Fetal congenital heart disease and placental pathology: a clinical spectrum from asymptomatic presentation to intrauterine death

Background Congenital heart disease is the most common fetal anomaly, with an incidence of 5-8 per 1000 live births. In recent years, it has become increasingly clear that the placenta is frequently abnormal in pregnancies with fetal CHD, with alterations affecting both macroscopic morphology and microscopic histological structure. However, all available literature presents a fundamental methodological limitation, the systematic exclusion of fetal deaths and pregnancy losses from the study cases, creating a clinically relevant gap, as fetuses that die represent the most severe segment of the fetal CHD spectrum. Aim of the Study This study aims to characterise the clinical and pathological spectrum of fetal CHD, from asymptomatic presentation at the time of termination of pregnancy to symptomatic intrauterine fetal demise, through systematic fetal autopsy examination of a large single-centre retrospective cohort from the intrauterine death Registry of the Veneto Region. We hypothesise that placental lesion patterns are not uniform across CHD subtypes but reflect the specific circulatory impact of each malformation on fetoplacental blood flow. Methods The analysis of total cases has been performed by collecting clinical data of mothers, ecographic data, genetic evaluation and placental histology using the Veneto Region SIUD Registry (2014–2026). Symptomatic CHD have been defined by cardiac domain criteria, including fetal hydrops, valvular dysfunction, pericardial effusion, and cardiomegaly. Placental examination followed the Amsterdam consensus criteria. Then, with a subset of the population, a retrospective case-control study was conducted using fetal CHD cases classified into five haemodynamic groups: left outflow obstruction (group 1), right outflow obstruction (group 2), mixing/parallel circulation (group 3), congestive heart failure (group 4) and with limited haemodynamic impact (group 5). The overall comparison of histological findings across the five hemodynamic classes was performed using Fisher’s exact test with Monte Carlo-simulated p-values (B = 20,000 replicates), given the expected sparsity of the contingency tables. The Kruskal–Wallis’s rank-sum test was used for continuous variables across classes. For pairwise comparisons of each hemodynamic class against controls, Fisher’s exact test (two-sided) was used for categorical variables and the Wilcoxon–Mann-Whitney test for continuous variables. Results. A total of 169 cases were analysed. The majority involved TOP (71.0%), followed by spontaneous abortion (11.8%), intrauterine death (11.8%) and early neonatal death (considering death by 7 days of life, 3.0%). The most common alterations were ventricular septal defects (20.1%). In second position was hypoplastic left heart syndrome (11.2%), followed by complete AVSD (10.1%). In the subsets stratified by hemodynamic classes, placental flow abnormalities appeared to correlate with specific histological patterns. We observed placental stress phenotype associated with inflammation in group 1, hypoxic-ischemic damage and villous congestion in group 2, placental maldevelopment and chronic hypoxia in group 3, vascular damage and congestion in group 4 and sustained villitis and obliteration of stromal villous vessels (p=0.05) in group 5. Conclusion This study provides the first systematic characterisation of placental pathology across the clinical spectrum of fetal CHD in cases of intrauterine death and TOP. It suggests the existence of specific patterns of placental abnormalities associated with different subtypes, likely resulting from the combined effects of altered fetal haemodynamic and overlapping gene expression pathways that regulate both cardiac and placental development. Notably, while placental abnormalities appeared to vary according to haemodynamic subtype, signs of fetal cardiac decompensation were relatively uniform across groups.