Interpretation
It has been indicated that the commonest indications of routine amniocentesis (between 16-24 gestational weeks) in China were the increased risk at maternal serum screening and advanced maternal age (35 years at the expected time of delivery) 17. However, late detected aberrant ultrasound findings (or a combination of ultrasound findings with other earlier indications) was the most frequent indication of late amniocentesis and has accounted for 88.3% in our cohort. Among the 67 cases, 13 cases with ultrasound findings show the same results with CMA reports. For instance, a fetus presenting with cardiac anomalies had a microdeletion of chr22q11.2 compatible with DiGeorge syndrome18. In another case, a fetus with the absence of cauda cerebelli was found to have a microdeletion on chr7p22.3p21.1 and chr8p23.3p23.2, which is associated with Dandy-Walker syndrome(type II)19. Compared to routine amniocentesis, the complication rate of late amniocentesis within one week and one month are 9.6% (11/115) and 11.3% (13/115), respectively. The overall complication rate was 9.0% (115/1272). As Daum and coworkers reported that only 18 complications were identified among their 291 patients undergoing late amniocentesis in Israel1, while the complication rate reported by Liao and coworkers was 1.9% (only two complications were found among 108 patients) after third-trimester amniocentesis20. Owing to the sample size is much more abundant in our cohort, the complication rates of our study are higher than theirs, but similar to that reported by Gabbay et al. 21 and consistent with a recent meta-analysis22. Although our complication rate is higher than that of routine amniocentesis23, it is reasonable to speculate that at least some of the complications are unlikely to have a direct association with amniocentesis owing to 88.7% (102/115) complications took place in fetuses with abnormal ultrasound findings. The main predictor of PTB in singletons was fetal malformations (24/26, 92.3%), mainly CNS anomalies (4/24, 16.7%) and FGR (4/24, 16.7%). The presence of fetal malformations obviously increases the risk of both PTB and IUD, compared to others without fetal malformations. And pregnancies with double puncture are more likely to suffer from PTB after late amniocentesis. This result may offer opportunities for doctors to consider both the indication for late amniocentesis and the risks of PTB comprehensively. On the other hand, the rate of detection of chromosomal aberrations via CMA and ES are 10.5% and 8.3% respectively, while 92.3% of pathogenic CNVs failed to be detected by karyotyping, suggesting that both CMA and ES achieve better diagnostic yield than traditional karyotyping does. Thus, advanced gene diagnosis technologies have a positive role in late amniocentesis. Not only in late amniocentesis but also in routine amniocentesis, the detection rate of CMA and ES, is higher than karyotyping obviously3, 24. In our cohort, the diagnostic rate reaches the highest (31%) when suspected prenatal diagnosis results become the indication of amniocentesis, following by Combination of ultrasound findings (23.1%). It is comparable with the diagnostic rate of routine amniocentesis following abnormal ultrasound findings24. The vast majority of women (86.4%) finally decide to terminate the pregnancies after receiving pathogenic genetic results. 24.4% of women with normal genetic results still terminate the pregnancies owing to the severe ultrasound findings.
A considerable disadvantage of late amniocentesis, especially late in pregnancy, was the identification of uncertain results like VOUS, likely pathogenic and likely benign. 41.5% fetuses with uncertain results were terminated. The reason of 85.2% of them was fetal abnormalities, while the other four were even without abnormal sonographic findings, suggesting that the unclear genetic results might have reinforced their decisions. Of note, except one patient was lost to follow up and the other one was IUD, Three out of the five fetuses whose one of the CMA and ES result showed pathogenic or likely pathogenic were terminated no matter with or without abnormal ultrasound finding. For instance, the couple was referred for genetic counseling during their second pregnancy due to the NIPT result showed trisomy 21 high risk. After amniocentesis, the CMA result showed trisomy 21, but no abnormal finding could be identified through ultrasound. Then the couple chose to have a WES test, and it showed normal afterward. The couple finally terminated the pregnancy.
Worth mentioning, all of the women pay close attention to their genetic test results, which made it reasonable to cogitate the importance and necessity of genetic information even if ultrasound findings are severely abnormal. Moreover, genetic information is also important for future pregnancies without any doubt. In order to increase the accuracy of diagnosis and save time, we also support the idea of offering CMA and ES simultaneously while indeterminate ultrasound findings were identified. However, the economic problem should be taken into account.