The risk for four specific congenital heart defects associated with assisted reproductive techniques: a population-based evaluation

Are the risks of hypoplastic left heart syndrome, transposition of great arteries, tetralogy of Fallot (TOF) and coarctation of the aorta increased in infants conceived by different assisted reproductive techniques (ARTs)? ARTs, and particularly intracytoplasmic sperm injection (ICSI), are specifically associated with a higher risk of TOF. ARTs are associated with an increase in the overall risk of birth defects. The risk for congenital heart defects (CHDs) associated with ARTs has been evaluated as a whole but there is limited information on the risks for specific CHDs. We conducted a casecontrol study using population-based data from the Paris registry of congenital malformations for the period 19872009 and a cohort study of CHD (EPICARD) on 1583 cases of CHDs and 4104 malformed controls with no known associations with ARTs. ARTs included ovulation induction only, IVF and ICSI. Exposure to ARTs was significantly higher for TOF than controls (6.6 versus 3.5, P 0.002); this was not the case for the other three CHDs. ARTs (all methods combined) were associated with a 2.4-fold higher odds of TOF after adjustment for maternal characteristics, paternal age and year of birth [adjusted odds ratios (OR): 2.4, 95 confidence interval (CI): 1.53.7] with the highest risk associated with ICSI (adjusted OR: 3.0, 95 CI: 1.08.9). No statistically significant associations were found for the other CHDs. Our study cannot disentangle to what extent the observed associations between the risk of TOF and ARTs are due to causal effects of ARTs and/or the underlying infertility problems of couples who conceive following ART. The developmental basis of the specific association between the risk of TOF and ARTs need to be further investigated. This work was supported by grants from the Agence de Biomdecine (Saint-Denis La Plaine, France) (to B.K.). The Paris Registry of Congenital Malformations received financial support from INSERM (Paris, France) and the Institut de Veille Sanitaire (Saint-Maurice, France). The EPICARD study was supported by three grants from the Ministry of Health (PHRC 2004, 2008 and 2011). Additional funding for the EPICARD study was provided by the AREMCAR Association (Association pour la Recherche et lEtude des Maladies Cardiovasculaires). None.