Correlation Between Tricuspid Regurgitation and Fetal Cardiac Structure, Signs, and Chromosomal Abnormalities in Fetuses at 12 +0 to 16 +0 Weeks of Gestation (2025)

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Objective

This study aimed to investigate the correlation between tricuspid regurgitation (TR) in fetuses at 12^+ 0 to 16^+ 0 weeks of gestation and fetal cardiac structure, signs, and chromosomal abnormalities.

Methods

A prospective collection of dynamic four-chamber view (4CV) color Doppler ultrasound images of fetuses at 12^+ 0 to 16^+ 0 weeks of gestation was performed to screen for TR. The correlation between the non-TR and TR groups in fetal cardiac structure or signs and chromosomal abnormalities was analyzed, as well as the correlation between different grades of TR and fetal cardiac structure, signs, and chromosomal abnormalities.

Results

(1) In this study, 1018 early gestational fetuses were included, with a 100% detection rate of dynamic 4CV color Doppler ultrasound images. (2) Among the 1018 fetuses, 942 were in the non-TR group, and 76 were in the TR group, yielding a TR detection rate of 7.47% (76/1018). In the TR group, 62 cases were mild, 6 cases were moderate, and 8 cases were severe. Among the TR group, 64 fetuses had no cardiac structural or echocardiographic signs of abnormalities or chromosomal abnormalities, with a TR occurrence rate of about 6.39% (64/1002) in normal fetuses. The risk of cardiac structural or echocardiographic abnormalities in the TR group was 17 times higher than that in the non-TR group, and the risk of chromosomal abnormalities in the TR group was 25 times higher than that in the non-TR group. After refining the TR grade, the proportion of mild and severe abnormalities of TR in cardiac structure or signs and chromosomal abnormalities gradually increased. (3) In the early stages of pregnancy, we observed significant differences in the prevalence of hypertension and diabetes between the non-TR group and the TR group (P < 0.05). (4) In the early stages of pregnancy, there were no significant differences in cardiac structure or echocardiographic signs of abnormalities, nor in chromosomal abnormalities between the non-TR group and the mild TR group (P > 0.05). However, significant differences were observed in these abnormalities between the non-TR group and the following TR groups: moderate TR, severe TR, moderate + severe TR, and mild + moderate + severe TR (P < 0.05). (5) We found no significant difference between moderate TR and severe TR in cardiac structural or echocardiographic abnormalities and chromosomal abnormalities (P > 0.05). However, statistically significant differences were observed between mild TR and severe TR, as well as between mild TR and moderate + severe TR, in cardiac structural or echocardiographic abnormalities and chromosomal abnormalities (P < 0.05).

Conclusion

Grading TR in fetuses at 12^+ 0 to 16^+ 0 weeks can provide important clues for early screening of fetal cardiac structural or echocardiographic abnormalities and chromosomal abnormalities. This method offers reliable evidence for clinical practice and has high application value.

Early gestation

fetus

tricuspid regurgitation

cardiac structural abnormality

chromosomal abnormality

1 Research object

A prospective collection of 1,018 early pregnancy fetal cases examined at the Haidian District Maternal and Child Health Hospital, Beijing, from December 2021 to June 2023 was included in this study. The maternal age ranged from 19 years to 52 years, with a mean age of 31.4 ± 3.8 years. The inclusion criteria were as follows: (1)gestational age between 12⁺⁰ and 16⁺⁰ weeks; (2) clear fetal color Doppler ultrasound images; (3) defined fetal cardiac structure and chromosome outcomes; and (4) voluntary agreement to participate and signed informed consent. Exclusion criteria included (1) loss to follow-up and (2) inability or refusal to cooperate. This study was approved by the Ethics Committee of the Haidian District Maternal and Child Health Hospital, Beijing (Ethical approval number: 2021-23). Prior to inclusion, the specific content of the ultrasound measurements required for the study was explained to the participants.

2. Instruments and Methods

2.1 Instruments: Fetal cardiac examination was performed using GE Voluson E8 and E10 color Doppler ultrasound diagnostic devices with a 2D abdominal convex probe, operating at a frequency of 4–8 MHz.

2.2 Methods: Following the guidelines of the International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) Practice Guidelines 2013 ^[8]and the 2021 ISUOG Statement on the Safe Use of Doppler Ultrasound in Early Pregnancy ^[9], referring to the conditions for the ultrasound equipment settings for fetal heart examinations, the mechanical index and thermal index were both set below 0.8. A dedicated fetal heart mode was used for examination. Pregnant women were placed in a supine position and instructed to breathe calmly. A prenatal screening-qualified physician conducted color Doppler ultrasound screening on the early pregnancy fetal hearts. The four-chamber view (4CV) was used to assess the presence and degree of TR. Fetal structural anomaly screening was performed between 20⁺⁰ and 24⁺⁶ weeks following the 2022 guidelines for mid-pregnancy ultrasound, with evaluations for CHD, TR, and the degree of TR. Fetuses with suspected heart structural abnormalities underwent further prenatal diagnostic ultrasound, followed by confirmation from two physicians with more than 10 years of experience in fetal cardiac ultrasound, who reached a consensus or validated the diagnosis through post-abortion autopsy findings. The accuracy of early pregnancy fetal CHD ultrasound diagnosis was then confirmed. The results of mid-pregnancy fetal chromosomal testing were also recorded. During early pregnancy, fetuses without TR were classified as the non-TR group, whereas those with TR were assigned to the TR group. The TR group was further stratified into mild, moderate, and severe categories based on the degree of TR. This study analyzed the correlation between cardiac structure or echocardiographic signs and chromosomal abnormalities in the non-TR and TR groups. Additionally, we examined the correlation between the severity of TR and the presence of cardiac structural or echocardiographic signs, as well as chromosomal abnormalities.

2.3 Evaluation Criteria: TR was evaluated using color Doppler ultrasound on the 4CV, showing systolic right ventricular to right atrial flow signals with a systolic reflux velocity >60cm/s, maintaining for more than half of the systolic phase. Through the semi-quantitative method^[4], TR was classified into mild, moderate, and severe categories based on the proportion of the reflux jet area relative to the right atrial area. The criteria for classification were mild (reflux area/RA area <20%), moderate (20%–40%), and severe (≥40%).

3 Statistical analysis

Data were analyzed using SPSS version 29.0. Normally distributed continuous data were expressed as mean ± standard deviation (x̅±s), and categorical data were presented as [n (%)] values. Independent sample chi-square tests and Fisher’s exact tests were used for comparison, with a significance level set at P < 0.05.

1. Display of dynamic 4CV color Doppler ultrasound images

In this study, the dynamic 4CV color Doppler ultrasound images of 1,018 early pregnancy fetuses were successfully displayed, achieving a display rate of 100% (Figure 1).

2. Comparison of TR condition, cardiac structure, signs, and chromosomal abnormalities of fetuses in early pregnancy

This study included 1,018 early pregnancy fetuses, with 942 cases in the non-TR group and 76 cases in the TR group. The incidence of TR was approximately 7.47% (76/1018). The TR group comprised 62 cases of mild TR, 6 cases of moderate TR, and 8 cases of severe TR. In the TR group, 64 cases had no cardiac structural or chromosomal abnormalities. The TR group showed a 17-fold increased risk of cardiac structural or sign abnormalities and a 25-fold increased risk of chromosomal abnormalities compared with the non-TR group. After stratifying TR into mild, moderate, and severe categories, the proportion of abnormalities in cardiac structure, signs, or chromosomal abnormalities progressively increased from mild TR to severe TR. A total of 76 cases of TR were identified in fetuses during early pregnancy. The degrees of TR, as well as the associated cardiac structure, signs, and chromosomal abnormalities, are summarized in Table 1.

Table 1: Comparison of TR, cardiac structural abnormalities, or signs or chromosomal abnormalities in fetuses in early pregnancy

3. Comparative analysis of the general characteristics and results between the Non-TR and TR groups

In the early stages of pregnancy, there were significant differences in the prevalence of hypertension and diabetes between the non-TR group and the TR group (P< 0.05), as shown in Table 2.

Table 2: Comparison of general characteristics between the TR and non-TR groups

Note: Corrected for continuity where applicable

4. Comparison of cardiac structure, signs, and chromosomal abnormalities between the non-TR group and various degrees of TR in early pregnancy

The results indicated no significant differences in cardiac structure or signs or chromosomal abnormalities between the non-TR group and the mild TR group (P > 0.05). However, significant differences were observed between the non-TR group and the moderate or severe TR groups, as well as between the non-TR and combined moderate and severe TR groups, in terms of cardiac structure and chromosomal abnormalities (P < 0.05). These findings are summarized in Table 3.

Table 3: Comparison of different degrees of TR with cardiac structure, signs, and chromosomal abnormalities in early pregnancy fetuses

Note: Corrected for continuity where applicable

5. Comparison of cardiac structure, signs, and chromosomal abnormalities among different degrees of TR in early pregnancy fetuses

The analysis revealed no significant differences in cardiac structural abnormalities or echocardiographic signs, nor in chromosomal abnormalities between the moderate and severe TR groups (P > 0.05), indicating a lack of statistical significance. By contrast, statistically significant differences were observed between the mild TR and severe TR groups, as well as between the mild TR and the combined moderate plus severe TR groups, with respect to cardiac structural abnormalities or echocardiographic signs and chromosomal abnormalities (P < 0.05). These findings are detailed in Table 4.

Table 4: Comparison of different degrees of TR with cardiac structure, signs, and chromosomal abnormalities in early pregnancy fetuses

Note: ^a Fisher’s test; ^b Continuity correction test.

TR is the most common valvular reflux during the fetal period, resulting from blood reflux into the right atrium due to incomplete valve closure during systole^[11]. Previous studies have indicated that early pregnancy fetal TR is associated with CHD or chromosomal abnormalities. Among fetuses with CHD, approximately 39.2% exhibit TR, while only 1.3% of normal fetuses present with TR^[12]. The incidence rates of TR in trisomic fetuses with Down syndrome (trisomy 21), Edwards syndrome (trisomy 18), Patau syndrome (trisomy 13), and Turner syndrome are approximately 56%, 33%, 30%, and 37.5%, respectively, whereas the incidence is around 1% in euploid fetuses^[13]. However, some studies suggested that TR can also occur as an isolated finding in early pregnancy fetuses with normal cardiac anatomy^[14]. Currently, studies on the correlation between TR and CHD are relatively few, and the conclusions are inconsistent. Moreover, the lack of large-scale studies may be attributed to the fact that TR is relatively common in clinical practice or that it is overlooked due to its unclear association with disease. This study aimed to refine and stratify the TR findings, categorizing them into mild, moderate, and severe TR, and further investigate the correlation between non-TR and TR groups with fetal cardiac structure or findings and chromosomal abnormalities. This study also explored the correlation of different degrees of TR with fetal cardiac structure, findings, and chromosomal abnormalities to provide clinical value for early pregnancy fetal screening.

According to the 2013 ISUOG practice guidelines, fetal cardiac ultrasound screening in early pregnancy can clearly visualize the fetal cardiac anatomy and demonstrate the image of the heart positioned normally in the left side of the thorax (levocardia). Most clinicians believe that directed fetal cardiac examination in early to mid-pregnancy (11⁺⁰ to 16⁺⁰ weeks) is the earliest period for such screening^[15]. However, Ebrashy et al.^[16] reported that from 12 weeks of gestation, the visibility of the fetal heart’s three-vessel view significantly increases, with a 96.1% detection rate for the 4CV. Therefore, this study selected fetuses at 12⁺⁰ to 16⁺⁰ weeks of gestation for early pregnancy screening of TR using color Doppler ultrasound. Before conducting the study, ultrasound technicians optimized the machine and imaging effects. The results from this study showed a 100% detection rate of dynamic 4CV color Doppler ultrasound images in 1,018 early pregnancy fetuses. Although there are no specific recommendations for routine fetal cardiac assessment when TR is present^[17], the dynamic 4CV measurement in this study indicated that the scan time for 8–12 cycles was approximately 4s, which was consistent with the ISUOG safety guidelines for Doppler fetal ultrasound in early pregnancy, emphasizing the “as low as reasonably achievable” principle^[8,18]. Therefore, obtaining TR images in early pregnancy is highly feasible.

In this study, the incidence of TR was 7.47% (76/1,018), with a TR occurrence of approximately 6.39% (64/1,002) in normal fetuses, consistent with previous reports^[19]. TR is one of the abnormal findings in cardiac screening, and the earliest detectable TR can be seen as early as 11⁺⁰ weeks of pregnancy. This finding can help diagnose certain heart valve and structural abnormalities, with blood reflux into the right atrium due to incomplete valve closure during systole. Therefore, TR is considered a reference factor for cardiac abnormalities in this study^[11]. The results indicated no significant differences between the non-TR and mild TR groups in terms of cardiac structural or sign abnormalities and chromosomal anomalies. In the fetal period, the tricuspid valve blood flow mainly consists of low-oxygen blood from the coronary sinus (97%–99%) and the superior vena cava and a small amount of highly oxygenated blood from the inferior vena cava, flowing into the right ventricle. Given the high resistance in the fetal pulmonary circulation, most of the blood (about 90%) is directed into the systemic circulation via the ductus arteriosus, whereas only a small portion (less than 10%) enters the pulmonary circulation^[20]. Therefore, TR signs can be found. However, TR is often mild, with a small and short color flow signal, which correlates with the dominance of the fetal right heart system; mild TR can be considered physiological. The results of this study showed significant differences among the non-TR, mild TR, and moderate to severe TR groups in terms of cardiac structure or signs and chromosomal abnormalities. Furthermore, as the degree of TR increased, the abnormal rates in cardiac structure or signs and chromosomal abnormalities increased, suggesting that the likelihood of abnormal cardiac structure or sings and chromosomal abnormalities rose with the severity of TR. The more severe the TR, the higher the probability of fetal abnormalities in cardiac structure or signs, as well as chromosomal abnormalities. Therefore, moderate and severe TR can be considered pathological.

This study found that the risk of cardiac structural or sign abnormalities in the TR group was 17 times higher than that in the non-TR group, whereas the risk of chromosomal abnormalities was 25 times higher in the TR group compared with that in the non-TR group. Maternal hypertension and diabetes are high-risk factors for TR findings in early pregnancy. When moderate or severe TR is detected in early pregnancy, a detailed examination of the fetal cardiac structure should be conducted, and fetal genetic testing should be actively pursued. Reviewing the literature, TR has predictive value for early pregnancy fetal CHD, enabling the diagnosis of 25% of cardiac valve abnormalities, 100% of pulmonary or tricuspid valve atresia, over 90% of left heart hypoplasia syndrome or atrioventricular septal defects, about 60% of complex congenital heart defects, 30%–40% of Tetralogy of Fallot, and 15% of transposition of the great arteries^[21]. Combining early pregnancy fetal screening with neck translucency and maternal serum markers achieves a detection rate of approximately 90% for chromosomal aneuploidy, with a 5% false-positive rate. Adding other ultrasound markers, such as TR, reversed A-wave in the venous duct, abnormal cardiac axis, and umbilical cord prolapse, can help avoid unnecessary invasive tests and their associated complications, while improving the detection rate of chromosomal abnormalities, particularly aneuploidies^[22].

Limitations: This study was conducted at a single center in a northern region, and the results may be influenced by sample size selection, leading to statistical bias. Although the number of enrolled cases exceeded 1,000, the low incidence of fetal CHD and the fact that TR is an abnormal cardiac finding require large sample sizes for further analysis of the correlation between TR and cardiac structure or findings and chromosomal abnormalities. Furthermore, neonatal cardiac ultrasound follow-up was limited and did not achieve comprehensive and continuous tracking.

In conclusion, the detailed stratification of TR into mild, moderate, and severe categories between 12⁺⁰ and 16⁺⁰ weeks of pregnancy provides important clues for early pregnancy screening of fetal cardiac structure, signs, and chromosomal abnormalities. This approach offers a reliable basis for clinical application and has significant value.

The Author Contribution declaration:

ZHENG SHUAI: Conceptualization, Writing – Original Draft, Writing – Review & Editing, Study Design, Investigation, Image Analysis, Image Processing, Data Analysis.

WANG JINGYI: Literature Review, Funding Acquisition.

SUN HAIRUI: Literature Review, Study Design, Investigation, Writing – Review & Editing.

HAN JIANCHENG: Supervision, Study Design, Investigation.

GUAN YUXUAN: Study Design, Image Analysis, Image Processing.

WANG HAIRUI: Study Design, Statistical Analysis.

ZHOU XIUYUN: Image Analysis, Data Analysis.

HE YIHUA: Supervision, Writing – Review & Editing, Final Approval.

All authors reviewed the manuscript.

There is no competition of interests in this study.

The name of the Approval Committee or the Internal Review Board (IRB):

Ethics Committee of Beijing Anzhen Hospital

Funding Declaration：

Beijing Natural Science Foundation, 7244325

Consent to Participate declaration: All authors participated in the creation of this article and agreed to its publication

Data Availability declaration:All the data are true and valid

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