Risk of Congenital Heart Defects in Offspring of Affected Mothers and Fathers

Abstract

Background: Smaller studies have reported a higher offspring risk of congenital heart defects (CHDs) for mothers with CHDs than for fathers with CHDs. In a large population-based study, we investigated whether offspring risk of CHD differed for mothers and fathers with CHDs.

Methods: All people born in Denmark, 1977 to 2011, with at least 1 registered parent, were included in our cohort (n=2 341 061). Parent-child recurrence of CHDs was evaluated using risk ratios (RRs) comparing risks of CHDs in individuals with and without a parent with a CHD, estimated using log-linear binomial regression.

Results: The RRs for any CHD in offspring were 5.39 (95% CI, 4.88-5.96) for mothers and 3.04 (95% CI, 2.59-3.57) for fathers affected with any CHD; the ratio of RRs for mothers versus fathers was 1.82 (P<0.0001). Recurrence RRs for the same cardiac phenotype in parent and offspring were significantly stronger for mothers than for fathers for conotruncal defects (ratio of RRs, 4.98), left ventricular outlet tract obstruction (ratio of RRs, 4.98), and ventricular septal defects (ratio of RRs, 2.51) but not for atrioventricular septal defects (ratio of RRs, 1.06). Birth rates among people with CHDs, relative to the general population, were 18% higher for women than for men, regardless of parental cardiac phenotype.

Conclusions: Recurrence risks of CHDs were significantly greater in the offspring of affected women than in the offspring of affected men. The excess maternal recurrence risks could not be explained by the slightly higher birth rates in women with CHDs.

Keywords: birth rate; cohort studies; epidemiology; genetics; heart defects, congenital; population; risk.

Figure 1.

Concordant cardiac phenotype in parent and offspring. Risk ratios (RRs) for congenital heart defects in offspring for concordant cardiac phenotypes for mother-offspring recurrence (red circles) and father-offspring recurrence (blue squares) among 2 341 061 singleton births in Denmark, 1977 to 2011. RRs with 95% CIs adjusted for year of birth and congenital heart defects in other family members (first-, second-, and third-degree relatives) in log-linear binomial regression analyses. A, Any concordant congenital cardiac defect overall (Any, same phenotype); left ventricular outflow tract obstruction (LVOTO); right ventricular outflow tract obstruction (RVOTO); any septal defect (Septal (any)); atrial septum defect (ASD); ventricular septum defect (VSD); valve defect (Valve); other specified cardiac defect (Other specified); and unspecified cardiac defect (Unspecified). B, Heterotaxy; conotruncal cardiac defect (Conotruncal); and atrioventricular septum defect (AVSD). There are no estimates for heterotaxia and RVOTO for father-offspring recurrence because there were no pairs where both father and child were affected.

Figure 2.

Forest plot with female birth rate ratios and male birth rate ratios among individuals with congenital heart defects relative to the general population* adjusted for age and period. APVR indicates anomalous pulmonary venous return; ASD, atrial septum defect; AVSD, atrioventricular septum defect; LVOTO, left ventricular outflow tract obstruction; PDA, persistent ductus arteriosus; RR, risk ratio; RVOTO, right ventricular outflow tract obstruction; and VSD, ventricular septum defect. *Birth rate ratios for women with congenital heart defects (relative to the birth rate in the general female population) and men with congenital heart defects (relative to the birth rate in the general male population) among 1 635 823 women and 1 692 165 men born in Denmark in or after 1970.

Figure 3.

Congenital heart defects: mother/father ratio of recurrence risks in offspring (y axis) by female/male ratio of birth rate ratios (x axis). Plot of the ratio of the female birth rate ratio and the male birth rate ratio among individuals with congenital heart defects relative to the general population* (x axis) and the ratio between the mother-offspring risk ratio and the father-offspring risk ratio for congenital heart defects† (y axis). ASD indicates atrial septum defect; AVSD, atrioventricular septum defect; LVOTO, left ventricular outflow tract obstruction; PDA, persistent ductus arteriosus; and VSD, ventricular septum defect. *The ratio compared birth rate ratios for women with congenital heart defects (relative to the birth rate in the general female population) and men with congenital heart defects (relative to the birth rate in the general male population) in 1 635 823 women and 1 692 165 men born in Denmark in or after 1970. †The ratio compared the offspring heart defect recurrence risk for women with congenital heart defects (relative to the offspring heart defect risk in unaffected mothers) and the offspring heart defect recurrence risk for men with congenital heart defects (relative to the offspring heart defect risk in unaffected fathers), in 2 341 061 singleton births in Denmark, 1977 to 2011.