In this retrospective study, 13,690 singleton pregnancies were evaluated. We found that the incidence of an ARSA was 0.87% in Chinese AMA and 0.65% in non-AMA women. The incidence of chromosomal abnormalities was much higher in AMA group and with ARSA detected it climbed as high as 20 % in AMA group and 10 % in non-AMA group. Among there, mostly detected was Down syndrome in both groups. Another chimeric Turner syndrome was found in an AMA woman with an isolated ARSA.
In most studies, the prevalence of a prenatal ARSA was studied in the entire population with a prevalence rate ranging from 0.4 % to 1.5 % [12,13]. Concordant with the previous studies, we found the incidence of ARSA in entire cohort was 0.69 %. And as a valuable complementarity, we confirmed there was no difference in the incidence of ARSA during AMA and non-AMA groups. On the timing of prenatal ultrasonic diagnosis of ARSA, Pico et al. presented the mean gestational age for ARSA detecting was 19 weeks + 5 days, ranging from 11 weeks + 5 days to 34 weeks; SD = 4 days). In another study concerning the predictive value of ARSA for Down syndrome, authors successfully checked pregnant women at 16 weeks of gestation . In our experience, ARSA can be detected as early as 12 weeks +4 days gestational age. However, due to the high omission diagnostic rate during the first trimester and the early mid-trimester, and in order to reduce the bias caused by the difference in technical level between examiners and ensure the accuracy, we set the threshold of 16 weeks of gestation for this study. The correlation between ARSA fetuses and chromosomal abnormalities such as Down syndrome was described by some scholars [10, 14,15]. As we found，whether isolated or nonisolated ARSA would increase the risk of chromosomal abnormalities. When it comes to the isolated ARSA, there a controversy should be proposed. Some authors insisted isolated ARSA correlated strongly with trisomy 21 . Reported by Paladini et al. , ARSA should be considered among the three most powerful ultrasound indicators of Down syndrome in the second trimester resembling nasal bone abnormality and increased nuchal fold. In their preliminary study, ARSA was found the only sonographic sign in 7.5% ( 8 / 106) relatively unbiased Down syndrome fetal, which was presented 1.5% in normal fetuses. While a weak association between isolated ARSA and chromosomal abnormalities were reported by other scholars . Recommended by Pico et al. , these fetus contained an isolated ARSA required a comprehensive evaluation instead of an invasive karyotype analysis considering isolated ARSA is a condition rarely associated with a chromosomal abnormality.
When concerning the nonisolated ARSA, in virtue of prenatal detected the ARSA with other ultrasound signs, the risk for trisomy 21 increased by factor of 45 described by Fehmi et al. . As in our study, the positive likelihood ratios of nonisolated ARSA for chromosomal abnormalities in the entire population and AMA group were as high as respectively 69.49 and 36.90. The study performed by Svirsky et al. was in support of our results. They claimed ARSA with additional ultrasound findings constitutes a strong predictor for aneuploidy.
What is more, when ARSA is found in AMA ones, we got a sharp increase in the incidence of chromosomal abnormalities. The prevalence rate of chromosomal abnormalities with ARSA in AMA group was 20 % ( 5 / 25) which is much higher when comparing to that in non-AMA group 10 % ( 7 / 70). And the positive likelihood ratios of nonisolated ARSA for chromosomal abnormalities were 36.90 in AMA group and 14.51 in non-AMA group. These findings may contribute to prenatal counseling especially for advanced maternal age pregnant women.
Last but not least, a chimeric ( 45X / 46XX) case with isolated ARSA was found in AMA group in our study. Turner syndrome is well known to be closely associated with cardiovascular malformations with the frequency of 23% to 45%. As reported by Lee et al. , an aberrant right subclavian artery was one of the most common major vessel abnormalities in the Turner syndrome patients ( 3 / 20 patients, 15 %). The obstruction of lymphocinesia during embryogenesis may be the possible mechanism of cardiovascular defects in Turner syndrome. In our case of Turner syndrome, we found the unique structural defect by prenatal ultrasound. The suspicious diagnosis clue of sex chromosome aneuploidies was presented by noninvasive prenatal screening with cell-free DNA. And it was eventually confirmed by chromosomal karyotype analysis with amniocentesis and SNP- Array chip inspection. The clinical effect of noninvasive prenatal screening in AMA pregnancy was discussed in a multicenter retrospective study . Authors found the detection efficiency was satisfactory with almost 100% accurate results. Even for sex chromosome aneuploidy in AMA pregnancy, the positive predictive value was approximately 41.30%. Considering the high prevalence of chromosome abnormality including sex chromosome, scholars strongly suggested noninvasive prenatal screening for AMA pregnancy, especially over 40. Therefore, we believe that although only isolated ARSA was found in advanced ones, vigilance will still be needed and the noninvasive prenatal screening might benefit. It would be very conducive to further managing and genetic counseling for advanced maternal women.
In a word, for AMA pregnancy, we suggest that ARSA should be used as a soft indicator of chromosomal abnormalities in genetic ultrasound. Once ARSA is found, a comprehensive assessment is essential. Although only isolated ARSA was found in AMA ones, the noninvasive prenatal screening would help to some degrees.
There were also some limitations in our study. Firstly, a small percentage of fetuses in non-AMA group did not undergo invasive karyotype analysis. The major aneuploidy abnormalities and karyotype abnormalities were excluded by the negative results of noninvasive DNA tests, detailed prenatal examinations and neonatal follow-up. In clinical practice, many people are reluctant to accept invasive karyotype analysis considering the possible risks of invasive operations. In theory, an isolated ARSA was not a sufficient indication for karyotype analysis . Reported by Ranzini et al. , all fetuses with ARSA and genetic anomalies totally had additional ultrasound findings. Thus, in similar studies ( respectively published in Fetal Diagn Ther and J Ultrasound Med) [5,6], the authors typically included fetuses have consistently classified fetuses with negative prenatal screening and postpartum follow-up as normal karyotypes. Therefore, we believe that the method adopted in this study is acceptable. Secondly, chromosomal microarray analysis was not analyzed in our current study. While it worth noting, quite a part of deformity might be neglected without chromosomal microarray analysis according to Maya et al. . What’s more, the incidence of ARSA in super-aged women ( ＞40) and its’ predictive value for chromosome abnormality were not evaluated individually in our current study. That may probably have profound guiding significance in this group. We look forward to further discussion of these issues in future studies.