Screening for triploidy by fetal nuchal translucency and maternal serum free beta-hCG and PAPP-A at 10-14 weeks of gestation

In 25 cases of triploidy at 10-14 weeks of gestation, compared with 947 controls, the median multiple of the median (MoM) fetal nuchal translucency (NT) thickness was significantly increased (1.89 MoM), and maternal serum total and free beta-human chorionic gonadotrophin (hCG) were increased (3.13 MoM and 4.59 MoM respectively), alpha fetoprotein (AFP) was increased (2.14 MoM), and pregnancy associated plasma protein A (PAPP-A) was decreased (0.12 MoM). There are two types of triploidy. In type I, where the additional chromosome set is of paternal origin, the placenta is partially molar and the fetus is relatively well-grown. Type II, where the extra chromosome set is of maternal origin, is characterized by a small normal looking placenta and severe asymmetrical fetal growth restriction. In type I triploidy there was increased fetal NT (2.76 MoM), maternal serum total hCG (4.91 MoM), free beta-hCG (8.04 MoM), and AFP (3.22 MoM), and mildly decreased PAPP-A (0.75 MoM). In type II triploidy fetal NT was not increased (0.88 MoM), and there was a decrease in maternal serum total hCG (0.16 MoM), free beta-hCG (0.18 MoM), PAPP-A (0.06 MoM) and AFP (0.77 MoM). We conclude that a large proportion of triploidy cases of both phenotypes could be identified in the first trimester using NT, maternal serum free beta-hCG and PAPP-A with a combination of trisomy 21 risk and an atypicality approach.     

Diagnosis and prediction of parental origin of triploidies by fetal nuchal translucency and maternal serum free beta-hCG and PAPP-A at 11-14 weeks of gestation

The study objective was to determine the parental origin of triploidy in relation to findings from early risk assessment in a combined screening program between 2004 and the end of 2006. Triploidy was diagnosed in six chorion villus samples and two samples from missed abortions. After informed consent, quantitative fluorescence polymerase chain reaction analysis was performed on the five cases where we received blood from both parents and tissue from fetuses. In four cases the origin of the triploidy was paternal and in one maternal, in accordance with previous findings in type I and type II triploidies. Finding triploidy is possible by risk assessment (ultrasound and double test), and thereby women may have the opportunity for early termination of pregnancy.     

Screening for trisomy 18 by fetal nuchal translucency and maternal serum free beta-hCG and PAPP-A at 10-14 weeks of gestation

In a study of 50 cases of trisomy 18 compared with 947 controls we have found the median multiple of the median (MoM) of maternal serum free beta human chorionic gonadotrophin to be significantly decreased (0.281 MoM) in samples collected between the 10th and 14th week of gestation. Similarly, maternal serum pregnancy associated plasma protein A (PAPP-A) levels are also decreased (0.177 MoM), whilst the median nuchal translucency is significantly higher (3.272 MoM). Free beta-hCG MoM was less than the 5th centile of normal in 64 per cent of cases of trisomy 18 and for PAPP-A was less than the 5th centile in 78 per cent of cases. Also, in 78 per cent of cases the nuchal translucency was above the 95th centile. When combined together in a multivariate algorithm with maternal age, we predict that 89 per cent of cases of trisomy 18 could be detected at a 1 per cent false-positive rate. We conclude that specific trisomy 18 risks should be part of developing risk algorithms combining maternal serum biochemistry and nuchal translucency for use in first trimester screening alongside those for trisomy 21.     

Screening for trisomy 13 by fetal nuchal translucency and maternal serum free beta-hCG and PAPP-A at 10-14 weeks of gestation

In 42 cases of trisomy 13 at 10-14 weeks of gestation, compared with 947 controls, the median multiple of the median (MoM) of maternal serum free beta-human chorionic gonadotrophin (beta-hCG) and pregnancy associated plasma protein A (PAPP-A) was significantly decreased (0.506 MoM and 0.248 MoM respectively), whilst fetal nuchal translucency was increased (2.872 MoM). In 38% and 71% of cases of trisomy 13 maternal serum free beta-hCG and PAPP-A was below the 5th centile of the appropriate normal range for gestation and in 62% of cases the nuchal translucency was above the 95th centile. When combined together in a multivariate algorithm with maternal age, 90% of cases of trisomy 13 could be detected at a 0.5% false positive rate or 84% at a 0.1% false positive rate. We conclude that specific trisomy 13 risks should be part of developing risk algorithms combining maternal serum biochemistry and nuchal translucency for use in first trimester screening alongside those for trisomy 21 and trisomy 18.     

A first trimester trisomy 13/trisomy 18 risk algorithm combining fetal nuchal translucency thickness,maternal serum free beta-hCG and PAPP-A

This study examines 45 cases of trisomy 13 and 59 cases of trisomy 18 and reports an algorithm to identify pregnancies with a fetus affected by trisomy 13 or 18 by a combination of maternal age fetal nuchal translucency (NT) thickness, and maternal serum free beta-hCG and PAPP-A at 11-14 weeks of gestation. In this mixed trisomy group the median MoM NT was increased at 2.819, whilst the median MoMs for free beta-hCG and PAPP-A were reduced at 0.375 and 0.201 respectively. We predict that with the use of the combined trisomy 13 and 18 algorithm and a risk cut-off of 1 in 150 will for a 0.3% false positive rate allow 95% of these chromosomal defects to be identified at 11-14 weeks. Such algorithms will enhance existing first trimester screening algorithms for trisomy 21.     

First-trimester screening for Down syndrome using nuchal translucency measurement with free beta-hCG and PAPP-A between 10 and 13 weeks of pregnancy--the combined test.

In a population of 1467 women attending the 'G. Gaslini' Institute for antenatal care, we evaluated first-trimester risk screening for Down syndrome using the 'combined test' based on ultrasound measurement of nuchal translucency (NT), maternal serum pregnancy-associated plasma protein A (PAPP-A) and free beta-hCG, and maternal age. No clinical action was taken on these results. The gestational age, determined by scan measurement of crown rump length, ranged from 10 weeks to 13 weeks 6 days. The median maternal age was 31 years 8 months. There were 13 Down syndrome pregnancies. The risk of having an affected pregnancy was estimated from a multivariate Gaussian distribution, using commercially available software. With a risk cut-off of 1 in 350, 11 affected pregnancies were detected (detection rate 85 per cent, 95 per cent confidence interval: 56-100 per cent) with a 3.3 per cent false-positive rate. The odds of being affected given a positive result were 1 in 30. Further data are needed to determine, with greater statistical reliability, the relative performance of the combined test with current second-trimester screening.     

First trimester screening with free beta-hCG,PAPP-A and nuchal translucency in pregnancies conceived with assisted reproduction

OBJECTIVE: To evaluate the effect of in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) on free beta-human chorionic gonadotrophin (beta-hCG), pregnancy-associated plasma protein A (PAPP-A) and nuchal translucency (NT). METHODS: First trimester maternal dried whole blood specimens from 74 singleton pregnancies (32 by IVF and 42 by ICSI) and 30 twin pregnancies (16 by IVF and 14 by ICSI) in which conception was achieved with assisted reproduction techniques were matched with five controls resulting in 370 singleton controls and 150 twin controls. NT was measured using the Fetal Medicine Foundation protocol. Free beta-hCG, PAPP-A and NT levels were compared between the IVF and control groups and between the ICSI and control groups using the Mann-Whitney U test. RESULTS: In singleton pregnancies, the only significant difference was a 21% (95% CI: -35%--7%) reduction in PAPP-A in IVF cases. In twin pregnancies, the only significant difference was a 12% (95% CI: -34%--3%) reduction in NT in IVF cases. In singleton pregnancies, the false-positive rate for Down syndrome screening was 1.4% and 1.9% greater for the IVF and ICSI groups, respectively, compared to controls for a general screening population. CONCLUSIONS: Patients undergoing assisted reproduction techniques should be counseled about the possibility of increased false-positive rates. Larger studies are needed to confirm this observation and to develop appropriate adjustment factors to reduce false-positive rates.     

The influence of fetal sex in screening for trisomy 21 by fetal nuchal translucency, maternal serum free beta-hCG and PAPP-A at 10-14 weeks of gestation

In a study of 2923 normal pregnancies and 203 pregnancies affected by trisomy 21 we have shown a significant difference in the median MoM of the markers: fetal nuchal translucency, maternal serum free beta-hCG and PAPP-A in the presence of a female fetus compared with a male fetus. For maternal serum free beta-hCG levels are higher by 15% if the fetus is chromosomally normal and by 11% if the fetus has trisomy 21. For maternal serum PAPP-A the levels in chromosomally normal fetuses are 10% higher in the presence of a female fetus and 13% higher if the fetus has trisomy 21. In contrast, fetal nuchal translucency is 3-4% lower in both chromosomally normal and trisomy 21 female fetuses. The consequence of such changes when screening for trisomy 21 will be a reduction in the detection rate in female fetuses by a factor of 1-2%. Correction of risk algorithms for fetal sex, however, is probably not feasible, since ultrasound detection of fetal sex is only 70-90% accurate in the 10-14 week period.     

Combined measurement of fetal nuchal translucency, maternal serum free beta-hCG, and pregnancy-associated plasma protein A for first-trimester Down's syndrome screening.

PURPOSE: It has been proposed that first-trimester Down's syndrome screening has a higher detection rate compared to second-trimester biochemical screening. This study investigated the accuracy of Down's syndrome screening during gestational weeks 10 to 13 using the combination of fetal nuchal translucency (NT) measurement with maternal serum concentrations of free beta-human chorionic gonadotropin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A). METHODS: A total of 1,514 women with singleton pregnancies were enrolled in this study. Fetal NT was measured using the criteria published by the Fetal Medicine Foundation. Maternal serum concentrations of free beta-hCG and PAPP-A were determined by microtiter-plate ELISA. Down's syndrome risk was calculated using multivariate Gaussian distribution and Alpha software. RESULTS: Seventeen (1.12%) of the 1514 screened pregnancies had a fetal NT of at least 3 mm, and 41.2% of these had a poor pregnancy outcome, including four fetal aneuploidies. The odds of a fetal aneuploidy when the NT was greater than 2.0 multiples of median (MoM) was 90, when serum PAPP-A concentration was less than 0.45 MoM, it was 8.6, and when serum free beta-hCG concentration was greater than 2.2 MoM, it was 4.7. Using a risk cut-off level of 1 in 400, nine of 10 fetal aneuploidies were identified with a 4.7% false-positive rate, including two with trisomy 21, one with trisomy 18, and three with Turner's syndrome. CONCLUSIONS: This study demonstrated that Down's syndrome screening using the combined test in the first trimester had a higher detection rate than that of serum screening in the second trimester. Implementation of NT measurement in the first trimester provides substantial advantages for Down's syndrome detection and early diagnosis of fetal structural abnormalities.     

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.     

First-trimester fetal nuchal translucency and inherited metabolic disorders

OBJECTIVES: To assess the association between inherited metabolic disorders and nuchal translucency (NT) measurements. METHODS: The NT measurements obtained from 66 fetuses at high risk for metabolic diseases prior to chorionic villus sampling (CVS) were retrospectively analysed. RESULTS: NT was found to be within the normal range in all of the 13 affected fetuses, which included three with Gaucher disease, two with glycogenosis type II, two with mucopolysaccharidosis type I and six others with Krabbe disease, metachromatic leukodystrophy, mucopolysaccharidosis type II, Niemann-Pick A disease, Pelizaeus-Merzbacher disease and sialidosis, respectively. An increased nuchal thickness was found only in one fetus affected with trisomy 21 but not affected with mucopolysaccharidosis type II. CONCLUSION: NT appears to have a limited role in identifying affected fetuses in pregnancies at high risk for inherited metabolic disorders. NT may be normal in early pregnancy even for fetuses affected with conditions known to be associated with non-immune hydrops fetalis.     

First-trimester maternal serum PAPP-A and free-beta subunit human chorionic gonadotropin concentrations and nuchal translucency are associated with obstetric complications: a population-based screening study (the FASTER Trial)

OBJECTIVE: The purpose of this study was to determine whether maternal serum levels of pregnancy-associated plasma protein A, free-beta subunit human chorionic gonadotropin, or nuchal translucency size are associated with obstetric complications. STUDY DESIGN: Data were obtained from the First and Second Trimester Evaluation of Risk trial. Pregnancy-associated plasma protein A and free-beta subunit human chorionic gonadotropin levels were analyzed, and nuchal translucency was measured between 10 weeks 3 days and 13 weeks 6 days of gestation in 34,271 pregnancies. RESULTS: Women with pregnancy-associated plasma protein A of < or =5th percentile were significantly more likely to experience spontaneous fetal loss at < or =24 weeks of gestation, low birth weight, preeclampsia, gestational hypertension, preterm birth ( P < .001) and stillbirth, preterm premature rupture of membranes, and placental abruption ( P < .02). Nuchal translucency at > or =99th percentile and free-beta subunit human chorionic gonadotropin at < or =1st percentile were associated with an increased risk of spontaneous loss at < or =24 weeks of gestation (adjusted odds ratios, 3.90, 3.62, respectively; P < .001). CONCLUSION: Low pregnancy-associated plasma protein A levels in the first trimester were associated strongly with a number of adverse pregnancy outcomes. Low free-beta subunit human chorionic gonadotropin levels and large nuchal translucency were both associated with early fetal loss.     

First trimester screening for Down's syndrome using maternal serum PAPP-A and free β=hCG in combination with fetal nuchal translucency thickness

The aim of this study was to evaluate the potential effectiveness of maternal serum pregnancy-associated plasma protein A (PAPP-A) and free β-hCG in combination with nuchal translucency thickness in first trimester screening for Down's syndrome. Maternal serum levels of PAPP-A and free β-hCG were assayed in stored sera from 32 Down's syndrome and 200 unaffected pregnancies. Fetal nuchal translucency was measured by ultrasound at the time of blood sampling. Screening of Down's syndrome using a combination of maternal age, PAPP-A, free β-hCG and nuchal translucency would achieve a detection rate of 75.8% for a false positive rate of 5%.     

Prediction of pregnancy complications by first-trimester maternal serum PAPP-A and free beta-hCG and with second-trimester uterine artery Doppler

BACKGROUND: Previous studies have shown an association between low first trimester maternal serum free beta-hCG and PAPP-A and subsequent development of pregnancy complications. Similarly, uterine artery Doppler in the late second trimester has shown that high impedance to flow is associated with increased risk for preeclampsia and fetal growth restriction. The objective of this study is to determine whether there is an association between the maternal serum concentration of PAPP-A and free beta-hCG at 11-13(+6) weeks with the uterine artery pulsatility index (PI) at 22-24 weeks, and secondly, to compare the screening characteristics of the two methods in the prediction of adverse pregnancy outcome. METHODS: Maternal serum PAPP-A and free beta-hCG at 11-13(+6) weeks and uterine artery PI at 22-24 weeks were measured in 4390 women with singleton pregnancies. Pregnancies with chromosomal defects or fetal anomalies were excluded. The biochemical and Doppler measurements were compared between those with normal outcome and those resulting in spontaneous preterm delivery, pre-eclampsia and fetal growth restriction (FGR). Detection rates using a combination of the biochemical and Doppler measurements were investigated. RESULTS: In the pregnancies resulting in pre-eclampsia (n = 64) and FGR (n = 172), the median PAPP-A was lower (0.844 and 0.813 MoM), the median uterine artery mean PI was higher (1.56 and 1.18) but the median free betahCG was not significantly different (0.923 and 0.933 MoM) than in the normal outcome group. In the preterm delivery group (n = 159), the median free beta-hCG (0.944 MoM) and uterine artery mean PI (1.06) were not significantly different from normal but the median PAPP-A (0.928 MoM) was significantly lower than normal. In screening for pre-eclampsia, the detection rate, for a 5% false-positive rate, was 14.1% for PAPP-A, 54.7% for uterine artery mean PI and 62.1% for a combination of PAPP-A and uterine artery mean PI. CONCLUSION: Maternal serum PAPP-A at 11-13(+6) of gestation is significantly lower in adverse pregnancy outcomes. The combination of first trimester serum PAPP-A and uterine artery mean PI at 22-24 weeks improves the screening efficacy for the prediction of pre-eclampsia.     

Pregnancy-associated plasma protein A, free beta-hCG, nuchal translucency, and risk of pregnancy loss

OBJECTIVE: To estimate the likelihood of clinical early and late pregnancy loss as a function of first-trimester maternal serum analytes and fetal nuchal translucency measurements. METHODS: Study subjects were recruited for a National Institute of Child Health and Human Development-sponsored multicenter cohort study initially designed to study the detection of Down syndrome during the first trimester of pregnancy. The cohort consisted of women who had a live fetus between 10 and 14 weeks of gestation and had no significant vaginal bleeding. Women with prior fetal trisomy (T21/18) and those with structural or chromosomal abnormalities in the index pregnancy were excluded. First-trimester screening consisted of pregnancy-associated plasma protein A (PAPP-A), free beta-hCG, and nuchal translucency. Pregnancy loss rates in women with various levels of PAPP-A, free beta-hCG, or nuchal translucency (less than 1st, less than 5th, more than 95th, and more than 99th percentile) were compared with losses in women with normal values (5th to 95th percentile). RESULTS: The mean gestational age at screening of 7,932 women meeting study criteria was 12.1 weeks. Loss rates were only 0.36% at less than 20 weeks after normal free beta-hCG, PAPP-A, and nuchal translucency. Conversely, low levels of PAPP-A and free beta-hCG as well as increased nuchal translucency were individually associated with increased early loss. These associations persisted after controlling for maternal age and race using logistic regression analysis. CONCLUSION: Normal values of PAPP-A, free beta-hCG, and nuchal translucency are associated with a very low risk of pregnancy loss at less than 20 weeks.     

Integrated ultrasound and biochemical screening for trisomy 21 using fetal nuchal translucency,absent fetal nasal bone,free beta-hCG and PAPP-A at 11 to 14 weeks

BACKGROUND: Screening for trisomy 21 by a combination of maternal age, fetal nuchal translucency (NT) thickness and maternal serum free beta-hCG and pregnancy-associated plasma protein-A (PAPP-A) at 11 to 14 weeks of gestation is associated with a detection rate of 90% for a false-positive rate of 5%. Recent evidence suggests that in about 70% of fetuses with trisomy 21, the nasal bone is not visible at the 11th- to 14th-week scan (Cicero et al., 2001). The aim of this study was to examine whether fetal NT thickness and the level of maternal serum biochemical markers is independent of the presence or absence of the nasal bone, and to estimate the performance of a screening test that integrates the two sonographic and the two biochemical markers. METHODS: This was a retrospective case-control study comprising 100 trisomy 21 and 400 chromosomally normal singleton pregnancies at 11 to 14 weeks of gestation. Ultrasound examination was carried out for measurement of fetal NT and assessment of the presence or absence of the fetal nasal bone. Maternal serum free beta-hCG and PAPP-A were measured using the Kryptor rapid random-access immunoassay analyser (Brahms Diagnostica GmbH, Berlin). The distribution of fetal NT, maternal serum free beta-hCG and PAPP-A in trisomy 21 fetuses with absent and present nasal bone was examined. RESULTS: The nasal bone was absent in 69 and present in 31 of the trisomy 21 fetuses. There were no significant differences in median maternal age, median gestational age, NT delta, free beta-hCG MoM and PAPP-A MoM in trisomy 21 fetuses with and without a visible nasal bone. For a false-positive rate of 5%, it was estimated that screening with the four markers in combination with maternal age would be associated with a detection rate of 97%. For a false-positive rate of 0.5%, the detection rate was 90.5%. CONCLUSIONS: An integrated sonographic and biochemical test at 11 to 14 weeks can potentially identify about 90% of trisomy 21 fetuses for a false-positive rate of 0.5%.     

Maternal serum free beta-hCG and PAPP-A in fetal sex chromosome defects in the first trimester

We have studied maternal serum free beta-hCG and PAPP-A, and fetal nuchal translucency (NT) in a series of 46 cases of fetal Turner's syndrome, 13 cases of other sex chromosomal anomalies and compared these with 947 control pregnancies in the first trimester. In cases of Turner's syndrome (45,X) the median fetal NT was significantly higher than in controls (4.76 MoM), the median PAPP-A was significantly lower (0.49 MoM), whilst the free beta-hCG was not significantly different (1.11 MoM). For NT, 93% (43/46) of cases were equal to or greater than the 95th centile of controls, for PAPP-A 35% (16/46) of cases were less than or equal to the 5th centile of controls and for free beta-hCG 15% (7/46) of cases were equal to or greater than the 95th centile of controls. For other sex chromosomal anomalies (47XXX, XXY, XYY) the median NT was increased (2.07 MoM) whilst PAPP-A was not significantly decreased (0.88 MoM) and free beta-hCG was not significantly different (1.07 MoM) from controls. Using a previously derived multivariate risk algorithm for trisomy 21, incorporating NT, PAPP-A, free beta-hCG and maternal age, 96% of the Turner's cases and 62% of the other sex chromosomal anomalies would have been identified.     

First-trimester Down syndrome screening using dried blood biochemistry and nuchal translucency

OBJECTIVE: To assess the effectiveness of free beta-hCG, pregnancy-associated plasma protein A, and nuchal translucency in a prospective first-trimester prenatal screening study for Down syndrome and trisomy 18. METHODS: Risks were calculated for Down syndrome and trisomy 18 based on maternal age and biochemistry only (n = 10,251), nuchal translucency only (n = 5809), and the combination of nuchal translucency and biochemistry (n = 5809). RESULTS: The study population included 50 Down syndrome and 20 trisomy 18 cases. Nuchal translucency measurement was done on 33 Down syndrome and 13 trisomy 18 cases. Down syndrome screening using combined biochemistry and ultrasound resulted in a false-positive rate of 4.5% (95% confidence interval [CI] 3.9%, 5.2%) and detection rate of 87.5% (95% CI 47%, 100%) in patients under age 35 years. In older patients, the false-positive rate was 14.3% (95% CI 12.7%, 15. 8%) and detection rate was 92% (95% CI 74%, 99%). For trisomy 18 screening, the false-positive rate was 0.4% (95% CI 0.24%, 0.69%) and detection rate was 100% (95% CI 40%, 100%) in younger patients, whereas in older patients the false-positive rate was 1.4% (95% CI 0. 9%, 2.0%) and detection rate was 100% (95% CI 66%, 100%). Using modeling, at a fixed 5% false-positive rate, the Down syndrome detection rate was 91%. Conversely, at a fixed 70% Down syndrome detection rate, the false-positive rate was 1.4%. CONCLUSION: First-trimester screening for Down syndrome and trisomy 18 is effective and offers substantial benefits to clinicians and patients.