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    Original Investigation
    February 24, 2020

    Associations of Assisted Reproductive Technology and Twin Pregnancy With Risk of Congenital Heart Defects

    Author Affiliations
    • 1OMNI Research Group, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
    • 2Department of Obstetrics and Gynecology, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada
    • 3School of Epidemiology and Public Health, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada
    • 4Nanhai Hospital, Southern Medical University, Foshan, Guangdong, China
    • 5Better Outcomes Registry & Network (BORN) Ontario, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada
    • 6Children’s Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada
    • 7Division of Cardiology, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada
    • 8Department of Pediatrics, University of Ottawa Faculty of Medicine, Ottawa, Ontario, Canada
    • 9Robinson Research Institute, University of Adelaide, Adelaide, South Australia, Australia
    JAMA Pediatr. Published online February 24, 2020. doi:10.1001/jamapediatrics.2019.6096
    Key Points

    Question  Is assisted reproductive technology associated with increased risk of congenital heart defects independent of its association with twin pregnancies?

    Findings  In this cohort study of 507 390 singleton or twin pregnancies, the prevalence of congenital heart defects was higher in assisted pregnancies (223 [2.2%]) than in nonassisted pregnancies (6057 [1.2%]). Twinning mediated 87.3% of the association between assisted pregnancy and congenital heart defects.

    Meaning  The findings suggest the association between assisted reproductive technology and congenital heart defects may be mediated by twinning.

    Abstract

    Importance  The extent to which assisted reproductive technology is associated with increased risk of congenital heart defects independent of its known association with twinning remains uncertain.

    Objective  To assess the extent to which assisted pregnancy is associated with increased risk of congenital heart defects independent of its known association with twinning.

    Design, Setting, and Participants  This retrospective cohort study linked records of congenital heart defect diagnoses with assisted reproductive technology cycles in 507 390 singleton or twin pregnancies (10 149 assisted pregnancies and 497 241 nonassisted pregnancies), including singleton and twin early pregnancy losses, stillbirths, and live births (follow-up to 1 year of age) in Ontario, Canada, between April 1, 2012, and October 31, 2015. Statistical analysis was performed from January 1, 2017, to September 9, 2019.

    Exposures  Assisted reproductive technology and its 2 subtypes: intracytoplasmic sperm injection and in vitro fertilization without intracytoplasmic sperm injection.

    Main Outcomes and Measures  The main outcome was congenital heart defects (prevalence and relative risk measured as odds ratios [ORs]). Mediation analysis was performed to assess the extent to which the association between assisted reproductive technology and congenital heart defects was mediated by twinning.

    Results  Of 507 390 mother-infant pairs with singleton or twin pregnancies evaluated, the prevalence of congenital heart defects in assisted pregnancies (223 [2.2%]) was higher than that in nonassisted pregnancies (6057 [1.2%]; crude OR, 1.82; 95% CI, 1.59-2.09). The strength of the association between assisted pregnancy and congenital heart defects decreased after adjusting for several risk factors simultaneously (adjusted OR, 1.70; 95% CI, 1.48-1.95). Further mediation analysis indicated that most of the association between assisted pregnancy and congenital heart defects was mediated by twinning (adjusted OR, 1.68; 95% CI, 1.44-1.92), and the natural direct association of assisted pregnancy with congenital heart defects among singleton pregnancies was 1.09 (95% CI, 0.93-1.25). Mediation of twinning accounted for 87.3% of the association.

    Conclusions and Relevance  Our study results suggest that the association between assisted reproductive technology and congenital heart defects may be mediated by twinning.

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