FOCUSED ISSUE OF THIS MONTH pissn 1975-8456 / eissn 2093-5951 https://doi.org/10.5124/jkma.2018.61.4.253 임신과갑상선질환 임창훈 단국대학교의과대학제일병원내과 Thyroid dysfunction during pregnancy Chang Hoon Yim, MD Department of Internal Medicine, Cheil General Hospital & Women s Healthcare Center, Dankook University College of Medicine, Seoul, Korea Thyroid dysfunction during pregnancy can result in serious complications for both the mother and infant. However, these complications can be prevented by the optimal treatment of overt maternal thyroid dysfunction. The serum thyroid-stimulating hormone (TSH) concentration is the most reliable measure of thyroid function during pregnancy. Due to the physiologic changes in TSH levels during pregnancy, the correct interpretation of thyroid function requires knowledge of the gestational week and the appropriate population-based reference interval. In addition to a TSH test, the measurement of thyroid peroxidase antibody helps determine whether to treat subclinical hypothyroidism during pregnancy. Since the use of antithyroid drugs during pregnancy is associated with birth defects, it is recommended to discontinue the medication and to perform repeated thyroid function testing during the first trimester. If therapy is needed during the first trimester, propylthiouracil is preferred over methimazole. Key Words: Pregnancy; Hyperthyroidism; Hypothyroidism 서론 갑상선질환은가임기여성에서흔한내분비질환으로, 임 신중갑상선기능이상은산모와태아의여러합병증을초래 할수있으며, 이러한합병증은산모의갑상선기능이상을치 료함으로써예방할수있다고알려져있다 [1]. 임신중갑상 선질환의관리에대한관심이높아짐에따라 2007 년이후미 국갑상선학회 (American thyroid association, ATA) 를비롯 한여러학회의지침이발표되었고 [2,3], 2014 년대한갑상선 학회에서도지침을발표하여진료에많은도움을주었다 [4]. Received: March 2, 2018 Accepted: March 16, 2018 Corresponding author: Chang Hoon Yim E-mail: changhoon.yim@cgh.co.kr Korean Medical Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons. org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 본종설에서는최근 ATA에서발표한개정된지침을바탕으로임신중갑상선기능이상환자의치료에대해소개하고자한다 [5]. 임신중갑상선기능의변화 임신에따른다양한호르몬의변화와신진대사의증가는갑상선기능에영향을끼친다. 임신동안의호르몬의주요변화는에스트로겐증가에의한티록신결합글로불린 (thyroxine binding globulin, TBG) 의증가와인융모성선자극호르몬 (human chorionic gonadotropin, hcg) 의증가에의한혈중갑상선자극호르몬 (thyroid stimulating hormone, TSH) 수용체의자극이다 [6]. 혈중 TBG는임신에따라증가하여 20주에약 2배로증가하며결과적으로혈중총티록신 (total thyroxine) 과총트리요오드사이로닌 (total 임신과갑상선질환 253
triiodothyronine) 이증가하게된다. 혈중 hcg는수정후증가하여임신 10-12주에최고점에도달하게되는데, hcg의증가에따라 TSH수용체가자극되어갑상선호르몬의생성이증가되고 TSH의농도는감소하게된다. 이후임신이진행됨에따라 TSH 농도는정상범위로돌아오고혈청유리티록신 (free thyroxine, FT4) 농도는감소하게된다 [7]. 모체의갑상선호르몬은태아의발달에중요한역할을하는데, 태아의갑상선은임신 16주이후에야갑상선호르몬을생성하기때문에임신초기에태아의발달은모체의갑상선상태에전적으로의존하게된다. 따라서산모의갑상선기능이상은산모뿐만아니라태아에게유해한결과를초래할수있다 [8]. 임신중갑상선기능검사의정상범위 임신중에는임신에따른다양한신체변화가나타나기때문에갑상선기능이상의전형적인증상이가려지는경우가많기때문에혈중갑상선기능검사는진단에중요한역할을한다. 혈중 TSH검사는예민하고, 간편하고, 가격이저렴하여갑상선기능이상의진단에필수적이다 [9]. 그러나임신중 TSH 농도는임신기간에따른변화를고려해야하므로, 2011년 ATA는분기별정상범위를사용할것을제안했고, 임신분기별 TSH 의정상범위가설정되어있지않다면, 임신 1분기 0.1-2.5, 2분기 0.2-3.0, 그리고 3분기 0.3-3.5 miu/l를사용할것을권고하였다 [2]. 그러나 ATA에서제시한임신 1분기의 0.1-2.5 miu/l는임신 9-12주산모들의자료를바탕으로나온결과이며, 이시기는임신중혈중 hcg 농도가최고점에도달하고 TSH 농도가가장낮은시기이므로이결과를임신초기특히임신 8주이전의산모에적용하기에는무리가있었다 [10]. 따라서이후에발표된임신중 TSH 정상범위를알아본대규모의연구에서 1분기의 TSH 상한선이 ATA 기준인 2.5 miu/l보다높게나와, 2.5 miu/l를상한선으로사용하게되면임신초기정상산모들을갑상선기능저하증으로진단할수있다는우려가나오게되었다 [11]. 이러한문제점을인식해서인지 2017년 ATA는지역과인종의차이가있으므로임신중 TSH 농도는 기관별, 임신기간별정상범위를사용할것을권고하였고, 설정되어있지않다면, 임신 7-12주에는 4.0 miu/l를정상범위의상한선으로사용할것을권고하였다 [5]. 임신중갑상선기능저하증 FT4가감소되고 TSH 증가또는 FT4 농도와관계없이 TSH 가 10 miu/l 이상증가된경우를현성갑상선기능저하증 (overt hypothyroidism, OH) 이라하며 [2], 임신중 OH 의유병률은 0.3-0.5% 로추정된다 [1]. 임신중에치료되지않은 OH 산모에서는조기출산, 저체중아출산및유산을포함한여러임신합병증의위험이증가하고 [12] 태아의신경발달에문제를일으킬수있으며, 임신중에갑상선호르몬으로적절한치료를할경우이를예방할수있다고알려져있다 [13]. 따라서임신중현성갑상선기능저하증은꼭치료를해야한다. TSH가증가된반면 FT4가정상인경우를무증상갑상선기능저하증 (subclinical hypothyroidism, SCH) 이라부르며, 임신중 SCH의유병률은 2-2.5% 로알려져있었다 [14]. 그러나 TSH의정상범위의상한을 2.5 miu/l로사용했던연구에서 SCH의유병률은 20-30% 로이전에비해서매우높게보고되었으나 [10,15], 최근에 ATA 기준이변경됨에따라유병률은달라질것으로생각된다. 다수의관찰연구에서산모의 SCH가유산, 조산등의임신합병증과연관된다고보고된반면 [14,16], 일부에서는다른결과를보여연관성을찾을수없다는연구도있었다 [17,18]. 그러나현재까지연구간의방법의차이가있기는하지만다수의잘고안된연구결과에서 SCH는임신에나쁜결과를초래할것으로생각된다. 산모의 SCH가태아의신경발달에해로운영향을끼치는지그리고치료를했을때예방할수있는지에대한연구는덜명확하다. 일부연구에서는임신초기의 SCH가태아의지적발달및운동발달과관련이있다는것을발견한반면 [19,20], 다른연구에서는모체의 SCH와자녀의신경발달사이의연관성을발견하지못했다 [21]. 최근에발표된대규모의전향적연구에서산모의 SCH에대한레보티록신 254 대한의사협회지
Yim CH Thyroid dysfunction in pregnancy (levothyroxine, LT4) 치료가 3세, 5세때아이의신경인지기능을개선시키지못했다는연구가있으나여러제한점을갖고있어아직치료효과에대한명확한결론을내리지는못하고있다 [22-24]. TSH 농도외에기능저하증의치료를결정하는중요한인자는항갑상선과산화효소항체 (thyroid peroxidase antibody, TPOAb) 의존재이다. TPOAb 양성인산모에서는임신이진행됨에따라갑상선기능저하증이될가능성이증가될뿐만아니라, 유산의위험이증가되며, TSH가 2.5 miu/l 이상이고 TPOAb 양성인산모에서 LT4 치료시임신합병증의감소가확인되었다 [25]. 따라서임신중 SCH에대한최근의 ATA 지침은 TSH가 4.0 miu/l 이상이거나, TPOAb 양성이고 TSH가 2.5-4.0 miu/l인경우에치료를고려할수있다고권고하였다 [5]. 태아의중추신경계는 T3가비교적통과되지않으므로임신중갑상선기능저하증의치료는 LT4를사용한다. 치료의목표는혈청 TSH를임신기간별정상범위로유지하는것이며, 갑상선기능검사는 1분기동안은 4-6주마다그리고 2, 3분기에한번씩실시하여 LT4의치료용량을조절해야된다 [2]. 임신전에이미갑상선기능저하증으로치료받았던여성은임신중 LT4 치료용량이 30-50% 까지증가될수있으며, 이런증량은임신 4-6주에시작하여, 16-20주까지서서히증가되며 [2,26], 출산후에는용량을임신전수준으로감량하고 6주뒤 TSH를측정하여평가하여야한다. 임신중갑상선기능항진증 임신중현성갑상선기능항진증의진단은 TSH의감소와정상범위를초과하는 FT4의증가로정의되며, 임신의 0.2-0.4% 에서발생한다 [27]. 임신중갑상선기능항진증의가장흔한원인은그레이브스병이지만, 임신초기에는임신성일과성갑상선중독증 (gestational transient thyrotoxicosis, GTT) 이임신의 2-3% 에서나타날수있다 [6,8]. 임신초기갑상선기능항진증이의심될때는그레이브스병과 GTT의감별질환이중요한데, 그이유는두질환의임상과정과치료가 다르기때문이다 [5]. 임신전갑상선질환의병력, 갑상선종, 안병증의증상, TSH 수용체항체 (TSH receptor antibody, TRAb) 양성은그레이브스병의가능성을알려준다. GTT는 FT4 농도가임신 14-18주에정상으로회복되기때문에항갑상선제치료가필요없다. 2011년 ATA 지침에는 GTT와그레이브스병의감별진단이어려운경우에는단기간의항갑상선제의치료가가능하다고하였으나, 2017년새지침에는항갑상선제의치료없이단기간의추적관찰할것을권고하였는데, 이는임신초기항갑상선제의부작용을가급적줄이기위한것으로보인다 [5]. 무증상갑상선기능항진증은혈청 TSH 농도가감소한반면, FT4는정상범위내에있는것으로정의되며, 임신에나쁜영향을끼치지않으므로, 무증상갑상선기능항진증을가진임산모의치료는필요하지않다 [28]. 그러나혈청 TSH 농도가감소하고, FT4가증가된현성갑상선기능항진증은자간전증, 심부전, 조기분만, 저체중아및태아손실의위험이높으므로치료가필요하다 [29]. 임신은기간에따라산모의갑상선기능항진증에영향을미치는데초기에는호르몬의변화로일시적으로악화되다가중기에들어서면서면역기능이억제되면서증상이호전되며, 출산후에는면역계의반동현상으로다시악화되므로, 임신및출산의기간별임상양상의변화를염두에두고치료계획을세워야겠다. 프로필티오우라실 (propylthiouracil, PTU) 과메티마졸 (methimazole, MMI) 은임신중갑상선기능항진증에사용되는약제인데, PTU는 MMI보다태반을덜통과하기때문에선천적기형유발이 MMI보다적은것으로알려져임신중갑상선기능항진증에주로사용되어왔다 [30]. 그러나미국식품의약국의 PTU의간독성위험에대한경고후, 1분기동안 PTU 치료를권장하고 2, 3분기에는 MMI로변경하여치료할것을권고하였다 [2,3]. 그러나대규모연구에서 MMI에비해서 PTU 에의한기형의빈도가낮고경증일뿐, MMI나 PTU 투여군모두에서태아기형이발생된다고알려졌다 [31]. 따라서임신을원하는갑상선기능항진증여성에서는항갑상선제치료로갑상선기능이안정화된후에임신하도록상담해야한다. 항갑상선제치료중에임신을하게되면기능이잘조절되는경우라면항갑상선제를중단하고임신 1분기동안에는 임신과갑상선질환 255
1-2 주간격으로갑상선검사를하면서추적관찰하며, 항갑 상선제중지시악화될가능성이있을때는 PTU 를사용할 것이권고되었다. 사가권고되는데, 최근우리나라에서는산모의연령이증가 하고, 다수의산모가 30 세이상이므로, 대다수의한국인산 모에서임신초기에 TSH 검사가필요할것이다 [11]. 임신중현성갑상선기능항진증치료의목표는혈중 FT4 농도를정상범위의상한선근처에맞출정도의최소용량의항갑상선제를사용하는것이다. 따라서 FT4와 TSH 농도를 2-4주마다측정하여항갑상선제의용량을조절하며, 기능이정상화되면 4-8주마다측정하여용량을조절한다 [2]. 그레이브스병은임신중기및후기로진행하면서대부분호전되므로, 항갑상선제용량조절이필요하며, 약 20-30% 환자에서항갑상선제를중단할수있다 [32]. 그레이브스병산모의태아갑상선기능항진증의유병률은 1-5% 이다 [33]. 지속적으로높은수준의모체혈청 TRAb는태아갑상선기능항진증과관련이있으므로임신 24-28주사이의 TRAb 검사는태아의갑상선기능장애를감별해내는데도움이된다 [34]. 산모의갑상선기능항진증이조절되지않거나 TRAb 역가가높은산모에서는초음파를시행하여태아의갑상선기능이상을의심할수있는소견 ( 태아의빈맥 [ 분당 170회이상 ], 성장제한, 갑상선종, 지나치게빠른골성숙등 ) 이있는지확인해야한다. 결론 임신중갑상선기능이상은산모와태아의여러합병증을초래할수있으며, 이러한합병증은산모의갑상선기능이상을치료함으로써예방할수있다고알려져있다. 따라서가장보편적으로사용되는혈중 TSH 검사가중요한데임신중 TSH의정상범위는지역, 인종에따라다양하고, 임신기간에따라다르므로기관별, 임신분기별정상범위를사용하여 TSH 결과를해석해야한다. 산모의무증상갑상선기능저하증의치료에대하여는아직도이견이있으므로, TPOAb를측정하여치료를결정하는데이용할수있다. 갑상선기능항진증은임신진행에따라임상양상이변하고항갑상선제는태반을통과하여태아에영향을미칠수있으므로, 임신초기에는항갑상선제를중단하고갑상선기능검사를자주측정하며, 중단이어려운경우에는 PTU 를사용한다. 임신중갑상선선별검사 찾아보기말 : 임신 ; 갑상선기능항진증 ; 갑상선기능저하증 모든산모를대상으로 TSH 선별검사를해야하는가에대 해서는아직도논란이있으나, 갑상선기능이상이임신결과 및태아에나쁜영향을줄수있다는것은명백하므로모든 ORCID Chang Hoon Yim, https://orcid.org/0000-0002-9019-4907 산모에서첫산전진찰시갑상선기능이상의병력등을물어 보아고위험군에해당되는산모에서 TSH 검사를할것을권고하고있다. 고위험군에는갑상선질환의개인병력, 가족병력, 갑상선질환의증상또는징후, 갑상선항체양성, 유산또는조산의병력, 자가면역질환, 30세이상의연령등이있다 [5]. 그러나고위험군만대상으로검사를한경우갑상선기능저하증산모의약 30-55% 를놓칠수있으므로, 모든산모를대상으로 TSH 선별검사를하자는연구가발표되기도하였다 [35]. 30세이상의산모는고위험군에속하여 TSH 검 REFERENCES 1. Klein RZ, Haddow JE, Faix JD, Brown RS, Hermos RJ, Pulkkinen A, Mitchell ML. Prevalence of thyroid deficiency in pregnant women. Clin Endocrinol (Oxf) 1991;35:41-46. 2. Stagnaro-Green A, Abalovich M, Alexander E, Azizi F, Mestman J, Negro R, Nixon A, Pearce EN, Soldin OP, Sullivan S, Wiersinga W; American Thyroid Association Taskforce on Thyroid Disease During Pregnancy and Postpartum. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011;21:1081-1125. 256 대한의사협회지
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28. Casey BM, Dashe JS, Wells CE, McIntire DD, Leveno KJ, Cunningham FG. Subclinical hyperthyroidism and pregnancy outcomes. Obstet Gynecol 2006;107:337-341. 29. Aggarawal N, Suri V, Singla R, Chopra S, Sikka P, Shah VN, Bhansali A. Pregnancy outcome in hyperthyroidism: a case control study. Gynecol Obstet Invest 2014;77:94-99. 30. Andersen SL, Olsen J, Wu CS, Laurberg P. Birth defects after early pregnancy use of antithyroid drugs: a Danish nationwide study. J Clin Endocrinol Metab 2013;98:4373-4381. 31. Andersen SL, Olsen J, Laurberg P. Antithyroid drug side effects in the population and in pregnancy. J Clin Endocrinol Metab 2016;101:1606-1614. 32. Hamburger JI. Diagnosis and management of Gravesʼ disease in pregnancy. Thyroid 1992;2:219-224. 33. Polak M, Le Gac I, Vuillard E, Guibourdenche J, Leger J, Toubert ME, Madec AM, Oury JF, Czernichow P, Luton D. Fetal and neonatal thyroid function in relation to maternal Gravesʼ disease. Best Pract Res Clin Endocrinol Metab 2004;18:289-302. 34. Matthews DC, Syed AA. The role of TSH receptor antibodies in the management of Gravesʼ disease. Eur J Intern Med 2011; 22:213-216. 35. Vaidya B, Anthony S, Bilous M, Shields B, Drury J, Hutchison S, Bilous R. Detection of thyroid dysfunction in early pregnancy: universal screening or targeted high-risk case finding? J Clin Endocrinol Metab 2007;92:203-207. Peer Reviewers Commentary 본종설은임신과관련된갑상선기능변화를이해하고, 관련질 환의적절한진단및치료를돕는데초점이맞추어져있다. 특히 2007 년이후각학회에서발표한진료지침과 2014 년대한갑 상선학회, 2017 년미국갑상선학회에서개정발표된임신관련 갑상선질환의진료지침내용을비교소개함으로써최신지견의 이해를돕고있다. 일부논란이있어왔던임신중갑상선기능검 사의정상범위관련내용이자세히기술되어있으며, 임신중갑 상선선별검사의기준, 무증상갑상선기능이상의치료결정요 인과임신중항갑상선제선택등에관련된연구결과들을소개하 고이를근거로한적절한치료방침을제시하고있어임상적판 단에많은도움이될것으로생각한다. [ 정리 : 편집위원회 ] 258 대한의사협회지