A normal 20‐week scan of a euploid fetus with a history of first‐trimester increased nuchal translucency: caution or reassurance?
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Increased nuchal translucency (NT) is a marker for aneuploidy. Measurement of the NT thickness in conjunction with maternal age and the biochemical markers pregnancy-associated plasma protein-A and free β-human chorionic gonadotropin in the first trimester of pregnancy has become an established method worldwide for identifying fetuses at risk for aneuploidy1-4 and has a sensitivity of 90% for a false-positive rate of 5%5. Nevertheless, NT is increased in 4.4% of chromosomally normal fetuses2, and these euploid fetuses are still at risk of a wide range of fetal malformations, dysplasias, disruptions, genetic syndromes and neurodevelopmental delay6. The number of abnormalities known to be associated with enlarged NT is still increasing. However, there remains a large group of fetuses with increased NT that present as healthy neonates. Therefore, all couples with a euploid fetus with increased NT should be offered a detailed ultrasound scan at 20–22 weeks' gestation to exclude or diagnose structural anomalies or subtle ultrasound markers that are associated with genetic syndromes. Establishment of a normal karyotype following the diagnosis of an increased NT still leaves parents with great uncertainty and requires extensive counseling from their clinician. Several parents will opt immediately for a termination of pregnancy. Others may remain anxious about the possible consequences associated with increased NT, for example developmental delay detectable in early childhood. Counseling about the chances of a favorable outcome is indicated after karyotyping, but also after the 20-week scan and after birth. The chance of an adverse pregnancy outcome such as miscarriage, fetal death and/or major fetal anomalies increases with increasing NT thickness3, 6-9. The prevalence of miscarriage or fetal death increases from 1.3% in the case of an NT between the 95th and 99th percentiles to about 20% for an NT of 6.5 mm or more3, 6, 8. The prevalence of major fetal abnormalities is reported to increase exponentially, from 2.5% for an NT between the 95th and 99th percentiles to about 45% for an NT of 6.5 mm or more, major fetal abnormalities being defined as those requiring medical and/or surgical therapy3, 6, 8. The chances of delivering a healthy baby are about 70% for an NT of 3.5–4.4 mm but about 15% for an NT of 6.5 mm or more6. It is important to realize that most reports provide data on the risk of an adverse pregnancy outcome after the diagnosis of increased NT. In addition, fetal death related to increased NT is reported to occur early in pregnancy, i.e. before 20–24 weeks of gestation3, 7, 10, 11. Less is known about the likelihood of a normal outcome at birth after the 20-week ultrasound examination reveals a normal fetal anatomy, and of the residual risk of developmental delay in childhood. Counseling parents is especially difficult under these circumstances and more studies which can provide the clinician with data on neonatal and pediatric outcome are, therefore, warranted. Only nine studies have reported the pediatric long-term follow-up of chromosomally and anatomically normal fetuses with increased NT (Table 1)3, 12-19. These studies report a developmental delay in early childhood of between 0 and 8.7%. It is difficult to assess the significance of these studies due to the limited number of neonates studied, the heterogeneous populations and the different cut-off values for increased NT. Furthermore, follow-up was incomplete in up to 15–32% of cases and only two studies used a control group. Nevertheless, all but one study include cases of developmental delay. The most recent study of Senat et al.19 reports the long-term follow-up of 162 chromosomally normal fetuses with previously increased NT and includes a large control group (n = 370). Both clinical examinations as well as Ages and Stages Questionnaires (ASQ) assessing development were performed. Senat et al. found a developmental delay in 1.2% and an ASQ score < 2 SD in 18% of the neonates with a history of increased NT, both of which were not significantly different from the results of the control group. In this issue of the Journal, Bilardo et al.20 make an important contribution by reporting the follow-up of 451 euploid fetuses with a previously increased NT. In agreement with previous studies, the incidence of an adverse pregnancy outcome was related linearly to the initial degree of NT enlargement, ranging from 8 to 80%. A 20-week scan was performed in 425 cases. After a normal 20-week scan, an adverse pregnancy outcome was observed in 4% of the cases. Neurodevelopmental delay was diagnosed in 7/425 (1.6%) fetuses. Bilardo et al. conclude that, when findings at the 20-week scan are normal, a favorable outcome can be expected and parents can be reassured, regardless of the previous NT thickness. Their report of a low prevalence of developmental delay is in agreement with the study of Senat et al.19 and several other studies3, 6, 13. Also, it can be concluded that once a targeted 20-week scan shows no abnormalities, the likelihood of a favorable outcome increases markedly6, 19, 20. However, in my opinion, several issues should be taken into account before giving reassurance during parental counseling. First, counseling parents in the case of a fetus with a previously extremely enlarged NT requires special consideration. Bilardo et al.20 argue that the favorable outcome after a normal 20-week scan applies to all degrees of initial NT thickness. However, the number of fetuses with a severely increased NT (6.5 mm or more) was small (n = 30), with only six of the fetuses in this group surviving. Also, the fact that 33% of the pregnancies were terminated at parental request may have caused bias. In the study of Senat et al.19, although close to the statistical significance threshold, the association between NT thickness and outcome was not significant. This study also contained only a small number of fetuses with an excessive NT. Presently, sufficient data with long-term follow-up are not available for fetuses with an extremely large NT, but in my opinion the high rate of fetal death associated with an extremely enlarged NT implies that caution instead of reassurance is warranted in parental counseling. Furthermore, Bilardo et al.20 recorded an adverse pregnancy outcome of 4% (16/375) after a normal 20-week scan, but seven of these cases were classified as 'potentially amenable' to ultrasound detection. They argue that, with exclusion of these cases, the chance of a healthy baby after a normal 20-week scan is 98%. Whether this exclusion is justified can be disputed. Senat et al.19 report a higher rate of abnormalities diagnosed postnatally of 11.1% (18/162). Half of these abnormalities were cardiac malformations. The differences between these studies might be explained by the fact that a pediatric cardiologist was present at the ultrasound scan in the study of Bilardo et al. Nevertheless, it is important to realize that ultrasound screening will never reach 100% sensitivity, even when performed by a highly experienced sonographer. Consequently, anomalies can be missed and diagnosed only after birth. Specifically, mild cardiac anomalies such as pulmonary stenosis in Noonan syndrome, are often missed on ultrasound21. Also, one third of the genetic syndromes did not show any potentially detectable ultrasound signs in the study of Bilardo et al.20, which is in agreement with the findings of other studies6, 17, 19. These issues should be addressed during parental counseling. A further important finding of the study of Bilardo et al.20 was the association between the presence of subtle suspicious ultrasound findings at the 20-week scan and an adverse pregnancy outcome. In three of seven cases with neurodevelopmental delay, subtle ultrasound findings were present (nuchal edema, mild pyelectasis, pericardial effusion). This is in agreement with other studies that confirm a higher risk of a genetic syndrome and/or developmental delay in the case of subtle suspicious ultrasound findings3, 6, 19. Other non-specific ultrasound markers include hydrothorax and polyhydramnios. After 14 weeks' gestation an increased NT normally resolves, but in some cases it evolves to second-trimester nuchal edema or cystic hygroma. Souka et al.3, 6 reported that in the case of increased nuchal fold thickness, the risk of evolution to hydrops, perinatal death or live birth with a genetic syndrome is 10% and they found the risk of neurodevelopmental delay to be 5% in these cases. This high risk of adverse outcome is in agreement with the studies of Bilardo et al.20 and Senat et al.19. Cystic hygroma is considered a different entity clearly associated with poor prognosis22. Follow-up studies including cystic hygroma report a poorer outcome at birth22-24. In conclusion, the study of Bilardo et al.20 makes an important contribution to the follow-up data on increased NT and should be of use in prenatal counseling. It can be concluded that when findings are normal at the 20-week scan, the chance of a favorable outcome increases markedly. However, caution is necessary in cases of extended NT (6.5 mm or more), a thickened nuchal fold and subtle non-specific ultrasound findings. Also, parents should be informed of the limitations of ultrasonography.Keywords:
Nuchal translucency
Nuchal Translucency Measurement
The Nuchal Translucency thickness measurement is made to identify the Down Syndrome in screening first trimester fetus and presented in this paper. The mean shift analysis and canny operators are utilized for segmenting the nuchal translucency region and the exact thickness has been estimated using Blob analysis. It is observed from the results that the fetus in the 14th week of Gestation is expected to have a nuchal translucency thickness of 1.87 plus or minus 0.25mm.
Nuchal translucency
Nuchal Translucency Measurement
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Nuchal translucency
Nuchal Translucency Measurement
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Nuchal translucency
Nuchal Translucency Measurement
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Nuchal translucency thickness (NT) measurement as a screening test for fetal Down syndrome has revolutionized obstetric ultrasound. For the first time, the performance and usefulness of a sonographic marker (NT) as a screening test for a fetal condition (trisomy 21) was tested prospectively and confirmed by many large-scale studies using the same or very similar methodology, prior to being accepted generally and incorporated into routine clinical practice. Based on these studies, it became very clear that the success of using a sonographic marker as a screening tool requires the development of a precise protocol, proper operator training, certification, auditing of performance and re-certification. When any of these elements is lacking, the high accuracy of NT screening is not achievable. The importance of adherence to a strict protocol and stringent quality assurance has been recognised for decades by our colleagues in the biochemistry department through their development of maternal serum screening for open neural tube defects and Down syndrome. In contrast, many sonographic tests, which are actually far more complicated and cumbersome than NT measurement, have been incorporated widely into clinical practice well before full evaluation, leading to much confusion and mismanagement. Of these, the second-trimester ‘soft markers’ is the best example. Soft markers are qualitatively different from structural anomalies. They are detected in a variable proportion of normal fetuses. They are of interest because of their statistical association with chromosomal abnormalities, making such markers potentially useful as a screening tool for fetal aneuploidies. Since the majority of cases of trisomies 13 and 18 are associated with structural anomalies that are detectable by ultrasound, the role of soft markers for screening of these conditions is limited. Therefore, the following discussion focuses on the clinical value of using soft markers as a screening test for trisomy 21. Unlike NT, the typical history of soft markers started with the documentation of a new proposed marker in a series of abnormal cases in a high-risk population, without controlling for confounding factors. The subsequent overwhelming enthusiasm led to the premature incorporation of assessment of the marker into routine clinical practice. Only with more experience did the denominator emerge which lowers the incidence and strength of association. New technologies and studies in ultrasound then showed the marker to be present in far more normal cases than was originally thought, reducing the positive predictive value further, even as far as to the background risk. Eventually, only after being used for several years, have many of these markers been found to be poor or even useless for trisomy 21 screening. Although ultrasound is a ‘non-invasive’ procedure, it is not without risk. Pregnant women referred for further assessment because of a soft marker have significantly higher levels of anxiety than do those referred for advanced maternal age only, at a level similar to those referred for abnormal maternal serum biochemistry1. This anxiety could lead to a cascade of additional, often unnecessary, tests and is often very difficult to resolve without an invasive diagnostic test. Therefore, all sonographic tests, like any medical test, must be evaluated properly, and should only be implemented if a clear benefit is demonstrated. So, how should we assess the usefulness of soft markers? If they are being used for the purpose of screening for trisomy 21, they should be examined as such. In other words, we should be satisfied that we have a well-characterized test that provides an acceptable sensitivity and specificity. Unfortunately, none of the soft markers used in clinical practice has undergone adequate vigorous scientific scrutiny, and the major problems are as follows. Firstly, the second-trimester ‘genetic sonogram’, which includes both soft markers and structural anomalies, when used by the most experienced operators was able to detect about 70% of cases of trisomy 21, with a false-positive rate (FPR) of about 10%2. This performance would be substantially lower if only soft markers were included, and is substantially inferior to other well-established screening protocols, such as first-trimester NT screening (detection rate of 76.8% at a 4.2% FPR3) or first-trimester combined screening (detection rate approaching 90%4). Therefore, it is quite clear that second-trimester soft markers alone should not be the screening test of choice for trisomy 21. Secondly, do we have a standardized methodology in applying soft markers as a screening test for trisomy 21? The answer, quite simply, is ‘No’. There are wide variations in the definition of individual markers; the methodology of examination is not standardized; and many of the reported studies were performed in referral centers on high-risk pregnancies. It is generally agreed that assessment of multiple markers is required to produce acceptable screening performance. However, there is no consensus as to how many markers should be examined, or how to integrate these markers. Some have proposed the simple approach of defining a high-risk group by the presence of two or more markers, or using a scoring system5, but there is much controversy over the relative importance of each marker and therefore the validity of such a simple approach. In contrast, the use of likelihood ratios (LR) appears to be a more scientific approach. The use of LR enables us to modify the background risk, taking into account all of the available information including prior screening test results. Unfortunately, there are wide variations in the reported LRs associated with each of the markers individually or in combination, due to the lack of consistent definitions and methodologies in their assessment. For example, the estimated LR for isolated echogenic intracardiac focus ranges from 1.1 (useless) to 5.4 (moderately strong marker)6-8. Which is correct? If we are going to use several markers, the ultimate uncertainty in the combined LR could be enormous. Thirdly, the absence of soft markers has been used to reduce the individualized risk of trisomy 21, with a reported negative LR as low as 0.159. The reported series are in general conducted in very specialized centers. It is still unclear what the exact negative LR should be, how many markers need to be included in the assessment, and the precise definition of each marker. What is certain, however, is that reproducible results cannot be achieved until the same methodology is used consistently. Therefore, it is recommended that a reduction of risk should not be applied ‘on the basis of a 16–20-week ‘screening’ scan, owing to the variety of imaging locations involved’10, unless the scan is ‘undertaken in an established centre performing tertiary-level ultrasound’11. We would add that such centers should either have the data to generate their own negative LR, or, if they are using reported negative LRs from the medical literature, should have adequate evidence to confirm that the methodology used is exactly the same as that described in the original reports, and that their performances are comparable. Fourthly, unlike first-trimester NT screening, there is no specific structured training for the assessment of each of these soft markers, nor is there any certification or recertification process. It is unlikely that adequate quality assurance programs are present in the majority of centers to audit the outcome and performance of the center or of individuals in using these soft markers. Experience from all screening programs, including first-trimester NT screening as the closest example, tells us that no screening program will be successful in the absence of a stringent certification and quality assurance process. It is quite clear that if a woman requests prenatal screening for trisomy 21, sonographic soft markers would not be the test of choice. Yet, there is a great temptation to use second-trimester sonographic markers to modify the individualized risk of trisomy 21 in patients who have received other forms of screening tests in early pregnancy. However, it does not seem logical to modify a risk calculated on the basis of a reliable test, which was well studied and had a clear protocol and quality assurance program, by a second test that lacks standardization or quality assurance—possibly with the exception of the few units which have considerable follow-up data of their own12, 13. We have no intention of disputing the association between second-trimester markers and fetal trisomy 21, in particular nasal bone hypoplasia, echogenic bowel and nuchal fold thickness. However, we do have concerns that these markers are being used in routine clinical settings before their effect on screening has been fully elucidated, with an uncertain effect on the overall screening performance. With the many effective screening programs currently available in the first and early second trimesters, it is likely that only very strong soft markers, such as those with a LR of more than 10, will contribute significantly to further improving the performance of trisomy 21 screening programs. Therefore, efforts should be focused on: (i) the development of a well-defined protocol for the evaluation of these few strong markers, including how to do it, when to do it, and who should do it; (ii) the development of an algorithm for incorporating these markers into existing screening programs, such as in the recent study by Borrell et al.14; and (iii) the confirmation of their efficacy as screening markers by large prospective studies in an unselected population. Over the last few years, we have been pleased to see that there have been more discussions in the medical literature concerning training and quality assessment in obstetric sonography15-17. This is encouraging. It should be remembered that a service without quality is worse than no service at all. We would like to conclude with the following quote: ‘The screening procedure should not be merely a test but must be a comprehensive program… . The screening process must allow patients to decline intervention at each step throughout the process. A screening program must undertake regular clinical audit to evaluate local performance’11. There is still much to be achieved before second-trimester soft markers find a definite role in fetal aneuploidy screening. The basic principle of medicine—‘First do no harm’—should always be observed. Any test, be it diagnostic or screening in nature, should not be used in clinical practice unless its efficacy has been established.
Nuchal translucency
Nuchal Translucency Measurement
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In Brief Screening for Down syndrome is an important part of routine antenatal care. The most common screening method in the United States involves the assessment of a combination of factors: maternal age, multiple second-trimester serum markers, and second-trimester ultrasonography (as a so-called “genetic sonogram”). More recently, however, there has been significant interest in first-trimester methods of screening, including screening for first-trimester serum markers and the sonographic measurement of fetal nuchal translucency. Multiple studies have demonstrated that fetal nuchal translucency has the potential of being a very powerful predictor of fetal aneuploidy. However, for clinicians a large void remains between this knowledge and the practical issues that must be addressed prior to endorsing this form of screening for widespread use. This article provides an objective assessment of the literature describing nuchal translucency, as well as some adjunct first-trimester sonographic techniques, such as ductus venosus flow and nasal bone studies. Additionally, a detailed description of practical problems that might limit the implementation of this form of screening is presented. First-trimester nuchal translucency sonography represents a great advance in the field of Down syndrome screening, although many practical implementation issues remain to be clarified prior to recommending widespread utilization of this technique.
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Since the introduction of 1st trimester NT Screening in North America following the FASTER trial, the debate among providers has been whether to limit the 1st trimester ultrasound evaluation to only measuring the crown–rump length (CRL) and NT. The purpose of this study was to ascertain the frequency of clinically important ultrasound findings derived from a detailed survey of fetal and uterine anatomy at the time of NT screening. All patients with a singleton pregnancy referred for NT screening between 11 weeks and 14 weeks of gestation underwent both transabdominal and endovaginal ultrasound evaluation of fetal and uterine anatomy. Power Doppler was used to examine the four-chamber and outflow tracts of the heart with a Thermal Index of 0.2 or less. All results were tabulated and grouped based upon whether the NT measurement was < 3 or 3 mm or greater. The study consisted of 2412 consecutive singleton fetuses. The CRL range was between 4.1 and 9.4 cm (mean 6.5 ± 0.9 SD), and was normally distributed. Fetal anatomy was imaged in 98% of fetuses. The NT was ≥ 3 in 1.4% (n = 34). The following table lists the distribution of findings categorized by the NT measurement. If a full anatomical study is performed in all patients undergoing NT screening, there is a significant yield of abnormal findings that have clinical relevance at the time of their identification. This would suggest that the protocol of only measuring the CRL and NT should be abandoned and a full study of the fetus and uterus should be undertaken at the time of NT screening. OC02.04: Table 1. Abnormal ultrasound findings
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To assess the learning curves for nuchal translucency thickness as measured by both manual and semi-automated methods. Fetal nuchal translucency was obtained by an experienced sonologist according to the FMF guidelines in a cohort of 32 consecutive first trimester fetuses at 11–13 weeks, and calculated by both manual and semi-automated methods (GE Voluson E6). Subsequently, two sonographer trainees with no prior experience in first trimester ultrasound examined archived images in separated occasions and measured the nuchal translucency first by the manual method and secondly with the semi-automated method. Each of the trainees was blinded to any pre-existing results. The average difference between the two trainees and the expert in both manual and semi-automated methods was calculated. A difference below 15% was considered as an accurate measurement. The average learning curve was delineated using the cumulative sum analysis (CUSUM). CUSUM plots demonstrated that the mean learning curve was achieved by 19 and 25 measurements for semi-automated and manual methods, respectively. For an inexperienced sonographer to become competent in nuchal translucency measurement in stored images, a minimum number of 19 and 25 measurements was required for the semi-automated and manual method, respectively.
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We sought to evaluate cutoff levels for first trimester nuchal translucency (NT) measurements and abnormal cardiac findings (ACF) detected on second trimester ultrasound in euploid fetuses. Retrospective analysis of singleton pregnancies seen in our ultrasound units between 1/1/06–1/30/10 for an NT screen [11-1/7 weeks–13-6/7 weeks] and follow-up second trimester scan [17-0/7 weeks–22-6/7 weeks]. Cases with an abnormal karyotype by chorionic villus sampling or amniocentesis were excluded. We determined the 95th percentile (%ile) for our centers using gestational age specific NT MoMs. Detection and false positive rates were based on ACF detected in the second trimester. 8,541 chromosomally normal singleton pregnancies, of which 33 cases of ACF were identified in the second trimester (3.8/1000). The mean (+SD) NT for the normal and ACF cases in the second trimester were 1.6 (+0.46) mm and 2.3 (+1.3) mm, respectively (P < 0.0001). With an NT measurement of < 2.0 mm, the incidence of ACF was 19 of 7240 second trimester ultrasound (2.6/1000). The 95%ile MoM cutoff was 1.402. Of the cutoff points evaluated, the > 95%ile and an NT of > 2.5 mm were the most efficacious (Table 1). Increased first trimester NT measurement was associated with a higher risk of ACF in the second trimester scan in euploid fetuses. Using the 95%ile MoM or an NT of > 2.5 mm was the most efficacious. Patients with unexplained elevations of NT should be referred for a fetal echocardiogram.
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Echogenicity
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