Maternal Age-Related Gender Bias in Trisomy 21 and Trisomy 18

The aim of this study was to investigate the underlying factors contributing to gender-based disparities in the prevalence of trisomy 21 (Downs's syndrome) and trisomy 18 (Edwards's syndrome).

Overall, 551 cases of trisomy 21 (T21) and 154 cases of trisomy 18 (T18) diagnosed through amniotic fluid karyotyping and chromosomal microarray analysis (CMA) between 2005 and 2023 at the Affiliated Women and Children's Hospital of Ningbo University. The study population consisted of fetuses at 19-23 gestational weeks across various maternal age groups. A control group comprising 662,453 newborns from the same institution between 2011 and 2018 was established for sex ratio comparison. Parental origin of diploids in T21 and T18 cases was determined using quantitative fluorescence-polymerase chain reaction (QF-PCR) analysis. Statistical significance of gender bias was evaluated using chi-squared tests, with a threshold of p < 0.05 considered statistically significant.

The study revealed distinct sex ratio patterns across different maternal age groups. The control group exhibited a sex ratio of 1.06 (male:female), while the overall sex ratio for T21 cases was significantly elevated at 1.32. Notably, the highest sex ratio (1.84) was observed in T21 cases among women aged 20-25 years, with a progressive decline in sex ratio corresponding to increasing maternal age. The sex ratio of newborns born to women aged ≥ 35 years approximated that of the control. In contrast, T18 cases demonstrated an overall female predominance, with a sex ratio of 0.67, reaching its lowest value (0.56) in the 25-30 years maternal age group. Regarding the parent origin of diploids, maternal meiosis errors accounted for > 90% of cases in both T21 and T18. However, a higher prevalence of paternal origin was observed in younger women (≤ 35 years). Male fetuses of paternal diploid origin of T21 were 2.5 times more than female fetuses.

In our sample of over 500,000 births, between 2005 and 2023 in Ningbo, China, fetuses with T21 were more likely to be males while fetuses with T18 were more likely to be females. However, this gender bias exhibited a significant age-dependent pattern, being predominantly observed in women under 35 years of age. Specifically, in T21 cases of paternal origin among women ≤ 35 years, the frequency of nondisjunction involving Y-chromosome-bearing sperm was 2.5-fold higher than that involving X-chromosome-bearing sperm.