Mid-gestation Down syndrome screening test and pregnancy outcome among unstimulated assisted-conception pregnancies

OBJECTIVES: Alteration of mid-gestation serum markers in assisted-conception pregnancies is believed to be attributable to ovarian superovulation treatment modalities. We compared alpha-fetoprotein (AFP), human chorionic gonadotrophin (hCG), and unconjugated estriol (uE(3)) in two groups of unstimulated assisted-conception pregnancies, that is, own-oocyte frozen embryos (own-FET) versus oocyte-donated (OD) embryos. METHODS: Forty-three OD-conceived and 31 own-FET-conceived singleton parturient women (aged 29 +/- 4 years and 31 +/- 4 years respectively, P < 0.05) were followed from embryo transfer throughout pregnancy. RESULTS: The daily pattern of first-trimester serum beta-hCG was similar in both groups. The OD group had only significantly increased AFP concentrations compared to the own-FET group (1.38 vs 0.99 median MoM respectively, P = 0.002). Although there were no chromosomal abnormalities and no fetal or neonatal deaths in either group, 12% OD women and 6.5% own-FET women were found screen-positive. Eight OD women and 11 FET women had an adverse obstetric outcome (P = NS). CONCLUSION: OD embryos are a unique clinical model for evaluating the uterine compartment and its contribution to mid-gestation serum marker secretion.     

Combined first- and second-trimester screening for Down syndrome: an evaluation of proMBP as a marker

OBJECTIVES: To estimate the screening performance of different combinations of first- and second-trimester markers, including a new marker, the proform of eosinophil major basic protein (proMBP). METHODS: The population comprised 195 singleton pregnancies with a normal outcome enrolled in the Copenhagen First Trimester Study, in which a serum sample was available from both the first and the second trimester. The performance of different marker combinations was estimated by receiver-operator-characteristics (ROC) analysis using a Monte Carlo simulation and distributions of log(10)MoM markers and their correlations, derived from our normal material and Down syndrome cases from the literature. RESULTS: Using a fixed screen-positive rate (SPR) of 5%, the first-trimester combined test [nuchal translucency (NT), PAPP-A and free beta-hCG] yielded a detection rate (DR) of 76%, and the integrated test (NT, PAPP-A, AFP, hCG, uE3 and inhibin A) yielded a DR of 86%. With a DR of 90%, the best combination was the first-trimester beta-hCG and NT with the second-trimester proMBP and AFP. ProMBP combined with the triple test increased the DR from 62 to 83%, whereas the addition of inhibin A only increased the DR to 69%. CONCLUSION: These results suggest that proMBP may be an important new marker in Down syndrome screening and, in particular, a good substitute for inhibin A.     

抑制素A在妊娠中期唐氏综合征筛查中的价值

目的 建立广东地区正常妊娠人群血清抑制素A在妊娠15～20+6周的参考值范围,评估抑制素A在四联唐氏综合征筛查中的价值. 方法 选择2008年3月至2010年12月在广州市妇女儿童医疗中心接受妊娠中期三联唐氏综合征筛查的单胎妊娠孕妇2802例.采用酶联免疫化学发光分析法检测孕妇血清中抑制素A水平,将检测值转换为中位数的倍数(multiples of the median, MoM),并根据母亲体重和孕周进行校正.采用SURUSS相关参数重新计算风险值并统计不同切割值水平的筛查效果.通过受试者工作特性曲线及曲线下面积评估单项和各标志物组合的筛查效果.结果 (1)正常单胎孕妇(对照组,2790例)妊娠15～20+6周时各孕周血清抑制素A浓度的中位数分别为286.60、267.10、249.10、243.40、242.30和256.60 pg/ml,各孕周浓度相对稳定.12例胎儿为唐氏综合征的孕妇血清中抑制素A的MoM值及平均浓度均显著高于对照组[MoM值:2.82与1;平均浓度:(852.83±370.04)pg/ml与(293.28±149.46)pg/ml,差异有统计学意义(t=5.37,P＜0.05)].(2)假阳性率为5.8％时,游离人绒毛膜促性腺激素-β、甲胎蛋白、未结合雌三醇和抑制素A组成的四联唐氏综合征筛查检出率为83.3％(10/12);当检出率为83.3％时,妊娠中期四联唐氏综合征筛查的假阳性率(5.8％)较游离人绒毛膜促性腺激素-β、甲胎蛋白和未结合雌三醇组成的三联唐氏综合征筛查(7.7％)降低了1.9％.受试者工作特性曲线上,假阳性率为5.0％时,抑制素A、甲胎蛋白、游离人绒毛膜促性腺激素-β和未结合雌三醇的曲线下面积分别为63.7％、20.5％、46.1％和4.8％;传统三联和四联唐氏综合征筛查的曲线下相对面积分别为45.5％和63.1％. 结论 建立了广东地区正常妊娠人群血清抑制素A在妊娠15～20+6周的参考值范围.证实抑制素A是最佳的妊娠中期血清筛查标志物,可结合现有标志物——游离人绒毛膜促性腺激素-β、甲胎蛋白和末结合雌三醇,用于我国人群妊娠中期唐氏综合征的筛查.     

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.     

Combined second-trimester biochemical and ultrasound screening for Down syndrome

OBJECTIVE: To evaluate the efficacy of a Down syndrome screening protocol that combines second-trimester maternal serum analytes and the continuous ultrasound measures of nuchal fold thickness and proximal long bone length. METHODS: Ultrasound measurements of nuchal fold, femur length, and humerus length were reviewed for 72 second-trimester Down syndrome and 7063 unaffected fetuses. Derived statistical variables for these parameters were entered into a multivariable Gaussian model together with the statistical variables used in the "quad" test (maternal serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin, and inhibin A). Maternal age-specific sensitivities, false-positive rates, and positive predictive values were generated together with receiver operating characteristic curves. Overall efficacy of ultrasound screening alone, the quad test, and the combination of the ultrasound and quad test were compared using a 1:270 second-trimester risk cutoff applied to 1999 US births. RESULTS: Using ultrasound, a sensitivity of 79.9% and false-positive rate of 6.7% may be achieved (positive predictive value: 1 in 42). The quad test has a sensitivity of 81.5% and false-positive rate of 6.9% (positive predictive value: 1 in 42). The combination of the quad test with nuchal fold and long bone measurements may achieve 90% sensitivity and a 3.1% false-positive rate (positive predictive value: 1 in 18). CONCLUSION: Combining second-trimester serum testing and fetal biometry is a feasible approach to Down syndrome screening, compatible with current obstetric practice. This modality is substantially more effective than either serum screening or ultrasound alone. Efficacy may be comparable to that reported for combined first- and second-trimester (integrated) screening.     

Incorporation of inhibin-A in second-trimester screening for Down syndrome

OBJECTIVE: To evaluate the efficacy of the second-trimester quadruple test (maternal serum alpha-fetoprotein, unconjugated estriol, human chorionic gonadotropin, and inhibin-A) in prenatal screening for Down syndrome. METHODS: All quadruple tests performed on singleton pregnancies over a 32-month period were reviewed. The sensitivity and false-positive rates were compared with the theoretic rates predicted by the screening model when applied to a population of women with the same maternal age distribution. RESULTS: Twenty-three thousand seven hundred four women with unaffected pregnancies and 45 women with Down syndrome-affected pregnancies received the quadruple test. Mean analyte values for both unaffected and affected pregnancies were similar to those expected. The sensitivity of the quadruple test, which was based on ascertainment of all viable affected pregnancies in the screened population, was 85.8%. This sensitivity did not significantly differ from an expected 83.8% (P =.8). The initial false-positive rate, 9.0%, was significantly below that expected (9.9%) (P =.002) and was further reduced to 8.2% after correction for major gestational age errors. The positive predictive value of the quadruple test was one in 51. Women with an affected pregnancy and a positive test result (true positives) generally had very high risks (median 1:22) relative to women with false-positive results (median risk 1:111). CONCLUSION: The quadruple test meets or exceeds performance expectations and appears to represent an improvement over the widely used triple test.     

Extreme second-trimester serum analyte values in Down syndrome pregnancies with hydrops fetalis

Objective: To compare second-trimester maternal serum analyte values in Down syndrome pregnancies with, and without, hydrops fetalis. Methods: Seven hydropic and 85 non-hydropic Down syndrome pregnancies were identified among women with positive second-trimester maternal serum screening results. Values for maternal serum α-fetoprotein (MSAFP), human chorionic gonadotropin (hCG), unconjugated estriol and inhibin-A, and risks for Down syndrome were compared using the non-parametric Mann-Whitney statistical test. Results: Hydropic Down syndrome pregnancies had significantly lower MSAFP and estriol concentrations, while hCG levels were higher. For subgroups of five hydropic and 42 non-hydropic cases, no statistically significant difference in the inhibin-A levels could be demonstrated. Conclusion: Second-trimester Down syndrome screening risks are significantly higher in affected pregnancies that are complicated by fetal hydrops.     

First- and second-trimester Down syndrome screening: current strategies and clinical guidelines

Down syndrome (DS) is the most common human disease caused by a structural chromosome defect. The original screening test for DS was maternal age or a history of a previously affected infant. Maternal serum screening has been incorporated into routine prenatal checkup in Taiwan since 1994. We used free beta-human chorionic gonadotropin and alpha-fetoprotein (double test) as the serum markers, and this was carried out between the 15th to 20th week of gestation. The overall detection rate was 56% and was compatible with studies of Caucasian populations. The impact of double tests in Taiwan has shown itself by a dramatic lowering of the rate of DS live birth from 0.63 before screening to 0.16 per 1,000 live births at present. However, because of its relatively low detection rate and poor cost-effectiveness, the double test is not justified as a routine screening tool currently. First-trimester combined test is now becoming more widely available and provides increased sensitivity when detecting DS; it has a detection rate of approximately 85% with a false-positive rate of 5%. Nuchal translucency measurement requires ongoing quality control and sufficient certified obstetricians; therefore, first-trimester ultrasound is limited only in designated centers. The quadruple test, having comparable detection rate, should be considered for incorporation into second-trimester screening in Taiwan in the near future. Other screening approaches and combinations have also been utilized in the Western countries. In this review, we outline the various options with respect to DS screening and hope that this will provide practical information for physicians offering such screenings.     

First- and second-trimester screening: detection of aneuploidies other than Down syndrome

OBJECTIVE: To evaluate the performance of first- and second-trimester screening methods for the detection of aneuploidies other than Down syndrome. METHODS: Patients with singleton pregnancies at 10 weeks 3 days through 13 weeks 6 days of gestation were recruited at 15 U.S. centers. All patients had a first-trimester nuchal translucency scan, and those without cystic hygroma had a combined test (nuchal translucency, pregnancy-associated plasma protein A, and free beta-hCG) and returned at 15-18 weeks for a second-trimester quadruple screen (serum alpha-fetoprotein, total hCG, unconjugated estriol, and inhibin-A). Risk cutoff levels of 1:300 for Down syndrome and 1:100 for trisomy 18 were selected. RESULTS: Thirty-six thousand one hundred seventy-one patients completed first-trimester screening, and 35,236 completed second-trimester screening. There were 77 cases of non-Down syndrome aneuploidies identified in this population; 41 were positive for a cystic hygroma in the first trimester, and a further 36 had a combined test, of whom 29 proceeded to quadruple screening. First-trimester screening, by cystic hygroma determination or combined screening had a 78% detection rate for all non-Down syndrome aneuploidies, with an overall false-positive rate of 6.0%. Sixty-nine percent of non-Down syndrome aneuploidies were identified as screen-positive by the second-trimester quadruple screen, at a false-positive rate of 8.9%. In the combined test, the use of trisomy 18 risks did not detect any additional non-Down syndrome aneuploidies compared with the Down syndrome risk alone. In second-trimester quadruple screening, a trisomy 18-specific algorithm detected an additional 41% non-Down syndrome aneuploidies not detected using the Down syndrome algorithm. CONCLUSION: First-trimester Down syndrome screening protocols can detect the majority of cases of non-Down aneuploidies. Addition of a trisomy 18-specific risk algorithm in the second trimester achieves high detection rates for aneuploidies other than Down syndrome. LEVEL OF EVIDENCE: II.     

Medically assisted reproduction and second-trimester maternal serum marker screening for Down syndrome

OBJECTIVES: To evaluate the effect of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) on total hCG, free ss-hCG, AFP and unconjugated estriol (uE3) used as markers for second-trimester Down syndrome maternal serum screening. METHODS: Second-trimester maternal sera from 1515 singleton pregnancies (970 by IVF, 545 by ICSI) were compared with control sera (21 014 cases). Free ss-hCG, total hCG, AFP and uE3 were compared between the control group and the medically assisted reproduction groups. The percentages of at-risk patients (>/=1/250) were also compared. RESULTS: No differences in values of the maternal serum markers were observed between the medically assisted and control groups. When maternal age was taken into account, the screen-positive rate for Down syndrome screening did not differ between the two groups. CONCLUSION: Patients undergoing assisted reproduction techniques can be counseled for maternal serum Down syndrome screening with the same efficacy as patients with naturally conceived pregnancies.     

Strict glycemic control in diabetic pregnancy-implications for second-trimester screening for Down syndrome

OBJECTIVES: Studies in the early 1990s showed that the normal levels of the biochemical markers used to screen for Down syndrome in the second trimester of pregnancy differ between healthy women and women with insulin-dependent diabetes mellitus (IDDM). Thereafter, most laboratories adopted correcting factors to adjust for these differences. However, the current validity of these factors in light of the recent improvements in glycemic control in diabetic pregnancy has not been investigated. METHODS: The sample consisted of 35 pregnant women with strictly controlled IDDM and 40 healthy controls matched for age and gestational week. All women had singleton pregnancies and were followed till delivery. RESULTS: Comparison of the triple test results between the two groups after adjustment with the traditional corrective factors yielded no significant differences in serum levels of any of the markers (unconjugated estriol, human chorionic gonadotrophin, alpha-fetoprotein). CONCLUSIONS: These results suggest that the recent improvement in glycemic control of pregnant women with IDDM changes the metabolic milieu that might cause the biochemical differences with healthy pregnant patients.     

Outcome of continued pregnancies after first- and second-trimester cervical dilatation by laminaria tents

In 21 pregnant women (seven in the first trimester and 14 in the second trimester), laminaria tents inserted for induction of elective abortion were removed after dilatation had been achieved, but upon the patient's request, the abortion was not carried out. Four patients again changed their minds and had uncomplicated induced abortion after reinsertion of the laminaria tents. Seventeen patients continued their pregnancies: Fourteen had term deliveries, two had premature deliveries, and one had a spontaneous abortion at 10 weeks' gestation, 2 weeks after laminaria removal. None of the patients suffered infectious morbidity, including three untreated patients with positive cervical cultures for chlamydia, who experienced normal pregnancies and deliveries.     

First- and second-trimester Down syndrome screening markers in pregnancies achieved through assisted reproductive technologies (ART): a FASTER trial study

OBJECTIVE: To determine whether first- and second-trimester Down syndrome screening markers and screen-positive rates are altered in pregnancies conceived using assisted reproductive technologies (ARTs). METHODS: ART pregnancies in the multicenter FASTER trial were identified. Marker levels were evaluated for five types of ART: in vitro fertilization with ovulation induction (IVF-OI), IVF with OI and egg donation (IVF-OI-ED), IVF with ED (IVF-ED), and intrauterine insemination with OI (IUI-OI) or without OI (IUI). Each group was compared to non-ART controls using Mann-Whitney U analysis. RESULTS: First-trimester marker levels were not significantly different between ART and control pregnancies, with the exception of reduced PAPP-A levels in the IUI-OI group. In contrast, second-trimester inhibin A levels were increased in all ART pregnancies, estriol was reduced and human chorionic gonadotropin (hCG) was increased in IVF and IUI pregnancies without ED, and alpha-fetoprotein (AFP) was increased in ED pregnancies. Second-trimester screen-positive rates were significantly higher than expected for ART pregnancies, except when ED was used. CONCLUSIONS: These data show that ART significantly impacts second-, but not first-, trimester markers and screen-positive rates. The type of adjustment needed in second-trimester screening depends on the particular type of ART used.     

Down syndrome screening in multiple pregnancies by nuchal translucency measurement

Various non-invasive screening methods for Down syndrome have been introduced in clinical practice during the last two decades. Specific problems were encountered when these methods were applied for multiple pregnancies (twins and high-order multiples). The aim of the current review is to explore these issues and propose an adjusted methodological approach for this highly selected population. Overall, more women with twin pregnancies (mainly those who conceived via assisted reproduction) are found to be false-positive for Down syndrome. This is because the standard screening algorithms include maternal age. In addition, mid-trimester maternal serum screening is associated with a higher false-positive rate, secondary to changes in the fetoplacental endocrinologic metabolism in assisted reproduction pregnancies. Therefore, in multiple pregnancies, mid-trimester maternal serum screening is of limited clinical value. In those pregnancies, screening for Down syndrome by means of nuchal translucency measurements at 10-14 weeks is associated with a lower false-positive rate than mid-trimester serum screening. Nuchal translucency measurement is among the best available and most efficient screening methods for multiple pregnancies. This method for screening enables us to specifically identify those fetuses at high risk of Down syndrome and other anomalies and thus contribute for a better outcome. In addition, it should be systematically performed before any fetal reduction in high-order multiples is planned.     

Biochemical screening for Down syndrome in pregnancies following renal transplantation

OBJECTIVE: To assess the performance of the double marker test [free beta-human chorionic gonadotrophin (beta-hCG) and alpha-fetoprotein (AFP)] as a screening test for Down syndrome in pregnant patients who had a prior renal transplant. DESIGN: A retrospective study. SETTING: The Fetal Medicine Unit, Royal Free Hospital, London, UK. METHODS: Detailed records of 14 post-renal transplant pregnancies were obtained from the Renal Unit of our hospital where the patients were followed up. The serum concentrations of urea, creatinine, free beta-hCG and AFP at the time of the double marker test were recorded, with a cut-off point of 1:250 for the double marker test. A control group of 14 normal pregnancies matched for age, parity and gestational age was used. The Mann-Whitney U-test and t-tests of unequal variance were applied to compare parameters of the study and the control groups. RESULTS: Two patients in each group were high risk for Down syndrome and amniocentesis revealed normal karyotype. No babies with Down syndrome were delivered in either group. Regression analysis showed significant correlation between free beta-hCG and urea concentrations (p<0.001) and free beta-hCG and creatinine concentrations (p<0.001), but not for AFP. CONCLUSIONS: The present study demonstrates that residual renal function alterations persisting after renal transplantation can affect the levels of free beta-hCG and AFP, thus resulting in false-positive screening for Down syndrome. First trimester nuchal translucency (NT) measurement in combination with second trimester ultrasonographic markers can be used in these patients, or alternatively the free beta-hCG levels should be corrected according to the serum creatinine levels.     

Combined first-trimester versus second-trimester serum screening for Down syndrome: a cost analysis

OBJECTIVE: The purpose of this study was to compare the cost-effectiveness of combined first-trimester screening for fetal Down syndrome with second-trimester maternal serum triple screening. STUDY DESIGN: A first-trimester screening approach that used nuchal translucency measurement and maternal serum screening was evaluated against second-trimester maternal serum triple screening in a hypothetic population. Screening sensitivities and screen-positive rates were 91% and 5% for the first-trimester approach and 70% and 7.5% for the second-trimester approach, respectively. The costs of fetal Down syndrome, live-born Down syndrome cost, and total costs (screening plus live-born costs) were calculated for each screening program. RESULTS: First-trimester screening was associated with lower screening and live-born Down syndrome costs versus second-trimester serum screening. Total Down syndrome screening costs were 29.1% lower with first-trimester screening. CONCLUSION: In this hypothetic model, combined first-trimester screening for fetal Down syndrome was more cost-effective than universal second-trimester triple serum screening.     

ADAM 12 as a second-trimester maternal serum marker in screening for Down syndrome

BACKGROUND: ADAM 12 is a placenta-derived glycoprotein that is involved in growth and differentiation. The maternal serum concentration of ADAM 12 is a potential first-trimester maternal serum marker of Down syndrome (DS). Here we examine the potential of ADAM 12 as a second-trimester maternal serum marker of DS. MATERIALS AND METHODS: The concentration of ADAM 12 was determined in gestational week 14-19 in 88 DS pregnancies and 341 matched control pregnancies. Medians of normal pregnancies were established by polynomial regression and the distribution of log(10) MoM ADAM 12 values in DS pregnancies and controls determined. Correlations with alpha-fetoprotein (AFP) and free beta-human chorionic gonadotrophin (free beta-hCG) were established and used to model the performance of maternal serum screening with ADAM 12 in combination with other second-trimester serum markers. RESULTS: The ADAM 12 maternal serum concentration was significantly increased with a median MoM of 1.85 and a mean log(10) MoM (SD) of 0.268 (0.2678) compared to a mean log(10) MoM (SD) of 0.013 (0.4318) in controls. ADAM 12 correlated with maternal weight and ethnicity (with the serum concentration increased in Afro-Caribbeans), but neither with maternal age nor gestational age, and only marginally with AFP (r(DS) = 0.078, r(controls) = 0.093) and free beta-hCG (r(DS) = 0.073, r(controls) = 0.144. The increase in detection rate-for a false positive rate of 5%--by adding ADAM 12 to the double test (AFP + free beta-hCG) was 4%, similar to that of adding uE3 to the double test. CONCLUSION: ADAM 12 is an efficient second-trimester marker for DS. Further studies should be conducted to determine whether it may be a useful additional or alternative marker to those currently used in the second-trimester.