冷凍胚胎移植的臨床應(yīng)用效果評(píng)價(jià)

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(píng)價(jià)

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(guó)及西班牙等國(guó)家，F(xiàn)ET周期已經(jīng)超過了新鮮胚胎移植周期，美國(guó)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(huì)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。現(xiàn)綜述如下。

1 移植成功率

美國(guó)疾控中心(CDC)統(tǒng)計(jì)了1997～2011年美國(guó)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(shí)間段內(nèi)，各個(gè)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(xiǎn)患者中行全胚凍存后FET有更高的臨床妊娠率[8]。考慮到行FET的多是質(zhì)量相對(duì)不好的胚胎，如果用質(zhì)量最好的胚胎行FET，可能成功率會(huì)更高。

最近一項(xiàng)包括三個(gè)隨機(jī)對(duì)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(jì)學(xué)差異。三個(gè)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(huì)對(duì)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(duì)象相對(duì)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(gè)RCTs均未報(bào)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(gè)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(huì)對(duì)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(cè)，全胚凍后行自然周期FET成功率可能會(huì)更高。

2 異位妊娠發(fā)生率

IVF-ET是異位妊娠的危險(xiǎn)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(huì)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(duì)于合并有其他高風(fēng)險(xiǎn)或不利條件的患者，例如OHSS高風(fēng)險(xiǎn)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(xiǎn)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(xiǎn)，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(gè)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(duì)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(duì)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(guó)家的大樣本隊(duì)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(gè)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(huì)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(shí)，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(zhǎng)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(zhēng)議。首先，凍存及凍融過程可能會(huì)對(duì)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(píng)估很難預(yù)測(cè)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(huì)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(huì)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(huì)增加患者的花費(fèi)，這主要取決于各個(gè)中心對(duì)FET的收費(fèi)、藥費(fèi)以及B超監(jiān)測(cè)費(fèi)用。另外，全胚凍存FET可能會(huì)延長(zhǎng)患者的治療時(shí)間。但如果考慮到FET可以顯著降低OHSS的風(fēng)險(xiǎn)、異位妊娠風(fēng)險(xiǎn)及母兒并發(fā)癥的風(fēng)險(xiǎn)，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)