双胎妊娠的产前筛查、诊断与干预：转诊是关键

双胎妊娠产前筛查和诊断具有极强的专业性和复杂性,颈项透明层（NT）厚度联合外周血游离DNA［无创产前检测（NIPT）］检测可提高非整倍体筛查的检出率,减少不必要的介入性产前诊断。双胎之一胎儿异常后的宫内干预需建立在精准的产前诊断基础之上。双胎妊娠的特殊并发症的诊治应转至专业的产前诊断中心或区域性的胎儿医学中心进行。     

Down syndrome screening in multiple pregnancies

First or second trimester screening in twin pregnancies is feasible and still efficacious by using either a combination of ultrasound and maternal serum biochemistry in the first trimester or maternal serum biochemistry in the second trimester. Special care, however, should be emphasized in what concerns biochemical screening, since it is much less sensitive in multiples. These "pseudo-risks" have been challenged for their scientific and clinical validity, however. Until more data are available from larger studies on the distribution of markers in concordant or discordant twins, nuchal translucency estimated for each fetus should be the predominant factor by which women who present with increased risk should be counseled regarding invasive testing. In dizygotic pregnancies, pregnancy-specific risk should be calculated by summing the individual risk estimates for each fetus. In monozygotic twins, the risk should be calculated based on the geometric mean of both nuchal translucency measurements, not forgetting that the false-positive rate of nuchal translucency screening is expectantly higher than in singletons.     

Strategies of antenatal diagnosis and management of pathologies related to multiple pregnancies

In the first trimester, ultrasound is crucial to screen for aneuploidies based on nuchal translucency, to diagnose major birth defects, and to establish chorionicity. Indeed prenatal diagnosis strategies as well as obstetrical management options are largely based on placental type. In the second trimester, maternal serum screening is not as effective, and ultrasound screening is more difficult in twins than in singletons. When a severe abnormality in found in one twin, selective termination of pregnancy may be considered. This technique is safe in dichorionic twins, but hazardous in monochorionic pregnancies. Selective termination in dichorionic twins is safer in the first trimester, underscoring the need for early prenatal diagnosis in twins. Monochorionic twin pregnancies carry specific risks, such as the twin-to-twin transfusion syndrome, which can be treated by endoscopic photo-coagulation of intertwin anastomoses in the severe early onset cases, or by amnioreduction in milder cases.     

双胎妊娠染色体异常的产前筛查及产前诊断

双胎妊娠发生胎儿畸形、染色体异常的风险较单胎妊娠高。近年来双胎妊娠发生率和高龄产妇数量不断增加,双胎妊娠的早期筛查以及产前诊断十分重要。早孕期,颈项透明层(nuchal translucency,NT)超声筛查是重要手段,不建议单独使用血清学筛查;中孕期超声结构筛查对检出胎儿结构异常有一定意义。无创产前基因检测技术的发展,对降低侵入性产前诊断的风险有重要意义,但由于目前临床证据尚不充分,双胎妊娠行无创基因检测仍需谨慎。     

First trimester screening for aneuploidy: Nuchal translucency sonography

Prenatal diagnosis of fetal aneuploidy is a continuously and rapidly evolving area of research. Currently in the United States, the standard of care for screening pregnancies for aneuploidy involves assessment of maternal age together with the use of multiple second trimester maternal serum markers. This screening approach identifies approximately 60% of pregnancies with fetuses affected with Down syndrome and provides results in the second trimester of pregnancy. First trimester screening for aneuploidy by using nuchal translucency sonography is one of the most promising areas of research in the detection of Down syndrome. This screening method involves measuring the normal space located between the cervical spine and overlying fetal skin at 10 to 14 weeks' gestation. Studies from both high risk and unselected patient populations suggest significant advantages to this approach for Down syndrome detection compared with currently available second trimester screening methods. The combination of first trimester biochemical screening and nuchal translucency measurements may further improve the efficacy of prenatal screening for aneuploidy. The article reviews studies suggesting a role for nuchal-translucency-based aneuploidy screening and describes areas of ongoing research in this field.     

Screening and diagnosis of chromosomal abnormalities in twin pregnancy

Twin pregnancies are at an increased risk of adverse pregnancy and perinatal outcome as compared to singleton gestations, mainly as the consequence of the higher rate of preterm birth, chromosomal as well as structural anomalies, placental abnormalities, and complications unique to monochorionic placentation.Screening for chromosomal anomalies poses diagnostic and management challenges when applied to twin pregnancies. The recent implementation of cell-free fetal DNA (cffDNA) in clinical practice raises the questions whether a more accurate test should be offered to twin pregnancies in view of the higher false positive rate of traditional screening and the higher risk of fetal loss following amniocentesis or chorionic villus sampling (CVS) in multiple gestations. Finally, twin pregnancies require a tailored approach for aneuploidy screening, such as nuchal translucency (NT) or crown rump length discordance, discordant fetal anomalies, or monoamniotic gestations.The present review aims to provide an up-to-date critical appraisal of screening and prenatal diagnosis of chromosomal abnormalities in twin pregnancies.     

Screening for trisomy 21 in twin pregnancies in the first trimester using free beta-hCG and PAPP-A, combined with fetal nuchal translucency thickness

In the first trimester of pregnancy the biochemical markers free beta-hCG and pregnancy associated plasma protein-A (PAPP-A) are used for the prenatal screening of trisomy 21, either alone or in combination with nuchal translucency (NT) thickness. In this study, I have analysed the distribution of these biochemical markers in 159 twin pregnancies and compared this with 3466 singleton pregnancies. On average free beta-hCG values are 2.099 times greater in twins than in singletons and PAPP-A some 1.86 times greater. The width of the analyte distribution in twins is very similar to that in singleton pregnancies. Using statistical modelling techniques I have predicted that at a 5% false positive rate the detection rate in twins discordant for trisomy 21 will be 52% and in twins concordant for trisomy 21 will be 55%, if correction for twin pregnancy is carried out using the 'pseudo risk' approach. The detection rate using biochemical parameters is less than that achievable for twins using NT (75%). However, the combination of NT and maternal serum biochemistry will give detection rates approaching 80%. These rates are some 10% less than in singleton pregnancies, but nevertheless combining NT and biochemistry will allow high rates of detection of affected twins with the benefit of ultrasound and NT being able to specifically locate the affected twin. Twin screening using both modalities should be considered when introducing first trimester screening.     

双胎妊娠胎儿染色体非整倍体产前筛查的研究进展

双胎妊娠胎儿染色体非整倍体疾病的发生率较单胎妊娠高,同时其筛查受到很多因素的影响。双胎妊娠的合子性质非常重要,直接影响风险率的计算模式,临床实践中多以妊娠早期绒毛膜性间接判断。目前双胎妊娠染色体非整倍体疾病筛查方案集中在妊娠早期胎儿颈部半透明层厚度(nuchal translucency,NT)筛查、妊娠早期联合筛查(NT+血清学筛查)、妊娠中期血清学筛查以及利用无创产前检测技术(noninvasive prenatal test,NIPT)进行胎儿染色体非整倍体疾病筛查。这些方案主要涉及染色体疾病中发病率较高的21-三体综合征和18-三体综合征。考虑到检出率、假阳性率以及经济学效应,妊娠早期联合筛查为目前双胎妊娠染色体非整倍体疾病筛查的主要方案,对近年来双胎妊娠染色体非整倍体产前筛查研究进展进行综述。     

Nuchal translucency in pregnancies conceived after assisted reproduction technology

PURPOSE OF REVIEW: Nuchal translucency is one of the important markers in the first trimester during antenatal screening for fetal Down's syndrome. With the observation of alterations in biochemical markers in pregnancies conceived after assisted reproduction, this review presents current information related to the thickness of nuchal translucency in these pregnancies. RECENT FINDINGS: Early small studies did not demonstrate any discrepancy in the thickness of nuchal translucency in fetuses from assisted reproduction and from spontaneous pregnancies, but there has been recent evidence to suggest an increased level of nuchal translucency in singletons from various modes of assisted-reproduction technology. Nuchal translucency in twins following assisted reproduction did not, however, show a similar increase. Although the effect of chorionicity was not specifically addressed, nuchal translucency thickness in twins born after assisted reproduction was reported to be comparable to that in spontaneous singletons. It is possible that singletons and twins after assisted reproduction exhibit different antenatal behavior and pregnancy courses. SUMMARY: Similar to other biochemical markers of fetal Down's syndrome, nuchal translucency is increased in singletons after assisted-reproduction technology. Further studies on twin pregnancies, in particular dichorionic twins, are necessary before conclusive evidence can be drawn for multiple pregnancies.     

Screening for trisomy 21 in twin pregnancies by maternal age and fetal nuchal translucency thickness at 10–14 weeks of gestation

Objective To determine the prevalence of increased fetal nuchal translucency thickness in twin pregnancies and to evaluate screening for trisomy 21 by a combination of translucency thickness and maternal age.
Design Prospective screening study at 10 to 14 weeks of gestation.
Setting Fetal Medicine Centre.
Population 22,518 self-selected pregnant women at 10 to 14 weeks of gestation, including 21,477 singleton and 448 twin pregnancies with live fetuses.
Methods Fetal nuchal translucency thickness was measured by ultrasound examination at 10–14 weeks. Sensitivity and false positive rates of screening for trisomy 21 by a combination of fetal nuchal translucency thickness and maternal age were calculated.
Main outcome measures Prevalence of increased nuchal translucency thickness and detection of trisomy 21.
Results In the 448 twin pregnancies the nuchal translucency thickness was above the 95th centile of the normal range (for crown-rump length in singletons) in 65/896 fetuses (7.3%), including 7/8 (88%) with trisomy 21. Increased translucency was also present in four fetuses with other chromosomal abnormalities. In the chromosomally normal twin prebmancies the prevalence of increased nuchal translucency was higher in fetuses from monochorionic (8.4%; 16/190) than in those with dichori-onic pregnancies (5.4%; 37/688). The minimum estimated risk for trisomy 21, based on maternal age and fetal nuchal translucency thickness, was 1 in 300 in 19.5% (175/896) of the twins including all eight of those with trisomy 21.
Conclusions In twin pregnancies the sensitivity of fetal nuchal translucency thickness in screening for trisomy 21 is similar to that in singleton pregnancies, but the specificity is lower because translucency is also increased in chromosomally normal monochorionic twin pregnancies.     

双胎妊娠非整倍体异常的产前筛查与产前诊断

双胎妊娠非整倍体产前筛查较单胎复杂。应在早孕期确定孕周、绒毛膜性并测量颈项透明层厚度。早孕期联合筛查优于中孕期血清学筛查,但检出率明显低于单胎妊娠。无创产前检查用于双胎筛查仍需更多研究数据。双胎之一胚胎停育将影响早孕期筛查的准确性。产前诊断时区分标记双胎是需要注意的重要问题。     

双胎妊娠的孕期胎儿监护

因绒毛膜性不同,单绒双胎较双绒双胎胎儿的特殊并发症较多,围产儿预后较差。如何减少双胎妊娠母胎并发症,除了加强规范产前检查与健康指导,应在孕早期尽早超声监测明确绒毛膜性。孕早中期超声测量胎儿颈项透明层厚度以及系统超声筛查胎儿结构畸形,及早发现胎儿异常尤其是单绒双胎一些特有的特殊并发症,进行个体化超声动态监测、胎儿脐血流及胎心电子监护等了解胎儿宫内安危,及时发现异常及时干预,必要时终止妊娠,以降低出生缺陷,改善围产儿预后,保障母儿安全。     

Prenatal diagnosis in twin gestations

Twin gestations face an increased risk of structural abnormalities compared with singleton gestations, as well as an increased risk of aneuploidy. Accordingly, there is a need for accurate prenatal diagnosis of fetal genetic disorders and structural anomalies in twin gestations. Given the increased risk of congenital anomalies, a detailed sonographic survey of fetal anatomy is recommended in the early second trimester of twin gestations. In addition, fetal echocardiography should be considered in monochorionic twin gestations and in dichorionic twin pregnancies conceived using assisted reproductive technologies given the increased risk of congenital heart disease in these populations. Although first- and second-trimester aneuploidy screening in twin gestations is available, screening is less accurate than in singleton gestations. Invasive prenatal diagnosis in twin pregnancies is associated with a risk of pregnancy loss that is higher than the baseline risk of loss among twin gestations. Precise procedure-related loss rates in twin gestations undergoing chorionic villus sampling or amniocentesis, however, remain unclear because of methodological differences between published studies investigating diagnostic procedures in twins.     

Predictive value of increased nuchal translucency as a screening test for the detection of fetal chromosomal abnormalities

Objective.?The study aimed to estimate the incidence of increased nuchal translucency in the first trimester ultrasound scan results (cut-off limit 2.5 mm) and to evaluate the predictive value of increased nuchal translucency as a screening test for the detection of fetal chromosomal abnormalities.

Methods.?We used the ultrasound scan results of nuchal translucency evaluation and the results of chromosomal analysis of the invasive prenatal control performed as a result of increased nuchal translucency.

Results.?We collected 2183 nuchal translucency ultrasound scans in which we detected 21 embryos with a pathologic value (0.96%). We collected the data of 168 cases of invasive prenatal control due to increased nuchal translucency from which 122 cases were found. A total of 122 cases of pregnant women undergone an invasive prenatal diagnostic method due to increased nuchal translucency, of which 11 fetuses were found with trisomy 21 (Down syndrome) (9%), 3 fetuses with trisomy 13 (Patau syndrome) (2.45%), 3 fetuses with monosomy 45XO (Turner syndrome) (2.45%) and 1 fetus with translocation (0.8%).

Conclusions.?The positive predictive value of the increased fetal nuchal translucency as a screening test for the detection of fetal chromosomal abnormalities based on the results of the chromosomal-genetic analysis of the invasive prenatal diagnostic procedures is 14.8%.     

Down syndrome screening in twins

Available methods for screening for Down syndrome (DS) in twin gestations include maternal age, first-trimester nuchal translucency, first-trimester combined screening, second-trimester genetic sonography, second-trimester quad screening, and combinations of tests across different gestational ages. Biochemical screening is generally associated with detection rates at least 15% less than in singleton pregnancies. Nuchal translucency measurement may help close that gap, but the best available data (based on modeling) show approximately 75% to 85% detection rates for DS, with a 5% false-positive rate. Patients accepting screening should be aware of all options should a diagnosis of fetal aneuploidy be confirmed, including pregnancy continuation, termination of the entire pregnancy, and selective termination of an aneuploid fetus.     

Prospective study of parental choice for aneuploidy screening in assisted conception versus spontaneously conceived twins

The aim of this study was to evaluate and compare parental choice towards the use of aneuploidy screening and diagnostic techniques after assisted conception versus spontaneously conceived pregnancy. A total of 193 patients with consecutive twin pregnancies participated in the study, including 143 who spontaneously conceived and 50 who conceived following assisted reproduction treatment. Patients were investigated prospectively for their choice in the prenatal screening/diagnosis of aneuploidy. In the group of patients who conceived spontaneously, 111 (77.6%) opted initially for the non-invasive screening based on nuchal translucency measurements, whereas in the assisted conception group, 44 (88%) opted for the non-invasive screening. In the spontaneous conception group, 32 (22.4%) presented because they had a positive serum screening test or because they had opted for a chorionic villus sampling (CVS) or an amniocentesis for advanced maternal age. In the assisted conception group only six patients (12%) opted for amniocentesis. The difference in choice of noninvasive versus invasive screening between those with spontaneous and those with assisted conception was not significant, but those who had conceived spontaneously after the age of 37 years were significantly more likely (P < 0.05) to request an invasive diagnostic procedure through all maternal age groups. When needed, an amniocentesis was preferred to CVS. These data also indicate that the antenatal counselling needs to be adapted to couples presenting with an assisted conception twin pregnancy.     

Current concepts of Down syndrome screening tests in assisted reproduction twin pregnancies: another double trouble

Assisted reproductive technologies (ART) have increased both the number of pregnancies in women beyond the age of 35 and the incidence of multiple pregnancies. Various methods of screening for Down syndrome (DS) were introduced in clinical practice during the last two decades, and specific problems were encountered when they were applied for twin pregnancies. The current review aims to explore the problematic issue of prenatal DS screening in ART twins. Overall, more women with twin pregnancies (mainly those who conceived via assisted reproduction) are found to be false positive for DS. This is because mid-trimester maternal serum screening is associated with a higher false-positive rate secondary to changes in the feto-placental endocrinologic metabolism, reflected mainly in high human chorionic gonadotrophin (hCG) levels in the ART pregnancies. First-trimester nuchal translucency (NT) measurement in twin pregnancies is not affected by the problems encountered in serum screening. This sonographic screening approach enables a fetus-specific identification of those fetuses at high risk of DS and is associated with a lower false-positive rate than mid-trimester serum screening. DS screening in ART twins presents several challenges in determining the most appropriate screening test modality. Whether there is any significant benefit of adding first-trimester biochemistry or nasal bone scanning in screening ART-conceived twins awaits further investigation.     

Prenatal diagnosis for multiple pregnancies

In multiple pregnancies, first trimester ultrasound is crucial to diagnose chorionicity, to detect major structural defects, and to screen for chromosomal abnormalities based on nuchal translucency measurement. The efficacy of nuchal translucency measurement screening in twins might be improved when combined with first trimester maternal serum screening. In twins as in singletons, the risk of fetal loss attendant to chorionic villi sampling and to amniocentesis are similar. When an invasive procedure is indicated in twins, chorionic villi sampling has, over amniocentesis, the advantage of allowing selective termination to be performed in the first trimester, when the procedure related risk of miscarriage is minimal. It has the disadvantage of leading to ambiguous results in up to 2% of cases. While chorionic villi sampling is the choice technique in pregnancies at very high risk, amniocentesis is still indicated in cases at more moderate risk. In monochorionic pregnancies, selective termination can now be performed using a variety of techniques including bipolar or monopolar cord coagulation, and, in acardiac twins, alcohol ablation. However, selective termination remains more hazardous in monochorionic than in dichorionic pregnancies. The outcome of the twin-to-twin transfusion syndrome has been substantially improved by laser photocoagulation of placental shunts and by amniodrainage, but randomized trials are needed to establish the optimal therapeutic strategy, and further pathophysiologic research might result in new treatments.     

Nuchal Translucency Thresholds in Prenatal Screening for Down Syndrome and Trisomy 18

ObjectiveTo determine if nuchal translucency (NT) can be used as a first trimester triage marker in prenatal screening for Down syndrome and trisomy 18.MethodsData from first trimester prenatal screening in 77 443 women were stratified by maternal and gestational ages. They were then analyzed to identify NT thresholds above or below which only positive (high-risk) or negative (low-risk) results were reported by a first trimester prenatal screening test combining PAPP-A, free β-hCG and NT.ResultsCombined prenatal screening was always positive for Down syndrome when NT thickness exceeded 4.0 mm. As women aged, this upper NT threshold value changed according to gestational age. In women aged 35 to 37 years, combined prenatal screening was always positive when NT exceeded 2.8 mm, 3.0 mm, and 3.4 mm at 11, 12, and 13 weeks of gestation, respectively. In women over 42 years of age, the upper threshold value for NT was 1.8 mm, 2.4 mm, and 2.7 mm at 11, 12, and 13 weeks of gestation, respectively. In women less than 35 years of age, we identified lower threshold values below which combined prenatal screening for Down syndrome was always negative.ConclusionIn prenatal screening for Down syndrome and trisomy 18, it is possible to identify NT threshold values above which biochemical screening provides no additional benefit. In pregnancies in which NT is above the established upper cut-offs, invasive prenatal screening can be offered without delay.