周文婷

(同濟(jì)大學(xué)第一婦嬰保健院,上海 200040)

1 原文摘要

Second-trimester Down syndrome maternal serummarkerscreening:aprospectivestudyof11 040twinpregnancies

The general approach to prenatal screening for Down syndrome(DS)is to estimate a woman's risk of having a trisomy 21-affected pregnancy on the basis of factors such asmaternal age,maternal serum markers(MSMs),and first-trimester nuchal translucency(NT)measurement.Maternal serum screening for DS in tw in p regnancies is fraughtwith difficulties(Cuck le,1998;Wald and Rish,2005).Firstly,serum marker levels in unaffected tw in pregnancies are considered to be double those observed in singleton pregnancies.In addition,the distributions of the serum markers in DS-affected tw in p regnancies are not known with any degree of reliability.Second ly,MSMlevels in tw ins are a reflection of both tw ins and m ay be confounded by the presence of an unaffected cotw in resulting in a lower detection rate than in a singleton pregnancy,while NT measurement is specific to each fetus.Thirdly,the patient-specific maternal age-related risk in twin p regnancies depends on zygosity and chorionicity.In monochorionic tw in pregnancies,DS risk due to maternal age is the same as in singleton pregnancies(but both fetuses are DS-affected),whereas in dichorionic twin pregnancies,the risk of having at least one aneup loid fetus is doub led(each with an a priori risk of aneup loidy).Whatever them ethod,because of specific p rob lems related to tw in p regnancies(doub le am niocentesis,selective TOP),DS screening in twins m ust be perform ed in tandem with multidiscip linary centers and clear informationmust be given to patients by a geneticist and an obstetrician.

Learning Objectives:A fter comp letion of this article,the reader should be able to know about the value of Down Synd rome(DS)secondtrimester maternal serum screening of tw in pregnancies,choose the method for secondtrimester DS screening to perform in tw in pregnancies.

2 論文核心內(nèi)容及點(diǎn)評

該論文發(fā)表在 TW IN RESEARCH AND HUMAN GENETICS,2009,JUN 12(3):237-245上。該文對孕中期唐氏綜合征的孕婦血清標(biāo)志物篩查在雙胎妊娠的應(yīng)用價值進(jìn)行了大樣本的前瞻性研究,主要內(nèi)容如下:

唐氏綜合征(Down Syndrome,DS)又稱21-三體綜合征,是1種由染色體異常導(dǎo)致的出生缺陷?；純罕憩F(xiàn)為智力障礙、生長發(fā)育遲緩、特殊面容、常伴有心臟、消化道等多系統(tǒng)畸形,是最常見的非致死性染色體疾病,因此也是產(chǎn)前篩查和診斷的焦點(diǎn)。通常唐氏綜合征的產(chǎn)前篩查是結(jié)合某些因素及檢查對孕婦懷有21-三體綜合征胎兒的風(fēng)險進(jìn)行評估,這些因素及檢查包括產(chǎn)婦年齡,孕婦血清標(biāo)志物和早孕期胎兒頸項透明層厚度(nuchal translucency,NT)的測量。在單胎妊娠中,這項篩查已經(jīng)普遍運(yùn)用于臨床,而在雙胎妊娠中,母體血清唐氏篩查卻困難重重。首先,目前認(rèn)為正常雙胎妊娠的孕婦的血清標(biāo)志物水平是單胎妊娠中觀察到的2倍,而從實際臨床中的數(shù)據(jù)顯示并非如此。此外,在有唐氏患兒的雙胎妊娠的孕婦的血清標(biāo)志物數(shù)值與唐氏綜合征發(fā)病率預(yù)測的相關(guān)性并不可靠。其次,雙胎妊娠的母體血清學(xué)指標(biāo)是反映2個胎兒的情況,可能由于1名正常胎兒的存在使檢出率低于單胎妊娠的檢出率。第三,在雙胎妊娠中,產(chǎn)婦的年齡相關(guān)性風(fēng)險取決于妊娠的卵型和絨毛膜型。在單絨毛膜雙胎妊娠中,唐氏綜合征的年齡相關(guān)性風(fēng)險與單胎妊娠相同(即2個胎兒均為唐氏綜合征患兒);而在雙絨毛膜雙胎妊娠中,至少懷有1個非整倍體染色體異常胎兒的風(fēng)險會增加1倍(每個胎兒均有非整倍體染色體異常的風(fēng)險)。

本文對1998～2006年間收集的全法國11 040例雙胎妊娠的孕中期孕婦血清標(biāo)志物(包括甲胎蛋白AFP以及游離β-hCG)情況進(jìn)行了前瞻性研究,比較了單胎妊娠與雙胎妊娠中21-三體綜合征的發(fā)病率、母體血清學(xué)標(biāo)記物對應(yīng)的患兒檢出率及假陽性率。21-三體綜合征在雙胎妊娠中的發(fā)病率為1/649(27/11 040例),而在單胎妊娠中為1/754(86/64 815例),這一結(jié)果無顯著差異。而在雙胎妊娠中,DS患兒檢出率為63%(2個胎兒均為DS患兒時檢出率為 71%,僅有 1名DS患兒的檢出率為60%);在單胎妊娠中,DS患兒檢出率為74.4%。而假陽性率在雙胎妊娠中為10.8%;在單胎妊娠中為10.3%,兩者無明顯差異。

同樣,作者對于這些孕婦也開展了孕早期的相關(guān)唐氏綜合征的篩查項目檢測。在孕早期對于雙胎妊娠的21-三體綜合征患病風(fēng)險的評估中,胎兒頸項透明層厚度(NT)篩查結(jié)果也是極具爭議的。該項檢測的敏感度與單胎妊娠檢測相近,但其假陽性率較之明顯升高。數(shù)據(jù)表明,在孕早期進(jìn)行母體血清學(xué)標(biāo)記物篩查(PAPP-A、游離β-hCG)結(jié)合胎兒NT篩查可以將唐氏患兒檢出率由64.9%提高到86.5%,而假陽性率也由2.3%升至4.7%。

綜上所述,作者認(rèn)為可以在雙胎妊娠開展孕中期唐氏綜合征的孕婦血清學(xué)標(biāo)志物篩查。但結(jié)合篩查方法的敏感性以及特異性,首先可以建議孕婦在早孕期間進(jìn)行胎兒頸項透明層厚度(NT)檢測,如有特殊情況或者孕婦拒絕此項篩查時,可于孕中期進(jìn)行母體血清學(xué)標(biāo)志物篩查。

點(diǎn)評:近年來,隨著孕產(chǎn)婦年齡增長而隨之開展了許多的輔助生殖技術(shù),這也致使雙胎及多胎妊娠發(fā)生率逐年增長,因此對于這部分孕婦胎兒的唐氏綜合征篩查方法的選擇引起越來越多臨床醫(yī)生的關(guān)注。與單胎妊娠比較,雙胎及多胎妊娠的唐氏篩查的檢出率及假陽性率受到更多因素的影響,諸如孕產(chǎn)婦的年齡、胎兒卵型等情況。因此,對雙胎妊娠進(jìn)行唐氏綜合征進(jìn)行篩查和診斷方法的選擇至關(guān)重要。

本文作者進(jìn)行了1項大樣本的關(guān)于雙胎妊娠的唐氏綜合征孕婦孕中期血清標(biāo)志物篩查的前瞻性研究,并將常用的早孕期篩查標(biāo)志物(PAPP-A、游離β-hCG、胎兒頸項透明層厚度等)與孕中期孕婦血清標(biāo)志物篩查的敏感性、檢出率及假陽性率進(jìn)行比較,指出在孕中期對雙胎妊娠孕婦可以進(jìn)行血清標(biāo)志物的篩查,但其風(fēng)險計算與單胎妊娠不同,需要進(jìn)行調(diào)整。文章還提出無論選擇何種篩查方法,都需要在明確孕婦情況后,由遺傳學(xué)家聯(lián)合產(chǎn)科醫(yī)生對孕婦進(jìn)行篩查結(jié)果的告知,這對于目前產(chǎn)前診斷及咨詢方式有很好的指導(dǎo)意義。