Maternal autoimmune diseases and offspring congenital heart defects: a national register-based study in Finland

Background Certain maternal immune-mediated or inflammatory conditions have been associated with increased risk of offspring congenital heart defects (CHD), possibly through autoantibody transfer and altered intrauterine inflammatory environments, or through underlying genetic factors, that disrupt cardiac development. Whether similar associations exist for other autoimmune diseases remains unknown. Methods In this nation-wide population-based study, we used data from the Medical Birth Register, the Register of Congenital Malformations, the Register of Primary Health Care Visits, and the Care Register for Health Care in Finland, which together provided information on all livebirths and stillbirths recorded between January 1, 1987 and December 31, 2023, plus maternal medical history and offspring health outcomes. Among women with a first recorded singleton livebirths, we assembled a cohort of mothers diagnosed with any of 19 autoimmune disorders prior to delivery, and a control cohort with up to five mothers matched on birth year, infant sex, maternal age, residence, and socioeconomic status among those free of autoimmune disorders. We identified any structural CHD in the offspring from the Register of Congenital Malformations, with diagnoses recorded antenatally up to one year after birth. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for CHD in offspring of mothers with and without autoimmune diseases. Findings Among 840,103 first singleton live births, 29,802 mothers had autoimmune diseases and were matched to 141,558 controls. CHD were diagnosed in 723 (2.4%) infants born to mothers with autoimmune diseases and in 2,156 (1.5%) matched controls (OR 1.60 [95% CI 1.47-1.74]). The increased odds were observed in a limited number of conditions - most notably type 1 diabetes (3.35 [2.90-3.88]), pernicious anaemia (2.65 [1.08-5.50]), Sjögren’s syndrome (2.27 [1.36-3.80]), and systemic lupus erythematosus (1.78 [1.07-2.97]) - whereas the remaining autoimmune diseases showed no clear signal of association (Figure). The association also differed across heart defect subtypes, with truncus arteriosus (8.15 [2.37-28.04]), congenital heart block (5.00 [2.25-11.13]), and single ventricle defects (4.29 [1.44-12.75]) showing notably elevated risks. Interpretation The increased risk of offspring CHD associated with maternal autoimmune disease appeared more pronounced for a subset of conditions, consistent with the possibility of disease-specific associations. Estimates for several individual diseases with small number of events should be interpreted with caution. The strongest associations were observed for rare and severe cardiac phenotypes thought to arise from early developmental disturbances, suggesting that the specificity of maternal immune dysregulation or autoantibodies may preferentially affect critical stages of cardiac morphogenesis and conduction system development.