Fertility status and risk of pediatric cardiovascular diseases: a population-based nested case-control study

Is parental fertility status and use of IVF associated with the risk of pediatric cardiovascular diseases among offspring aged 0-13 years, and is this association mediated by perinatal factors?

Children conceived through IVF and those born to parents with subfertility (defined as one partner with an infertility diagnosis and not using ART for the study pregnancy) have an increased risk for congenital heart defects, partly explained by multiple gestations.

Evidence indicates that children born following IVF have an increased risk of premature vascular aging. However, the risk of developing cardiovascular diseases during childhood and the extent to which such risks are associated with adverse perinatal outcomes remains uncertain.

This nationwide, population-based, nested case-control study included registry data from 2 228 073 parents-child triads in Taiwan from 1 January 2004 to 31 December 2017. Offspring were categorized into three groups based on their parents' fertility status (fertile [achieved spontaneous conception, no infertility diagnosis], subfertility, and IVF [conception via IVF, including ICSI]). The three groups were followed from birth (between 1 January 2004 and 31 December 2017) until they developed the outcomes of interest, met any exclusion criteria, died, or until the end of the study period (31 December 2017), whichever came first.

In the study cohort, we identified 41 113 children with newly diagnosed pediatric cardiovascular diseases and used incidence density sampling to match each case to four controls (n = 169 850), based on age, sex, mother's residential township at delivery, and the calendar date of the pediatric cardiovascular disease diagnosis. Pediatric cardiovascular diseases included diagnoses of congenital heart defects, hypertensive diseases, cardiomyopathy, and arrhythmia. Conditional logistic regression was performed to examine the association between fertility status and pediatric cardiovascular diseases. Causal mediation analysis was used to test for mediation by multiple gestations, preterm birth, and low birth weight.

During 11.5 million person-years of follow-up (median [interquartile range, IQR], 6 years [2-10]), IVF conception was associated with an increased risk of congenital heart defects compared with subfertility (odds ratio [OR], 1.47; 95% CI, 1.36-1.60; incidence rate difference [IRD], 375.1 per 100 000 person-years [95% CI, 331.8-418.3]) and fertile group (OR, 1.72; 95% CI, 1.60-1.85; IRD, 445.7 per 100 000 person-years [95% CI, 403.0-488.3]). Subfertility was associated with a 1.19-fold higher risk of congenital heart defects (95% CI, 1.16-1.23; IRD, 70.6 per 100 000 person-years [95% CI, 61.9-79.4]) than fertile group. Multiple gestations accounted for 31.16% of the association between IVF and congenital heart defects compared with subfertility and for 54.26% of the association compared with fertile group. No significant associations were found between fertility status and hypertensive diseases, cardiomyopathy, or arrhythmias.

Although the national data with a long follow-up period were used, the duration may still be insufficient to detect potential risks for hypertensive diseases, cardiomyopathy, and arrhythmia. Lack of data on pregnancy terminations could lead to underestimation of congenital heart defects risk.

These findings suggest that a reduction in the occurrence of multiple gestations may help reduce the risk of congenital heart defects related to IVF conception. IVF conception should prompt consideration of fetal echocardiography, particularly in mothers with multiple gestations.

This study was supported by grants from Shin Kong Wu Ho-Su Memorial Hospital (No. 109GB006-1). The funders had no role in the study design, data collection, analysis, interpretation, report writing, or the decision to submit the article for publication. The authors have no competing interests to disclose.

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