We detected increased odds of having offspring with cleft palate, diaphragmatic hernia, RVOTO, PVS, and multiple or complex defects (overall) with each year increase in paternal age. While the incremental increase per year in the ORs does not appear large, consistent with previous findings, the difference in odds faced by men several years apart in age could be substantial. For example, we found an OR of 1.04 (95% CI: 1.02, 1.06) per year increase in paternal age for diaphragmatic hernia. This means that a 40 year old father would have twice the odds of having a child with diaphragmatic hernia compared with a 20 year old. Our findings are consistent with previous studies which found associations between advanced paternal age and offspring with cleft palate (13
We found an increased OR with each year increase in paternal age for APVR, cataracts, coarctation of the aorta, encephalocele, and esophageal atresia, but only when fathers were younger. At older paternal ages, the ORs did not change with increasing paternal age, but instead reached a plateau. Yang et al. (24
) also observed a correlation between increasing paternal age and offspring with esophageal atresia.
Young maternal age has been established as a risk factor for gastroschisis (30
). Young paternal age appears not to contribute further to this elevated risk, as evidenced by the non-significant OR observed when both parents were young. However, younger paternal age showed an association with gastroschisis when the mother was aged 28 (average maternal age in our study) and 35 (advanced maternal age). Thus, both young paternal and maternal age could be independent risk factors for gastroschisis, with the maternal factor predominating when both parents are young. Our findings are consistent with earlier studies which identified an association between young paternal age and gastroschisis (25
). Previous studies hypothesized that the increased risk for younger mothers could be due to behavioral factors and exposures more common among this age group, such as illicit drug use, smoking, diet, and infections (36
), as well as the combination of younger maternal age and lower BMI (37
). Younger fathers might share some of these risk factors and could influence the behavior of mothers whose age would otherwise place them in a lower risk category. However, our study cannot differentiate whether the increased odds with younger paternal age is due to biological or lifestyle factors, especially since most of these paternal exposures were not ascertained.
Omphalocele, spina bifida, all orofacial clefts, and septal heart defects mainly showed associations with advanced paternal age when maternal age was young. Omphalocele, all orofacial clefts, and septal heart defects were associated with the combination of younger paternal age and advanced maternal age. These findings suggest that a difference in age between the mother and father could be associated with these defects. Different exposures more common at either end of the age spectrum could have similar effects, for example, illicit drugs and prescription medications. However, our study cannot distinguish whether the increased odds are due to environmental or biological factors. Interestingly, previous studies have reported spina bifida or neural tube defects in offspring to be associated with both younger paternal age (21
) and older paternal age (21
). Offspring with orofacial clefts have been associated with advanced paternal age (19
), while offspring with omphalocele have been associated with younger paternal age (24
). Although we observed associations with paternal age for the combined category of septal heart defects, we did not see significant associations for ASDs or VSDs individually. This could be due to inadequate sample size to detect an association in the individual categories or could indicate that our findings are spurious. However, in support of our results, previous studies have described associations between advanced paternal age and offspring with ASDs and VSDs (20
Multiple or complex defects could be due to unrecognized syndromes with monogenic etiologies. Thus, the association with advanced paternal age, which has already been linked to certain single gene conditions, would not be surprising. Consistent with this, Harville et al. (15
) found that older parents were more likely than younger parents to have offspring with cleft palate accompanied by other defects. Zhu et al. (23
) found an association between advanced paternal age and syndromes affecting multiple systems. The associations with advanced paternal age that we observed for the multiple and complex defects (overall) category, as well as for the individual defect categories, could reflect a subset of these defects with a monogenic etiology. NBDPS excludes birth defects with a known single gene etiology; however, defects could be due to novel, unrecognized, or currently unknown genetic anomalies.
Compared with previous work, our study had important strengths. Due to the relatively large sample size, we were able to model both paternal and maternal age as continuous variables, using linear and quadratic terms, and to include potential interactions between maternal and paternal age. In contrast, most previous studies only considered paternal and maternal age categorically and did not include interaction terms between maternal and paternal age. Others have shown that residual confounding could occur in studies on the effect of paternal age when maternal age was controlled for categorically (38
); this was not an issue with our analyses. The increased sample size in our study allowed evaluation of individual birth defects, rather than grouped outcomes, providing greater likelihood of observing risks specific to certain defects. We could control for several demographic, behavioral, and medical factors that might affect the outcomes, a unique feature of this study. All case records in the NBDPS are reviewed by a medical geneticist and specific diagnostic criteria must be met for inclusion. Thus, the defect categories in our study might represent more homogenous groups than those in other studies. The population-based selection of cases and controls might reduce selection bias, and response rates by maternal age were similar. Also, unlike many risk factors, paternal age reporting should not be affected by recall bias.
Our study had some limitations. The number of multiple comparisons evaluated in our modeling approach likely produced some spurious findings. Paternal age information was provided by the mother and could not be independently verified. A larger percentage of younger mothers had missing paternal age information, and some centers did not interview mothers who were under 18 years of age. While the percentage of missing paternal age overall was low, Archer et al. (27
) found that bias could exist even when only a small percentage of paternal ages are missing. We did not have enough information to calculate the prevalence by maternal age for cases with and without paternal age information, as Archer et al. (27
) did. If present, this selection bias could have decreased associations seen with younger paternal age and increased associations with advanced paternal age. With the exception of maternal age, all confounders were dichotomized, because further subdividing confounders into multiple categories would have reduced our sample size and power to detect associations. However, controlling for some confounders categorically might have been better in terms of biological plausibility. For example, we examined paternal race and ethnicity as two categories, nonHispanic whites and all other races and ethnicities. As shown in Supplementary Table 6
, a larger percentage of nonHispanic Black, Hispanic, and Native American/Alaskan Native fathers were 24 and under and a lower percentage were 25–34 and 35 and over, compared with nonHispanic White and Asian/Pacific Islander fathers, which could result in population stratification for defect categories more prevalent in certain races and ethnicities. However, when we performed analyses using either the categories nonHispanic whites, nonHispanic blacks, and all other races and ethnicites or nonHispanic whites, Hispanics, and all other races and ethnicities, we did not see any significant differences compared with when race and ethnicity were dichotomized (data not shown).
Current guidelines on genetic risk assessment and counseling for advanced paternal age are general and provide no clear definition of what age constitutes advanced paternal age (40
). No screening or diagnostic test panels specifically target conditions associated with advanced paternal age. Our findings on gastroschisis, omphalocele, orofacial clefts (overall), spina bifida, and septal heart defects indicate that maternal and paternal age should be considered together in assessing risk.
In summary, our study indicates that paternal age is associated with certain birth defects, and this association could provide clues to the etiology of these conditions. Ultimately this might lead to consideration of paternal as well as maternal age in counseling couples about risk for affected offspring.