A total of 471 pregnant women with fetal CHD underwent invasive sampling procedures, including 169 amniocenteses and 302 cordocenteses. The mean age of the pregnant women was 28.73 ± 4.80 years (range, 18–45 years), while the median gestational age at ultrasound examination was 26.91 ± 1.96 weeks (range, 20–28).
A total of 23 CHDs were identified in this study, and the top 10 CHDs were, in order, ventricular septal defects (VSDs; 245 cases, 52.02%), right aortic arch (13 cases, 2.76%), tetralogy of Fallot (11 cases, 2.34%), Ebstein anomaly (9 cases, 1.91%), hypoplastic left heart syndrome (9 cases, 1.91%), endocardial cushion defects (5 cases, 1.06%), coronary sinus malformation (5 cases, 1.06%), cardiac tumor (4 cases, 0.85%), hypoplastic right heart syndrome (4 cases, 0.85%), and right and left pulmonary artery crossing (4 cases, 0.85%). The top 10 CHDs accounted for 65.60% of the cases. Among the 471 cases of CHDs, 254 (53.93%) showed abnormalities on ultrasound examinations. Central nervous system (CNS) ultrasound abnormalities and choroid plexus cysts accounted for 32.28% and 19.7%, respectively, of fetal CHD abnormalities. Among the non-CNS abnormalities, placenta and umbilical cord abnormalities accounted for 23.23% of the cases, followed by polyhydramnios and digestive abnormalities. Some patients also showed concomitant pathological ultrasound findings such as widened renal pelvis and abnormal limb development (Table 1).
Table 1
Fetal CHD presenting with other ultrasound abnormalities
Ultrasound abnormalities | Total | Rate/(%) |
Central Nervous System | 82 | 32.28 |
Ventriculomegaly | 23 | 9.06 |
Choroid plexus cyst | 45 | 17.72 |
Abnormal cavum of septum pellucidum | 10 | 3.94 |
Blake’s pouch cyst | 3 | 1.18 |
Meningocele | 1 | 0.39 |
Digestive system | 38 | 14.96 |
Digestive tract obstruction | 20 | 7.87 |
Small or undetected stomach vesicles | 11 | 4.33 |
Gallbladder enlargement | 7 | 2.76 |
Extremity | 17 | 6.69 |
Abnormal posture | 15 | 5.90 |
Shortness | 1 | 0.39 |
Polydactyly | 1 | 0.39 |
Abnormalities of the renal system | 29 | 11.42 |
Hydronephrosis | 23 | 9.05 |
Enlarged kidney | 6 | 2.36 |
Face & neck | 6 | 2.36 |
Neck cyst | 4 | 1.57 |
Nasal bone dysplasia | 2 | 0.78 |
Other | | |
Single umbilical artery | 46 | 18.11 |
Polyhydramnios | 39 | 15.35 |
Nuchal translucency thickening | 4 | 1.57 |
Intrauterine growth restriction | 2 | 0.78 |
Umbilical hernia | 2 | 0.78 |
Visceral version | 1 | 0.39 |
Umbilical cord cyst | 13 | 5.12 |
Herniation of the diaphragm | 1 | 0.39 |
Note: Cases were counted twice if the same fetus showed ≥ 2 abnormal ultrasound indices |
*** Table 1***
Chromosomal abnormalities were detected in 93 (19.75%) of the 471 cases of fetal CHD in this study. Groups A, B, C, and D showed 11 (8.59%), 34 (27.42%), 9 (10.11%), and 39 (30%) cases of chromosomal abnormalities, respectively. In comparisons of groups A and B, B and C, and C and D, the differences were statistically significant. The remaining comparisons did not show significant differences (P > 0.05), as reported in Table 2.
Table 2
Results of chromosome analyses of 471 fetal CHD cases
Groups | Total | Abnormal results | Frequency of chromosomal abnormalities (%) |
simple fetal CHD | 128 | 11 | 8.59% |
simple fetal CHD with extracardiac abnormalities | 124 | 34* | 27.42% |
complex fetal CHD | 89 | 9# | 10.11% |
complex fetal CHD with extracardiac abnormalities | 130 | 39% | 30.00% |
Note: *p < 0.05 vs. simple fetal CHD; # p < 0.05 vs. simple fetal CHD with extracardiac abnormalities; %− p < 0.05 vs. complex fetal CHD. |
*** Table 2***
The karyotyping of the 471 fetuses revealed 85 abnormalities. This study identified 10 cases of structural chromosome abnormalities and 75 cases of chromosome number abnormalities, including 38 cases of 47,XN,+18, 26 cases of 47,XN,+21, and three cases of 47,XN,+13. Four cases showed sex chromosome abnormalities, including two cases of 45,X, one case of 47,XYY, and one case of 47,XXX. One case showed a 48,XXX,+18 sex chromosome and three cases showed chromosome chimerism: 47,XXY/46,XY, 45,X/46,XX, and 46,XY/46,XX. More details are provided in Table 3, and a part of the chromosomal karyotype is shown in Fig. 1. BoBs, FISH, and SNP-array examinations were performed in 32, 13, and 89 fetuses, respectively. Some of the BoBs results are plotted in Fig. 2. While the results of all BoBs and FISH examinations were consistent with the results of the karyotype analyses, only 85 of the 89 SNP-array examinations showed results consistent with the results of the karyotype analyses. In the remaining four cases, karyotype results were normal, but chromosomal SNP-array results suggested the presence of microdeletions in three fetuses and microduplications in one fetus (Table 4). Among of the 26 fetuses that underwent CNV-seq examination, 22 showed results consistent with the results of karyotype analysis. Among the remaining four fetuses, karyotype analyses indicated normal results, but chromosomal CNV-seq results indicated the presence of microdeletions (Table 5). SNP-array and CNV-seq analyses increased the detection rate of chromosomal abnormalities by 8.60%.
Table 3
Results of chromosomal karyotyping analysis of fetal CHD
Chromosome abnormalities | Total [n(1)(%)] | A [n(2)(%)] | B [n(3)(%)] | C [n(4)(%)] | D [n(5) (%)] |
Numerical abnormalities | 75(15.92) | 9(7.03) | 30(24.19) | 5(5.62) | 31(23.85) |
Trisomy-18 | 38(8.07) | 2(1.56) | 17(13.71) | 0 | 19(14.62) |
Trisomy-21 | 26(5.52) | 4(3.13) | 11(8.87) | 2(2.25) | 9(6.92) |
Trisomy-13 | 3(0.64) | 0 | 0 | 1(1.12) | 2(1.54) |
Abnormal number of sex chromosomes | 4(0.85) | 2(1.56) | 0 | 1(1.12) | 1(0.76) |
Abnormal numbers of sex chromosomes with autosomal staining. | 1(0.21) | 1(0.78) | 0 | 0 | 0 |
Chromosome chimerism | 3(0.63) | 0 | 2(1.61) | 1(1.12) | 0 |
Structural abnormalities | 10(2.12) | 0 | 4(3.23) | 2(2.25) | 4(3.08) |
Total | 85(18.05) | 9(7.03) | 34(2.74) | 7(7.87) | 35(26.92) |
Note: (1) total of 471; (2) total of 128; (3) total of 124; (4) total of 89; (5) total of 130. Group A, simple fetal CHD; group B, simple fetal CHD with extracardiac abnormalities; group C, complex fetal CHD; and group D, complex fetal CHD with extracardiac abnormalities. |
Table 4
Fetal CHD with normal karyotype and abnormal SNP-array results
Age (years) | Gestation (week) | Ultrasound Findings | Area | Size | Type | Nature | |
25 | 26 + 2 | Abnormal intraabdominal circumference of the umbilical vein, absence of venous catheters, enlarged right heart, wider inferior vena cava, thicker hepatic echoes, intrahepatic strong echoes, and enhanced intestinal wall echoes. | Chromosome 15 | 512.3Kb | Missing | Clinical significance unknown | |
33 | 29 + 6 | Congenital complex cardiovascular malformations of the fetus right aortic and left arterial catheter (ring formation) | Chromosome 22 | 2.88Mb | Missing | Clinical significance unknown | |
24 | 30 | Increased right heart proportion, large tricuspid valve regurgitation, smaller mitral regurgitation, and larger axis. | Chromosome 1 | 2.387Mb 1.972Mb | Missing, Missing | Pathogenicity | |
24 | 24 | Congenital complex cardiovascular abnormalities in the fetus (double right ventricular outlet, ventricular septal defect, right aortic arch, enlarged right heart proportion) fetal hemivertebral body, right polycystic dysplastic kidney, umbilical artery. | Chromosome X | 1.695Mb | Repeat | Clinical significance unknown | |
Table 5
Fetal CHD with normal karyotype and abnormal CNV-seq
Age (years) | Gestation (week) | Ultrasound Findings | Area | Size | CNV Type | Nature |
19 | 27 | VSD; malproportion of main and pulmonary arteries; tricuspid mitral regurgitation | Chromosome 1 | 0.38Mb | LOH | Clinical significance unknown |
29 | 28 | Bilateral aortic arch in the fetus; perpetual left superior cavity. | Chromosome 16 | 1.24Mb | Missing | Pathogenicity |
30 | 22 | Hydrocystoma of fetal lymphatic vessels with widening of the coronary venous sinus and perpetual left superior cavity | Chromosome 14 | 2.64Mb | Missing | Clinical significance unknown |
24 | 26 + 6 | Fetal dysplasia of the nasal bones with small axial angle | Chromosome 21 | 2.34Mb | LOH | Pathogenicity |
Note: LOH, loss of hybridization |
*** Table 3.4.5***
Among the 471 pregnant women, 418 were aged < 35 years, of whom 77 (18.42%) had chromosomal abnormalities. Fifty-three women were aged ≥ 35 years, of whom 16 (30.19%) had chromosomal abnormalities. Older pregnant women showed a significantly higher incidence of chromosomal abnormalities than younger pregnant women (P < 0.05).
Among the 471 cases of fetal CHD, 453 (96.18%) were followed-up. Fetal CHD resulted in termination of 166 pregnancies (36.64%); among the pregnancies that were not terminated, seven (1.55%) ended in intrauterine death, 280 (61.81%) were delivered as live births; and seven (1.54%) involved neonatal death after birth. The rate of pregnancy terminations progressively increased from group A to D and was 36.84%, 67.65%, 85.71%, and 98.67%, respectively, in these four groups (P < 0.005 for all differences). As shown in Table 4, the survival rates of fetuses in cases of continued pregnancy in groups A, B, C, and D were 96.30%, 98.63%, 90.91%, and 92.16%, respectively (Table 6). Thus, the survival rate of continued pregnancies was the highest in cases showing simple fetal CHD combined with extracardiac anomalies. Tables 7 and 8 show that the pregnancy termination rate and continued pregnancy outcomes differed significantly among the four groups (P < 0.05). Further two-by-two comparisons were made using Bonferroni's method, and the corrected α was calculated as 0.05/4×(4 − 1)/2 = 0.0083, which indicated no statistically significant differences were observed in the outcomes(The rate of pregnancy terminations and the survival rates of fetuses in cases of continued pregnancy) between groups B and C (χ2 = 0.028, P = 0.868; χ2 = 2.646, P = 0.104), while the differences among the remaining groups were statistically significant (P < 0.05).
Table 6
Pregnancy outcomes by group
Groups | Effective tracking | Termination | Intrauterine death | Dying | Survival | Continued pregnancy survival |
A | 123 | 15(12.20%) | 1 | 3 | 104 | 96.30%(104/108) |
B | 116 | 43(37.07%) | 1 | 0 | 72 | 98.63%(72/73) |
C | 89 | 34(28.20%) | 2 | 3 | 50 | 90.91%(50/55) |
D | 125 | 74(59.20%) | 3 | 1 | 47 | 92.16%(47/51) |
Note: Group A, simple fetal CHD; group B, simple fetal CHD with extracardiac abnormalities; group C, complex fetal CHD; and group D, complex fetal CHD with extracardiac abnormalities. |
Table 7
Comparison of pregnancy termination outcomes by group
Groups | Valid Tracking | Termination | χ2 | p |
Simple fetal CHD | 123 | 15 | 59.164 | 0.000 |
Simple fetal CHD with extracardiac abnormalities | 116 | 43* |
Complex fetal CHD | 89 | 34* |
Complex fetal CHD with extracardiac abnormalities | 125 | 74*#% |
Note: *p < 0.05 vs. simple fetal CHD; # p < 0.05 vs. simple fetal CHD with extracardiac abnormalities; % p < 0.05 vs. complex fetal CHD. |
Table 8
Comparison of survival outcomes in cases with continued pregnancy by group
Groups | Valid Tracking | Delivery survivals | χ2 | P |
Simple fetal CHD | 123 | 104 | 59.936 | 0.000 |
Simple fetal CHD with extracardiac abnormalities | 116 | 72* |
Complex fetal CHD | 89 | 50* |
Complex fetal CHD with extracardiac abnormalities | 125 | 47*#% |
Note: *p < 0.05 vs. simple fetal CHD; # p < 0.05 vs. simple fetal CHD with extracardiac abnormalities; % p < 0.05 vs. complex fetal CHD. |
*** Table 6.7.8***