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Increased nuchal translucency (NT) is a common finding as, by definition, 5% of fetuses will have increased measurements > 95th centile. A large body of evidence has shown that increasing measurements of NT are associated with an increased risk for chromosomal abnormalities, genetic syndromes, structural abnormalities (mainly congenital heart defects), intrauterine infection and fetal demise; with NT measurements of > 6.5 mm, the chance of a liveborn and healthy baby is as low as 15%1, 2.
The long-term neurodevelopmental outcome of children who had increased NT as fetuses has recently attracted attention. Many of the conditions associated with increased first-trimester NT are themselves accompanied by neurodevelopmental delay. However, much less is known about the neurodevelopmental outcome of children with increased NT and a normal karyotype that were apparently healthy at birth (i.e. did not have structural abnormalities of recognizable genetic syndromes). Most of these data are circumstantial, being scattered across reports focusing generally on the outcome of fetuses with increased NT and a normal karyotype, without using formal tools for neurodevelopmental assessment.
Our aim was to systematically review evidence on the neurodevelopmental outcome of fetuses with increased first-trimester NT and no chromosomal, structural or recognizable syndromic conditions at birth.
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We have found that the pooled rate for neurodevelopmental delay in studies of fetuses with increased first-trimester NT, normal fetal karyotype and lack of structural defects or identifiable syndromes is in the region of 1%, both for the overall population of fetuses characterized as having increased NT and for the more meaningful cut-off of NT > 99th centile. This rate is, at worse, no higher than the rates reported for the general population, which lie in the region of approximately 3%24–26.
Increased first-trimester NT has long been recognized as a risk factor for chromosomal abnormalities, fetal structural defects (mostly congenital heart defects), genetic syndromes and prenatal or perinatal demise27. Many of the syndromes associated with increased NT have developmental delay as a clinical feature, and, in turn, an underlying etiology (e.g. chromosomal, genetic, metabolic or structural abnormalities) can be found in approximately half (55–60%) of the children with global or motor delay28, 29. So, although the association between increased NT and fetal abnormalities (structural, chromosomal or syndromic) is well established, much less is known about the neurodevelopment of apparently healthy children with increased NT, and this is the group we focused on. We have to stress here the term ‘apparently’, as published studies did not provide data on how laborious and time consuming was the diagnostic workup in cases of developmental delay or disorder, and therefore some of their cases may actually be syndromic.
The low rate for developmental delay did not differ across the subgroup analyses we performed. Thus, there was no significant difference between fetuses with a normal second-trimester scan and those which were found to be normal at birth. This is explained by the facts that (1) the detailed anomaly scan has a high sensitivity for detecting structural defects and (2) the majority of non-syndromic cases have normal anatomy anyway. Therefore, pregnant women with a fetus with increased NT and a normal karyotype can be reasonably reassured of its developmental outcome after a normal second-trimester scan.
We have also found that the pooled rate of developmental delay did not differ according to the cut-off used to define increased NT (95th centile, 99th centile and 3.0 mm). In order to explore this further, we identified the individual NT measurements (when available) of fetuses with neurodevelopmental delay. The most suitable population for this was the pool of fetuses with NT > 95th centile, but unfortunately there were only five cases with known NT measurements. The NT was > 3.5 mm in four (80%); this may indicate an over-representation given that NT measurements of > 3.5 mm comprise only one fifth of NTs > 95th centile, but the sample was too small to draw any conclusions. For the more skewed population of fetuses with NT > 99th centile, the median NT for cases with neurodevelopmental delay was 4.0 mm (individual measurements were available for 10 fetuses). Finally, our secondary analysis did not indicate significant differences between fetuses with persistent or absent nuchal edema in the second trimester; it should be highlighted, however, that the group of fetuses with nuchal edema was small and the 95% CIs were wide. Intuitively, we were expecting to find a stronger association between higher NT measurements and developmental delay if NT was associated with delay at all. If, on the other hand, increased NT is not associated with delay, then it is reasonable that cases with delay are randomly scattered across different NT levels.
The results of our review should be interpreted with caution in general, as the data have further limitations.
First, there is no firm consensus on the definition of developmental delay. According to the American Academy of Pediatrics, developmental delay refers to the condition in which a child is not developing and/or achieving skills in the expected time frame, as opposed to developmental disorder (or disability), which refer to a childhood mental or physical impairment, or combinations of those, resulting in substantial functional limitations in major life activities30. However, the two terms are sometimes used interchangeably, and the term ‘delay’ is often used to describe mental retardation31. The studies included in our review appear to follow the definition of delay in achieving developmental milestones; therefore, many of the cases with delay are not expected to develop a permanent handicap.
Second, screening for, and ascertainment of, developmental delay can be problematic. Most of the studies used telephone interviews with parents in order to screen for delay. Asking the parents simple questions about their child's behavior and development may elicit quality information, but parents may be underestimating or overestimating their concerns about the development of their children26, 30. The most structured tools for developmental screening in the studies of our review were the ASQ, which has sensitivity and specificity in the region of 70–90%32 and was used in three studies8, 22, 23, and the BINS30, 33, with a similar performance to the ASQ, which was used in two studies9, 10. Both of these tools are screening tests, which means than in cases of high-risk score, a more detailed neurodevelopmental assessment is warranted. Only the two most recent studies8, 23 give detailed data on both abnormal ASQ and clinically assessed delay; 30 infants had abnormal ASQ scores and only four (13%) were eventually diagnosed with delay (one had del22q11 diagnosed at 2 years of age). In the rest of the studies it is not clear whether the diagnosis of delay refers to high-risk results at screening or to formal diagnosis after clinical assessment. Therefore, it appears that there are two possible sources of bias: screening bias, resulting from the suboptimal methods to identify children at risk, and ascertainment bias, resulting from insufficient information about the steps which followed identification of high-risk infants at screening. This problem is partially solved in case–control studies, when the same methodology is applied to both groups; the four case–control studies in our review20–23 did not report different rates of developmental delay between the two groups.
The different definitions, sample sizes, screening and ascertainment methods for developmental delay may also be responsible for the heterogeneity between studies, which was profound in some instances.
Third, it is not certain that syndromes can always be reliably identified. At least five of the 28 cases reported in our review had an unidentified genetic syndrome, of which developmental delay is a part, and there are probably even more cases not recognized as such. Three of the more recent studies reported supplementary chromosomal analysis using high-resolution comparative genomic hybridization (HR-CGH)10 or multiplex ligation-dependent probe amplification (MLPA)8, 10, 23 either for their whole sample or when a syndrome was suspected, and it appeared that these methods did not increase the detection of syndromes. We chose to include these cases for pragmatic reasons; if these conditions cannot be identified as specific syndromes prenatally or postnatally, from the viewpoint of prenatal counseling they are grouped together with the other apparently isolated cases.
Still, despite all these potential sources of bias, it is highly unlikely that fetuses with apparently isolated increased NT have an increased risk for developmental delay. In fact, many of the bias sources (e.g. the preselected nature of the ‘high-risk’ infant population, or the inclusion of syndromic cases which would increase the numerator) would err in the direction of an increased rate of delay in children with increased NT.
In conclusion, it appears that the risk for developmental delay in fetuses with increased first-trimester NT is not increased compared with the general population, after chromosomal abnormalities, structural defects and genetic syndromes are excluded. With the exception of a minority of studies focusing on this topic, most of the available data are scattered across studies reporting in general on the outcome of children with increased NT and fetal karyotype, which, at last partly, explains the inconsistency of methodology and results among different studies.
SUPPORTING INFORMATION ON THE INTERNET
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Table S1 Technical characteristics of the ultrasound machines used and operators performing the assessments.
Table S2 The Newcastle–Ottawa scale for quality assessment of the included studies.