Comprehensive comparison of fetal right and left atrial isomerism: cardiac and extracardiac malformations, diagnostic accuracy, and survival outcomes

Introduction

Heterotaxy syndrome is a rare and complex congenital condition involving abnormal left-right arrangement of thoracoabdominal organs and associated cardiovascular malformations (1,2), accounting for approximately 3% of all congenital heart defects (3,4). Its two major subtypes—right atrial isomerism (RAI) and left atrial isomerism (LAI)—exhibit distinct cardiac and visceral patterns (5), with RAI often associated with asplenia and severe defects such as atrioventricular septal defects (AVSD) and anomalous pulmonary venous return (APVR) (6,7), whereas LAI is commonly linked to polysplenia and left ventricular outflow tract obstruction (LVOTO) (8-11). Although prior studies have described the anatomical and clinical spectrum of heterotaxy syndrome, most have been based on postnatal or mixed neonatal/pediatric cohorts. Prenatal studies with postnatal confirmation and integrated outcome analysis remain scarce. Our study directly addresses this gap by analyzing a well-defined fetal heterotaxy cohort with verified postnatal subtype classification and detailed follow-up, providing a more accurate prenatal-to-postnatal translation of prognosis and management needs.

Advances in fetal echocardiography have improved the prenatal detection of heterotaxy (12,13), yet accurate differentiation between RAI and LAI remains challenging due to overlapping features and phenotypic variability (14). Although prior studies have described the anatomical spectrum of heterotaxy, direct prenatal comparisons between RAI and LAI remain limited (15,16). Moreover, reported survival outcomes are inconsistent, with some studies indicating poorer prognosis in RAI due to complex malformations and immune compromise, yet others suggesting higher early survival rates than in LAI (1,17,18).

To address these gaps, we performed a retrospective cohort study of fetuses with prenatally diagnosed heterotaxy syndrome, with the following aims: compare the distribution of cardiac and extracardiac anomalies in RAI versus LAI; evaluate the diagnostic accuracy of prenatal echocardiographic subtype classification; and assess perinatal and one-year survival outcomes. We further propose a diagnostic algorithm to improve prenatal subtype recognition and support individualized perinatal management. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1189/rc).

Methods

Study design and population

This was a single-center, retrospective cohort study conducted at the Hubei Provincial Clinical Research Center for Accurate Fetus Malformation Diagnosis, Xiangyang No. 1 People’s Hospital, Hubei University of Medicine, encompassing a seven-year period from January 2016 to December 2022. All singleton pregnancies with a prenatal diagnosis of heterotaxy syndrome were screened for eligibility. The inclusion criteria were as follows: (I) comprehensive fetal echocardiographic and abdominal ultrasound assessments; (II) postnatal confirmation via echocardiography, surgical findings, or autopsy; and (III) availability of complete follow-up data through at least one year of life or until death. Fetuses with multiple anomalies of chromosomal or syndromic etiology, ambiguous classification, or insufficient imaging documentation were excluded (Figure 1). This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was provided by all participants, and the study protocol received approval from the Ethics Committee of the Xiangyang No.1 People’s Hospital (Approval No. 2021KYLX01).

Figure 1 Flow diagram illustrating the selection, classification, and outcome assessment of fetuses with heterotaxy syndrome included in this study.

Subtypes of heterotaxy were classified as RAI or LAI based on a combined analysis of atrial appendage morphology, systemic and pulmonary venous return patterns, cardiac situs, and splenic anatomy (Figures 2,3). In addition, detailed anatomical evaluation was conducted for key cardiovascular anomalies, including the level of left or right ventricular outflow tract obstruction (LVOTO or RVOTO, respectively; categorized as subvalvular, valvar, or supravalvular), presence of hypoplastic left heart syndrome, and classification of total anomalous pulmonary venous return into supracardiac, cardiac, infracardiac, or mixed types. All cases were independently verified by two fetal cardiologists and a senior radiologist.

Figure 2 Representative imaging findings in a fetus with RAI. From left to right and top to bottom. (A) Axial abdominal view demonstrating ST and left-sided liver, indicating situs ambiguous. (B) Transverse thoracoabdominal view showing juxtaposition of DAO, H, and T, consistent with midline liver positioning. (C) Four-chamber grayscale echocardiographic view revealing abnormal cardiac structure. (D) Color Doppler image showing APVR with multiple pulmonary veins (arrows) draining aberrantly. (E) Identification of R-PV and L-PV converging toward a common chamber (W), supporting diagnosis of total APVR. (F) Additional view demonstrating pulmonary venous confluence and drainage pattern abnormalities (arrows). (G) Axial abdominal view displaying absence of identifiable spleen, suggestive of asplenia. (H) Postmortem gross specimen confirming RAA morphology and asplenia, characteristic of RAI. APVR, anomalous pulmonary venous return; DAO, descending aorta; H, right-sided heart; LAA, left atrial appendages; L-PV, left pulmonary vein; R-PV, right pulmonary vein; RAA, right atrial appendage; RAI, right atrial isomerism; ST, right-sided stomach; T, transverse liver.

Figure 3 Prenatal and postmortem imaging features of a fetus with LAI. (A,B) Axial abdominal ultrasound views with and without color Doppler demonstrating classic features of interrupted IVC with AZ, midline DAO, and bilateral hepatic venous drainage into the atria. A visible SP is noted, consistent with polysplenia. (C) Four-chamber grayscale image revealing a morphologically normal heart with RV and LV and a prominent SA. (D) Color Doppler imaging showing bifurcation of systemic outflow with both RCA and LCA origins from a common trunk. (E) Axial thoracoabdominal view showing symmetric PA bifurcation, double descending aorta (RDA, LDA), and midline liver. (F,G) Postmortem images confirming hallmark features of LAI, including bilateral LAA, duplicated SVC, midline liver, ST, SP, and bilateral bilobed lungs. (H) Three-dimensional vascular reconstruction demonstrating bilateral superior vena cava (RSVC, LSVC), bilateral pulmonary venous return, and duplicated arterial branching patterns, consistent with left atrial isomerism and polysplenia syndrome. ARCH, aortic arch; AZ, azygos continuation; DAO, descending aorta; IVC, inferior vena cava; LAA, left atrial appendages; LAI, left atrial isomerism; LCA, left coronary artery; LDA, left descending aorta; LSVC, left superior vena cava; LV, left ventricle; PA, pulmonary artery; RCA, right coronary artery; RCCA, right common carotid artery; RDA, right descending aorta; RSCV, right subclavian vein; RSVC, right superior vena cava; RV, right ventricle; SA, single atrium; SP, spleen; ST, left-sided stomach; SVC, superior vena cava.

Sample size estimation was based on preliminary data suggesting a 30% difference in one-year survival between RAI and LAI groups. With α=0.05 and power =0.8, a minimum of 25 fetuses per group was required to detect this difference, accounting for an estimated 15% attrition rate.

Imaging acquisition and parameters

Fetal echocardiography and abdominal ultrasounds were performed using GE Voluson E8, E10 (HE HealthCare, Chicago, IL, USA) and Philips EPIQ 7 (Philips, Amsterdam, The Netherlands) ultrasound systems equipped with high-frequency transducers (RM6C/RAB6-D for GE; C9-2 for Philips). Scanning was conducted at 18–34 gestational weeks, following International Society of Ultrasound in Obstetrics and Gynecology (ISUOG) guidelines for congenital heart disease.

Key imaging parameters included the following: two-dimensional (2D) imaging frame rate: 50–70 fps; color Doppler velocity range: ±30–60 cm/s; power doppler gain: 65–85% optimized manually per fetus; spatiotemporal image correlation (STIC) was utilized in selected cases for four-dimensional (4D) heart reconstruction.

Prenatal diagnosis of spleen status (asplenia or polysplenia) was supported by color Doppler vascular mapping of splenic arteries and veins. All imaging datasets were digitally archived and re-reviewed offline for this study.

Image interpretation and quality control

All ultrasound and echocardiographic data were interpreted independently by two senior fetal cardiologists with >10 years of experience. Discordant findings were resolved through a third-party expert review. Interobserver agreement for key variables (e.g., AVSD, APVR, splenic morphology) was assessed using Cohen’s kappa (κ), with values >0.80 considered excellent.

Postnatal confirmation and clinical follow-up

Postnatal anatomical confirmation was obtained via transthoracic echocardiography (Philips iE33 or GE Vivid E9), computed tomography (CT) angiography, cardiac magnetic resonance imaging (MRI), surgical reports, or autopsy findings. Follow-up data included gestational age at delivery, neonatal birth weight, neonatal intensive care unit (NICU) admission, cardiac surgical interventions (univentricular or biventricular repair), and survival status up to one year of age. Neonatal outcomes were verified through the institutional pediatric cardiology registry.

Diagnostic accuracy evaluation

To assess the diagnostic accuracy of prenatal ultrasound, prenatal findings were compared against confirmed postnatal diagnoses for each anatomical anomaly (e.g., AVSD, APVR, spleen status). Sensitivity, specificity, and diagnostic agreement were calculated for both RAI and LAI cohorts. Subgroup analysis examined modality-specific accuracy (e.g., 2D vs. color Doppler vs. STIC).

Statistical analysis

All statistical analyses were conducted using the software SPSS 26.0 (IBM Corp., Armonk, NY, USA). Continuous variables were summarized as mean ± standard deviation (SD) or median (IQR), and compared using independent-samples t-tests or Mann-Whitney U tests depending on distribution normality (verified via Shapiro-Wilk test). Categorical variables were compared using Chi-squared or Fisher’s exact tests, as appropriate.

One-year survival was analyzed via Kaplan-Meier survival curves, with intergroup differences assessed using the log-rank test. Cox proportional hazards regression models were applied to determine independent predictors of 1-year mortality, including anatomical variables (e.g., single ventricle, APVR), surgical type, splenic status, and atrial isomerism subtype. Variables with P<0.1 in univariate analysis were included in the multivariable model. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported. A P value <0.05 was considered statistically significant.

Results

Distribution and comparison of cardiac malformations in fetuses with RAI and LAI

The distribution of cardiac malformations in fetuses with heterotaxy syndrome revealed significant differences between RAI and LAI. In terms of cardiac position, levocardia was more common in LAI (72%) compared to RAI (55.3%), but this difference was not statistically significant (P=0.155). Dextrocardia occurred more frequently in RAI (39.5%) than it did in LAI (20%) (P=0.082). AVSD were significantly more prevalent in RAI (84.2%) compared to LAI (56%) (P=0.011), particularly unbalanced AVSD (65.8% in RAI vs. 28% in LAI, P=0.002). RAI also exhibited a higher incidence of single ventricle malformations (65.8%) compared to LAI (24%) (P=0.001), as well as RVOTO in 68.4% of RAI cases versus 40% in LAI (P=0.024). In contrast, LVOTO was more frequent in LAI (32%) compared to RAI (10.5%) (P=0.032). Conotruncal anomalies, including double outlet right ventricle (DORV), were more common in RAI (55.3%) than they were in LAI (32%) (P=0.062). Systemic venous anomalies, particularly persistent left superior vena cava (PLSVC), were more frequent in RAI (63.2%) compared to LAI (32%) (P=0.018), whereas juxtaposition of the aorta and inferior vena cava (IVC) was almost exclusive to RAI (94.7% vs. 4% in LAI, P<0.001). Pulmonary venous anomalies, including APVR, were significantly more common in RAI (44.7%) than they were in LAI (12%) (P=0.007), and supracardiac APVR was found in 21.1% of RAI cases, but was not detected at all in LAI (P=0.016). Fetal sinus rhythm was observed more frequently in LAI (88%) than it was in RAI (57.9%) (P=0.008) (Table 1).

Visceral organ arrangement and extracardiac anomalies in fetuses with heterotaxy syndrome

Our results indicate notable variations in the arrangement of visceral organs, especially the spleen, between fetuses with RAI and LAI, with RAI showing a higher incidence of asplenia and LAI being more frequently associated with polysplenia. The distribution of visceral organ arrangements and extracardiac anomalies in fetuses with RAI and LAI is summarized in Table 2.

In terms of visceral organ arrangement, the stomach was predominantly right-sided in both groups, with 68.4% in RAI and 52.0% in LAI, although this difference was not statistically significant (P=0.189). The gallbladder was also predominantly right-sided in both groups, with 68.4% in RAI and 64.0% in LAI (P=0.703). Liver positioning showed a significant difference, with a higher proportion of central liver positioning in RAI (60.5%) compared to LAI (36.0%) (P=0.050). Regarding the spleen, a striking contrast was found between the groups: asplenia was much more common in RAI (76.3%) than in LAI (4.0%) (P<0.001), while polysplenia was predominantly observed in LAI (72.0%) compared to RAI (18.4%) (P<0.001).

In terms of extracardiac anomalies, gastrointestinal abnormalities such as biliary atresia, intestinal malrotation, and gastrointestinal atresia were similarly distributed between the two groups, with no statistically significant differences. However, RAI fetuses had a slightly higher incidence of hiatal hernia (7.9%) compared to LAI (0%) (P=0.265). Neurological and other anomalies were generally rare in both groups, with no significant differences observed in the occurrence of ventriculomegaly, ambiguous genitalia, renal agenesis, or cleft lip palate. Pes equinovarus was observed in 8.0% of LAI cases, but not in any RAI cases (P=0.151).

Diagnostic accuracy of prenatal ultrasound for RAI versus LAI-associated fetal malformations

Our results revealed that although ultrasound is generally effective in detecting fetal malformations in both RAI and LAI, it performs better in detecting systemic venous and pulmonary venous anomalies in LAI. Specifically, the comparative diagnostic accuracy of prenatal ultrasound for fetal malformations associated with RAI and LAI is summarized in Table 3. Overall, ultrasound detection showed high accuracy in both groups for most categories of fetal malformations. For cardiac position abnormalities, the detection rate was 94.4% in RAI and 95.8% in LAI (P=1.000). AVSD were detected in 93.8% of RAI cases and 85.7% of LAI cases (P=0.572), with no significant difference between the groups. Ventricular abnormalities were detected in 88.0% of RAI cases compared to 66.7% in LAI (P=0.135), whereas outflow tract obstructions were found in 88.5% of RAI cases and 80.0% of LAI cases (P=0.628). Conotruncal anomalies were detected in 90.9% of RAI cases and 83.3% of LAI cases (P=0.621).

Systemic venous anomalies were more accurately detected in LAI (96.0%) compared to RAI (77.8%) (P=0.049), and pulmonary venous anomalies were detected in 70.6% of RAI cases versus 33.3% in LAI (P=0.042). Regarding spleen abnormalities, 83.3% of RAI cases were detected, compared to 72.0% of LAI cases (P=0.259). Visceral organ arrangement was detected in 92.1% of RAI cases and 96.0% of LAI cases (P=1.000), showing no significant difference. Finally, the detection of extracardiac malformations showed no significant difference between RAI (70.0%) and LAI (80.0%) (P=1.000).

Perinatal and neonatal outcomes in fetuses with heterotaxy syndrome

Our results demonstrated that RAI fetuses generally had better perinatal and neonatal outcomes, including higher rates of live birth and one-year survival, whereas LAI fetuses had higher rates of fetal death and neonatal mortality. The perinatal and neonatal outcomes for fetuses with RAI and LAI are summarized in Table 4. In terms of pregnancy outcomes, the termination of pregnancy was similar between the two groups, with 26.3% in RAI and 24.0% in LAI (P=0.842). However, fetal death was significantly more common in LAI (28.0%) compared to RAI (5.3%) (P=0.018). Live births were more frequent in RAI (68.4%) than they were in LAI (48.0%), yet this difference was not statistically significant (P=0.108). Regarding delivery characteristics, the gestational age at delivery was comparable between the two groups, with an average of 38.1±1.2 weeks in RAI and 37.8±1.5 weeks in LAI (P=0.401). Birth weight was also similar between the groups, with RAI fetuses weighing 3,095±502 g and LAI fetuses weighing 2,950±530 g (P=0.287). For neonatal outcomes, male gender was more common in RAI (73.1%) compared to LAI (33.3%) (P=0.037). NICU admission rates were high in both groups, with no significant difference (76.9% in RAI vs. 83.3% in LAI, P=1.000). In terms of surgical interventions, cardiac surgery was performed in 84.6% of RAI cases and 75.0% of LAI cases (P=0.673); univentricular repair was more common in RAI (61.5%) compared to LAI (25.0%) (P=0.049). Biventricular repair was similar between the groups, with 23.1% in RAI and 41.7% in LAI (P=0.283). Regarding mortality, neonatal death was significantly higher in LAI (41.7%) compared to RAI (11.5%) (P=0.046). One-year survival was higher in RAI (65.4%) compared to LAI (33.3%), though this difference was not statistically significant (P=0.096) (Table 4).

One-year survival outcomes and prognostic factors in fetuses with heterotaxy syndrome

Kaplan-Meier survival analysis revealed that fetuses with RAI had significantly higher 1-year survival probabilities compared to those with LAI (P=0.018). The survival rate for the RAI group remained consistently superior throughout follow-up, whereas the LAI group exhibited a rapid decline, falling below 50% by approximately 6 months. The shaded regions in the curve indicate 95% CIs, emphasizing a statistically significant difference between the two groups (Figure 4). In multivariable Cox regression analysis, RAI was independently associated with a reduced risk of 1-year mortality compared to LAI (HR =0.42, 95% CI: 0.18–0.98, P=0.044). Cardiac structural anomalies, including single ventricle physiology (HR =3.10, 95% CI: 1.55–6.22, P=0.001), unbalanced AVSD (HR =2.05, P=0.047), and APVR (HR =2.30, P=0.018), were significant predictors of poor prognosis. Outflow tract obstructions (RVOTO and LVOTO) did not significantly affect survival, whereas univentricular repair was associated with increased mortality risk (HR =3.80, 95% CI: 1.80–8.02, P=0.001). Asplenia was linked to a trend toward poorer survival (HR =1.90, P=0.071), though not reaching statistical significance. Fetal sex and biventricular repair were not significantly associated with survival outcome (Table 5).

Figure 4 Kaplan-Meier survival curves comparing one-year postnatal survival between fetuses with RAI and LAI. The red curve represents the RAI group (n=26), while the blue curve represents the LAI group (n=12). Shaded areas denote 95% confidence intervals. Fetuses with RAI demonstrated significantly higher one-year survival compared to those with LAI (log-rank test, P=0.018). The number of patients at risk is indicated below the time axis at specified monthly intervals. Notably, survival in the LAI group declined below 50% by approximately 6 months postnatally, whereas the RAI group maintained over 50% survival throughout the follow-up period. LAI, left atrial isomerism; RAI, right atrial isomerism.

Diagnostic algorithm for RAI and LAI

Accurate prenatal diagnosis of RAI and LAI is critical for early risk stratification and perinatal management in visceral ectopic syndrome. The diagnostic differentiation between RAI and LAI involves a multi-step evaluation of structural and anatomical anomalies. Initial assessment prioritizes the identification of abnormal cardiac positioning, atypical visceral arrangement, or complex congenital heart defects, such as intricate structural cardiac anomalies. Subsequent analysis focuses on systemic venous return patterns, with specific attention to the spatial juxtaposition of the aorta (AO) and IVC, as well as potential interruptions in IVC continuity. Definitive classification requires detailed examination of atrial appendage morphology and splenic status: RAI is confirmed by bilateral right atrial morphology (e.g., triangular-shaped appendages with broad bases) and frequent asplenia, whereas LAI is distinguished by bilateral left atrial morphology (finger-like appendages with narrow origins) and associated polysplenia. Integration of advanced cardiac imaging (e.g., echocardiography, fetal MRI), visceral anatomical mapping, and splenic evaluation is critical to resolving diagnostic uncertainties, particularly in cases with overlapping features. This systematic approach not only clarifies isomerism subtypes but also informs tailored clinical management, including surgical planning and monitoring for associated complications (e.g., immune dysfunction in asplenia). The comprehensive diagnostic algorithm is summarized in Figure 5.

Figure 5 Diagnostic algorithm for prenatal differentiation RAI and LAI. The flowchart outlines a stepwise prenatal diagnostic approach for fetuses with suspected heterotaxy syndrome. Initial evaluation includes assessment of abnormal cardiac positioning, visceral situs anomalies, and complex structural heart defects. Systemic venous return is then examined to identify either juxtaposition of the AO and IVC, suggestive of RAI, or interrupted IVC, suggestive of LAI. Subsequent confirmation relies on detailed evaluation of atrial appendage morphology and splenic anatomy. The presence of bilateral right atrial appendages with or without asplenia supports a diagnosis of RAI, whereas bilateral left atrial appendages with or without polysplenia confirms LAI. This diagnostic strategy improves subtype classification and informs perinatal management. AO, aorta; IVC, inferior vena cava; LAI, left atrial isomerism; RAI, right atrial isomerism.

Discussion

This study provides a comprehensive comparative analysis of fetal RAI and LAI, highlighting key differences in cardiac and extracardiac anomalies, diagnostic accuracy, and survival outcomes. Our findings not only reaffirm several known subtype-specific characteristics but also present new insights into prognostic factors and diagnostic challenges in the prenatal setting.

Cardiac malformations and hemodynamic burden

Our results confirm that RAI is significantly associated with more severe intracardiac defects. Specifically, we found markedly higher incidences of unbalanced AVSD (65.8% vs. 28.0%, P=0.002) and single ventricle physiology (65.8% vs. 24.0%, P=0.001) in RAI compared to LAI. This is in line with previous literature indicating that RAI is more likely to be associated with conotruncal abnormalities and defects incompatible with biventricular repair (19). The higher rate of APVR in RAI (44.7% vs. 12.0%, P=0.007) observed in our cohort further supports this assertion, as APVR has consistently been reported as a key hemodynamic complication that impairs pulmonary venous return and increases early mortality risk (20,21).

In addition to structural malformations, rhythm abnormalities were also evaluated. Fetal sinus rhythm was significantly less common in RAI compared to LAI (57.9% vs. 88.0%, P=0.008). Although only two fetuses in the RAI group exhibited higher-degree atrioventricular block (5.3%), this finding is clinically relevant given the known association of LAI with conduction system abnormalities. Continuous fetal heart rate monitoring and serial echocardiography were utilized for surveillance, and interdisciplinary counseling was provided in cases of detected rhythm disorders to guide perinatal management.

Interestingly, although LVOTO was more common in LAI (32.0% vs. 10.5%, P=0.032), it was not a significant predictor of mortality in our multivariable analysis. This finding corroborates the extensive experience reported by Alemany et al. (22) in their seminal study, which established that isolated outflow tract obstructions typically permit successful surgical correction without significantly compromising survival. Their analysis of 182 heterotaxy patients demonstrated comparable 10-year survival between those with (78%) and without (82%) LVOTO when adequately repaired.

Visceral and splenic arrangement: diagnostic and prognostic implications

A striking contrast in splenic status was evident between subtypes: asplenia was present in 76.3% of RAI cases, whereas polysplenia was identified in 72.0% of LAI. This mirrors embryologic models of lateralization and confirms the high diagnostic value of splenic morphology. Though not statistically significant, asplenia showed a trend toward poorer one-year survival (HR =1.90, P=0.071), aligning with findings from Waldman et al. (23), who reported that immune dysfunction in asplenic patients contributes to late sepsis-related mortality, especially in settings lacking aggressive prophylaxis.

In our cohort, extracardiac gastrointestinal anomalies—such as intestinal malrotation and biliary atresia—were equally distributed between subtypes, with no significant impact on survival. This supports the notion that visceral anomalies, although anatomically important, may not be the primary drivers of fetal or early postnatal prognosis, a conclusion also drawn by Choi et al. (24).

Prenatal diagnosis and diagnostic accuracy

We demonstrated high overall diagnostic accuracy of prenatal ultrasound, with detection rates exceeding 90% for AVSD and situs anomalies. However, the detection of pulmonary venous anomalies remained suboptimal in LAI (33.3%) compared to RAI (70.6%, P=0.042). This discrepancy likely reflects technical limitations in visualizing subtle APVR variants, especially in the setting of preserved systemic venous flow and structurally near-normal hearts, which are more common in LAI (25).

Notably, systemic venous anomalies were more accurately detected in LAI (96.0%) than RAI (77.8%, P=0.049)—possibly due to the more straightforward drainage patterns or better alignment of imaging planes. These findings support the use of STIC and advanced Doppler techniques, as proposed by Yoo et al., to enhance prenatal detection of complex venous connections (26).

Survival outcomes: a paradox revisited

Perhaps the most clinically relevant finding of this study is the paradoxical survival advantage of RAI over LAI, despite the former’s more complex cardiac pathology. One-year survival was significantly higher in RAI (65.4%) than it was in LAI (33.3%, P=0.018). This finding aligns with Lim et al. (27), who also observed superior early survival in RAI and attributed it to earlier recognition and more proactive surgical strategies. Early prenatal detection of characteristic systemic or pulmonary venous anomalies in RAI may allow for better perinatal planning and timely postnatal interventions. However, this early survival advantage must be interpreted with caution. MacDonald et al. (18) reported better long-term outcomes in LAI, which may reflect reduced vulnerability to complications such as sepsis or protein-losing enteropathy. Similarly, Marathe et al. (28) and d’Udekem et al. (29) highlighted that although early postoperative survival in heterotaxy patients undergoing Fontan procedures has improved, the long-term burden remains substantial. Complications such as Fontan failure, chronic low cardiac output, and increased risk of infections—particularly in asplenic RAI patients—may eventually erode early survival benefits. These findings underscore the importance of evaluating survival across multiple temporal phases, rather than focusing solely on infancy.

Our multivariate Cox regression confirmed RAI as an independent protective factor (HR =0.42, P=0.044). Conversely, single ventricle physiology (HR =3.10), unbalanced AVSD (HR =2.05), and APVR (HR =2.30) emerged as strong predictors of poor survival. These associations are consistent with established risk models and underscore the need to focus prognosis not solely on isomerism subtype, but also on the specific constellation of cardiovascular anomalies (29,30).

To further elucidate the mortality burden, we reviewed causes of death in both subtypes. In LAI, higher fetal and neonatal death rates appeared to be primarily related to progressive heart failure from left-sided obstructive lesions and unrecognized conduction abnormalities, including complete heart block. In RAI, although initial survival was better, deaths were often attributed to surgical complications, low cardiac output post-Fontan, or extracardiac factors such as overwhelming sepsis—likely related to asplenia. These findings highlight the importance of integrating both anatomical severity and systemic vulnerability into perinatal counseling, and support the need for tailored timing and modality of intervention based on each fetus’s unique risk profile.

Toward subtype-specific perinatal strategies

Given the considerable anatomical and prognostic divergence between RAI and LAI, our findings support individualized perinatal management plans. The proposed diagnostic algorithm, integrating situs assessment, systemic/pulmonary venous flow, and splenic morphology, offers a practical prenatal tool that can improve diagnostic certainty and guide delivery planning.

Importantly, the higher rate of univentricular repair in RAI (61.5% vs. 25.0%) underscores the urgent need for prenatal counseling regarding long-term palliation, especially given the known complications associated with Fontan circulation. Univentricular pathway patients typically undergo a three-stage surgical approach (Norwood or equivalent palliation, Glenn, and Fontan procedures), which allows for early hemodynamic stabilization even in complex anatomies. This structured and early surgical timeline may partially explain the better 1-year survival observed in RAI despite its more severe cardiac lesions. Although life-prolonging, this approach carries risks such as protein-losing enteropathy, arrhythmia, thromboembolism, and eventual heart failure. Early postoperative survival is generally acceptable; however, long-term prognosis remains guarded, with a significant proportion requiring transplant evaluation in adolescence or adulthood.

Conversely, LAI’s higher rate of biventricular repair (41.7%)—despite less favorable early survival—suggests a selective advantage in those who survive the neonatal period, warranting tailored postnatal follow-up and immune surveillance (31). Biventricular repair is typically pursued in the early infancy period, once ventricular balance and atrioventricular valve morphology are deemed suitable by echocardiographic and intraoperative assessment. When feasible, this offers improved long-term quality of life and cardiac output stability, but requires meticulous anatomical suitability—especially regarding atrioventricular valve morphology and balanced ventricular function. The relatively lower early survival in LAI may reflect the initial complexity of surgical planning and patient selection for biventricular repair. However, among successful cases, the long-term outcomes are generally superior to those undergoing Fontan palliation.

Conclusions

Our study demonstrates that fetal RAI and LAI exhibit profoundly different anatomical, diagnostic, and prognostic profiles. Although RAI is associated with more severe cardiovascular malformations, it paradoxically carries better early survival, which may be attributed to earlier prenatal detection, timely referral, and more aggressive postnatal surgical intervention. This survival advantage underscores the critical role of prenatal diagnosis and coordinated perinatal planning in influencing postnatal outcomes, particularly in high-risk subtypes.

Subtype classification alone is insufficient to predict outcomes; rather, detailed analysis of specific cardiac lesions such as single ventricle, AVSD, and APVR provides stronger prognostic guidance. Our findings reinforce the importance of lesion-specific prenatal assessment over anatomical laterality subtypes when counseling families and planning postnatal care.

STIC imaging, by capturing spatiotemporal datasets across the cardiac cycle, markedly improves the assessment of systemic and pulmonary venous connections, especially in complex or ambiguous cases. Nevertheless, the evaluation of pulmonary venous return remains technically challenging in the fetus due to its small caliber, variable connections, and interference from adjacent structures, even with advanced imaging. Comprehensive prenatal imaging, coupled with structured diagnostic algorithms, can improve subtype differentiation and inform individualized perinatal strategies. However, widespread application of techniques such as STIC and high-resolution Doppler may be limited in lower-resource settings, underscoring the need for simplified and scalable diagnostic approaches in global clinical practice.

Several limitations should be acknowledged. First, the single-center, retrospective design may have introduced referral and selection biases, potentially overrepresenting more complex or severe heterotaxy cases. Second, the follow-up duration was limited to one year, preventing evaluation of long-term outcomes such as Fontan-related complications, neurodevelopmental impairment, and infection susceptibility. Third, the relatively small sample size—especially in subgroups with specific extracardiac anomalies—may limit statistical power and generalizability. To address these limitations, future research should aim for multicenter, prospective designs with standardized imaging protocols, inclusion of genetic and immunologic workups, and extended longitudinal follow-up. Such studies would allow a more comprehensive understanding of heterotaxy spectrum disorders and facilitate validation of prenatal prognostic indicators across diverse populations.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1189/rc

Data Sharing Statement: Available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1189/dss

Funding: This work was supported by Hubei Provincial Natural Science Foundation (No. 2025AFB845) and The Graduate Innovation and Entrepreneurship Fund of Wuhan University of Science and Technology (No. JCX2024044).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-2025-1189/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Written informed consent was obtained from all participants, and the study protocol received approval from the Ethics Committee of the Xiangyang No. 1 People’s Hospital (Approval No. 2021KYLX01).

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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