Abstract and Introduction
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.
Prospero Registration Number: CRD42019135061.
Congenital heart defects (CHD) are the most frequent congenital malformation, with a total prevalence of about 9 per 1000 births (Khoshnood et al., 2012). They are a leading cause of infant morbidity and mortality in industrialized countries and account for about 50% of mortality due to malformation (Lee et al., 2001; Dolk et al., 2011). CHDs are a heterogeneous group of anomalies in terms of their embryology, anatomy, etiology, physiopathology and clinical spectrum. CHD may be isolated or associated with chromosomal or other anomalies, including genetic syndromes.
CHD result from complex interactions between inherited and non-inherited causes. For example, known genetic factors include the transcription factor NOTCH1 involved in the Noonan syndrome and GATA4 involved in several isolated and syndromic CHD (Wolf and Basson, 2010) as well as Down syndrome, Turner syndrome and the 22q11 deletion. Previous studies have identified non-inherited risk factors for CHD, including maternal factors such as age (Miller et al., 2011), ethnicity (Nembhard et al., 2010), diabetes mellitus (Cedergren et al., 2002), periconceptional smoking (Karatza et al., 2011), rubella (Jenkins et al., 2007), maternal exposures to occupational and environmental risk factors (Snijder et al., 2012) and assisted reproductive technologies (Tararbit et al., 2011; Giorgione et al., 2018). In addition, there is some, although limited, evidence suggesting the implication of advanced paternal age (Olshan et al., 1994; Yang et al., 2007; Materna-Kiryluk et al., 2009) as well as paternal smoking, and paternal occupational and environmental exposures (Cresci et al., 2011; Snijder et al., 2012).
Paternal age has substantially increased in the past decades (Khandwala et al., 2017). In 2015 in France, 40% of newborns had a father aged 35 or over (Bellamy, 2016). In the USA, over the past 20 years, there has been a 20% increase in children born to fathers over 35 years (Martin et al., 2013). Recently, several studies pointed to the potential involvement of advanced paternal age in a wide range of adverse health conditions in offspring. These include genetic diseases such as Apert syndrome, which is mainly caused by a spontaneous mutation of paternal origin of the gene FGFR2 (fibroblast growth factor receptor) (Yoon et al., 2009). Other examples include achondroplasia, which is caused by a mutation of the gene FGFR3 (Shinde et al., 2013), and chromosomal anomalies such as trisomy 21 (Yang et al., 2007). Advanced paternal age was shown to be also associated with other congenital anomalies, including orofacial clefts (Green et al., 2010; Oldereid et al., 2018).
Previous studies of the association between advanced paternal age and CHD have produced inconsistent results. This is probably at least in part due to differences in study population and case mix, insufficient sample size and variability in methods for analyzing the data (Zhan et al., 1991; Pradat, 1992; Olshan et al., 1994; Yang et al., 2007; Materna-Kiryluk et al., 2009; Su et al., 2015).
Two previous evidence syntheses have been published (Oldereid et al., 2018; Peng et al., 2019). However, there were important caveats and limitations in these reviews. Some of the issues included: (i) inconsistencies in criteria applied for inclusion of studies (for Peng et al.: Pradat, 1992; Olshan et al., 1994; Materna-Kiryluk et al., 2009; Su et al., 2015; for Oldereid et al.: Zhan et al., 1991; Pradat, 1992; Bassili et al., 2000; Cedergren et al., 2002; Baltaxe and Zarante, 2006; Wang et al., 2015; Yuan et al., 2015; Abqari et al., 2016), (ii) seeming inaccuracies and inconsistencies in data extraction (Cedergren et al., 2002; Kazaura et al., 2004), (iii) pooling results from studies that used different cut-off points for paternal age and different reference (Archer et al., 2007; Green et al., 2010) and (iv) pooling of heterogeneous outcomes (all CHD and different groups of specific CHD) (Ewing et al., 1997; Zhu et al., 2005,; Archer et al., 2007; Green et al., 2010).
Given these limitations, we report the results of a systematic review and meta-analysis of all studies assessing the association (or lack thereof) between advanced paternal age and risk of CHD.
Hum Reprod. 2020;35(9):2113 © 2020 Oxford University Press