馬俊芳

(天津市中心婦產(chǎn)科醫(yī)院，天津，300100)

冷凍胚胎移植的臨床應(yīng)用效果評價

馬俊芳

(天津市中心婦產(chǎn)科醫(yī)院，天津，300100)

體外受精-胚胎移植治療不孕癥的過程中，相比新鮮胚胎移植，冷凍胚胎移植(FET)移植成功率類似，但是異位妊娠發(fā)生率、圍產(chǎn)期并發(fā)癥發(fā)生率更低，新生兒結(jié)局較好。

輔助生殖技術(shù)；冷凍胚胎移植;新鮮胚胎移植

近年來隨著胚胎凍存技術(shù)的不斷提高，體外受精-胚胎移植(IVF-ET)治療不孕癥的過程中，冷凍胚胎移植(FET )的應(yīng)用不斷增多[1，2]。2006年歐洲數(shù)據(jù)顯示[3]，F(xiàn)ET占全部輔助生殖(ART)周期的20%，在瑞典、德國及西班牙等國家，F(xiàn)ET周期已經(jīng)超過了新鮮胚胎移植周期，美國同期數(shù)據(jù)表明[4]，F(xiàn)ET周期占全部ART周期的16.0%。ART協(xié)會數(shù)據(jù)顯示[5]，2006～2012年FET周期數(shù)增加了82.5%，而新鮮周期僅增加了3.1%。最近研究結(jié)果也顯示，相比新鮮胚胎移植，F(xiàn)ET移植成功率類似，但異位妊娠發(fā)生率、圍產(chǎn)期并發(fā)癥發(fā)生率更低，新生兒結(jié)局較好?，F(xiàn)綜述如下。

1 移植成功率

美國疾控中心(CDC)統(tǒng)計了1997～2011年美國生殖醫(yī)學(xué)中心新鮮胚胎移植和FET的成功率[6]，結(jié)果顯示在此時間段內(nèi)，各個年齡組新鮮胚胎移植及FET成功率都得到了提高，例如在年齡<35歲組，新鮮周期的活產(chǎn)率由31%升高至40%，F(xiàn)ET的活產(chǎn)率由21%升高至39%。FET周期的成功率并不低于新鮮移植。有學(xué)者認(rèn)為，在目前比較新鮮胚胎移植與FET成功率的大多數(shù)研究中，較好的胚胎都是在新鮮胚胎移植周期進(jìn)行移植，而在這些研究中，新鮮胚胎移植周期與FET的成功率并無差異[7]。有研究表明，在卵巢過度刺激綜合征(OHSS)高風(fēng)險患者中行全胚凍存后FET有更高的臨床妊娠率[8]?？紤]到行FET的多是質(zhì)量相對不好的胚胎，如果用質(zhì)量最好的胚胎行FET，可能成功率會更高。

最近一項(xiàng)包括三個隨機(jī)對照實(shí)驗(yàn)(RCTs)、633名參與者的Meta分析比較了全胚凍存FET組及新鮮胚胎移植組的臨床妊娠率(CPR)、持續(xù)妊娠率及流產(chǎn)率[9]，發(fā)現(xiàn)全胚凍組CPR 、持續(xù)妊娠率較新鮮移植組高，兩組流產(chǎn)率無統(tǒng)計學(xué)差異。三個RCTs得出了相似的結(jié)論，而且不論是卵裂期胚胎移植[10]還是囊胚移植[11，12]，均不會對結(jié)論產(chǎn)生影響。但我們?nèi)孕鑷?yán)謹(jǐn)?shù)亟忉屔鲜鼋Y(jié)論。上述RCTs中研究對象相對年輕(年齡27～33歲)，研究結(jié)果是否適用于年老者及預(yù)后不佳的患者尚需進(jìn)一步研究。有研究認(rèn)為，在年齡>35歲預(yù)后較差患者中也能得出相似的結(jié)論[13]。遺憾的是，上述三個RCTs均未報道有關(guān)圍產(chǎn)期結(jié)局的數(shù)據(jù)。值得注意的是，在上述三個RCTs中，所有患者均采用激素替代周期解凍，有研究[14]表明，激素的干預(yù)可能會對子宮內(nèi)膜容受性產(chǎn)生不利影響，從而影響成功率，由此我們可以推測，全胚凍后行自然周期FET成功率可能會更高。

2 異位妊娠發(fā)生率

IVF-ET是異位妊娠的危險因素之一，IVF-ET后異位妊娠的發(fā)病率為2%～5%[15]，遠(yuǎn)高于自然妊娠的1%～2%[16]，但體外受精(IVF)后異位妊娠高發(fā)生率的機(jī)制并不明確。有學(xué)者[17]認(rèn)為，控制性超促排卵本身及之后增大的卵巢刺激腹膜以及取卵等都會加強(qiáng)子宮的收縮，從而導(dǎo)致異位妊娠的發(fā)生。既往研究表明，控制性超促排卵后內(nèi)分泌環(huán)境的改變可能是新鮮周期異位妊娠發(fā)生率較高的原因[18]。目前，大量研究表明 FET較新鮮胚胎移植異位妊娠的發(fā)生率較低[19]。尤其是對于合并有其他高風(fēng)險或不利條件的患者，例如OHSS高風(fēng)險患者。在這類患者中應(yīng)用全胚凍存FET，發(fā)生OHSS及異位妊娠的風(fēng)險較低。目前尚無有效方法判斷哪些患者具有異位妊娠的高風(fēng)險，雖然有學(xué)者[20]的研究發(fā)現(xiàn)，輸卵管因素不孕患者中異位妊娠發(fā)生率較高，但異位妊娠同樣也可以發(fā)生于非輸卵管因素不孕患者，因此將全胚凍FET常規(guī)應(yīng)用于所有患者似乎是一個降低異位妊娠整體發(fā)生率的方法。

3 圍產(chǎn)期并發(fā)癥及新生兒結(jié)局

隨著ART應(yīng)用的普及，其安全性問題得到了廣泛的關(guān)注。早在2004年有學(xué)者[21]就提出用新的度量標(biāo)準(zhǔn)，即BESST標(biāo)準(zhǔn)來衡量IVF結(jié)局，該指標(biāo)強(qiáng)調(diào)了足月健康活產(chǎn)兒的出生這一不孕癥夫婦的最終關(guān)注點(diǎn)。基于這一理論，目前的研究表明，F(xiàn)ET對于IVF患者及新生兒來說都是一種更為安全的選擇。

一項(xiàng)澳大利亞的研究以自然妊娠為對照組，研究了FET出生缺陷及新鮮移植出生缺陷發(fā)生率[22]，結(jié)果發(fā)現(xiàn)，與自然妊娠相比，新鮮胚胎移植后出生缺陷發(fā)生率明顯高，而FET組與自然妊娠組相比出生缺陷發(fā)生率無差異。來自澳大利亞的另一人口學(xué)研究發(fā)現(xiàn)[23]，新鮮胚胎移植與自然妊娠相比，芽生出生缺陷發(fā)生率明顯較高,而FET組與自然妊娠組相比無差異。

另外，一項(xiàng)Meta分析了FET組及新鮮胚胎移植組圍產(chǎn)期并發(fā)癥及新生兒結(jié)局[24]，發(fā)現(xiàn)FET組早產(chǎn)、小于胎齡兒、低出生體重、產(chǎn)前出血的發(fā)生率較新鮮胚胎移植組低，F(xiàn)ET組新生兒圍產(chǎn)期死亡率也較低。最近，一項(xiàng)來自北歐國家的大樣本隊列研究印證了上述結(jié)論[25]，然而，研究者發(fā)現(xiàn)FET組單胎妊娠出生兒大于胎齡兒及巨大兒發(fā)生率較新鮮胚胎移植組高，而且最近的一項(xiàng)研究表明，單純母體因素并不能完全解釋FET后巨大兒的高發(fā)生率[26]。

新鮮胚胎移植較差的圍產(chǎn)期結(jié)局可能與早期胎盤形成不良有關(guān)。這可能與新鮮胚胎移植孕婦超生理劑量的E2水平相關(guān)。研究表明，E2水平與妊娠前3個月較低的妊娠相關(guān)血漿蛋白A(PAPP-A)水平有關(guān)。另外，有研究表明，升高的血清E2水平與小于胎齡兒及子癇前期的高發(fā)生率[27]有關(guān)。

就整體情況而言，F(xiàn)ET妊娠結(jié)局較新鮮胚胎移植好。由于上述研究均為回顧性研究，質(zhì)量較好的胚胎均在新鮮胚胎移植組進(jìn)行移植，如果在新鮮胚胎移植周期行全胚凍FET，且選擇質(zhì)量最好的胚胎，則圍產(chǎn)期結(jié)局可能會更好，但目前關(guān)于全胚凍存FET的圍產(chǎn)期結(jié)局尚無研究。同時，F(xiàn)ET后出生兒大于胎齡兒及巨大兒高發(fā)生率的機(jī)制也有待進(jìn)一步研究， 出生兒大于胎齡兒與巨大兒后代的長期健康狀況也需要進(jìn)一步闡明。

雖然上述臨床證據(jù)表明，胚凍存FET較新鮮胚胎移植預(yù)后較好，但就以下問題仍有爭議。首先，凍存及凍融過程可能會對胚胎發(fā)育產(chǎn)生不利影響，凍存后胚胎的植入潛能與其解凍后質(zhì)量密切有關(guān)，有研究表明，解凍后完整的胚胎較損傷的胚胎有更高的發(fā)育及植入潛能[28]，但也有研究表明，只有少數(shù)卵裂球完整的胚胎仍能正常植入、妊娠，因此，僅靠形態(tài)學(xué)評估很難預(yù)測解凍后胚胎植入能力。解凍后培養(yǎng)是判斷凍存后胚胎活性更為嚴(yán)格的標(biāo)準(zhǔn)，從而有效提高胚凍存FET成功率。有研究表明，雙原核受精卵解凍后培養(yǎng)可有效避免移植嚴(yán)重凍存損傷胚胎，從而使植入率達(dá)到70%[29]。但解凍后培養(yǎng)可能使可移植胚胎數(shù)目減少，從而影響FET成功率。其次，有研究發(fā)現(xiàn)，解凍后囊胚紡錘體異常發(fā)生率較新鮮囊胚高，但研究者發(fā)現(xiàn)，雖然解凍后囊胚紡錘體異常發(fā)生率較高，但它們解凍后存活率并不受影響，這說明紡錘體異常本身并不會影響有絲分裂及胚胎的進(jìn)一步發(fā)育。再次，有研究發(fā)現(xiàn)，解凍后胚胎與新鮮胚胎相比，基因表達(dá)有所不用[30]，與相同發(fā)育階段的新鮮胚胎相比，解凍組與凋亡/壓力通道(BAX)、全能性通道(NANOG、SOX2、CDX2)有關(guān)的基因以及母系影響基因(ZAR1、E1F1AX、TSC2)等會發(fā)生改變。最后，全胚凍后行PET與新鮮胚胎移植相比，可能會增加患者的花費(fèi)，這主要取決于各個中心對FET的收費(fèi)、藥費(fèi)以及B超監(jiān)測費(fèi)用。另外，全胚凍存FET可能會延長患者的治療時間。但如果考慮到FET可以顯著降低OHSS的風(fēng)險、異位妊娠風(fēng)險及母兒并發(fā)癥的風(fēng)險，患者的整體花費(fèi)可能反而低于新鮮移植。

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10.3969/j.issn.1002-266X.2017.35.034

R714.7

A

1002-266X(2017)35-0102-04

2017-03-22)