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.     

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.     

First-trimester ultrasonographic screening for trisomy 21 using fetal nuchal translucency and nasal bone

OBJECTIVE: To report our experience with first-trimester screening for trisomy 21 by using the combination of nuchal translucency thickness and nasal bone assessment. METHODS: Pregnant women from a predominantly Latin American population consisting of patients at both low risk and high risk for chromosomal defects underwent first-trimester ultrasonographic screening. Nuchal translucency thickness and nasal bone were assessed by two accredited fetal medicine specialists. Cases of trisomy 21 were identified from the cytogenetics laboratory logbook. RESULTS: Over a 3-year period, 1,287 consecutive singleton pregnancies were screened. The median maternal age was 33 years (range 14-47 years), with 456 (35.4%) women aged 35 years or older at the time of the scan. Overall, 110 fetuses (8.5%) had nuchal translucency thickness greater than the 95th percentile for gestational age and 25 (1.9%) had absent nasal bone. Trisomy 21 was diagnosed in 31 cases. Among them, the nuchal translucency thickness was increased in 28 and the nasal bone was absent in 13 (detection rates of 90.3% and 41.9%, respectively; P<.01). All but one (92.3%) of the trisomy 21 fetuses with absent nasal bone had increased nuchal translucency. Only two of the normal fetuses had an absent nasal bone in the first trimester. CONCLUSION: In our population, increased nuchal translucency thickness is the most important ultrasonographic marker of trisomy 21. In contrast, the nasal bone seems to have a less prominent role in identifying the fetus at risk for trisomy 21 due to its lower detection rate. However, an absent nasal bone should be considered as a highly predictive marker of trisomy 21.     

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.     

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.     

Increased fetal nuchal translucency at 11-14 weeks

Nuchal translucency (NT) is the sonographic appearance of a subcutaneous collection of fluid behind the fetal neck. The measurement of fetal NT thickness at the 11-14-week scan has been combined with maternal age to provide an effective method of screening for trisomy 21; for an invasive testing rate of 5%, about 75% of trisomic pregnancies can be identified. When maternal serum free-beta human chorionic gonadotrophin (beta-hCG) and pregnancy-associated plasma protein-A (PAPP-A) at 11-14 weeks are also taken into account, the detection rate of chromosomal defects is about 90%. Increased NT can also identify a high proportion of other chromosomal abnormalities and is associated with major defects of the heart and great arteries, and a wide range of skeletal dysplasias and genetic syndromes. In monochorionic twins, discordancy for increased NT is an early marker of twin-to-twin transfusion syndrome (TTTS). As with the introduction of any new technology into routine clinical practice, it is essential that those undertaking the 11-14-week scan are adequately trained and their results are subjected to rigorous audit.     

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.     

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.     

Screening for trisomy 21 with maternal age, fetal nuchal translucency and maternal serum biochemistry at 11-14 weeks: a regional experience from Germany

OBJECTIVE: To examine the efficacy of first trimester screening for trisomy 21 using a combination of maternal age, fetal nuchal translucency (NT), maternal serum free beta-human chorionic gonadotropin (free beta-hCG) and pregnancy-associated plasma protein A (PAPP-A) in a regional setting [maternity unit of the Women's University Hospital, Hannover Medical School (study center); two regional private centers for prenatal diagnosis and human genetics; laboratory for prenatal diagnosis and human genetics]. METHODS: Fetal NT, crown-rump length, maternal serum free beta-hCG and PAPP-A were measured at 11-14 weeks of gestation. Risk calculation was carried out using the FMF computer algorithm. The patients were informed and counseled about possible invasive test options if the risk was 1 in 300 or greater. Fetal outcome was obtained by questionnaires given to the patients or sent to their gynecologists. The detection and false-positive rates for the different screening strategies were calculated. RESULTS: Pregnancy outcome was obtained in 2,497 cases, of which 2,196 cases had completed first trimester screening with NT and maternal serum biochemistry and 301 additional cases had NT measurement only. The median age was 32.5 years. In our population 11 affected fetuses were found. The estimated risk for trisomy 21 was 1 in 300 or greater in 64, 82, 88 and 88% of affected fetuses using maternal age alone, in combination with nuchal translucency, with maternal serum biochemical markers or with both NT and biochemical markers for a false-positive rate of 28.2, 5.1, 15.3 and 4.0%. CONCLUSIONS: First trimester screening using maternal age, NT, free beta-hCG and PAPP-A is highly effective for the detection of trisomy 21 and is associated with a sensitivity of about 90% for 5% false-positive patients.     

Cystic hygromas, nuchal edema, and nuchal translucency at 11-14 weeks of gestation

OBJECTIVE: To estimate the incidence of septations in fetuses with increased nuchal translucency (NT) thickness, and to investigate the relationship between the length and thickness of the translucency and whether the length or septations provide useful information concerning the fetal karyotype in addition to that provided by the NT thickness alone. METHODS: We examined 386 fetuses with NT thickness equal to or above the 95th percentile for crown-rump length (CRL). A transverse suboccipitobregmatic section of the fetal head was taken to determine whether the sonolucency was septated, and a midsagittal longitudinal section was used to measure NT thickness, CRL, the longitudinal distance between the occiput and the lower end of the sonolucency toward the fetal sacrum (NT length) and the length between the occiput and the sacral tip (spinal length). Logistic regression analysis was used to investigate the effect on abnormal karyotype of CRL, NT thickness, and percentage of NT length to spinal length. RESULTS: Septations within the translucency were observed in all fetuses. The fetal karyotype was abnormal in 83 (21.5%) pregnancies, and multiple regression showed that the only significant independent predictor of abnormal karyotype was fetal NT thickness. CONCLUSION: Septations within the translucency can be seen in all fetuses, and therefore this feature cannot be used to distinguish between increased NT and cystic hygromas. The length of the translucency is related to its thickness and does not give useful information concerning the fetal karyotype in addition to that provided by the NT thickness alone. LEVEL OF EVIDENCE: II-2.     

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.     

Absence of fetal nasal bone and aneuploidies at first-trimester nuchal translucency screening in unselected pregnancies

OBJECTIVES: The absence of nasal bone (NB) has been noted in trisomy 21 fetuses at first-trimester ultrasound, in high-risk pregnancies. In this study, the nasal bone was evaluated in relation to fetal karyotype, in unselected pregnancies. METHODS: From September 2001 to September 2002, the fetal facial profile was examined at the 11 to 14 weeks' scan for screening by nuchal translucency (NT). Risks for trisomy 21 were calculated using the Fetal Medicine Foundation's software, and the presence or absence of NB was noted. Prenatal karyotype and pregnancy outcomes were recorded. RESULTS: NT screening was performed in 5532 fetuses from 5425 pregnancies (85 twins, 8 triplets, 2 quadruplets). The visualization of fetal profile was obtained in 5525 fetuses (99.8%), and in 5491 fetuses (99.4%) the NB was present and in 34 cases (0.6%) it was absent. Fetal karyotype and pregnancy outcome were available in 3503 pregnancies, and 40 chromosomal abnormalities were diagnosed (27 trisomies 21, 5 trisomies 18, 2 trisomies 13, 3 Turner syndromes, 1 partial trisomy 9 and 2 others). The NB was absent in 19 (70%) trisomies 21, 4 trisomies 18 (80%), 2 Turner syndromes (66%), in the partial trisomy 9, in 7 normal karyotype fetuses (0.2%), and in a case with spontaneous first-trimester abortion before prenatal diagnosis. A significant difference was found between NT thickness, expressed as a multiple of the median, in trisomy 21 fetuses with present and absent nasal bone. CONCLUSIONS: The absence of NB at 11 to 14 weeks is more frequent in fetuses with trisomy 21 and other aneuploidies than in normal karyotype fetuses.