The present study reported one the largest cohorts of invasive prenatal diagnosis by amniotic fluid specimens from a representative database of a single cytogenetics laboratory in China. An advantage of the study was that the data was collected from the same prenatal diagnosis center, thus avoiding bias in the medical performance, and it was from a teaching hospital of well-known universities with a case ascertainment of approximately 100% with high data quality. In addition, the level of misdiagnosis could be determined by strictly following the national guideline and follow-up system. In the study, the incidence of all SCAs (8.77‰, about 1/114), 45,X (1.27‰, 1/787), 47,XXY (3.42‰, 1/292), 47,XXX (2.16‰, 1/463), 47,XYY (1.91‰, 1/524) was much higher than earlier publication [4–5]. There were several factors that might affect this result. The most important reason might be that the current knowledge about the incidence of chromosomal abnormalities in the general population came from studies in newborns carried out in the 1970s, this data has not been updated and the earlier studies had technical and methodological limitations. Especially, amniocentesis was only performed on women who were already marked as higher risk. This is a different incidence rate than the earlier referenced incidence rate that was reported in terms of all live births. Second, as the largest prenatal diagnosis center and the main referral centers in Zhejiang Province, many patients with the referral indications of amniocentesis were likely to be referred to the hospital for further evaluation and management. And this study did not exclude pregnant women with family history of chromosomal abnormalities, ultrasound abnormalities, adverse pregnancy history and other indicators, which might increase the proportion of chromosomal abnormalities. Moreover, new screening technologies as alternatives had been used to detect chromosomal abnormalities, especially, the increasing reliability of NIPT has facilitated far more first trimester screening for the major aneuploidies [14]. NIPT as a successful application in routine clinical practice has been widely used to detect trisomy 21, 18, 13 and SCAs [15]. In the present study, it was found that 19.00% of pregnant women with fetal SCAs had the indication of abnormal NIPT results, and the indication had the highest positive predictive value for SCAs (83.74‰). However, it must be noted that NIPT has only been available in China since 2012, and given the length of the study period, this might have a significant impact on the result. The discrepancy might also be related to the age distribution of the participants since the frequency of some chromosomal abnormalities was directly associated with maternal age [16]. In this study, the percentage of AMA women has gradually increased since 2012, especially in 2016 and 2017 reaching 56.04% and 57.57%, respectively, which might be due to the implementation of the “second-child policy” in China. In addition, due to the incompleteness of the data, this study failed to rule out confounding factors such as maternal parity history and father's age, however, previous studies have found that fetal chromosomal aneuploidies might be related to these factors [17–18]. Therefore, it was reasonable to have a higher incidence rate of fetus SCAs.
The incidence of fetal SCAs depends on clinical indications [19]. AMA was the most frequent referral indication for 47,XXY, 47,XXX and 47,XYY, while abnormal ultrasound findings was the most frequent referral indication for 45,X, which was consistent with the previous study [20]. This study indicated that the incidence of fetal SCAs was significantly related to maternal age, ranging from the lowest of 5.81 per 1,000 fetuses at the 24–28 years to the highest of 10.92 per 1,000 fetuses at the 39 + years. The incidence of fetal SCAs was significantly different among groups, but not significantly different between adjacent groups. This study also found that the incidence of 45,X and 47,XXY was significantly related to maternal age, while the incidence of 47,XXX and 47,XYY was not related to maternal age. And the incidence of 45,X and 47,XXY was significantly different only between the 29–33 years and the 34–38 years. Specifically, unlike the incidence of 47,XXY, which gradually increased with advancing maternal age, the incidence of 45,X reached the peak of 2.35‰ (1: 426) at the 29–33 years, and then decreased sharply to 0.44‰ (1: 2272) at the 34–38 years. However, because the number of research subjects for each type of abnormality was too small, we could not tell at what age the cutoff occured.
Turner’s syndrome is the only complete monosomy that is viable in human beings. Some studies have shown that the loss of the X chromosome in the peripheral blood lymphocytes increased with maternal age [21–23], but clinical studies have shown that young women have a higher incidence of 45,X [24]. However, the incidence of 45,X increased with maternal age and reached the peak at a specific maternal age, then tended to decline at the upper limit of the age range, which was consistent with as Ferguson-Smith et al described [9]. Does this mean that when the age of pregnant women reaches a certain threshold, the incidence of 45,X will decline? Does this happen by accident? Uematsu A [25] found that 45,X is not related to advanced maternal age and it is more likely due to instability of the Y chromosome since 75–80% of X chromosomes in patients with 45,X are maternal in origin. The study failed to rule out confounding factors such as father's age, which required expanding the sample size to seek possible influencing factors in the further studies.
47,XXY is the most frequent genetic disorder and accounts for approximately two-thirds of all the cytogenetic abnormalities [26]. In the study, 47,XXY was the most common SCAs and accounted for 39.11% of all SCAs. Similar to previous studies [9–11], we found that 47,XXY showed significant correlation with maternal age. The incidence of 47,XXY was basically positively correlated with maternal age, except for the ≤ 23 years, which might be due to the number of patients and affected fetuses was very small in size. According to the results of this study, the incidences of 47,XXX and 47,XYY were not found to be significantly correlated with maternal age. However, trend in the incidence of fetal SCAs showed that the incidence of 47,XXX was completely independent of maternal age, while the incidence of 47,XYY was completely dependent on the maternal age before the 34–38 years and then decreased sharply at the 39 + years, this necessitates further studies on larger cohorts in the future. In addition, the incidence of 47,XXY, 47,XXX and 47,XYY was found to increase dramatically at the age of 44. However, because the number of cases at the age of 44 or older was very small, analysis of the correlation between fetal chromosomal abnormalities and extreme maternal age was not possible.