翻譯：何麗珊 廈門理工學(xué)院
審校：鄭劍蘭 廈門大學(xué)附屬成功醫(yī)院（陸軍第73集團(tuán)軍醫(yī)院）
妊娠期甲狀腺疾病
甲狀腺功能亢進(jìn)和甲狀腺功能減退都與妊娠不良結(jié)局有關(guān)。還存在母親臨床甲狀腺疾病對(duì)胎兒發(fā)育的影響。此外，影響母親甲狀腺的藥物可以透過(guò)胎盤影響胎兒甲狀腺。本文回顧了妊娠期甲狀腺相關(guān)的病理生理變化,以及母親臨床和亞臨床甲狀腺疾病對(duì)母嬰結(jié)局的影響。本實(shí)踐公報(bào)更新了孕婦甲狀腺疾病診斷和管理的相關(guān)信息，包括一種妊娠期甲狀腺疾病管理的臨床新路徑。
妊娠期甲狀腺功能的變化
妊娠期甲狀腺的生理變化相當(dāng)大，可能會(huì)與母親甲狀腺異常混淆。妊娠晚期，母親甲狀腺體積增加10%到30%，可歸因于妊娠期間細(xì)胞外液和血容量的增加[1]。此外，整個(gè)妊娠期甲狀腺激素水平和甲狀腺功能也有變化。表1描述了正常妊娠、以及臨床和亞臨床甲狀腺疾病中甲狀腺功能檢查結(jié)果的變化。首先，母親總甲狀腺激素或結(jié)合甲狀腺激素水平隨血清甲狀腺結(jié)合球蛋白（TBG）濃度增加而增加。其次，促甲狀腺激素（也稱為甲狀腺刺激激素TSH）的水平在許多甲狀腺疾病的篩查和診斷中起重要作用，妊娠早期TSH分泌降低是由于妊娠12周前大量人絨毛膜促性腺激素（HCG）刺激TSH受體，繼而刺激甲狀腺激素分泌，使血清游離甲狀腺素四碘甲腺原氨酸（FT4）水平增加，抑制下丘腦促甲狀腺激素釋放激素（TRH），從而限制垂體分泌TSH。妊娠早期后，TSH回到基線水平，妊娠晚期逐漸上升，這與胎盤生長(zhǎng)和胎盤脫碘酶的產(chǎn)生有關(guān)[2]。在解讀妊娠期甲狀腺功能檢查結(jié)果（表1）時(shí)，應(yīng)考慮這些生理變化。
縮寫：T4，四碘甲狀腺素；TSH，促甲狀腺激素。
妊娠期甲狀腺功能檢查
理想情況下，妊娠期甲狀腺功能的參考值是根據(jù)本地?zé)o甲狀腺疾病的孕婦人群水平確定的。美國(guó)甲狀腺協(xié)會(huì)建議，當(dāng)?shù)貨](méi)有參考值時(shí)，妊娠早期末期的TSH參考值下限可降低0.4mU/L，參考值上限可降低0.5mU/L[3]。妊娠早期以后，TSH逐漸向非妊娠期的參考值[3]接近，可以使用非妊娠期的參考值?？偧谞钕偌に豑4（TT4）和總甲狀腺激素T3（TT3）的參考值也應(yīng)根據(jù)妊娠情況進(jìn)行調(diào)整。妊娠16周后，TT4和TT3的參考值上限可增加約50%[3,4]。妊娠16周前，與未妊娠的成年人相比，TT4和TT3逐漸增加。TT4和TT3參考值的調(diào)整對(duì)于解釋妊娠期甲狀腺結(jié)合球蛋白（TBG）的增加是必要的[3]。
胎兒甲狀腺功能
胎兒甲狀腺在妊娠12周左右開始攝碘并合成甲狀腺激素[5,6]。也就是說(shuō)，母親的T4在整個(gè)妊娠期都會(huì)轉(zhuǎn)移到胎兒，對(duì)胎兒大腦的正常發(fā)育至關(guān)重要，尤其是在胎兒甲狀腺開始起作用前[7]。分娩時(shí)臍帶血清中的T4約30%來(lái)源于母親[8]。應(yīng)將母親甲狀腺疾病史，特別是妊娠期服用過(guò)的丙基硫氧嘧啶( PTU) 和甲巰咪唑 ( MMI)，或已知母親甲狀腺受體抗體病史均告知出生后將照顧嬰兒的新生兒科醫(yī)生或兒科醫(yī)生，因?yàn)檫@些藥物和抗體會(huì)影響新生兒甲狀腺功能。
甲狀腺功能亢進(jìn)癥
臨床甲亢的特征是TSH水平降低和FT4水平升高（表1）。0.2-0.7%的孕婦存在甲亢，其中約95%為毒性彌漫性甲狀腺腫( Graves病)[9,10]。甲亢的癥狀體征包括緊張，震顫，心動(dòng)過(guò)速，大便頻繁，出汗過(guò)多，不耐熱，體重減輕，甲狀腺腫，失眠，心悸和高血壓。Graves病的顯著特征是眼?。w征包括眼裂增寬、眼瞼活動(dòng)滯緩和眼瞼攣縮）和皮膚病（體征包括局部或脛前粘液性水腫）。盡管甲亢的一些癥狀與正常妊娠或某些非甲狀腺相關(guān)疾病的癥狀相似，但血清甲狀腺功能檢測(cè)結(jié)果可將甲狀腺疾病與其他情況區(qū)分開。治療不當(dāng)?shù)募谞钕俣景Y孕產(chǎn)婦比已治療或控制好的甲狀腺毒癥孕產(chǎn)婦導(dǎo)致重度子癇前期、母親心力衰竭和甲狀腺危象等的風(fēng)險(xiǎn)更高[11-14]。
胎兒和新生兒的影響
妊娠結(jié)局通常取決于在妊娠前和妊娠期間是否實(shí)現(xiàn)代謝控制[15]。治療不當(dāng)?shù)募卓号c醫(yī)學(xué)指征早產(chǎn)，低出生體重，流產(chǎn)和死胎死產(chǎn)的增加有關(guān)[11,12,16,17]。Graves病相關(guān)的胎兒和新生兒風(fēng)險(xiǎn)不僅與疾病本身，還與硫酰胺類藥物（PTU或MMI）的治療有關(guān)。由于母親抗體的持續(xù)存在，所有Graves病史的孕婦都應(yīng)考慮胎兒甲狀腺毒癥的可能性[9]。胎兒甲狀腺毒癥通常表現(xiàn)為胎兒心動(dòng)過(guò)速和胎兒生長(zhǎng)發(fā)育不良。若懷疑胎兒甲狀腺毒癥，應(yīng)咨詢具有此類疾病專業(yè)知識(shí)的臨床醫(yī)生。
由于女性很大一部分甲狀腺疾病是由通過(guò)胎盤的抗體介導(dǎo)的，因此擔(dān)心新生兒患免疫介導(dǎo)的甲減或甲亢的風(fēng)險(xiǎn)。Graves病的孕婦可有甲狀腺刺激免疫球蛋白（TGI）和TSH結(jié)合抑制性免疫球蛋白（也稱為促甲狀腺激素結(jié)合抑制性免疫球蛋白TBI-I），分別能刺激或抑制胎兒甲狀腺。在某些情況下，Graves病的母親TBI-I可能導(dǎo)致新生兒出現(xiàn)短暫性甲減[18,19]。此外，這些新生兒中有1-5%的甲亢或新生兒Graves病是由母親的TGI透過(guò)胎盤傳遞引起的[20,21]。在新生兒中的母親抗體清除速度不如硫代酰胺類藥物的快，這有時(shí)會(huì)導(dǎo)致新生兒Graves病的延遲出現(xiàn)[21]。因此，分娩時(shí)應(yīng)告知兒科醫(yī)生母親Graves病的信息，并跟蹤新生兒是否存在Graves病的潛在發(fā)展[21]。新生兒Graves病的發(fā)病率與當(dāng)時(shí)母親的甲狀腺功能無(wú)關(guān)。妊娠前接受過(guò)手術(shù)治療或放射性碘-131治療、且不需要硫代酰胺治療的Graves病女性，其新生兒仍可能具有循環(huán)抗體，仍有新生兒Graves病的風(fēng)險(xiǎn)，應(yīng)進(jìn)行相應(yīng)的監(jiān)測(cè)[3]。
亞臨床甲狀腺功能亢進(jìn)癥
亞臨床甲亢約占孕婦的0.8-1.7%[22,23]，其特征是血清TSH濃度低于正常下限，F(xiàn)T4水平在正常參考值范圍內(nèi)[24]（表1）。重要的是，它與不良妊娠結(jié)局無(wú)明顯關(guān)系[22,25,26]。不建議對(duì)亞臨床甲亢孕婦進(jìn)行治療，因?yàn)閷?duì)母胎沒(méi)有明顯的益處。此外，理論上還對(duì)胎兒有風(fēng)險(xiǎn)，因?yàn)榭辜谞钕偎幬锿ㄟ^(guò)胎盤，可能對(duì)胎兒甲狀腺功能產(chǎn)生不良影響。
甲狀腺功能減退癥
每1000例妊娠中有2-10例并發(fā)臨床甲減[10]。甲減是根據(jù)實(shí)驗(yàn)室結(jié)果診斷的，TSH高于參考值上限，F(xiàn)T4低于參考值下限（表1）。甲減可伴有非特異性的臨床發(fā)現(xiàn)，可能與妊娠常見(jiàn)的癥狀體征沒(méi)有區(qū)別，如疲勞，便秘，不耐寒，肌肉痙攣和體重增加。其他臨床表現(xiàn)包括水腫，皮膚干燥，脫發(fā)和深層肌腱反射的弛緩時(shí)間延長(zhǎng)。甲狀腺腫可能存在也可能不存在，并且更可能發(fā)生在患有橋本甲狀腺炎（也稱為橋本病）或生活在地方性碘缺乏地區(qū)的女性。橋本甲狀腺炎是妊娠期甲減的最常見(jiàn)原因，其特征是自身抗體，特別是抗甲狀腺過(guò)氧化物酶抗體（TPOAb）破壞腺體。
母親攝入足量碘是孕婦及胎兒合成T4所必需。生活在美國(guó)的大多數(shù)女性碘的攝入量充足[3]。但其他低碘地區(qū)的育齡婦女面臨更高的風(fēng)險(xiǎn)。推薦孕婦日常飲食的每日膳食碘攝入量為220μg，哺乳期女性為290μg[27]。妊娠期常規(guī)補(bǔ)碘，特別是生活在碘輕度缺乏地區(qū)的女性，其益處尚無(wú)明確證據(jù)[28,29]。應(yīng)注意的是，補(bǔ)充多種維生素中（包括產(chǎn)前維生素）并不總是含碘。此外，市場(chǎng)上并非所有鹽都加碘。
圍產(chǎn)期不良結(jié)局，如自然流產(chǎn)，子癇前期，早產(chǎn)，胎盤早剝和死胎與未治療的臨床甲減有關(guān)[30,31]。對(duì)妊娠期臨床甲減患者進(jìn)行適當(dāng)?shù)募谞钕偌に靥娲委熆蓪⒉涣冀Y(jié)局的風(fēng)險(xiǎn)降至最低[32,33] 。
胎兒和新生兒的影響
明顯的，未經(jīng)治療的母親甲減與低出生體重以及后代神經(jīng)智力發(fā)育受損的風(fēng)險(xiǎn)增加有關(guān)[25,31]。然而，母親甲狀腺抑制性抗體（TFIAb）很少透過(guò)胎盤并引起胎兒甲減。橋本甲狀腺炎女性的后代中，胎兒甲減的患病率僅約占新生兒的18萬(wàn)之1[34]。
亞臨床甲狀腺功能減退癥
亞臨床甲減定義為FT4水平正常時(shí)血清TSH水平升高[24]（表1）。妊娠期亞臨床甲減的患病率約為2-5%[10, 35-37]。在其他情況健康的女性中，亞臨床甲減在妊娠期發(fā)展為臨床甲減的可能性不大。
未診斷的母親甲減可能與后代神經(jīng)發(fā)育受損有關(guān)[38,39]，這兩項(xiàng)觀察研究激起提高了對(duì)妊娠期亞臨床甲減的興趣。然而，2012年發(fā)表的一項(xiàng)大型隨機(jī)對(duì)照試驗(yàn)，即控制性產(chǎn)前甲狀腺篩查（稱為CATS）試驗(yàn)， 2017年發(fā)表在母胎醫(yī)學(xué)網(wǎng)的甲狀腺素治療亞臨床甲減或甲狀腺素血癥的隨機(jī)試驗(yàn)顯示，在接受亞臨床甲減篩查和治療的女性后代直到5歲的神經(jīng)認(rèn)知發(fā)育沒(méi)有差異[40,41]。此外，CATS研究隨訪到9歲兒童證實(shí)，接受治療女性的后代神經(jīng)發(fā)育沒(méi)有改善[42]。在一些研究中，已證明母親的亞臨床甲減與早產(chǎn)，胎盤早剝，新生兒入住重癥監(jiān)護(hù)室，嚴(yán)重子癇前期和妊娠期糖尿病的發(fā)病率高相關(guān)[25,26,35,43]。然而，其他研究尚未確定母親亞臨床甲減與這些產(chǎn)科不良結(jié)局之間的聯(lián)系[17,36,44]。目前，沒(méi)有證據(jù)表明妊娠期亞臨床甲減的識(shí)別和治療可改善這些結(jié)局[40-42,45]。
臨床考慮和建議
哪些孕婦應(yīng)該接受甲狀腺疾病篩查？
不建議對(duì)妊娠期甲狀腺疾病進(jìn)行普遍篩查，因?yàn)樯形醋C明母親亞臨床甲減的識(shí)別和治療可改善妊娠結(jié)局和后代神經(jīng)認(rèn)知功能。對(duì)于有甲狀腺疾病，I型糖尿病、臨床懷疑甲狀腺疾病、及有家族史的女性應(yīng)進(jìn)行甲狀腺功能檢測(cè)。在甲狀腺輕度腫大的無(wú)癥狀孕婦中進(jìn)行甲狀腺功能研究是沒(méi)必要的，因?yàn)槿焉锲诩谞钕倌[大高達(dá)30%[46]。對(duì)于甲狀腺明顯腫大或甲狀腺結(jié)節(jié)的孕婦，甲狀腺功能研究是合適的，因?yàn)檫@些體格檢查結(jié)果被認(rèn)為是超出正常妊娠的可接受范圍。
CATS研究和2017年母胎醫(yī)學(xué)網(wǎng)對(duì)甲狀腺素治療妊娠期亞臨床甲減或甲狀腺素血癥的隨機(jī)試驗(yàn)結(jié)果表明，篩查和治療妊娠期亞臨床甲減的女性，并不能改善她們后代分別在3歲和5歲時(shí)的認(rèn)知功能[40,41]。因此，美國(guó)婦產(chǎn)科學(xué)院，內(nèi)分泌學(xué)會(huì)和美國(guó)臨床內(nèi)分泌學(xué)家協(xié)會(huì)建議不要在妊娠期對(duì)甲狀腺疾病進(jìn)行普遍篩查，并建議僅對(duì)有臨床甲減風(fēng)險(xiǎn)的女性進(jìn)行妊娠期檢測(cè)[47,48]。美國(guó)甲狀腺協(xié)會(huì)發(fā)現(xiàn)，目前沒(méi)有足夠的數(shù)據(jù)支持或反對(duì)普遍的甲狀腺篩查[3]。
妊娠期間使用哪些實(shí)驗(yàn)室檢查來(lái)診斷甲狀腺疾??？
TSH和甲狀腺激素水平都用于診斷妊娠期甲狀腺疾?。▓D1）。如果有必要，評(píng)估甲狀腺狀態(tài)的一線篩查試驗(yàn)應(yīng)是檢測(cè)TSH水平。假設(shè)下丘腦-垂體功能正常，則血清TSH與血清甲狀腺激素之間存在逆對(duì)數(shù)線性關(guān)系，因此循環(huán)激素水平的微小變化將導(dǎo)致TSH發(fā)生較大變化。此外，由于大多數(shù)臨床實(shí)驗(yàn)室使用游離激素測(cè)定法而不是物理分離技術(shù)，如平衡透析，因此檢測(cè)結(jié)果取決于單獨(dú)的結(jié)合蛋白水平，僅代表實(shí)際循環(huán)FT4濃度的估計(jì)值。因此，TSH是甲狀腺狀態(tài)最可靠的指標(biāo)，因?yàn)樗g接反映了垂體所感知的甲狀腺激素水平。當(dāng)TSH水平異常高或低時(shí)，應(yīng)后續(xù)研究檢測(cè)FT4水平，以確定是否存在臨床甲狀腺功能障礙。在疑似甲亢的病例中，還應(yīng)檢測(cè)TT3（圖1）。TT3比FT3優(yōu)先考慮，因?yàn)橛糜贔T3的檢測(cè)方法不如FT4的方法可靠[4]。應(yīng)檢測(cè)接受甲亢治療孕婦的FT4水平，并相應(yīng)調(diào)整抗甲狀腺藥物（硫代酰胺）的劑量，使FT4達(dá)到正常妊娠參考值的上限。在患有T3甲狀腺毒癥的女性中，應(yīng)檢測(cè)TT3，使目標(biāo)水平在正常妊娠參考值的上限
應(yīng)用什么藥物治療妊娠期臨床甲亢，妊娠期間應(yīng)如何管理和調(diào)整這些藥物？
臨床甲亢孕婦應(yīng)接受抗甲狀腺藥物（硫代酰胺類）治療。PTU或MMI均為硫代酰胺類藥物，可用于治療臨床甲亢孕婦。藥物的選擇取決于妊娠時(shí)期，對(duì)以前治療的反應(yīng)，以及甲狀腺毒癥主要是T4或T3。應(yīng)通過(guò)共同決策制定適當(dāng)?shù)闹委熡?jì)劃，向女性提供有關(guān)這兩種硫代酰胺類藥物的風(fēng)險(xiǎn)和益處的咨詢。MMI在妊娠早期通常避免服用，因?yàn)樗c一種罕見(jiàn)的胚胎病有關(guān)，其特征是食道或鼻后孔閉鎖以及一種先天性的皮膚發(fā)育不全[49]。2012年回顧分析5967例分娩的Graves病女性，服用MMI的患者比服用PTU 的患者發(fā)生胎兒重大畸形的風(fēng)險(xiǎn)增加了2倍[49]。具體是指9例服用MMI的嬰兒中，有7例皮膚發(fā)育不全，1例食管閉鎖。因此，PTU通常用于控制妊娠早期的甲亢服。
妊娠早期以后，MMI或PTU均可用于治療甲亢。極少數(shù)情況下，PTU會(huì)導(dǎo)致臨床上嚴(yán)重肝毒性[4]，這促使一些醫(yī)療保健專業(yè)人員在妊娠早期以后改用MMI。然而，將PTU改為MMI可能導(dǎo)致甲亢控制不佳。兩種藥物都有已知的副作用，必須相互權(quán)衡并與患者討論[4]。因此，一些女性在整個(gè)妊娠期都用PTU治療。此外，PTU可減少T4至T3的轉(zhuǎn)化率，應(yīng)優(yōu)先用于T3為主的甲狀腺毒癥[4]。通常應(yīng)與內(nèi)分泌學(xué)或母胎醫(yī)學(xué)?？漆t(yī)生一起決策是否以及如何將一種藥物換為另一種藥物。如果合適，建議PTU與MMI的劑量比為20:1 （圖1）。
服用硫代酰胺類藥物的孕婦中，高達(dá)10%會(huì)發(fā)生短暫性白細(xì)胞減少癥，但這種情況不需要停止治療。然而，其中不到1%的患者會(huì)突然出現(xiàn)粒細(xì)胞缺乏癥，并要求停藥。粒細(xì)胞缺乏癥的發(fā)生與劑量無(wú)關(guān)，并且由于其急性發(fā)作，治療期間連續(xù)檢測(cè)白細(xì)胞計(jì)數(shù)是無(wú)濟(jì)于事的。因此，如果出現(xiàn)發(fā)燒或喉嚨痛，應(yīng)命令患者立即停止服用該藥物并報(bào)告全血細(xì)胞計(jì)數(shù)[50]。
最初的硫代酰胺劑量是經(jīng)驗(yàn)性的。如果選擇PTU，則可根據(jù)臨床嚴(yán)重程度，100–600mg開始，每日分三次口服[3]。一般患者的標(biāo)準(zhǔn)劑量是每天200-400mg。如果服用MMI，建議初始劑量為5–30 mg，每日分二次口服（雖然隨著維持治療的建立，頻率可能會(huì)減少至每日一次）。目的是用盡可能小的硫代酰胺劑量進(jìn)行治療，以維持FT4水平輕度升高或在參考值的高線水平，不用考慮TSH的水平如何[3]。對(duì)于以T3為主的甲狀腺毒癥女性，應(yīng)檢測(cè)TT3。
Β腎上腺受體阻滯劑可用于癥狀性心悸的輔助治療。妊娠期首選普萘洛爾，起始劑量為10–40 mg，每天服用3至4次[4]。
圖1.妊娠期甲狀腺疾病管理的臨床路徑?？s寫：T3，三碘甲狀腺原氨酸；T4，甲狀腺素；TRAb，甲狀腺受體抗體；TSH，促甲狀腺激素；TSI，促甲狀腺免疫球蛋白。* PTU 應(yīng)在妊娠早期服用，因?yàn)镸MI與出生缺陷有關(guān)。對(duì)于癥狀性心悸或其他甲亢高代謝癥狀的女性，可用普萘洛爾,以10-40mg的劑量開始,每6-8小時(shí)一次。妊娠期TT3參考值范圍是未妊娠期的1.5倍。
專家簡(jiǎn)介
鄭劍蘭，主任醫(yī)師，教授，研究生導(dǎo)師
廈門大學(xué)附屬成功醫(yī)院、陸軍第73集團(tuán)軍醫(yī)院暨全軍計(jì)劃生育優(yōu)生優(yōu)育技術(shù)指導(dǎo)中心婦兒科主任，全軍婦產(chǎn)科專業(yè)委員及產(chǎn)科學(xué)組秘書長(zhǎng)，南京軍區(qū)婦產(chǎn)科副主任委員，英國(guó)帝國(guó)理工大學(xué)母嬰研究中心簽約學(xué)者，全球健康中心及美國(guó)辛辛那提大學(xué)交流學(xué)者，中華醫(yī)學(xué)會(huì)圍產(chǎn)醫(yī)學(xué)分會(huì)委員，中國(guó)醫(yī)師協(xié)會(huì)母胎醫(yī)學(xué)分會(huì)委員，中國(guó)對(duì)外交流促進(jìn)會(huì)婦產(chǎn)科分會(huì)委員，中國(guó)婦幼保健協(xié)會(huì)高危妊娠常務(wù)委員，中國(guó)研究型醫(yī)院學(xué)會(huì)孕產(chǎn)期母兒心臟病專業(yè)委員會(huì)常務(wù)委員，福建省圍產(chǎn)醫(yī)學(xué)分會(huì)委員、優(yōu)生優(yōu)育及婦幼保健協(xié)會(huì)盆底委員會(huì)常務(wù)委員、骨質(zhì)疏松及骨礦鹽學(xué)會(huì)委員，廈門市圍產(chǎn)醫(yī)學(xué)分會(huì)候任主任委員、婦產(chǎn)科副主任委員、產(chǎn)科質(zhì)控中心副主任，SCI期刊《ANZJOG》 及《JOGR》審稿專家。
婦產(chǎn)科臨床工作30多年，擅長(zhǎng)婦科腔鏡及產(chǎn)科危急重癥搶救，近年來(lái)主要從事圍產(chǎn)醫(yī)學(xué)研究。主編專著2部；發(fā)表SCI及國(guó)內(nèi)核心期刊論著20余篇；主持國(guó)家自然科學(xué)基金面上項(xiàng)目，省市及軍隊(duì)科研項(xiàng)目10項(xiàng)；引進(jìn)Bakri產(chǎn)后止血球囊和CRB促宮頸成熟及引產(chǎn)球囊；發(fā)明Zheng子宮壓迫縫合術(shù)，第一完成人獲國(guó)家專利3項(xiàng)，并獲軍隊(duì)和福建省、廈門市醫(yī)療成果及科技進(jìn)步獎(jiǎng)9項(xiàng)，享受軍隊(duì)一類科技人才崗位津貼，是軍隊(duì)334工程拔尖人才和廈門大學(xué)科技創(chuàng)新人才，多次榮立軍隊(duì)二等功及三等功。
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