A normal 20‐week scan of a euploid fetus with a history of first‐trimester increased nuchal translucency: caution or reassurance?

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.