Interpretation
These data agree with previous studies reporting an increased risk of adverse pregnancy outcome for mildly increased NT (NT 95th-99thpercentile)4;21-22. Bardi et al. reported that 21.3% of fetuses with an NT between the 95th and the 99th percentile had congenital abnormalities, either genetic or structural.
The reported prevalence of healthy live-born children varied between 83%4 and 78.2%22, similar to our study (74.96% of fetuses were born alive and healthy). A long term follow up is crucial in terms of reporting adverse postnatal outcome, in fact, in our cohort a high number of unfavourable diagnoses such as genetic syndromes and neurodevelopmental delay were made between 6 months and 2 years of age.
The incidence of chromosomal abnormalities and genetic syndromes varied in previous studies. Kagan et al. in 20066 reported a prevalence of 7.1% for NT between 95th and 99th percentile, but the only genetic investigation performed was however standard karyotype. In a study by Tekesin et al.22 the incidence of abnormal fetal karyotype was 18.2% in a selected high risk population with NT between 95th and 99th percentile. In our study group, which mainly included a low risk population, fetuses with these conditions accounted for 13.49% of cases.
Furthermore, according to recent studies23-24, the use of CGH-arrays in fetuses with NT>3.5 mm can reveal approximately 5% copy number variants (CNVs) with pathogenetic or uncertain significance. Despite the level of anxiety that variants of unknown significance (VOUS) could bring, it is now mandatory that couples who are offered karyotyping are at least informed on the existence of this genetic test.
The most common malformations reported in our population were cardiac defects (40.35% of all malformations detected). This result is consistent with the incidence reported in a meta-analysis by Sotiriadis et al.10 where 45% of fetuses with cardiac malformation showed an NT >95thpercentile, but only in 20% of them NT was above 99thpercentile. Therefore, the majority of fetuses with cardiac defects showed an NT between 95th and 99thpercentile. Similar percentages (34.1%-41.57%) can be observed in more recent studies21-22. These data suggest that an NT>95th percentile could be the proper cut off to offer fetal echocardiography.
With regards to neurodevelopmental delay , Hellmuth et al. in 201725 found no increased risk in a cohort of children with NT between 95th and 99th percentile at first trimester scan, with a mean follow up of 4.4 years. The present study confirms the reported results, showing that the incidence of those disorders is 1.95% in our population, not significantly different from the general population.
A critical point in the management of pregnancies with NT between 95th and 99th percentile is the level of investigations that should be offered to couples. At the moment, international guidelines do not include NT>95th percentile among the cases that should benefit from further examinations than the routine ones. Souka et al. in 20053 proposed a specific management for fetuses with NT between 95th and 99th percentile which included a detailed ultrasound at 20 weeks with examination of fetal heart, preferably performed by a fetal echocardiography specialist. This protocol was also recommended by De Domenico et al.9. Moreover, both authors stated that fetal karyotype should be performed based on patients-specific risk for chromosomal anomalies. Based on the high prevalence of chromosomal anomalies and genetic syndromes in our cohort, we suggest that fetal karyotyping should be offered also in case of NT between 95th and 99th percentile.