Abstract
Persistent left superior vena cava (PLSVC) is the most common systemic venous anomaly detected prenatally, yet the risk of chromosomal abnormalities in truly isolated cases remains uncertain. This systematic review and meta-analysis aimed to determine the rate of chromosomal anomalies in fetuses with isolated PLSVC by including only fetuses who underwent chromosomal analysis. A systematic search of PubMed/MEDLINE, EMBASE, and the Cochrane Library was performed from January 2000 through March 2026. Studies reporting chromosomal data for fetuses with sonographically confirmed isolated PLSVC were eligible. Isolated PLSVC was defined as PLSVC in the absence of intracardiac or extracardiac structural anomalies, irrespective of the presence of the right superior vena cava. Only isolated fetuses with prenatal or postnatal chromosomal analysis were included; untested fetuses were not assumed to be chromosomally normal. The pooled proportion was calculated as the total number of events divided by the total number of genetically assessed isolated fetuses, with 95% confidence intervals (CIs) calculated using the Wilson score method. Twelve studies were included, comprising 892 isolated PLSVC fetuses, of whom 302 underwent genetic testing. Eight chromosomal anomalies were identified, yielding a pooled chromosomal anomaly rate of 2.6% (95% CI: 1.3-5.1%). In the leave-one-out sensitivity analysis, the pooled rate ranged from 1.3% to 4.8%. The risk of chromosomal abnormalities in isolated PLSVC is low but not negligible. Because genetic testing was performed more often in higher-risk pregnancies, this estimate probably overestimates the background risk. The available evidence does not support a universal recommendation for invasive prenatal diagnosis based solely on an isolated PLSVC; decision-making should be individualized based on maternal age, serum screening or cell-free DNA results, nuchal translucency, detailed fetal anatomical assessment, and patient preference.
Introduction
Persistent left superior vena cava (PLSVC) is the most common thoracic systemic venous anomaly and usually results from the persistence of the left anterior cardinal vein. In most fetal cases, bilateral superior vena cava are present and the left superior vena cava drains into the right atrium through a dilated coronary sinus(1). PLSVC is estimated to occur in approximately 0.2-0.5% of low-risk fetal populations and in up to 9% of fetuses with congenital heart disease(2), underscoring its frequent association with structural cardiac anomalies and the clinical importance of distinguishing isolated from non-isolated cases.
Prenatal detection of PLSVC has increased with the routine use of the three-vessel and tracheal view. The finding appears as an additional vessel located to the left of the pulmonary artery. Once PLSVC is identified, the most important clinical step is to distinguish truly isolated PLSVC from PLSVC associated with intracardiac anomalies, extracardiac anomalies, heterotaxy, or aortic arch abnormalities(3).
The need for invasive prenatal genetic testing in cases of isolated PLSVC remains controversial. The influential 2016 meta-analysis by Gustapane et al.(4) reported an approximately 7% rate of chromosomal anomalies in isolated PLSVC, but this estimate was largely based on small high-risk referral cohorts. Since then, larger cohorts from low-risk or mixed screening settings have become available. In addition, some studies reported all isolated cases, although chromosomal analysis was performed only on a subgroup; treating untested cases as chromosomally normal would underestimate the risk.
Therefore, the aim of this systematic review and meta-analysis was to estimate the chromosomal anomaly rate in isolated PLSVC, including only fetuses who underwent chromosomal analysis and to provide a cautious clinical interpretation to inform prenatal counseling.
Materials and Methods
Ethical Considerations
This study is a systematic review and meta-analysis of published aggregate data; no primary patient data were collected. Ethics committee approval was not required. The study was conducted in accordance with the ethical standards described in the Declaration of Helsinki (revised 2024). Individual patient informed consent was not applicable.
Protocol and Registration
This systematic review and meta-analysis was conducted according to PRISMA 2020(5) and MOOSE(6) recommendations. The protocol was registered in PROSPERO (CRD420261416967). The protocol was prospectively registered under the broader title “Genetic and Perinatal Outcomes of Isolated Persistent Left Superior Vena Cava.” The current analysis focuses on chromosomal anomaly rates in the genetically assessed isolated subgroup; analyses of perinatal outcomes and copy-number variants are planned as separate reports. The requirement for bilateral superior vena cavae was removed from the definition of isolated PLSVC, deviating from the registered protocol.
Eligibility Criteria
Studies were eligible if they reported fetuses with sonographically confirmed PLSVC and provided extractable chromosomal data for isolated cases. In this study, isolated PLSVC was defined in a clinical/structural sense rather than an anatomical one, as a PLSVC without associated intracardiac or extracardiac structural anomalies, regardless of the presence or absence of the right superior vena cava. Case reports, narrative reviews, conference abstracts, and duplicate cohorts were excluded.
Exclusion Criteria
Studies were excluded if they lacked prenatal PLSVC data; were postnatal-only or adult-only; were case reports, reviews, editorials, letters, or conference abstracts; were technical imaging studies without eligible outcome data; or did not provide extractable data for isolated PLSVC. Studies were also excluded when the isolated PLSVC subgroup could not be separated from non-isolated cases or when chromosomal outcomes were not reported for isolated cases. In the case of overlapping cohorts, the most recent, largest, or most complete report was retained.
Search Strategy
A systematic search was performed from January 2000 to March 2026 in PubMed/MEDLINE, EMBASE, and the Cochrane Library using the following search strategy: (“persistent left superior vena cava” OR “PLSVC” OR “bilateral superior vena cava”) AND (“chromosome*” OR “karyotype*” OR “aneuploid” OR “prenatal”). Reference lists of relevant reviews and included articles were hand-searched.
Data Extraction
Two reviewers independently extracted study characteristics, study setting, total PLSVC cases, isolated PLSVC cases, genetically tested isolated PLSVC cases, chromosomal anomalies, and genetic investigation methods. The primary analysis included only fetuses with isolated PLSVC who underwent genetic testing. Genetic testing, performed either prenatally or postnatally, was accepted. Clinically isolated fetuses without genetic testing were not considered chromosomally normal.
Chromosomal events occurring only in non-isolated groups were not attributed to the isolated cohort. Copy-number variants detected by chromosomal microarray were counted as chromosomal abnormalities only if classified as pathogenic or likely pathogenic by the original study authors. This definition was applied consistently across all included studies, and variants of uncertain significance were not counted as events.
Statistical Analysis
The primary outcome was the proportion of genetically assessed fetuses with isolated PLSVC who had a chromosomal anomaly. Because events were rare and most studies contributed small denominators, the pooled proportion was calculated as the total number of events divided by the total number of genetically assessed isolated fetuses. The 95% confidence intervals (CIs) for the pooled and individual study proportions were calculated using the Wilson score method. Between-study heterogeneity was assessed using Cochran’s Q and I2 statistics calculated on Freeman-Tukey double arcsine transformed proportions(7). The crude pooled proportion does not incorporate between-study heterogeneity, which is acknowledged as a limitation. An exploratory funnel plot is provided in Supplementary Figure S1; formal tests of funnel-plot asymmetry were not performed because the number of studies and events was insufficient for a meaningful evaluation. Analyses were performed in Python.
A leave-one-out sensitivity analysis was performed to evaluate the influence of individual studies on the primary pooled estimate. Each study was sequentially excluded, and the pooled proportion was recalculated for the remaining k-1 studies.
Risk of Bias and Quality Assessment
The methodological quality and risk of bias of the included observational studies were assessed independently by two reviewers using an 8-domain framework adapted from the Joanna Briggs Institute critical appraisal tools for prevalence studies and case series. The domains were: sampling frame; inclusion criteria; validity of PLSVC diagnosis; definition of isolation; completeness of follow-up; ascertainment of chromosomal outcome; statistical analysis; and participation rate. Overall risk of bias was categorized as low (6-8 “yes” responses), moderate (4-5), or high (≤3). Disagreements were resolved through discussion and consensus. Studies were not excluded solely on the basis of quality assessment. As the official Joanna Briggs Institute tools do not specify this scoring format, the authors adapted it (Supplementary Table S1).
Results
Study Selection
The initial search yielded 1,103 records. After the removal of 394 duplicates, 709 records were screened by title and abstract, and 666 were excluded. Fourty three full-text reports were assessed for eligibility; 31 were excluded. Twelve studies were included in the quantitative synthesis, comprising 2,314 PLSVC cases, of which 892 were classified as isolated. Genetic testing was performed on 302 isolated fetuses, and 8 chromosomal abnormalities were identified. Chaoui et al.(8) and Head et al.(9) were excluded because they did not provide extractable chromosomal outcome data for an isolated PLSVC subgroup. Durand et al.(10) reported aortic coarctation outcomes without extractable isolated PLSVC chromosomal data. Esin et al.(11) was excluded because karyotyping was recommended but not performed in isolated cases; chromosomal status in these fetuses was considered normal on the basis of neonatal examination findings rather than genetic testing. Du et al.(12) was excluded because, in fetuses without prenatal karyotyping, the karyotype was assumed to be normal if the newborn appeared clinically normal; consequently, the 44 isolated PLSVC fetuses (two with an abnormal karyotype) could not be separated into genetically tested and clinically presumed normal cases, and the number of genetically tested isolated fetuses could not be determined. Berg et al.(3) was excluded because karyotype results were reported only for syndromic cases; genetic testing of the seven isolated PLSVC fetuses was not reported, and the number of genetically tested isolated fetuses could not be determined. The PRISMA flow diagram is presented in Figure 1.
Study Characteristics
The 12 included studies were published between 2002 and 2026 and comprised a total of 2,314 fetuses with PLSVC, of whom 892 were classified as having isolated PLSVC. Four studies were conducted in China, three in Türkiye, two in France, and one each in Belgium, Korea, and Canada. Of the 12 studies, 11 were retrospective and one [Durand et al.(13)] was prospective. Genetic testing was performed in 302 of the 892 isolated fetuses (33.9%), and the proportion of isolated fetuses tested ranged from 1.8% to 100% across studies. Conventional karyotyping was the only genetic method in seven studies, whereas chromosomal microarray or copy-number variation sequencing was used either alone or together with karyotyping in five studies. The characteristics of the included studies are presented in Table 1.
Risk of Bias and Quality Assessment
Of the 12 included studies, 6 were rated as low risk of bias [Barrea et al.(14), Esmer et al.(15), Özsürmeli et al.(16), Durand et al.(13), Cao et al.(17), Kahramanoğlu et al.(18)], 5 as moderate risk [Machevin-Surugue et al.(19), Choi et al.(20), Minsart et al.(21), Li and Wu(22), Wei et al.(23)], and 1 as high risk [Yang et al.(24)]. The principal sources of methodological concern were incomplete genetic testing of isolated fetuses and variable definitions of isolation. No study was excluded on the basis of quality rating alone (Supplementary Table S1).
Meta-analysis Results
Overall, eight chromosomal abnormalities were identified among 302 genetically tested, isolated PLSVC fetuses, corresponding to a crude chromosomal abnormality rate of 2.6% (95% CI: 1.3-5.1%). Between-study heterogeneity was moderate (Cochran’s Q=17.5, df=11, p=0.094; I2=37%). Eight of the 12 studies contributed no events to the analysis. Among the eight chromosomal abnormalities reported in fetuses with isolated PLSVC, two were trisomy 21 and one was a pathogenic 1q21.1q21.2 microduplication. The remaining five abnormalities were reported by Wei et al.(23); however, the specific chromosomal diagnoses of these five isolated cases were not individually provided. Therefore, the exact chromosomal spectrum of these five cases could not be determined from the available data. The forest plot is shown in Figure 2.
Sensitivity Analysis
In the leave-one-out analysis, the pooled rate ranged from 1.3% (95% CI: 0.4-3.6%) when Wei et al.(23) was excluded to 4.8% (95% CI: 2.4-9.1%) when Li and Wu(22) was excluded. Exclusion of any other single study yielded pooled rates between 2.4% and 2.8%. Wei et al.(23) contributed five of the eight events, whereas Li and Wu(22) reported no chromosomal abnormalities in the isolated PLSVC group.
Publication Bias and Small-study Assessment
An exploratory funnel plot is shown in Supplementary Figure S1.
Discussion
This systematic review and meta-analysis estimates the rate of chromosomal anomalies in genetically assessed fetuses with isolated PLSVC to be 2.6% (95% CI: 1.3-5.1%). This rate is lower than the 7.0% estimate reported in the 2016 meta-analysis(4), and the upper limit of its CI remains below that figure. This difference likely reflects the inclusion of more recent and larger cohorts, including low-risk and mixed screening populations. Consistent with this low estimate, a cohort in which all isolated PLSVC fetuses were karyotyped reported no chromosomal anomalies (0/14)(25); although this study was not included in the pooled analysis because it was available only as a conference abstract, its findings support the low risk observed in the present analysis.
Of the 892 clinically isolated fetuses in the included studies, only 302 (33.9%) underwent chromosomal analysis.
The clinical implications are balanced. Isolated PLSVC should not be treated in the same way as non-isolated PLSVC, which is associated with a higher risk of genetic and structural abnormalities. However, the risk in isolated cases is not zero. The most defensible counseling approach involves individualized decision-making that takes into account maternal age, first-trimester screening, cell-free DNA, nuchal translucency measurement, detailed anatomic survey, cardiac assessment, and parental preference. In practice, a normal first-trimester combined screening result or a low-risk cell-free DNA result substantially reduces the residual risk of common aneuploidies and may reasonably support a non-invasive approach, although it does not exclude submicroscopic copy-number variants. By contrast, an abnormal screening result, an increased nuchal translucency, or any subtle additional finding on detailed fetal echocardiography should prompt reconsideration of invasive testing. When invasive testing is pursued, chromosomal microarray rather than conventional karyotyping is the preferred platform because most included studies relied on karyotyping, and submicroscopic abnormalities may otherwise be missed. No single threshold applies uniformly: the counseling discussion should explicitly convey the low but non-negligible background risk identified here, contextualize it alongside the patient’s other screening results, and incorporate parental risk tolerance before a shared decision is reached.
The available data suggest that the genetic spectrum associated with isolated PLSVC may include both common aneuploidies and submicroscopic copy-number variants. In the present analysis, trisomy 21 was reported in two cases, while Cao et al.(17) identified a pathogenic 1q21.1q21.2 microduplication. Although Wei et al.(23) did not provide the individual chromosomal diagnoses of the five abnormal cases in their isolated PLSVC subgroup, the authors noted that chromosomal abnormalities associated with isolated PLSVC may predominantly involve microdeletions or microduplications. This observation highlights the potential relevance of submicroscopic copy-number variants and underscores the importance of detailed case-level genetic reporting in future studies evaluating isolated PLSVC.
Beyond the comparison with Gustapane et al.(4), the individual cohorts included here show variability that merits discussion. Eight of the 12 studies contributed no events, whereas a single cohort [Wei et al.(23)] contributed five of the eight anomalies observed. In the leave-one-out analysis, the pooled rate ranged from 1.3% after exclusion of Wei et al.(23) to 4.8% after exclusion of Li and Wu(22). Li and Wu(22) reported no chromosomal abnormalities in the isolated PLSVC group. The pooled estimate should therefore be interpreted as a range of plausible risks, rather than a precise value. This pattern may reflect differences in referral or workup practices, rather than a true difference in underlying risk. Differences in genetic testing strategy (karyotype alone versus karyotype plus microarray), population source (referral versus routine screening), and regional screening infrastructure likely contribute to the variability across studies and should be considered when extrapolating the pooled estimate to a specific clinical setting.
The strengths of this analysis include a registered protocol, PRISMA-based reporting, a predefined definition of isolation, and inclusion of only genetically tested fetuses. Limitations include the retrospective design of most included studies, variable genetic testing strategies, possible selection bias regarding who underwent invasive testing, a small absolute number of events, and the use of aggregate rather than individual-patient data. The crude pooled proportion does not account for between-study heterogeneity. In some studies, it could not be determined whether isolated fetuses reported as chromosomally normal had actually been tested, or had been assumed to be normal on the basis of a clinically normal newborn. Three cohorts were excluded because normality in isolated fetuses was partly based on clinical assessment or genetic testing of isolated fetuses was not reported, so that the number of genetically tested isolated fetuses could not be determined [Esin et al.(11), Du et al.(12), and Berg et al.(3)]. Notably, Du et al.(12) reported two chromosomal anomalies among isolated fetuses; its exclusion may have slightly lowered the pooled estimate. Furthermore, most included studies predate the routine use of chromosomal microarray or copy-number variant sequencing; therefore, the pooled estimate is largely based on conventional karyotyping and may underestimate the true rate of submicroscopic chromosomal abnormalities.
A critical limitation warrants a dedicated discussion. The analysis was based primarily on genetically tested isolated PLSVC fetuses, rather than on all such fetuses identified sonographically. Because invasive testing was typically driven by concurrent risk factors (advanced maternal age, abnormal serum screening, abnormal nuchal translucency, or parental request), the genetically assessed subgroup was systematically enriched for higher-risk pregnancies. This indication bias (workup bias) means that the pooled estimate of 2.6% likely overestimates the true background rate of chromosomal anomalies in unselected, low-risk, isolated PLSVC pregnancies. Prospective cohort studies that offer standardized genetic evaluation to all isolated PLSVC cases, regardless of concurrent risk factors, are required to establish the true population-level rate.
Conclusion
In genetically tested fetuses with sonographically isolated PLSVC, the pooled chromosomal anomaly rate is approximately 2.6% (95% CI: 1.3-5.1%). Because genetic testing was more often performed in higher-risk pregnancies, this rate likely overestimates the background risk in unselected pregnancies. The available evidence does not support a universal recommendation for invasive prenatal diagnosis based solely on isolated PLSVC. A comprehensive risk assessment incorporating maternal age, serum screening or cell-free DNA, nuchal translucency, detailed anatomic evaluation, and patient preference should guide counseling; individualized decision-making remains the most appropriate management strategy. If invasive testing is selected, chromosomal microarray analysis may be considered in accordance with current prenatal genetic practice.
