Sex differences for major congenital heart defects in Down Syndrome: A population based study

About 40% of infants with DS have a major congenital heart defect (CHD). Among them, atrioventricular septaldefects (AVSD), atrial septal defects (ASD), ventricular septal defect (VSD) and Tetralogy of Fallot (ToF) are themost common. The aim of this study was to estimate the sex difference in the occurrence of CHD in infants withDS comparing it with non-DS infants.Method: Live birth cases of DS diagnosed by the first year of life were extracted from the Registry of CongenitalAnomalies of Tuscany (2003-2015 period). CHDs associated with DS were detected both from the registry andthe hospital discharge data. Sex differences in total CHDs and ASD, VSD, AVSD, severe CHDs, ToF subgroupswere investigated. Relative Risks between males and females (RRMF) with p-values and 95% confidence interval(95% CI) were estimated. RRMF of CHD in infants with DS was compared to RRMF in infants without DS. The ratiobetween relative risks (RRR) was estimated.Results: A total of 230 live birth cases of DS were analyzed, with a prevalence of 5.70 per 10,000 births. SexratioMF was 1.3. One hundred and one DS cases (43.9%) were associated with at least one CHD. Among them,CHDs are more frequent in females (total CHD: RRMF=0.62; 95% CI: 0.46-0.83, ASD: RRMF=0.40; 95% CI:0.21-0.77, severe CHD: RRMF=0.58; 95% CI: 0.35-0.95, AVSD: RRMF=0.57; 95% CI: 0.32-1.00, VSD:RRMF=0.59; 95% CI: 0.35-1.00). Four cases of ToF were observed (all males). Sex difference was more evidentin DS than in non-DS infants (RRR=0.63; 95% CI: 0.52-0.77), in particular for severe CHDs (RRR=0.38; 95%CI: 0.25-0.57).Conclusion: The increased sex difference for CHDs in DS suggests a possible role of sex as effect modifier in theassociation between DS and CHD. The results enforce the evidence on sex differences for CHDs in DS and canstimulate future genetic research activities.