Association of paternal age with prevalence of selected birth defects

BACKGROUND: Unlike maternal age, the effect of paternal age on birth defect prevalence has not been well examined. We used cases from the Texas birth defect registry, born during 1996-2002, to evaluate the association of paternal age with the prevalence of selected structural birth defects. METHODS: Poisson regression was used to calculate prevalence ratios (PRs) and 95% confidence intervals (CIs) associated with paternal age for each birth defect, adjusting for maternal age, race/ethnicity, and parity. RESULTS: Relative to fathers ages 25-29 years, fathers 20-24 years of age were more likely to have offspring with gastroschisis (PR 1.47, 95% CI: 1.12-1.94), and fathers 40+ years old were less likely to have offspring with trisomy 13 (PR 0.40, 95% CI: 0.16-0.96). No association was seen between paternal age and prevalence of anencephaly and encephalocele. A selection bias was observed for the other birth defects in which cases of younger fathers were more often excluded from study. CONCLUSIONS: In studies of birth defect risk and paternal age, the source of information may affect the validity of findings.     

Paternal age and Down syndrome.

The frequency of Down syndrome (DS) in infants of older fathers has been examined in two sets of data. The effect of maternal age was controlled by single years of age. Lack of tight control has been an important weakness of other studies on this subject. Data obtained in metropolitan Atlanta by an intensive case-ascertainment program showed no overall excess of DS infants born to older fathers. Nor was there evidence of such an effect in recent birth certificate data made available by the National Center for Health Statistics. The Atlanta data suggest an increased number of DS infants born to older fathers who had children by women less than or equal to 34 years. However, there was a small deficiency of DS infants born to older fathers by women greater than or equal to 35 years. The possibility of a paternal-age effect remains open, but the available data suggest that, if it exists, it is quite small.     

Paternal age and trisomy among spontaneous abortions

Summary The relationship of paternal age to specific types of trisomy and to chromosomally normal loss was investigated in data drawn from a case-control study of spontaneous abortions. Differences in paternal age between karyotype groups and controls delivering after 28 weeks gestation were tested using an urn model analysis which adjusted, by regression, for maternal age and, by stratification, for the effects of design variables (payment status, phase of study) and demographic factors (language, ethnicity). The magnitude of paternal age differences was estimated using least squares regression analysis. For chromosomally normal cases there was no association with paternal age. Among the fourteen trisomy categories examined, four (7, 9, 18, 21) showed increased paternal age ( 1 year above expectation), three (13, 20, 22) showed decreased paternal age and the rest, including the most common, trisomy 16, showed negligible differences. Only the association with trisomy 22 was statistically significant (P = 0.012), with a predicted reduction in paternal age of 2.1 years (95% CI -4.9, -0.5 years). This association did not vary with maternal age, payment status, phase of study, language or ethnicity. Because previous observations are extensive, the relation of paternal age to trisomy 21 was examined further. The overall association was not significant ( = 0.8 years; 95% CI -0.8, 2.4 years). Moreover, there was evidence that the magnitude and direction of paternal age associations vary significantly within the sample, although not between subgroups defined on the basis of payment, phase of study, language or ethnicity. With respect to maternal age, the trend is towards a greater paternal age difference for trisomy 21 losses in younger women (P = 0.058). Given the number of tests performed, the finding for trisomy 22 and reduced paternal age could be due to chance. Among trisomy types, the direction of paternal age associations was not consistent for chromosomes grouped according to characteristics that might relate to the probability of nondisjunction, such as size, arm ratio, or nucleolar organizer region content, or to the potential viability of the trisomy. Thus, neither on statistical nor biological grounds do the data provide compelling evidence of paternal age effects on the trisomies found among spontaneous abortions, or on chromosomally normal losses.     

Paternal age and Down syndrome in British Columbia

Among Down syndrome cases born in 1964--1976 reported to the British Columbia Registry for Handicapped Children, the mean parental age was about half a year greater than in the entire population of live births after controlling for maternal age, a difference significant at the .05 level. After adjustment for maternal age, a regression analysis was consistent with an increase of 1.024-fold for each year of paternal age. Among Down syndrome cases in 1952--1963, however, for which ascertainment appears likely to be less complete, there was no evidence for a significant paternal age effect. The reasons for the variation between the two groups investigated here and the heterogeneity in results among studies of other populations are discussed.     

The relation between small size for gestational age and the sex ratio of children with birth defects

BACKGROUND: Infants with birth defects are more likely to be born small for gestational age (SGA) than are other infants. This study describes a relation noted between the percentage SGA and the percentage male among children with various defect types. The data source was case records collected by the Metropolitan Atlanta Congenital Defects Program, a population-based, active surveillance system, during 1968 through 1998. METHODS: The study calculated the correlation between the percentage male and the percentage SGA for isolated cases of 44 different defect types for male-dominant and female-dominant defects separately. RESULTS: The correlation coefficient was -0.47 (P < 0.01) for male-dominant defects and 0.20 (P > 0.05) for female-dominant defects. Male-dominant defects were more likely to show less than 15% SGA and more likely to show the strongest risk differences by sex. CONCLUSIONS: These results are consistent with genetic causation of strongly skewed sex ratios, at least among male-dominant defects. Review of the literature suggests that defects with sex ratios closer to 1 are likely to have lower recurrence risks and therefore are less likely to be inherited than are other defects with skewed sex ratios. Sex ratios closer to 1 and a high percentage SGA may be markers of acquired or environmental birth defects.