Browse the corpus

Congenital heart diseases (CHD) are the most common congenital anomalies and represent a significant global health problem. Their incidence varies from 4 to 10 per 1000 live births []. Prenatal diagnosis of CHD enables healthcare providers to counsel families on prognosis, plan adequate obstetric follow-up, and refer pregnant women to tertiary care facilities for delivery and postnatal management []. Fetal echocardiography is the gold standard for prenatal diagnosis; however, the detection rate of CHD ranges from 30% to 60%, even in developed countries []. Major CHD is defined as a lesion that requires surgery or intervention catheter in the first year of life []. Prenatal detection of major CHD is associated with cardiac death in the absence of general population screening [].

Cardiac embryogenesis occurs during the first 6–7 weeks of human development. Many major CHD develop during this time. Many of these lesions continue to evolve, while others develop during the latter half of gestation. Ventricular inflow or outflow tract and arch obstruction, as well as ventricular or great artery hypoplasia, may develop or progress []. Hypoplastic left heart syndrome (HLHS) is a major CHD with adverse perinatal outcomes whose treatment options include surgical palliation to a functionally univentricular circulation, neonatal heart transplantation after birth, or termination of pregnancy. Fetal aortic valvuloplasty (FAV) is a prenatal treatment option for aortic stenosis to prevent the progression to HLHS []. A recent systematic review and meta-analysis showed that FAV has a high technical success rate in achieving biventricular circulation and a low procedure-related mortality rate when performed by experienced practitioners []. On the other hand, the rates of fetal cardiac intervention (FCI) complications needing treatment such as bradycardia and pericardial effusions are high [].

Despite the growing interest in FCI and its potential to alter the natural progression of certain CHD, the overall impact on long-term survival remains unclear. While some studies have demonstrated improved postnatal hemodynamics and a higher likelihood of achieving biventricular circulation, consistent evidence showing a significant increase in survival rates is still lacking []. Therefore, we aimed to conduct a systematic review and meta-analysis addressing the impact of prenatal cardiac intervention among fetuses with CHD on perinatal outcomes.

Two authors (H.P. and L.K.A.T.) independently searched PubMed/Medline, Embase, AND Cochrane Library from inception to 30 April 2025. Furthermore, the references from all included studies, previous systematic reviews, and meta-analyses were also searched manually for any additional studies. Eventual conflicts were resolved by consensus among the authors. The following terms were used without filters, publication date, or language restrictions: (fetal OR fetus) AND (((heart OR cardiac) AND (surgery OR intervention OR procedure OR “fetal therapies”[mh])) OR “Balloon Valvuloplasty”[mh] OR valvuloplasty OR septoplasty) AND (intrauterine OR “in utero” OR “in uterus”) AND (random* OR case–control OR cohort) NOT (“case report” OR “systematic review” OR review).

Search results were imported into Rayyan software, where duplicate records were removed. Two reviewers (H.P. and L.K.A.T.) independently screened the titles and abstracts according to predefined eligibility criteria. Subsequently, the full texts of potentially relevant studies were assessed for inclusion. Any discrepancies were resolved through discussion with a third reviewer (E.A.J.).

Two authors (H.P. and L.K.A.T.) extracted the following data from selected studies: (1) country; (2) sample size; (3) cardiac malformation; (4) type of prenatal intervention; (5) mean gestational age; (6) perinatal mortality; and (7) overall survival. Perinatal mortality was defined as a composite outcome of stillbirth and neonatal death. Overall survival encompassed the number of subjects who remained alive until discharge or end of follow-up.

Two reviewers (H.P. and L.K.A.T.) evaluated the risk of bias using the Newcastle–Ottawa Quality Assessment Form for Cohort Studies. Each study was rated as having low, moderate, or high risk of bias on the basis of the assessment criteria. Discrepancies between reviewers were resolved through discussion and consensus.

We computed the proportions of perinatal mortality and overall survival events using random effects models and 95% confidence intervals (CI) as a measure of effect size to address potential variations in both clinical and methodological characteristics across studies, heterogeneity was assessed using Cochran’s Q test and the I 2 statistic. The I 2 values were interpreted as follows: less than 25% indicated low heterogeneity, 25–75% moderate, and greater than 75% high heterogeneity. All statistical analyses were performed using RStudio (version 4.2.2; R Foundation for Statistical Computing, Vienna, Austria).

The initial search yielded 981 records. After duplicates were removed and unique studies were screened for eligibility, 16 studies met the criteria for full-text review based on predefined eligibility criteria (Fig. ). Ultimately, 12 studies involving a total of 485 patients were included in the final analysis.

Among the 12 studies, we observed FCI targeting severe CHD, with a focus on critical aortic stenosis (CAS) and its progression to evolving or established hypoplastic left heart syndrome (eHLHS/HLHS). Interventions were predominantly performed between 23 and 29 weeks of gestation. Sample sizes varied widely (4–123 cases), and reported estimated fetal weights ranged from 500 to 1843 g. FAV was the most employed technique, typically ultrasound-guided and sometimes associated with atrial septoplasty or other adjunct procedures. Findings indicate a growing trend toward early intrauterine intervention with the goal of altering the natural progression of complex CHD. These data support the emerging role of fetal heart valvuloplasty as a promising and increasingly standardized therapeutic strategy in fetal cardiology. The characteristics of included studies are summarized in Table .

Figure provides a summary of the individual evaluation of each included study in the systematic review using the Newcastle–Ottawa Quality Assessment Form for Cohort Studies. Out of a total of 12 studies, the cohort studies ranged from low to moderate risk of bias. Specifically, six studies had a moderate risk of bias, and six others were classified as having a low risk of bias.

Among the included studies, the pooled overall survival proportion was 57.4% (95% CI 39.8–73.3; Fig. ). Substantial heterogeneity ( I 2 = 88.0%) was observed, indicating considerable variability between studies. Survival proportions ranged from 20.0% to 90.2%. The largest study reported a survival rate of 90.2% (95% CI 83.6–94.6), while several smaller studies reported much lower proportions with wide confidence intervals. In the combined analysis, perinatal mortality was 31.5% (95% CI 21.0–44.2), with significant heterogeneity ( p < 0.001; I 2 = 79.8%; Fig. ). Individual study estimates varied widely, with mortality proportions ranging from 9.8% to 66.7%.

This systematic review and meta-analysis synthesized data from 12 observational studies evaluating FCI for severe CHD. The most important finding was a pooled overall survival rate of 57.4% (95% CI 39.8–73.3), suggesting moderate survival following prenatal intervention. Additionally, the pooled perinatal mortality rate was 31.5% (95% CI 21.0–44.2), underscoring the significant risks associated with these complex procedures. Substantial heterogeneity was observed across studies, reflecting variability in clinical practice, patient selection, and procedural techniques. These findings emphasize the evolving yet still limited effectiveness of FCI in improving perinatal outcomes.

Our results align with the heterogeneous outcomes reported in the literature on FAV for critical aortic stenosis and eHLHS. Corroenne et al. [] described a biventricular circulation (BVC) rate of 48.3%, with 73.7% of liveborn infants achieving BVC and a 78.6% survival rate among them at a median follow-up of 23.3 months. Vorisek et al. [] reported a 46% BVC rate, increasing to 52% when the procedure was technically successful. Freud et al. [] found that 38 of 88 liveborn infants achieved BVC, with 5- and 10-year survival rates of 96% and 84%, respectively. Other studies report more modest benefits, such as Mendel et al. [], who observed a 33% BVC rate and 20% mortality, and Tulzer et al. [], who found a 55% BVC rate 1 year after successful FAV. These findings suggest that although FAV can improve circulatory anatomy and survival in selected cases, success remains inconsistent across centers.

This variation may reflect key prognostic factors highlighted in the literature. Technical success is strongly associated with improved survival and biventricular repair [, ]. Favorable fetal echocardiographic markers—such as larger left ventricular (LV) size, higher LV pressure, increased ascending aortic diameter, and better diastolic function—are consistently linked to postnatal BVC [, ]. Sustained antegrade flow in the aortic arch, appropriate mitral/aortic valve growth, and favorable foramen ovale flow patterns also predict better outcomes [–]. Some studies have proposed multivariable models to stratify candidates most likely to benefit from FCI [], reinforcing the importance of meticulous patient selection and prenatal counseling. In our study, the substantial heterogeneity in survival and mortality estimates likely reflects differences in inclusion criteria (e.g., eHLHS vs. established HLHS or isolated aortic stenosis), procedural techniques, and institutional expertise. Centers with higher procedural volumes and standardized protocols tend to report better outcomes, and adjunct techniques such as atrial septoplasty may further influence results. Additionally, inconsistent definitions of survival and varying follow-up durations may have contributed to the observed variability.

Despite this variability, our findings support FCI as a promising but highly selective option for fetuses with life-threatening cardiac malformations. In appropriately selected cases—particularly those with eHLHS and biventricular potential—FCI may modify disease progression and reduce the need for univentricular palliation. Nonetheless, these procedures carry substantial risks, including fetal demise, preterm birth, and complications such as premature rupture of ovular membranes and bradycardia. The technical complexity and need for multidisciplinary expertise limit their availability to specialized centers. Therefore, FCI should be viewed not as a definitive solution but as one component of a continuum of care integrating prenatal and postnatal management strategies.

The moderate survival rate reported likely reflects both the severity of underlying defects and the limitations of prenatal intervention. Most fetuses in the included studies had CAS or eHLHS—conditions with poor prognosis even in the absence of intervention. Additionally, timing (often late second trimester), fetal size, and technical barriers may reduce procedural success or limit postnatal surgical options. A learning curve effect may also explain the variability, as earlier studies may reflect lower success rates due to limited institutional experience. These findings underscore the need for standardized protocols, careful candidate selection, and high-volume expertise to translate anatomical improvements into consistent survival benefits. This study has several strengths. It is, to our knowledge, the most up-to-date systematic review and meta-analysis focusing specifically on FCI for CHD, synthesizing data from 12 studies and nearly 500 fetuses. The methodology adhered to PRISMA guidelines, included a pre-registered protocol, and involved an exhaustive search without language or publication restrictions. We also applied rigorous statistical methods and used the Newcastle–Ottawa Scale to assess study quality.

Nevertheless, limitations must be acknowledged. All included studies were observational, limiting causal inference and increasing susceptibility to bias. Sample sizes were often small, definitions of key outcomes were inconsistent, and long-term functional and neurodevelopmental follow-up data were largely absent. Heterogeneity in patient selection, procedural technique, and institutional experience further complicates interpretation of pooled estimates. Given the complexity of FCI and the variability in outcomes, future research should prioritize multicenter prospective registries and standardized protocols to improve comparability and generalizability. Defining uniform selection criteria—particularly to identify candidates with the highest likelihood of postnatal biventricular repair—will be essential. Further studies should explore long-term cardiac, neurodevelopmental, and quality-of-life outcomes. Cost-effectiveness analyses and ethical frameworks are also needed, particularly as access to fetal therapy remains limited to a few specialized centers.

FCI represents a promising but technically demanding strategy for managing severe CHD. While current data suggest moderate overall survival and notable perinatal risks, these outcomes may improve with refined patient selection, procedural standardization, and multidisciplinary expertise. Ongoing collaborative research will be essential to clarify the role of FCI and ensure its responsible and evidence-based integration into fetal and neonatal cardiac care.