Association between advanced paternal age and congenital heart defects: a systematic review and meta-analysis

STUDY QUESTION: Is there an association between advanced paternal age and congenital heart defects (CHD)? SUMMARY ANSWER: Advanced paternal age is associated with a 16% increase in the overall odds of CHD. WHAT IS KNOWN ALREADY: CHD are the most common congenital malformations. Several risk factors for CHD have been identified in the literature, but the association between advanced paternal age and CHD remains unclear. STUDY DESIGN, SIZE, DURATION: We conducted a systematic literature search on MEDLINE and EMBASE (1960-2019) to identify studies assessing the association between advanced paternal age (>= 35 years) and the risk of CHD, unrestrictive of language or sample size. We used a combination of Medical Subject Headings (MeSH) terms and free text words such as 'paternal age', 'paternal factors', 'father's age', 'parental age', 'heart', 'cardiac', 'cardiovascular', 'abnormalities, congenital', 'birth defects', 'congenital malformations' and 'congenital abnormalities'. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included observational studies aiming at assessing the association between paternal age and CHD. The included population could be live births, fetal deaths and terminations of pregnancy for fetal anomaly. To be included, studies had to provide either odds ratios (OR) with their 95% confidence interval (CI) or sufficient information to recalculate ORs with 95% CIs per paternal age category. We excluded studies if they had no comparative group and if they were reviews or case reports. Two independent reviewers selected the studies, extracted the data and assessed risk of bias using a modified Newcastle-Ottawa Scale. We used random-effects meta-analysis to produce summary estimates of crude OR. Associations were also tested in subgroups. MAIN RESULTS AND THE ROLE OF CHANCE: Of 191 studies identified, we included nine studies in the meta-analysis (9 917 011 participants, including 34 447 CHD), including four population-based studies. Five studies were judged at low risk of bias. Only one population-based study specifically investigated isolated CHD. The risk of CHD was higher with advanced paternal age (summary OR 1.16, 95% CI, 1.07-1.25). Effect sizes were stable in population-based studies and in those with low risk of bias. LIMITATIONS AND REASONS FOR CAUTION: The available evidence did not allow to assess (i) the risk of isolated CHD in population-based studies, (ii) the association between paternal age and the risk for specific CHD and (iii) the association between paternal age and CHD after adjustment for other risk factors, such as maternal age. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest that advanced paternal age may be a risk factor for CHD. However, because the association is modest in magnitude, its usefulness as a criterion for targeted screening for CHD seems limited. STUDY FUNDING/COMPETING INTEREST(S): None.