“輔助生殖導(dǎo)致孕婦血清中妊娠相關(guān)血漿蛋白-A水平降低并導(dǎo)致唐氏綜合征妊娠早期篩查中假陽(yáng)率升高”點(diǎn)評(píng)

相玉倩

（復(fù)旦大學(xué)生物醫(yī)學(xué)研究院發(fā)育生物學(xué)與出生缺陷研究所，上海 200032）

1 論文題目及原文摘要

Pregnancies conceived using assisted reproductive technologies（ART）have low levels of pregnancy-associated plasma protein-A （PAPP-A）leading to a high rate of false-positive results in first trimester screening for Down syndrome

Pregnancy screening for Down syndrome（DS）and other chromosome abnormalities has become part of routine antenatal care over the last 20 years.The measurement of second trimester biochemical markers in the blood of pregnant women to improve screening for DS based on maternal age alone was first described in 1988.Over the last 10 years，second trimester serum screening has been progressively replaced by first trimester combined screening.The first trimester combined screen measures maternal serum levels of free beta-human chorionic gonadotrophin（fβ-hCG）and pregnancy-associated plasma protein-A（PAPP-A）at 9-12 weeks gestation and measures nuchal translucency（NT）by ultrasound at 11-13 weeks gestation.These measurements are combined with maternal age，weight and gestational age to produce a risk estimate of the fetus having DS or trisomy 18 （T18）.For pregnancies at increased risk，prenatal diagnostic testing，CVS or amniocentesis，can be offered.In the Victorian population，the sensitivity of the first trimester combined screen for DS is 91%（using a risk threshold of 1 in 300 at the time of ultrasound），with the proportion of unaffected pregnancies receiving an increased risk result（false positive rate，F(xiàn)PR）being 3.9%.Pregnancies conceived using assisted reproductive technologies（ART）now account for 3%of all live births in Australia.Previous studies of second trimester serum screening have shown that serum markers in ART pregnancies differ from natural conceptions，leading to an increased FPR.We hypothesized that in pregnancies conceived using ART，factors exist that are absent in natural conceptions，potentially influencing the marker levels，and consequently，risk results of the first trimester combined screen.The aims of this study were to investigate in a large population-based sample，the effect of ART on the individual markers of the first trimester combined screen （fβ-hCG，PAPP-A and NT）and on the FPR.We also aimed to investigate the effect of different ART modalities on these markers，and the impact of ART and screening results on the uptake of prenatal diagnostic testing（CVS and amniocentesis）following first trimester combined screening.

Learning Objectives：Through this article，the readers should be aware of the effects of ART on first trimester screening for Down syndrome and the factors exiting in the ART that cause the effect.

2 論文核心內(nèi)容及點(diǎn)評(píng)

本研究論文發(fā)表在Human Reproduction，2009，24（16）：1330-1338上。作者通過(guò)對(duì)大樣本人群調(diào)查，研究輔助生殖技術(shù)（ART）對(duì)早期妊娠檢測(cè)標(biāo)志物（fβ-hCG、PAPP-A和 NT）和假陽(yáng)性率的影響，同時(shí)作者還研究了不同ART形式對(duì)上述結(jié)果影響的差別，以及ART和篩查結(jié)果對(duì)后續(xù)產(chǎn)前診斷（如絨毛膜取樣和羊膜腔穿刺）的影響。該論文的核心內(nèi)容如下：

唐氏綜合征妊娠早期篩查包括檢測(cè)母親血漿中游離β-絨毛膜促性腺激素（fβ-hCG）和妊娠相關(guān)血漿蛋白-A（PAPP-A）及超聲探測(cè)胎兒頸部透明層厚度（NT），并結(jié)合母親年齡、體重及孕齡，對(duì)胎兒患唐氏綜合征的風(fēng)險(xiǎn)進(jìn)行評(píng)估。

本研究以2000～2004年間澳大利亞的維多利亞州的1 739例ART單胎妊娠孕婦和50 253例自然受孕單胎妊娠孕婦為調(diào)查對(duì)象，比較了ART孕婦和自然受孕孕婦血清標(biāo)記物（包括游離β-hCG和PAPP-A）的水平及對(duì)應(yīng)患兒檢出的假陽(yáng)性率。在ART孕婦中PAPP-A濃度為0.83 Mo M，而在非-ART孕婦中為1.00 Mo M，與自然受孕孕婦相比，ART孕婦的PAPP-A水平顯著降低（P＜0.001），同時(shí)ART孕婦孕期并發(fā)癥和產(chǎn)科并發(fā)癥的發(fā)病率明顯升高，且并發(fā)癥孕婦中PAPP-A水平更低，排除妊娠綜合征病例后，這種顯著性差異仍然存在。與非ART孕婦相比，ART孕婦早期篩查中假陽(yáng)性率升高（OR 2.71，95%CI 2.19～3.35；P＜0.001），從而導(dǎo)致需要進(jìn)行絨毛膜取樣或者羊膜腔穿刺的ART孕婦的數(shù)目增多（OR 2.10，95%CI 1.76～2.50；P＜0.001）。作者同時(shí)分析了不同的ART對(duì)早期妊娠檢測(cè)標(biāo)志物（fβ-hCG、PAPP-A和 NT）和假陽(yáng)性率的影響。作者研究表明，與冰凍胚胎移植相比，新鮮胚胎移植更容易導(dǎo)致PAPP-A水平的降低，此外激素等因素也會(huì)引起PAPP-A水平的降低，從而增加了患兒檢出的假陽(yáng)性率。

綜上所述，輔助生殖技術(shù)的應(yīng)用顯著降低了唐氏綜合征產(chǎn)前篩查血清標(biāo)志物PAPP-A水平，增加了患兒檢出的假陽(yáng)性率，這使得需要進(jìn)行絨毛膜取樣或者羊膜腔穿刺的ART孕婦增多。絨毛膜取樣和羊膜腔穿刺對(duì)孕婦和胎兒都存在一定的危害性。作者最后指出，ART孕婦，尤其是接受激素處理的ART孕婦，在篩查中存在假陽(yáng)性率高的因素，如何準(zhǔn)確評(píng)估所引起的風(fēng)險(xiǎn)改變，有待進(jìn)一步的研究。

點(diǎn)評(píng)：輔助生殖技術(shù)（assisted reproductive technology，ART）是指所有涉及體外操作人的卵子和精子或胚胎，以達(dá)到妊娠目的的方法。近年來(lái)，隨著輔助生殖技術(shù)的開展，越來(lái)越多的不孕不育患者借助各種ART技術(shù)懷孕。ART包括體外受精、卵胞漿內(nèi)精子注射技術(shù)和體外受精-胚胎移植技術(shù)等，ART的應(yīng)用使得高齡產(chǎn)婦和雙胎（或多胎）孕婦增加，與自然受孕孕婦相比，ART孕婦接觸的各種影響因素更多，這很可能影響了妊娠早期篩查中的分子標(biāo)志物的水平及假陽(yáng)性率，并最終影響篩查結(jié)果的準(zhǔn)確性。