Histopathological findings of the nose of Down syndrome abortuses

Recent reports of absent nasal bone in fetuses with Down syndrome have sparked much interest in the use of this finding for the screening of Down syndrome. We describe the histopathological findings of nasal bones of two fetuses with Down syndrome, one with absence and the other with normal ossification of the nasal bone. We propose that histopathological examination of the nasal bone could improve the accuracy of diagnosis of nasal hypoplasia among Down syndrome abortuses. Copyright © 2003 John Wiley & Sons, Ltd.     

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. Copyright © 2005 John Wiley & Sons, Ltd.     

Nuchal translucency thickness and outcome in chromosome translocation diagnosed in the first trimester

In order to determine the significance of nuchal translucency thickness on the subsequent natural history of first-trimester fetuses with a chromosome translocation, seven consecutive cases diagnosed between 11 and 13 weeks of gestation were reviewed. Nuchal translucency measurements were successfully obtained before chorionic villus sampling (CVS) in all cases. Three fetuses had an unbalanced translocation and all were associated with increased nuchal translucency and multiple anomalies at the detailed second-trimester scan. There were no survivors in this group. The remaining four fetuses had a balanced translocation; all had normal nuchal translucency thickness and no structural anomalies were detected in the second trimester. Three of these fetuses were born at ≥35 weeks of gestation and were phenotypically normal. However, an unexpected single fetal demise occurred in a dichorionic twin pregnancy at 28 weeks of gestation. It is concluded that nuchal translucency measurements provide important prognostic information on pregnancy outcome in first-trimester fetuses with a chromosome translocation. In parents with a known balanced translocation, the detection of increased nuchal translucency at 11–14 weeks of gestation is associated with unbalanced translocations, structural anomalies and poor pregnancy outcome. Copyright © 2001 John Wiley & Sons, Ltd.     

Role of the second-trimester ‘genetic sonogram’ for Down syndrome screen in the era of first-trimester screening and noninvasive prenatal testing

Ultrasonography for the screening of Down syndrome was first introduced about 25 years ago. Different combinations of markers detectable at second-trimester ultrasonography have been proposed under the banner of ‘genetic sonogram’. In recent years, several developments in first-trimester screening and the recent introduction of noninvasive prenatal testing for aneuploidy screening have had important implications for the prevalence of these conditions in the second-trimester and the screening performance of a genetic sonogram. Several second-trimester sonographic markers for Down syndrome have been reported; meta-analysis has shown that the most powerful predictors are mild ventriculomegaly, increased nuchal fold, hyperechoic bowel, and absent or hypoplastic nasal bone. Whereas use of individual markers should be discouraged and scoring systems of multiple markers are now obsolete, use of combined likelihood ratio and logistic regression analysis formulae provides better accuracy. However, there is significant heterogeneity in results among studies. Despite such limitations, the genetic sonogram will continue to have a place in prenatal screening, particularly in twin and higher-order multiple pregnancies, in countries with limited access to the most recent genetic screening tests, in cases with borderline results at maternal serum screening tests, and as noninvasive supplementary test for high-risk women reluctant to undergo invasive diagnostic testing. © 2014 John Wiley & Sons, Ltd.     

Early amniocentesis and fetal nuchal translucency in women requesting karyotyping for advanced maternal age

Fetal nuchal translucency was measured at 11–14 weeks' gestation in 97 pregnancies referred for early amniocentesis for advanced maternal age. The nuchal translucency was abnormal in 11 fetuses and the fetal karyotype was abnormal in five of these 11 cases. The karyotype was normal in 86 cases with normal nuchal translucency. The culture failure and miscarriage rates associated with early amniocentesis were 3·3 per cent and 2·2 per cent respectively. Amniotic fluid leakage occurred in 6 per cent of cases. In women requesting fetal karyotyping for advanced maternal age without additional biochemical screening, fetal nuchal translucency should be measured at 11–14 weeks. If the nuchal thickness is ≥ 3 mm, a first-trimester diagnostic procedure is indicated; however, if it is <3 mm, amniocentesis should be delayed until 16 weeks' gestation.     

Serum PAPP-A measurements in first-trimester screening for Down syndrome

Serum PAPP-A measurements taken from 254 women in the first trimester are reported. Eleven chromosomal abnormalities were detected. The mean serum PAPP-A levels in cases of Down syndrome were 0.44 MOM at 9 weeks gestation, 0.15 MOM at 10 weeks, and 0.29 MOM at 11 weeks. The PAPP-A level at 10 weeks was below those of pregnancies which aborted spontaneously. At 11 weeks, the pregnancies with Down syndrome recorded the lowest PAPP-A levels at that gestation. On this small sample, offering chorionic villus sampling to women with singleton pregnancies and a PAPP-A level below 0.3 MOM (approximately 6.5 per cent of this at-risk group) would have detected all the Down syndrome fetuses at 10 weeks and 50 per cent at 11 weeks without selecting those cases destined to abort. This suggests that serum PAPP-A should continue to be investigated as a potential first-trimester screening test for Down syndrome.     

Prenatal diagnosis of haemoglobin disorders by cordocentesis at 12 weeks' gestation

Prenatal diagnosis of haemoglobin disorders is accepted to be a useful procedure to avoid births of infants with homozygous diseases. Advances in sampling and molecular techniques, such as polymerase chain reaction (PCR) and chorionic villus sampling (CVS), have made earlier and safer first-trimester prenatal diagnosis possible. However, these procedures need previous studies of at-risk couples, which can be very time-consuming when a number of different β-thalassaemia mutations occur in the region. We describe the possibility of making a first-trimester prenatal diagnosis by cordocentesis and fetal blood analysis at the 12th week of gestation. We found no statistically significant difference (p>0.05) between β/γ values in fetuses at the 12th and 18th weeks of gestation. In seven affected fetuses aborted at the 12th week of gestation, the diagnosis was confirmed in all cases by PCR analysis. These findings suggest that early cordocentesis could be an alternative procedure to CVS and PCR analysis.     

Early detection of fetal cardiac abnormalities: how effective is it and how should we manage these patients?

Congenital heart defects (CHDs), the most commonly occurring congenital malformations, cause significant mortality and morbidity. With the recognition of early markers for CHD and the development of better ultrasound resolution, interest has turned toward performing a screening anomaly scan, including the heart, together with the nuchal scan. It is also possible, with adequate skill and training, to competently perform an echocardiogram <16 weeks' gestation. This article reviews the detection of major CHD in the first trimester and early second trimester including specific markers that help to identify high-risk groups for early fetal echocardiography (EFEC). CHD detection during first-trimester screening is low (2.3–56%) depending on the center's experience and the population studied. An increased nuchal translucency, abnormal ductus venosus flow, and tricuspid regurgitation in the first trimester are associated with an increased CHD risk and can be used together to identify high-risk fetuses for EFEC. EFEC requires skilled scanning and the expertise of a fetal echocardiographer. In high-risk populations, it is 78.5% sensitive with a 74.5% concordance between the EFEC and the mid-gestational echocardiogram. The availability of qualified personnel and diagnostic accuracy are prerequisites before EFEC can be introduced into management protocols. The limitations of EFEC should be recognized, and a later confirmatory echocardiogram is recommended. © 2014 John Wiley & Sons, Ltd.     

First-trimester maternal serum schwangerschafts protein 1 (SP1) in pregnancies associated with chromosomal anomalies

The relationship between first-trimester maternal serum Schwangerschafts protein 1 (SP1) and the karyotype of the pregnancy was examined in 692 women who underwent chorionic villus biopsy at 6–12 weeks. There were 30 pregnancies with abnormal karyotypes, consisting of 14 Down's syndrome (DS), eight trisomy 18, and eight other anomalies, two of which were mosaics. The normal ranges and medians for gestation were defined from the 662 cases in which the karyotype was normal. The median SP1 (0·5 MOM) of the abnormal group was significantly lower than that of the normal group (10 MOM). This relationship was maintained for the DS pregnancies (0·4 MOM) and for anomalies other than trisomy 18 (0·43 MOM) but not trisomy 18 (1·1 MOM). It is possible that the use of SP1 as a screening test for chromosome anomalies in the first trimester could have a 43 per cent detection rate for a 5 per cent false-positive rate.     

Screening for fetal aneuploidies at 11 to 13 weeks

Effective screening for major aneuploidies can be provided in the first trimester of pregnancy. Screening by a combination of fetal nuchal translucency and maternal serum free-β-human chorionic gonadotrophin and pregnancy-associated plasma protein-A can identify about 90% of fetuses with trisomy 21 and other major aneuploidies for a false-positive rate of 5%. Improvement in the performance of first-trimester screening can be achieved by firstly, inclusion in the ultrasound examination assessment of the nasal bone and flow in the ductus venosus, hepatic artery and across the tricuspid valve, and secondly, carrying out the biochemical test at 9 to 10 weeks and the ultrasound scan at 12 weeks. Copyright © 2011 John Wiley & Sons, Ltd.     

The history of the second-trimester sonographic markers for detecting fetal Down syndrome,and their current role in obstetric practice

This review summarizes the development, history and use of second-trimester sonographic markers for the detection of fetal Down syndrome over three decades. Starting with the nuchal fold thickening in 1985 and culminating in the genetic sonogram in the 1990s. The combination of second-trimester serum screening with the ultrasound markers improved the detection rate of affected fetuses but also allowed patients to decrease their risk of carrying a fetus with Down syndrome if the genetic sonogram was normal. More recently the role of the genetic sonogram and its markers have changed with the wide spread use of first-trimester screening. This prior screening ultimately decreases the prevalence of fetal Down syndrome in the second trimester to less than 85% of what it was in the first-trimester as most fetuses with Down syndrome are now identified early. Current interpretation of the second-trimester Down syndrome markers must be based on the result of the first trimester and combined screening to achieve the most accurate risk estimate of an affected fetus. Copyright © 2010 John Wiley & Sons, Ltd.     

An increase in cost-effectiveness of first trimester maternal screening programmes for fetal chromosome anomalies is obtained by contingent testing

We assessed the discriminatory efficiency and cost-effectiveness of a novel way of organising first trimester screening for Down syndrome (DS), contingent testing, where a serological test (PAPP-A and β-hCG: the double test) is made in early first trimester and followed by nuchal translucency testing (NT) only in women with an intermediate risk, e.g. <1:65 and >1:1000, and not in all women as in normal first trimester screening (NFTS). Using Monte Carlo simulation contingent testing had a detection rate (DR) of 78.9% and a false-positive rate (FPR) of 4.0% for DS with 19.4% of women offered NT testing. The DR of NFTS was 85.5% and the FPR 4.4%. The decrease in NT screening was associated with an increase from 23% to 29% in the proportion of DS cases born. The cost of the contingent testing programme was £53 000 per DS case not born and £91 000 in NFTS. The number of aborted fetuses per DS case were 0.35 and 0.36, respectively. Thus, contingent testing is an organisation of first trimester screening where costs can be reduced with a marginal decrease in performance. Contingent testing is attractive in areas where NT screening is the bottleneck preventing the introduction of first trimester screening. Copyright © 2002 John Wiley & Sons, Ltd.     

Ultrasound screening for chromosomal anomalies in the first trimester of pregnancy

For the last 6 years, sonographic signs for excessive fluid accumulation in the backs of 10- to 12-week-old fetuses have been looked for prior to transabdominal chorionic biopsy. In 1400 pregnancies, subsequent karyotype analyses revealed 28 cases of Down syndrome. In 15 ( = 54 per cent), a large fluid cushion over most of the back had been documented at the time of biopsy. Only a few chromosomally normal fetuses with the same peculiarity were observed. The cushion was also present in fetuses with trisomies 18 and 13 , and in Turner syndrome. Systematic first-trimester screening for nuchal fluid accumulation seems to be a recommended method for the detection of Down syndrome and other chromosome anomalies in young pregnant women at low risk. It compares favourably with current methods of maternal serum screening performed at 16–18 weeks which require a higher number of invasive procedures.     

Analysis of maternal serum alpha-fetoprotein and free beta human chorionic gonadotrophin in the first trimester: Implications for down's syndrome screening

The aim of this study was to determine the maternal population, pregnancy, serum alpha-fetoprotein (AFP) and free β subunit of human chorionic gonadotrophin (FβhCG) parameters in a large series of women attending prenatal clinics before 15 weeks' gestation and to assess the practical problems of population screening for Down's syndrome in the first trimester using these markers. Serum samples were collected from 8600 women attending prenatal clinic booking visits. Maternal serum AFP and FβhCG medians were calculated for each day of gestation (49–104 days), using both dates and ultrasound estimates of gestation. The effects of maternal weight, twin pregnancies, and threatened abortion on AFP and FβhCG levels were analysed. The median age of the population was 27.1 years and the median weight 62.1 kg. Twenty-six per cent of samples were collected before 70 days and 50 per cent before 78 days' gestation. Eighty-nine per cent of all samples had gestational estimates by dates, 60 per cent by ultrasound and 52 per cent by both dates and ultrasound. The AFP median was 5 kU/1 at 49 days, 5.9 kU/1 at 70 days, and 17.9 kU/1 at 100 days. The peak median FβhCG level was 66.4 ng/ml at 64 days, falling to 20.6 ng/ml at 100 days' gestation. Both AFP and FβhCG levels showed log Gaussian distributions but the standard deviation for AFP was 20 per cent greater than that found in the second trimester. AFP and FβhCG levels showed an inverse relationship with maternal weight and were increased in twin pregnancies (1.68 and 1.97 multiples of the median, respectively). AFP and FβhCG can be readily measured in a large screening population in the first trimester. Down's syndrome screening protocols based on these markers could be refined by the use of gestations in individual days but AFP is likely to be a less effective marker and detection rates are likely to be lower than in the second trimester. To realize the potential of first-trimester screening, more women should be encouraged to attend the prenatal clinic in early pregnancy and ultrasound dating should be carried out for all pregnancies at this stage.     

Crown—rump length in aneuploid fetuses: Implications for first-trimester biochemical screening for aneuploidies

This study examined the effect of estimation of gestational age from the menstrual history compared with that from crown—rump length (CRL) measurement on the detection rate of screening for aneuploidies in the first trimester. Pregnancy-associated plasma protein A (PAPP-A) was assayed in blood collected prior to chorionic villus sampling in 356 women with unaffected pregnancies and 28 women with an aneuploid pregnancy. There were 14 Down's syndrome (DS) pregnancies. All pregnancies were dated from menstrual history and CRL measurement. The average CRL gestation in the aneuploid population was 2.5 days less than that derived from the LMP (95 per cent confidence interval (CI) for LMP—CRL gestation: using the algorithm based on unaffected pregnancies 0–3.5 days; using the matched case—control approach 1–4.5 days). The average CRL gestation in the DS population was 2 days less but this did not reach statistical significance (95 per cent CI for LMP—CRL gestation: using the algorithm — 1 to 4.5 days; using the matched case—control approach 0 to 5.5 days). The detection rate of aneuploidies in the first trimester using maternal serum PAPP-A was reduced by 7 per cent (and by 3 per cent for DS) for a 5 per cent false-positive rate when using CRL rather than LMP to date the pregnancy. This phenomenon is a consequence of an apparent reduction of gestational age when estimated by CRL in the aneuploid population. Further studies are required to evaluate whether CRL is an unbiased estimate of gestation for Down's syndrome pregnancies.     

Can gestational dates routinely derived from very early ultrasound be used to interpret maternal serum alpha-fetoprotein measurements?

This study assesses the reliability of estimating gestational age via crown-rump or gestational sac measurements obtained at 8 weeks' gestation or earlier as part of routine physician office practice. To accomplish this, we studied 88 pregnancies managed at 45 different sites in which both an early first-trimester ultrasonically-derived gestational age estimate and a second-trimester biparietal diameter (BPD) estimate were available. The first-and second-trimester determinations were highly correlated, but the first-trimester determinations were, on average, 0.43 weeks earlier than the second. The first-trimester estimates were satisfactory for use in interpreting maternal serum alpha-fetoprotein (MSAFP) screening measurements, but second-trimester BPD measurements obtained prior to MSAFP screening should be the method of choice for interpreting MSAFP values, due to the increased sensitivity for detecting open spina bifida.     

Humerus and femur length in fetuses with down syndrome

The aim of the study was to assess the value of sonographic measurement of fetal humerus and femur lengths in the second trimester as a screening tool for Down syndrome (DS). We reviewed retrospectively fetal sonographic biometry made at the time of amniocentesis between 15 and 19 weeks. The study group consisted of 27 DS fetuses. The control group comprised 500 normal fetuses chosen randomly. The expected humeral and femoral lengths for a given biparietal diameter were estimated by linear regression equations from the 500 normal fetuses. Receiver operating characteristic curve analysis was performed to evaluate both the detection rate and the false-positive rate of different cut-off values of measured to expected lengths ratios. The median femur and humeral lengths in DS fetuses were 0·91 times the expected values. No significant differences in the detection rate and false-positive rate were found between the humerus and femur lengths. When the humeral and femoral lengths were combined, we observed a remarkable reduction in the false-positive rate. A measured to expected length ratio of 0·91 detected 44·4 per cent of DS fetuses with 7·6 per cent false positives. These results suggest that the combination of femoral and humeral lengths may permit a more efficient use of ultrasound in screening for Down syndrome than the use of either alone.     

Shortened fetal long bones: A notable intrauterine phenotypic feature in SHOX-associated skeletal dysplasia

Objective

To explore the intrauterine phenotypic spectrum of short stature homeobox-containing (SHOX) gene-associated skeletal dysplasia and provide genetic counseling at-risk pregnancies.

Method

We analyzed the fetuses with SHOX-microdeletions identified by single nucleotide polymorphism (SNP)-array. The intrauterine phenotypes and outcomes were further elaborated.

Results

Nine fetuses carrying a single SHOX-microdeletion were reported, with deletion sizes ranging from 0.134 to 1.35 Mb. Shortened long bones were observed in all fetuses, varying from −2.0 standard deviation (SD) to −5.3 SD. Moreover, all cases had a femur length/foot ratio less than 0.87 and a femur/abdominal circumference ratio greater than 0.16, suggesting that non-lethal skeletal dysplasia may be involved. Two fetuses showed intrauterine growth restriction, and two had nasal bone hypoplasia. Prenatal ultrasonography did not reveal other obvious anomalies, including the Madelung deformity. Five microdeletions were inherited and one was de novo. Five terminations and four newborns were recorded. Two newborns had normal stature, and two were short-statured (height <3rd percentile), with one having inflexible wrists.

Conclusions

SHOX haploinsufficiency may manifest with shortened fetal long bones. The combination of history taking, prenatal ultrasonography, and SNP-array can prompt early prenatal diagnosis and timely postnatal treatment of SHOX-associated skeletal dysplasia.     

Is there still a role for nuchal translucency measurement in the changing paradigm of first trimester screening?

Objectives

To give an overview of the genetic and structural abnormalities occurring in fetuses with nuchal translucency (NT) measurement exceeding the 95th percentile at first-trimester screening and to investigate which of these abnormalities would be missed if cell-free fetal DNA (cfDNA) were used as a first-tier screening test for chromosomal abnormalities.

Methods

This is a national study including 1901 pregnancies with NT≥95th percentile referred to seven university hospitals in the Netherlands between 1 January 2010 and 1 January 2016. All cases with unknown pregnancy outcome were excluded. Results of detailed ultrasound examinations, karyotyping, genotyping, pregnancy and neonatal outcomes, investigation by a clinical geneticist and post-mortem investigations were collected.

Results

In total, 821 (43%) pregnancies had at least one abnormality. The rate of abnormalities was 21% for fetuses with NT between 95^th and 99^th percentile and 62% for fetuses with NT≥99^th percentile. Prevalence of single-gene disorders, submicroscopic, chromosomal and structural abnormalities was 2%, 2%, 30% and 9%, respectively.

Conclusion

Although cfDNA is superior to the combined test, especially for the detection of trisomy 21, 34% of the congenital abnormalities occurring in fetuses with increased NT may remain undetected in the first trimester of pregnancy, unless cfDNA is used in combination with fetal sonographic assessment, including NT measurement.     

First-trimester fetal heart block and increased nuchal translucency: an indication for early fetal echocardiography

Prevalence of congenital heart disease increases with nuchal translucency (NT) thickness. First-trimester fetal bradycardia may result from heart block associated with complex congenital heart disease. We report two cases detected in the first trimester of pregnancy, in which both fetuses showed an increased nuchal translucency and bradycardia. Fetal karyotype was normal in both fetuses. First-trimester fetal echocardiography was performed and, in both cases, complex congenital heart disease was diagnosed. We discuss the added role of fetal heart rate in first-trimester ultrasound screening, in fetuses with increased nuchal translucency and normal karyotype. We stress, as well, the importance of echocardiography performed in the first trimester as a potential tool for early diagnosis in selected cases. Copyright © 2005 John Wiley & Sons, Ltd.