胎盤標(biāo)志物對單絨雙羊雙胎妊娠合并雙胎輸血綜合征的預(yù)測:深部動靜脈吻合的形態(tài)學(xué)分析 點評

趙德鵬

(同濟大學(xué)附屬第一婦嬰保健院,上海 200040)

1 原文摘要

ObjectivesThe aim of this study w as to perform a detailed p rospective m orphometric analysis of a large consecutive series of m onochorionic tw in placentas in order to determine the frequency of candidate p lacental markers in TTTS p lacentas and,in particular,to determ ine the potential role of unbalanced deep AV anastom oses.

DesignA cohort of 284 consecutive monochorionic p lacentas was exam ined betw een 2001 and 2008.T riplet and quadrup let placentas,monochorionic-m onoamniotic placentas,p lacentas of gestations comp licated by tw in reversed arterial perfusion(TRAP)sequenceand placentas w ith remote(＞48 h prior to delivery)fetal demise of one tw inwere excluded.Of the remaining 253 diamniotic-monochorionic tw in p lacentas,53 were com plicated by TTTS, based on clinical and ultrasound evidence.O f the 53 TTTS cases,29 were treated by laser coagu lation of communicating vessels.These laser-coagulated TTTS p lacentas were excluded from this study.Thus 24 TTTS placentas w ere compared w ith 200 placentas of non-TTTS diamniotic-m onochorionic tw in gestations.Results

1)clinical data

The gestational age at delivery and the birth weights of the TTTS tw ins w ere lower than those of non-TTTS tw ins(Table 1).

2)General p lacental anatomy

The p lacental weights of TTTS tw ins were significantly low er than those of non-TTTS contro l tw ins. The p lacental markers, including velamentous insertion,frequency ofmarginal cord insertion,magistral or m ixed magistral/disperse vascular distribution patterns,＞25%difference in p lacental territory between twins and a single umbilical artery,were compared between non-TTTS control placentas and TTTS placentas(Table 2).

3) Choriovascular anatomy: superficial anastomoses(AA and VV)

The total number o f anastom oses visualized in the chorionic plate varied w idely between cases and reached amaximum of 23 in both TTTS and non-TTTS controlgroups.Superficial AA anastomoses were significantly more frequent in non-TTTS p lacentas than in TTTS.None of the TTTS p lacentas had m ore than one AA anastom osis.Among the non-TTTS cases,two p lacentas had 2 and one had 3 AA anastom oses.The diameter of AA anastomoses ranged from 0.05 to 0.4 cm in TTTS p lacentasand from 0.05 to 0.6 cm in non-TTTS controls.

VV anastomoses were more than tw ice as frequent in TTTS p lacentas as in non-TTTS controls.None of the TTTS p lacentas had m ore than one VV anastomosis,whereas six non-TTTS control placentas had 2 VV anastomoses.The maxim al diam eter o f VV anastom oseswas 0.6 cm in TTTS placentas and 0.4 cm in non-TTTS controls.

4)Choriovascular anatomy:deep AV anastom oses

AV anastomoses were seen in95% TTTS placentas and 96%of non-TTTS placentas.The median net number of AV anastom oses w as 2 in both groups,with values ranging from 0 to 7 in TTTS and from 0 to 15 in non-TTTS p lacentas(Table 2).The NCSA was significantly sm aller in TTTS placentas than in non-TTTS controls.Sensitivity and specificity of key p lacentalmarkers as post-hoc predictors of TTTS are shown in Tab le 3. None of the individual candidate p lacental variables,how ever are reliable post-hoc predictors of TTTS.

2 論文核心內(nèi)容及點評

該文發(fā)表在 Placenta 2010年第31卷269-276頁上。該文對雙胎輸血綜合征(TTTS)病因的傳統(tǒng)觀點作一深入的直接的研究和分析。主要內(nèi)容如下:

傳統(tǒng)觀點認為雙胎間存在動靜脈(AV)吻合,而AV吻合中的血流是單向的,因此正是AV吻合中的單向血流造成雙胎間血液分配不平衡,進而發(fā)生TTTS。盡管認為AV吻合是TTTS的主要病因,但以往的研究大多集中在胎盤表面的動動脈(AA)和靜靜脈(VV)吻合,對AV吻合的直接研究很少。因此可以說AV吻合是TTTS的主要病因還只是1種觀察實驗的推測。并無直接實驗驗證。這可能與AV吻合在胎盤深部,無法直接觀察,且研究費時有關(guān)。

因此在2001～2008年之間,該研究以200例未合并TTTS的單絨雙羊雙胎妊娠和24例合并TTTS的單絨雙羊雙胎妊娠為樣本,采用分娩后胎盤灌注技術(shù),對兩者的胎盤進行了分析比較。為了對2組胎盤進行盡可能準(zhǔn)確的比較,該研究應(yīng)用凈AV吻合數(shù)、凈AV吻合橫截面積,即考慮到AV吻合內(nèi)血流既有供血兒流向受血兒也有受血兒流向供血兒,因此可相互抵消,最終轉(zhuǎn)化為實際的AV吻合數(shù)和AV吻合面積。

該研究結(jié)果顯示:首先,non-TTTS胎盤AV吻合(96%)較TTTS胎盤AV 吻合(95%)更常見,non-TTTS胎盤無論凈AV吻合數(shù)還是AV吻合凈橫截面積都較TTTS多。而且non-TTTS極值情況更易見。甚至在本研究中有1例TTTS胎盤并無AV吻合(表1和表2)。因此傳統(tǒng)觀點認為 AV吻合是TTTS的病因可能不合理。其次,該研究通過分娩后胎盤灌注比較后,對TTTS胎盤特征進行了總結(jié)并深入分析了這些胎盤特征預(yù)測TTTS的特異性和敏感性。研究發(fā)現(xiàn)TTTS胎盤特征包括胎盤不均衡分配(雙胎間胎盤面積差異＞25%)、缺乏AA吻合、VV吻合較多、臍帶帆狀附著等。各胎盤特征的特異性和敏感性見下(表3)。最后,該研究還發(fā)現(xiàn)AV吻合內(nèi)血流方向與供血兒 受血兒的鑒別并無肯定的聯(lián)系。因為AV吻合中的血流既可以從 供血兒 流向 受血兒 ,亦可從受血兒 流向 供血兒 。

表1 胎盤數(shù)據(jù)

表2a 胎盤

表2b 絨毛膜血管吻合

表3 胎盤檢查確診TTTS的準(zhǔn)確性

血液在血管中的流動受許多因素的影響包括:血管直徑、血液壓力、血液黏度、血管活性因子及各種感受器等。而以往研究(包括該研究),主要針對血管形態(tài)學(xué)。因此以往從形態(tài)學(xué)研究得出的結(jié)論最終又被形態(tài)學(xué)研究否定。但這也提示TTTS病因可能并非形態(tài)學(xué)異常,而是各種非形態(tài)學(xué)因素。現(xiàn)在已經(jīng)有一些研究證實這一觀點。Bajoria R等和Sooranna SR等分別發(fā)現(xiàn)TTTS供血兒體內(nèi)胰島素樣生長因子-II及瘦素水平較受血兒低,這與胎盤的生長紊亂有關(guān),而與血流無關(guān)。Bajoria R、Galea P、Mahieu-Caputo D等還發(fā)現(xiàn)血管活性因子腦鈉鈦(BNP)、內(nèi)皮素-1及腎素-血管緊張素(RAS)系統(tǒng)異常可能是導(dǎo)致、維持并促使TTTS惡化的原因。

該研究發(fā)現(xiàn)雙胎間胎盤面積差異＞25%及胎盤血管單支分布是TTTS特異性較高的標(biāo)志?？勺鋈缦峦普?假設(shè)雙胎所占胎盤面積分別為A和B。若發(fā)生TTTS的風(fēng)險較小(考慮胎盤共享)應(yīng)滿足:A+B＞100%且 A-B＜25%?？梢缘贸?B＞37.5%。據(jù)上述推論單絨雙羊雙胎時,每個胎兒所占胎盤面積可能應(yīng)大于37.5%。TTTS胎盤標(biāo)志為胎盤不均衡分配(雙胎間胎盤面積差異＞25%)、缺乏AA吻合、臍帶帆狀附著、血管單支分布等似乎都與胎盤面積有關(guān)。這也提示在對于MCDA的雙胎胎盤的病理學(xué)檢查中,要將以上幾個指標(biāo)納入常規(guī)的病理解剖報告中。

胎盤是胎兒-母體進行物質(zhì)交換的場所。TTTS實質(zhì)是胎盤異常,包括胎盤血管的構(gòu)建和功能異常。而正常胎盤的形成需要細胞增殖與新生血管形成兩者之間密切協(xié)調(diào)。而且有多種細胞(如巨噬細胞)和細胞因子(如有血管內(nèi)皮生長因子(VEGF)、酸性堿性成纖維細胞生長因子(FGF)、轉(zhuǎn)化生長因子(TGF)、血小板源生長因子(PDGF)、胎盤生長因子(PIGF)、腫瘤壞死因子(TNF)、血管生成素(angiopoietins)等共同參與胎盤血管形成的調(diào)節(jié)。而且胎盤形成是動態(tài)變化的過程,不同孕周胎盤血管生成的形態(tài)及調(diào)節(jié)因素是不同的。因此TTTS胎盤異常應(yīng)該包括形態(tài)學(xué)異常和非形態(tài)學(xué)異常。甚至非形態(tài)學(xué)的異常,包括各種細胞因子和血管活性因子,在TTTS發(fā)生發(fā)展中可能起決定作用。TTTS胎盤特征也提示TTTS胎盤中可能存在著抗血管生成的因素。

近9%～15%的單絨雙羊雙胎妊娠并發(fā)TTTS,胎兒發(fā)病率和死亡率高達70%以上。而至今尚無預(yù)測TTTS的理想指標(biāo)和方法。綜合這幾年文獻,各種血管活性因子和促進血管形成的細胞因子可能是TTTS病因和預(yù)測進一步的研究方向。