù)甲功異常程度和既往用藥情況,、TRAb水平等決定是否需要繼續(xù)應(yīng)用或啟用ATDs治療。而對(duì)于孕期Graves病的管理尚有較多不明確或有待探討的問(wèn)題,，如孕早期停用ATDs的甲功閾值,、孕中期是否需從PTU轉(zhuǎn)換為MMI、孕期甲亢KI治療的有效性和副作用,、導(dǎo)致孕期TBAb的高表達(dá)的相關(guān)因素等,，目前仍均缺乏相關(guān)新的研究報(bào)道和進(jìn)展，亟待更多的內(nèi)分泌科和產(chǎn)科醫(yī)生投身于此領(lǐng)域的科研和臨床調(diào)查工作,。 參考文獻(xiàn) 1.Caron, P. Management of thyrotoxicosis and pregnancy: Review of the current literature and an update of the care pathway. Ann. Endocrinol. S0003-4266(22)00017–8 (2022) doi:10.1016/j.ando.2022.01.006. 2.Cooper, D. S. & Laurberg, P. Hyperthyroidism in pregnancy. Lancet Diabetes Endocrinol. 1, 238–249 (2013). 3.Boelaert, K. et al. ENDOCRINOLOGY IN THE TIME OF COVID-19: Management of hyperthyroidism and hypothyroidism. Eur. J. Endocrinol. 183, G33–G39 (2020). 4.Léger, J., Delcour, C. & Carel, J.-C. Fetal and Neonatal Thyroid Dysfunction. J. Clin. Endocrinol. Metab. 107, 836–846 (2022). 5.Lee, S. Y. & Pearce, E. N. Testing, Monitoring, and Treatment of Thyroid Dysfunction in Pregnancy. J. Clin. Endocrinol. Metab. 106, 883–892 (2021). 6.Pearce, E. N. MANAGEMENT OF THYROTOXICOSIS: PRECONCEPTION, PREGNANCY, AND THE POSTPARTUM PERIOD. Endocr. Pract. Off. J. Am. Coll. Endocrinol. Am. Assoc. Clin. Endocrinol. 25, 62–68 (2019). 7.Decallonne, B., Martens, P.-J., Van den Bruel, A., Vanhole, C. & Kahaly, G. J. Graves Disease With Thyroid-Stimulating Hormone Receptor-Blocking Autoantibodies During Pregnancy. Ann. Intern. Med. 172, 767–769 (2020). 8.Brown, R. S., Alter, C. A. & Sadeghi-Nejad, A. Severe unsuspected maternal hypothyroidism discovered after the diagnosis of thyrotropin receptor-blocking antibody-induced congenital hypothyroidism in the neonate: failure to recognize and implications to the fetus. Horm. Res. Paediatr. 83, 132–135 (2015). 9.Lee, S. Y. & Pearce, E. N. Assessment and treatment of thyroid disorders in pregnancy and the postpartum period. Nat. Rev. Endocrinol. 18, 158–171 (2022). 10.Kahaly, G. J., Diana, T. & Olivo, P. D. TSH RECEPTOR ANTIBODIES: RELEVANCE & UTILITY. Endocr. Pract. Off. J. Am. Coll. Endocrinol. Am. Assoc. Clin. Endocrinol. 26, 97–106 (2020). 11.Kahaly, G. J. et al. 2018 European Thyroid Association Guideline for the Management of Graves’ Hyperthyroidism. Eur. Thyroid J. 7, 167–186 (2018). 12.Muller, I. et al. 2019 European Thyroid Association Guidelines on the Management of Thyroid Dysfunction following Immune Reconstitution Therapy. Eur. Thyroid J. 8, 173–185 (2019). 13.Kinomoto-Kondo, S. et al. The effects of gestational transient thyrotoxicosis on the perinatal outcomes: a case-control study. Arch. Gynecol. Obstet. 295, 87–93 (2017). 14.Ge, G. M. et al. Maternal Thyroid Dysfunction During Pregnancy and the Risk of Adverse Outcomes in the Offspring: A Systematic Review and Meta-Analysis. J. Clin. Endocrinol. Metab. 105, dgaa555 (2020). 15.Yuan, X., Wang, J., Gao, Y., Wang, H. & Yu, B. Impact of maternal thyroid hormone in late pregnancy on adverse birth outcomes: A retrospective cohort study in China. Endocr. J. 68, 317–328 (2021). 16.Scappaticcio, L. et al. Abnormal Liver Blood Tests in Patients with Hyperthyroidism: Systematic Review and Meta-Analysis. Thyroid Off. J. Am. Thyroid Assoc. 31, 884–894 (2021). 17.Alexander, E. K. et al. 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid Off. J. Am. Thyroid Assoc. 27, 315–389 (2017). 18.Yu, W. et al. SIDE EFFECTS OF PTU AND MMI IN THE TREATMENT OF HYPERTHYROIDISM: A SYSTEMATIC REVIEW AND META-ANALYSIS. Endocr. Pract. Off. J. Am. Coll. Endocrinol. Am. Assoc. Clin. Endocrinol. 26, 207–217 (2020). 19.Tan, S., Chen, L., Jin, L. & Fu, X. The efficiency and safety of methimazole and propylthiouracil in hyperthyroidism: A meta-analysis of randomized controlled trials. Medicine (Baltimore) 100, e26707 (2021). 20.Rivkees, S. A. & Szarfman, A. Dissimilar hepatotoxicity profiles of propylthiouracil and methimazole in children. J. Clin. Endocrinol. Metab. 95, 3260–3267 (2010). 21.Li, H. et al. Congenital anomalies in children exposed to antithyroid drugs in-utero: a meta-analysis of cohort studies. PloS One 10, e0126610 (2015). 22.Agrawal, M. et al. Antithyroid drug therapy in pregnancy and risk of congenital anomalies: Systematic review and meta-analysis. Clin. Endocrinol. (Oxf.) (2021) doi:10.1111/cen.14646. 23.Yoshihara, A. et al. Exposure to Propylthiouracil in the First Trimester of Pregnancy and Birth Defects: A Study at a Single Institution. J. Endocr. Soc. 5, bvaa204 (2021). 24.Yoshihara, A. et al. Characteristics of Patients with Graves’ Disease Whose Thyroid Hormone Levels Increase After Substituting Potassium Iodide for Methimazole in the First Trimester of Pregnancy. Thyroid Off. J. Am. Thyroid Assoc. 30, 451–456 (2020). 25.van Dijk, M. M., Smits, I. H., Fliers, E. & Bisschop, P. H. Maternal Thyrotropin Receptor Antibody Concentration and the Risk of Fetal and Neonatal Thyrotoxicosis: A Systematic Review. Thyroid Off. J. Am. Thyroid Assoc. 28, 257–264 (2018). 26.Momotani, N., Noh, J. Y., Ishikawa, N. & Ito, K. Effects of propylthiouracil and methimazole on fetal thyroid status in mothers with Graves’ hyperthyroidism. J. Clin. Endocrinol. Metab. 82, 3633–3636 (1997). 27.Kitahara, C. M. et al. Association of Radioactive Iodine Treatment With Cancer Mortality in Patients With Hyperthyroidism. JAMA Intern. Med. 179, 1034–1042 (2019). 28.Tonacchera, M., Chiovato, L., Bartalena, L., Cavaliere, A. F. & Vitti, P. Treatment of Graves’ hyperthyroidism with thionamides: a position paper on indications and safety in pregnancy. J. Endocrinol. Invest. 43, 257–265 (2020). 最新《國(guó)際糖尿病》讀者專屬微信交流群建好了,，快快加入吧！掃描左邊《國(guó)際糖尿病》小助手二維碼（微信號(hào)：guojitnb）添加后拉您入群,，或訂閱號(hào)搜索idiabetes查看更多內(nèi)容,！
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