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To study the outcome of pregnancy in chromosomally normal fetuses with increased nuchal translucency thickness (NT), with respect to fetal loss, structural defects and genetic syndromes with developmental delay, and to provide information that would be helpful for parental counseling on the residual risk of adverse outcome when ultrasound findings are normal.
We reviewed the outcome of all pregnancies presenting at the Academic Medical Centre in Amsterdam with increased NT between January 1994 and March 2005. Fetal karyotyping and two-step ultrasound investigation at 13–18 and 20–24 weeks' gestation were offered in all cases. Particular attention was paid to the relationship between normal karyotype, ultrasound findings at the 20–24-week scan and subsequent pregnancy outcome. An adverse outcome was defined as miscarriage, intrauterine death, termination of pregnancy at parental request or the finding of one or more structural defects or genetic disorders.
A total of 675 fetuses with increased NT, known karyotype and known pregnancy outcome was analyzed. A chromosomal anomaly was detected in 224 (33%) fetuses. In 451 (67%) fetuses, the karyotype was normal. The overall incidence of an adverse pregnancy outcome in this group was 19% and, when analyzed according to the initial degree of increase in NT, the likelihood of an adverse outcome increased with increasing NT, ranging from 8% to 80%. 425 fetuses underwent a detailed second-trimester ultrasound scan. Anomalies were detected, at the time of ultrasound or after birth, in 54 (13%) of these fetuses (17 isolated cardiac defects, 14 other structural defects and 23 genetic disorders). An adverse pregnancy outcome was recorded in 4% of cases in which there were normal findings at the 20-week scan. Seven of these cases were classified as ‘potentially amenable’ to ultrasound detection. With exclusion of these cases, the chance of a healthy baby, if the 20-week scan was completely normal, was 98%. Genetic syndromes with dysmorphic features and neurodevelopmental delay occurred in seven (1.6%) of the fetuses with normal karyotype. In three of these pregnancies, non-specific suspicious ultrasound findings (nuchal edema, mild pyelectasis, pericardial effusion) were observed at the mid-trimester scan and in two others, subtle cardiac defects were detected after delivery. In the remaining two cases (0.5%) the mid-trimester scan was completely normal and no structural defects were observed after delivery.
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In the late first trimester of pregnancy, a transient subcutaneous fluid collection, known as nuchal translucency (NT) is visible at the back of the neck in all fetuses1, 2. An excessive nuchal fluid collection is often associated with chromosomal anomalies, especially Down syndrome1, 3. When the karyotype is normal but the NT is increased, the fetus is still at increased risk of a broad spectrum of congenital anomalies, varying from isolated structural defects to genetic syndromes and neurodevelopmental delay, which often become manifest in the first years of life4–7. The number of known syndromal developmental disorders signalled by association with an increased NT at 11–14 gestational weeks is constantly growing8. Different pathophysiological explanations have been proposed for excessive nuchal fluid accumulation in early pregnancy9–11; it is likely that it is a common symptom of various different developmental disorders.
As an increased NT is associated with chromosomal anomalies and many other defects, parents with an increased fetal NT are first offered karyotyping and then, if the karyotype is normal, they are offered detailed ultrasound examinations later in the pregnancy. The finding of an increased fetal NT and the subsequent diagnostic work-up is a stressful event for parents. In daily clinical practice it is of great importance both to know at which stage of the diagnostic work-up, including karyotyping and ultrasound investigations, it is possible to reassure parents with confidence on the high likelihood of a normal outcome, and to provide clinicians with reliable figures on the residual risk of postnatal developmental delays not amenable to prenatal detection12. To address this issue, we reviewed our database and investigated the ultrasound findings and the pregnancy outcome of all fetuses with increased NT, focusing on those with normal karyotype.
In the Academic Medical Centre in Amsterdam, all pregnancies with increased NT, both those diagnosed at our institution and those referred from other centers, undergo a first-trimester ultrasound examination (Toshiba SSA 250A, Tokyo, Japan; Hitachi EUB 565, Tokyo, Japan, HDI 3000 ATL, HDI 5000, ATL, Philips, Bothell, WA, USA; iU 22, Philips, Best, The Netherlands) and fetal karyotyping by chorionic villus sampling or amniocentesis. Because at the time of the study there was not yet a nationwide screening program for chromosomal anomalies in The Netherlands, this study refers mainly to a selected population of fetuses referred because of increased NT. Increased NT is defined as a measurement above the 95th percentile for the normal range, according to the medians of The Fetal Medicine Foundation (www.fetalmedicine.com). No distinction was made between a septate NT or cystic hygroma, because both entities are associated with chromosomal anomalies and require the same diagnostic work-up.
In the case of normal karyotype, it is our policy to schedule a detailed structural ultrasound examination at 13–18 weeks' gestation (depending on the gestational age at which the karyotype is known). A second examination is scheduled at 20–24 weeks. In the case of considerably increased NT or in the presence of non-specific suspicious findings (e.g. persistence of nuchal fluid, hydrothorax or pericardial effusion), ultrasound examinations are repeated monthly until the early third trimester. From the year 2000 onwards, a pediatric cardiologist has been present at the time of the detailed ultrasound examination. In the case of suspicious findings, sonographic follow-up, including echocardiography, is repeated as indicated throughout the pregnancy. In all cases with considerably increased NT or antenatal suspicion of abnormal development, the infant is checked after delivery by a neonatologist and a pediatric cardiologist.
In this study we searched our database for all pregnancies with increased fetal NT managed in our prenatal diagnosis department from January 1994 to March 2005. Information on the outcome of pregnancy and on neonatal development was obtained from forms returned by the parents or from hospital or midwife reports, and, in the case of missing information, by telephone contact with the parents. For children born before 2001, parents were contacted twice in order to check specifically for developmental delays that emerged later in infancy. Only pregnancies with known outcome were included in the study. The length of follow-up ranged from 6 months to 5 years (median, 2 years). An adverse pregnancy outcome was interpreted broadly and included miscarriage, intrauterine death or termination of pregnancy on parental request and in the absence of specific fetal anomalies, and all structural defects or genetic disorders diagnosed before or after delivery.
Six hundred and ninety-three pregnancies with increased NT and known pregnancy outcome were identified. There were an additional 24 in which the follow-up was not known and these cases were therefore excluded. Eighteen further cases were excluded because of intrauterine death before invasive testing or because the parents declined karyotyping. Figure 1 shows a flowchart of the outcomes of the remaining 675 pregnancies at different stages of the diagnostic work-up. The karyotype was abnormal in 224 (33%) and in 451 (67%) cases the karyotype was normal. Of these, 425 underwent a detailed second-trimester ultrasound examination.
Table 1 shows the pregnancy outcome of the 451 fetuses with increased NT and normal karyotype. The chance of an adverse outcome increased with increasing degree of increase in NT, ranging from 8% to 80% (P < 0.05), with an overall chance of adverse outcome of 19%.
Table 1. Pregnancy outcome of 451 chromosomally normal fetuses in relation to degree of increase in nuchal translucency thickness (NT)
Adverse outcome (n (%))
TOP (severe hydrops)
Structural/ genetic anomalies
Live birth, no defects (n (%))
IUD, intrauterine death; TOP, termination of pregnancy.
Of the 425 fetuses that underwent the second-trimester ultrasound exam, there were 54 (13%) cases with anomalies; Table 2 describes these and indicates the time of diagnosis (before or after delivery). In the vast majority of cases (80%), the anomaly was detected prenatally, by ultrasound investigation or DNA testing. Of the 54 cases with abnormal findings, 31 involved isolated structural anomalies, of which cardiac anomalies were the most frequent (17/31 cases, 55%).
Table 2. Disorders and pregnancy outcome in 54 euploid fetuses with increased nuchal translucency thickness (NT)
Disorder (Case #)
Diagnosis by US/DNA or postpartum
Outcome of pregnancy
This pregnancy ended in miscarriage at 14 weeks and pathological examination showed a cleft lip and palate.
No obvious structural defects, but suspicious ultrasound findings (mild pyelectasis, nuchal edema, pericardial effusion). ASD, atrial septal defect; AVSD, ventricular septal defect; CRL, crown–rump length; DH, diaphragmatic hernia; DNA, DNA testing because of history, carriership; DORV, double outlet right ventricle; IUD, intrauterine death; PA, pathological examination; PND, postnatal death; PP, postpartum; SMA, spinal muscular atrophy; TGV, transposition of the great vessels; TOF, tetralogy of Fallot; TOP, termination of pregnancy; US, ultrasound; VSD, ventricular septal defect.
There were seven cases of genetic syndromes with mild or more severe developmental delay diagnosed at delivery or in infancy (Table 3). Three presented with non-specific suspicious ultrasound findings (nuchal edema, mild pyelectasis, pericardial effusion), in two cases a minor cardiac defect was detected after delivery and in the remaining two cases there were no features amenable to prenatal ultrasound diagnosis. In this study the overall incidence of genetic syndromes with developmental delay was therefore 1.6% (7/425), of which one third were judged to be not amenable to ultrasound diagnosis (0.5%).
Table 3. Genetic syndromes with mild or severe developmental delay, diagnosed in the postnatal period or in infancy, in seven fetuses with increased nuchal translucency thickness (NT) and normal karyotype
Case numbers correspond to those in Table 2. AVSD, ventricular septal defect; CRL, crown–rump length; VSD, ventricular septal defect.
At delivery: no anomalies detected. At 3 years: psychomotor delay, abnormal eye slanting.
Unspecified genetic syndrome
At delivery: dysmorphic features, transient cardiomyopathy. Later in infancy: developmental delay.
Unspecified genetic syndrome
Nuchal edema, pericardial effusion
At delivery: dysmorphic features, severe hypotonia. Neonatal death at 5 months.
At delivery: small VSD, pulmonary valve stenosis, dysmorphic features.
Coffin Siris syndrome
At delivery: mild AVSD, abnormal genital development, hypotonia. Surgery at 5 months, postnatal death at 6 months.
Unspecified genetic syndrome
At delivery: no anomalies detected. At 5 months: dysmorphic features, possibly mild developmental delay.
At delivery: dysmorphic features, abnormal position of digits. Later in infancy: abnormal language/motor development.
Unspecified genetic syndrome
Table 4 presents, for different degrees of increased NT, an overview of the frequency of normal/abnormal karyotype, normal/abnormal mid-trimester ultrasound examination after normal karyotype and the residual chance of an adverse outcome if the mid-trimester scan did not reveal anomalies. If karyotype and mid-trimester ultrasound scan were normal, the chance of a healthy infant ranged from 77 to 100%. Overall, in fetuses with normal karyotype and normal ultrasound findings, an adverse outcome occurred in 4% of cases (16 fetuses); details of these cases are given in Table 5. Seven of them could be classified as ‘overlooked’ at ultrasound examination. With exclusion of these cases, the overall chance of an adverse pregnancy outcome, in the case of normal karyotype and normal ultrasound investigation, would be 2.4% (9/375).
Table 4. Chances of normal/abnormal karyotype, normal/abnormal anomaly scan and adverse/favorable outcome, in relation to degree of increase in nuchal translucency thickness (NT)
Normal karyotype; ultrasound examination:
Normal karyotype; normal US; adverse
Alive and well if scan is
Normal (% (n))
Normal (% (n))
outcome (% (n))
Twenty-six cases were excluded between karyotyping and sonography because of intrauterine death or termination before the scan.
Genetic syndromes with cardiac defects (47, 49, 54)
Cleft palate (24)
‘No structural defects’ to be detected by ultrasound (n = 9)
Esophageal atresia with tracheo-esophageal fistula (21)
Genetic syndromes without structural defects (50, 53)
Intrauterine death after sonography
Table 6 provides details on the ultrasound findings and outcome of 11 fetuses (2.6%) in which, at the second-trimester ultrasound examination, there was some sort of nuchal fluid accumulation still present (edema, hydrops, cystic hygroma).
Table 6. Details of 11 fetuses with increased nuchal translucency thickness and normal karyotype in which persistence of some sort of nuchal edema at the second-trimester ultrasound (US) examination was documented
US findings in the neck at second-trimester scan
Other US findings
Case numbers correspond to those in Table 2. CDH, congenital diaphragmatic hernia; CHD, congenital heart defect; FADS, fetal akinesia deformation sequence; IUD, intrauterine death; NND, neonatal death; TOP, termination of pregnancy.
Alive and well
Alive and well
Unspecified genetic syndrome
CDH, multicystic kidneys
CHD, hydronephrosis, spina bifida, hydrocephaly
Alive and well
Very premature delivery, NND
Small thorax, contractures
Hydrops, short bones, poorly echogenic spine
Achondrogenesis Type II
This study provides an overview of the pregnancy outcome of 675 fetuses referred because of increased NT at 11–14 weeks' gestation. It confirms that fetuses with increased NT and normal karyotype are at increased risk of adverse pregnancy outcome (19%; 85/451) and that this risk is related to the initial degree of increase in NT4, 6, 13. Conversely, the overall chance of a healthy infant decreased, from 92% for a minimal degree of increase in NT (NT < 3.5 mm), to 20% in the case of NT ≥ 6.5 mm. However, in fetuses with normal karyotype, if subsequent ultrasound investigations showed no structural anomalies or suspicious findings, the chance of a normal pregnancy outcome was high, and this applied to all degrees of initial increase in NT.
Severe increase in NT and normal karyotype
In fetuses with an NT of ≥ 6.5 mm and normal karyotype, the rate of spontaneous fetal loss was high, with only one out of five pregnancies resulting in a live birth (Table 1). Spontaneous lethality in these fetuses may have been due to severe developmental disorders leading to fetal demise through cardiac failure. The poor prognosis, however, was due not only to spontaneous fetal loss or structural defects, but also to the fact that in this group parents requested termination of pregnancy in 33% of the cases. To see the extreme nuchal enlargement, often accompanied by varying degrees of hydrops, has a profound impact on parents; it is sometimes difficult to motivate them to wait for a possible spontaneous resolution of the nuchal edema, and to set their hopes on the low chance of favorable outcome in such cases14–16. However, of the 30 fetuses with NT ≥ 6.5 mm and normal karyotype, in spite of the high pregnancy loss attributable to miscarriage, intrauterine death or termination, the pregnancy outcome was uneventful in all five surviving fetuses: the edema resolved and no structural anomalies were detected at subsequent ultrasound investigations. This made the chance of a normal pregnancy outcome after ‘normal’ ultrasound findings high, even in cases of severely increased NT. However, in view of the very small number of surviving fetuses and of a possible coincidental favorable outcome, caution is necessary in interpreting these results.
Increased NT, normal karyotype and abnormal ultrasound findings
In 2.6% of fetuses, the nuchal fluid accumulation had not completely resolved at the second-trimester scan. Overall, in 50/425 (12%) cases the second-trimester scan detected a structural defect or findings suspicious of abnormal development (nuchal edema, mild pyelectasis, pericardial effusion). This study confirms that, of all isolated structural defects associated with increased NT, cardiac defects are the most common (55% in this series)5, 6, 14 and wide ranging. The second most common isolated structural defect was cleft lip and/or palate (13%). Of these four cases of cleft lip/palate, only two were detected prenatally. This defect is not commonly amenable to prenatal detection, although three-dimensional technology has been proposed as a potentially effective diagnostic tool17.
Twenty-three genetic disorders were associated with increased NT and normal karyotype. The majority was diagnosed or suspected at ultrasound investigation or by DNA analysis. With the exception of six cases in which the fetus was known to be at increased risk of inheriting a genetic disorder, they were all ‘de novo’ genetic syndromes. Syndromes manifesting themselves as skeletal or neuromuscular disorders were the most common and these were all detected prenatally. The nuchal fluid accumulation in these cases may be caused by impaired venous return to the heart due to the small thorax, altered composition of the extracellular matrix or impaired lymphatic fluid drainage9, 11.
Increased NT, normal karyotype and normal ultrasound findings
In 16 fetuses in this series, structural or genetic disorders were detected after delivery following a negative diagnostic work-up (Table 5). Although not all of these disorders were severe, we defined them as adverse outcome, based on the fact that they were unexpected. Cardiac defects were the most commonly overlooked anomaly (6/20 cases, 30%). This confirms the difficulty in reaching high sensitivity for sonographic diagnosis in this field18–24. However, since we established close collaboration with a pediatric cardiologist, our diagnostic ability to detect cardiac defects has improved remarkably25.
Increased NT, normal karyotype and neurodevelopmental delay
The finding of an increased NT is always a stressful event for the parents12, 26. Even after a normal karyotype is found, the fear of non-detectable anomalies can induce anxiety and sometimes trigger a request for termination of a wanted pregnancy. The most worrying aspect is that a genetic syndrome with neurodevelopmental delay may manifest unexpectedly in the postnatal period.
In this study we recorded seven cases of mild to severe developmental delay, likely in the setting of a genetic syndrome (Table 3). These fetuses all had an NT > 4 mm. In three cases, non-specific suspicious findings were detected by ultrasound investigation, while in another two, subtle cardiac defects were overlooked at ultrasound. In the remaining two infants, no demonstrable structural anomalies were found after delivery. This means that, even assuming an extremely high sensitivity for sonographic detection of structural defects, some developmental delays may not show sonographically detectable features. A relationship between persistence of nuchal edema, subtle suspicious ultrasound findings (hydrothorax, pericardial effusion) and neurodevelopmental disorders later in infancy has been reported previously6, 27. It may be speculated that in these fetuses a search for submicroscopic chromosomal anomalies (microdeletions, loss of telomeric integrity) could identify genetic markers of neurodevelopmental disorders28, 29. Moreover, three-dimensional reconstruction of the fetal face may improve recognition of even mild dysmorphic features in these fetuses30.
Three cases of neurodevelopmental delay became evident later in infancy and were signalled by parents at the second long-term follow-up, after they had initially reported normal postnatal development. This emphasizes the importance of long-term follow-up, ideally with a clinical developmental assessment in such fetuses27. We found that infants with slightly increased NT and classified as normal after the second-trimester scan were allowed, according to the Dutch obstetric system, to be delivered under the care of a midwife and without immediate neonatal control after delivery. Neonatal, infant and child-care is organized very efficiently and uniformly in The Netherlands by national pediatric and youth outpatient clinics. Experienced clinicians evaluate growth and development until the age of 18 according to uniform standards. Abnormal development is, therefore, always detected. The percentage of loss to follow-up cases excluded from the study, in which, theoretically, abnormal development may have played a role, was 3.3%.
The reported incidence of neurodevelopmental delay in fetuses with increased NT and normal chromosomes, whether or not in the setting of a recognizable genetic syndrome, varies from 0 to 13%5–8, 14, 31–39. However, different cut-offs used for the definition of increased NT and differences in the completeness and length of postnatal follow-up make comparison of studies difficult. In a recent French cohort study on infants delivered after having increased NT, clinical examination and questionnaires assessing development showed a prevalence of abnormal or delayed development similar to that of the control group27.
The overall incidence of neurodevelopmental disorders in our population of 451 fetuses with increased NT and normal karyotype was 1.5% (7/451). Excluding the five cases in which some form of sonographically detectable anomaly was present, the incidence of a totally unexpected developmental delay was 0.5% (2/375). This is similar to the findings of Senat et al.27, in which a developmental delay was found at the age of two in 2/162 infants (1.2%), one of which (0.6%) was without concomitant abnormal features.
In fetuses with increased NT and normal karyotype, when initially NT is < 4 mm there is an extremely high chance of favorable outcome. At higher degrees of increase in NT, the majority of associated anomalies are detectable by ultrasound investigation. After normal ultrasound findings at the second-trimester scan, the residual chance of unfavorable outcome, including developmental delay, does not seem increased in comparison with that of the general population and this seems to be the case for all degrees of increased NT.
In this study we have provided data that may help in the counseling of parents and to increase their confidence in a favorable pregnancy outcome.