Congenital Heart Disease in Children Born after Assisted Reproductive Technology: A Nordic Cohort Study.

Abstract Study question Do children conceived after assisted reproductive technology (ART) have a higher risk of Congenital Heart Disease (CHD) in comparison with children born after spontaneous conception? Summary answer Children born after ART have a higher risk of a major CHD compared with children born after spontaneous conception. What is known already It is well-known that children born after ART have higher risk of birth defects compared to children born after spontaneous conception. Congenital heart disease (CHD) is the most common birth defect, accounting for almost 50% of all major birth defects. Several cohort studies and systematic reviews have also found an increased risk of CHD in children born after ART, a recent review included 41 studies and 25 856 ART children covering CHDs in ART children. Conflicting results have been reported for specific CHDs. Study design, size, duration This Nordic registry-based cohort study from CoNARTaS (Committee of Nordic ART and Safety) included 171 774 live births born after use of ART and 7 772 474 live births born after spontaneous conception during a study period of up to three decades (Denmark 1994-2014, Finland 1990-2014, Norway 1984-2015, and Sweden 1985-2015). National data from ART registries, medical birth registries, malformation registries, patient registries, cause of death registries, and population registries were crosslinked. Participants/materials, setting, methods International Classification of Diseases (ICD) versions 8, 9, 10 were used for CHD codes at birth and up to one year of age. Major CHDs were defined according to European Concerted Action on Congenital Anomalies and Twins (EUROCAT). According to EUROCAT, 26 of the major CHDs were considered as severe. All major CHDs were further classified into six different groups in a hierarchical order. Minor CHDs as well as stillbirths and pregnancy terminations were excluded. Main results and the role of chance Data from Sweden included a total of 3 228 526 singletons and multiples; 62 243 children conceived after use of ART and 3 166 283 children after spontaneous conception. Among ART children, 2.27% (n = 1411) were diagnosed with any major non-chromosomal CHD during their first year of life, corresponding figures for children born after spontaneous conception was 1.43% (n = 45 310) (Odds Ratio [OR] 1.60; 95% Confidence Interval (CI) 1.51 to 1.69, p < 0.0001). Severe CHD occurred in 0.40% (n = 249) in the ART group and 0.31% (n = 9 795) in the spontaneous conception group (OR 1.29; 95% CI 1.14 to 1.47, p < 0.0001). Ventricular septal defect was the most common CHD, 0.97% (n = 603) in the ART vs 0.64% (n = 20 343) in the spontaneous conception group (OR 1.51; 95% CI 1.39 to 1.64, p < 0.0001), followed by atrial septal defect; 0.84% (n = 525) in the ART and 0.42% (n = 13 363) in the spontaneous conception group (OR 2.00; 95% CI 1.83 to 2.19, p < 0.0001). Limitations, reasons for caution This analysis included only non-adjusted Swedish data. Further analysis will include Danish, Finnish, and Norwegian data with adjustments, and subgroup analysis on singletons and multiples. No data are available on prenatal diagnosis, or pregnancies not ending to a live birth. A skewed distribution in these outcomes might introduce a bias. Wider implications of the findings Pregnancies conceived after use of ART may benefit from screening with fetal echocardiography. Although most children with CHD reach adulthood, the mortality rate is still high for this group during the first years of life. Early detection with antenatal diagnosis and pre/postnatal intervention may be beneficial and improve the outcome. Trial registration number Not applicable