Advanced Maternal Age in Polyploidy With Concurrent Aneuploidy

Chromosome abnormalities occur in humans at a rate of approximately 1 in every 150 live births. They are seen in approximately 50% of first-trimester and 20% of second-trimester spontaneous abortions [Jorde et al., 2006]. Of all chromosome abnormalities, aneuploidy is the most common, occurring in 25% of miscarriages [Hassold et al., 1996]. Most aneuploidy is due to nondisjunction arising in oogenesis, which can occur during meiosis I or II. As a woman’s age increases she has an increased risk of meiotic nondisjunction, resulting in aneuploidy and an increased risk of spontaneous abortion. In contrast to aneuploidy, increased maternal age is not a risk factor for polyploidies such as triploidy or tetraploidy [Eiben et al., 1990; Ford et al., 1996]. Determining which classes of chromosome abnormalities in products of conception are related to maternal age is an important factor in establishing accurate recurrence risk information for a woman for future pregnancies. In a small series, Ford et al. [1996] suggested that the maternal age distribution for cases with combined polyploidy– aneuploidy is very similar to karyotypically normal cases. However, in such combined cases, it is not known which anomaly arises first, that is, whether an aneuploid gamete occurs first followed by triploidy or tetraploidy, or whether a triploid or tetraploid zygote might occur followed by mitotic nondisjunction leading to aneuploidy. If aneuploidy arises first, there may be a similar maternal age effect as seen in typical aneuploidy, and a similar small increased risk of aneuploidy in subsequent pregnancies [Warburton et al., 2004]. The primary objective of our study was to test for a maternal age effect in products of conception cases that had combined polyploidy–aneuploidy in the same cell line, for example, a triploid chromosome complement with additional or missing chromosome(s) (69,XXY, 21 or 70,XXY, þ21 or 71,XXY, þ18, þ21). We hypothesized that if aneuploidy occurs first, there would likely be a maternal age effect. Conversely, if polyploidy occurs first and is followed by mitotic nondisjunction to produce the aneuploid, we would expect to see no maternal age effect. With IRB approval, we collected maternal age at the time of pregnancy loss and karyotype results on 6,782 aneuploid or polyploidy (or both) products of conception cases sent to the Mayo Clinic Cytogenetic Laboratory from December 1999 to April 2011. Cases were assigned to one of six groups: trisomy (n1⁄4 4,448), monosomy X (n1⁄4 1,043), triploid (n1⁄4 936), aneuploid–triploid (n1⁄4 112), tetraploid (n1⁄4 214) and aneuploid–tetraploid (n1⁄4 29). The trisomy and monosomy X groups served as positive and negative controls for advanced maternal age, respectively. Analysis of variance was used to test for differences in maternal age across groups. To account for multiple comparisons, a P-value threshold of 0.01 was used to declare statistical significance. The cytogenetic distribution of the 6,782 products of conception cases and the comparison of maternal age between groups are shown in Tables I and II, respectively. The mean maternal age for monosomy X was not significantly different from either the triploid or tetraploid groups. The mean maternal age for aneuploid-triploid was significantly greater than the monosomy X (P1⁄4 0.001) and triploid groups (P1⁄4 0.008), but was significantly less than the trisomy group (P< 0.0001). The aneuploid-tetraploid cases represented the most uncommon karyotype group, with only 29 cases. Nevertheless, the mean maternal age for the aneuploid–tetraploid group was significantly greater than monosomy X (P1⁄4 0.009), trended greater than the tetraploid group (P1⁄4 0.079), and trended less than the trisomy group (P1⁄4 0.024). The mean maternal age for the aneuploid–triploid group (32.2 years) and the aneuploid–tetraploid group (33.2 years)