Sex differences late after tetralogy of Fallot repair: a systematic review and meta-analysis

Sex differences in long-term outcomes of patients with repaired tetralogy of Fallot (TOF) are increasingly recognised. However, the sex-specific timing of re-intervention is still unclear.

A systematic review and meta-analysis was performed across six electronic databases from inception to February 2025. Inclusion criteria were studies that reported outcomes of sex differences in right ventricular (RV) volume, function, and right ventricular outflow tract obstruction (RVOTO) in patients after repaired TOF. Studies were identified and data were extracted by two independent reviewers. Data were extracted and pooled using random effects models and Review Manager 5.4 software.

The findings of three studies with 767 patients who underwent cardiac magnetic resonance (CMR) and one study of 148 patients who underwent echocardiography were included. The mean QRS interval reported in three studies was 148.9 ± 27.9 ms in males and 134.7 ± 24.6 ms in females; this was significant in all three studies [1-3]. Males had higher indexed right ventricular end-diastolic volume (RVEDVi) and indexed right ventricular end-systolic volume (RVESVi). In contrast, they had lower mean right ventricular ejection fraction (RVEF). Males had higher mean indexed left ventricular end-diastolic volume (LVEDVi) and mean indexed left ventricular end-systolic volume (LVESVi). Similarly, males had lower mean left ventricular ejection fraction (LVEF). Echocardiography findings showed that LVEF and strain were lower in males. Cardiopulmonary exercise test (CPET) findings reported in one study showed that males had a higher peak oxygen uptake and lower ventilation per unit of carbon dioxide production (VE/VCO₂) slope than females.

In view of significant long-term outcome differences in RV function and volume between males and females, we recommend a sex-specific threshold rather than a unisex threshold when it comes to consideration of the timing of re-intervention. More multi-centred studies are required to understand this better.Central message We have shown that there are long-term outcome differences between males and females. Therefore, we recommend sex-specific thresholds when it comes to consideration of timing for re-intervention. [Table: see text].