CHROMOSOMAL ABNORMALITIES IN EARLY PREGNANCY LOSSES: A STUDY OF 900 SAMPLES
Bozhinovski Gj, Terzikj M, Kubelka-Sabit K, Jasar Dz, Lazarevski S, Livrinova V, Plaseska-Karanfilska D
*Corresponding Author: * Corresponding Author: Professor, Dijana Plaseska-Karanfilska,MD, PhD, Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov”, Macedonian Academy of Science and Arts, Skopje, North Macedonia, mail: dijana@manu.edu.mk
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RESULTS
The QF-PCR analysis performed on 900 POC sam- ples showed maternal DNA contamination in 14.66%. These samples were excluded from further investigation and MLPA analyses were performed on a total of 768 POC samples.
Chromosomal abnormalities - overall incidence
Chromosomal abnormalities were present in 56.25% of uncontaminated POC samples. Chromosomal trisomies were detected in 66.20%, triploidy in 15.28%, and mono- somies were present in 10.88% of the positive cases. The group of monosomies consisted of monosomy X which was predominant (91.49%) and monosomy 21 was pres- ent in 8.51%.
All chromosomes, apart from chromosomes 1 and 19, were affected by trisomy; the most common was trisomy 16, present in 26.57% of all trisomy samples, followed by tri- somy 22 (15.73%), 21 (10.13%) and 15 (9.09%) (Figure 1).
Partial chromosomal abnormalities (terminal deletions and duplications), multiple chromosomal aneuploidies, and chromosomal aneuploidies accompanied by partial chro- mosomal abnormality were found in 3.70%, 3.01%, and 0.93% of all positive samples (Table 2). A detailed descrip- tion of the later three groups of chromosomal abnormalities is provided in Figure 2. Chromosomes 20, 21, 22 and X were most involved in multiple aneuploidies, chromosomes 1, 13 and 18 in partial aneuploidies, while chromosomes 15, 16 and 22 were found in combination with a partial aneuploidy. In cases of partial chromosomal abnormalities, parental karyotyping could not be performed at the time.
Chromosomal abnormalities and maternal age
As shown in Table 2 the overall frequency of chro- mosomally abnormal POCs increased with maternal age (43.40% in the women <30 years of age, 53.94% in women 31-35 years and 71.37% in woman >36 years). The odds for chromosomally abnormal EPLs were 1.52 higher in the group of women 31-35 years of age (95% CI: 1.07-2.16; p=0.018) and 3.25 higher in women >36 years (95% CI: 2.26-4.66; p<0.0001), when compared to the group of women <30 years of age (Table 3).
The spectrum of the chromosomal abnormalities differed in the three groups of women according to their age. In the group >36 years, the trisomies were predominant (79.68%), while triploidy and monosomies were present in small portions (6.42% each). In the group of women <30 years of age, a more even distribution of the chromo- somal abnormalities was observed, with trisomies pres- ent in 48.70%, triploidy in 26.09% and monosomies in 16.52%. The odds for EPLs with trisomy were 1.88 times higher in the group of women 31-35 years of age (95% CI: 1.26-2.81; p=0.0017) and 4.92 higher in women >36 years (95% CI: 3.35-7.21; p<0.0001), when compared to the group of women <30 years of age (Table 3).
Multiple chromosomal trisomies were more com- mon among the group >36 years (5.88%), while partial chromosomal aneuploidies were more frequent in women <35 (Table 2).
Considering the individual trisomies, trisomy 16 had the highest incidence in the group <30 years (39.29%), and lowest in the group >36 years of age (16.78%). Fur- thermore, trisomies 13 and 14 were also more common among the group <30 years (12.50% and 12.50% each), than in the other two groups. By contrast, trisomy 22 was more common in the group >36 years (23.49%) than in the group 31-35 years (12.35%). It was entirely absent in the youngest group of women (<30 years of age). Similarly, the trisomy 15 was most common in the group of women >36 (14.77%) than in other groups (0.00% and 4.94% in groups of women <30 and 31-35 years, respectively) (Table 4). The odds of EPLs with trisomy 16 were 0.31 lower in the group of women >36 years (95% CI: 0.15-0.62; p=0.0009) while for trisomy 22, the odds were 16.59 higher in the group of women 31-35 years of age (95% CI: 0.95-289.31; p=0.054) and 35.03 higher in women >36 years (95% CI: 2.11-581.6; p=0.013) when compared to the group of women <30 years of age. The odds for trisomy 15 were higher (OR=19.94, 95% CI: 1.18-334.53; p=0.037), while for trisomies 13 and 14 were lower in women >36 years (OR=0.29, 95% CI: 0.09-0.91; p=0.034 and OR=0.24, 95% CI: 0.07-0.80; p=0.02, respectively) when compared to the group of women <30 years of age (Table 3).
Although not statistically significant, a higher inci- dence of chromosomally abnormal POCs were detected in the Macedonian ethnic group (58.52%) in comparison to the Albanian group (50.96%; p=0.06) (Table 2). Trip- loidy and chromosomal monosomies were significantly more common among the Albanian ethnic group (25.47% and 15.09% respectively; p=0.0001) than in the Macedo- nian group (12.30% and 9.39% respectively). In contrast, chromosomal trisomies were more prevalent in POCs of Macedonian ethnic origin (69.90%) than in the Albanian group (54.72), (p=0.0044).
Regarding the individual trisomies, the most evident difference was observed in trisomy 16, being more com- mon among Albanians (32.76%, p=0.207) than among Macedonians (24.54%). Trisomy 22 was found to be more frequent in the Macedonian group compared to the Alba- nian (18.52% vs. 6.90%, respectively, p=0.035) (Table 4). However, these differences can be explained by the age distribution of samples with different ethnicity. Namely, most Macedonians (41.47%) belonged to the >36 years group and only 24.81% were in the group <30, while the majority of Albanians (58.17%) belonged to the group <30, and only 16.82% were in the group >36. This is in ac- cordance with the tendency of earlier childbearing among Albanian women.
Chromosomal abnormalities and history of EPLs
The frequency of chromosomal abnormalities in POCs from women with sporadic EPLs was higher than in those with RPLs (61.19% vs. 55.21%, respectively, p=0.164), this difference, however, was not statistically significant (Table 2). No evident difference was observed between these two groups regarding the presence of dif- ferent classes of chromosomal abnormalities and chromo- somal trisomies (Tables 2 and 4).
Chromosomal abnormalities and previous live birth
In the group of women with a previous live birth, a slightly higher, but not significantly different, incidence of chromosomally abnormal POCs was found compared to the group of women without a live birth (61.97% vs. 56.92%, respectively, p=0.297) (Table 2). However, this is most probably due to the higher mean age of the women with a live birth (34.66 years) in comparison to that of women with no live birth (32.57 years). Triploidy and trisomies did not differ much among these groups, while monosomies were more common in the group with (15.91%, p=0.119) compared to the group without live births (9.63%), but without statistical significance.
Trisomy 16 and 21 were more prevalent in the group without live births (27.97% and 8.39%, respectively) than in the group with live births (15.00%, p=0.049 and 3.33%, p=0.195; respectively), while trisomy 15 was more com- mon in the group with live births (18.33%, p=0,041) vs those without (8.39%) (Table 4). These findings were sta- tistically significant for trisomies 16 and 15, but not for trisomy 21.
Chromosomal abnormalities and maternal blood groups/RhD status
The highest incidence of chromosomally abnormal POCs was detected in women with the AB blood group (63.89%), followed by A (62.84%), O (56.28%) and B (50.75%) (Table 2). The O blood group had the highest incidence of monosomies (14.56%) in contrast to the B with the lowest rate of monosomies in our study (8.82%) (p=0.312). The opposite was observed concerning the trisomies, where B had the highest, and O the lowest in- cidence (76.47% and 61.17%, respectively) (p=0.176).
Higher presence of trisomy 22 was observed among women of the AB blood group (43.75%), in comparison to women of other (combined B, A and O) blood groups (17.46%) (p=0.012). Furthermore, trisomy 21 was more frequently observed among women in the O blood group (9.52%; 6/63), compared to other groups (2.52%) (p=0.034) (Table 4).
Women with positive RhD positive (RhD+) had slightly higher incidence of abnormal POCs (59.51%) than the RhD negative (RhD-) women (52.54) (p=0.310).
Chromosomal abnormalities according to the gestational age
Overall, increased incidence of chromosomal ab- normalities was present in advanced gestational age. The POCs eliminated in gestational week (gw) 10 showed the highest incidence of chromosomal abnormalities (66.67%), followed by gw 9 (63.08%), while the lowest rate was observed in the POCs eliminated in the gw 6 (52.78%).
Higher incidences of triploidy and monosomies were observed in POCs eliminated between gw 9 and gw 11 (p=0.135 and p=0.0015, respectively), while trisomies were more common among studied POCs from gw 6 to 8 (p=0.0026) (Table 2).
Chromosomal abnormalities and POCs sex
Among the 768 POCs, 379 were male sex (49.34%) and 389 were of female sex (50.65%). A slightly lower number of chromosomally abnormal male POCs was observed (53.56%) in comparison to the female POCs (58.86%). Triploidies were more common among male POCs in contrast to the females (25.56% vs. 13.75%, re- spectively; p=0.026). Chromosomal monosomies were more prevalent in female than in male POCs (28.12% vs. 1.7%; p<0.0001), but this was expected since monosomy X was predominant (95.55%) in this group, and there were only 2 cases with monosomy 21 (4.44%). Regarding the chromosomal trisomies, no significant difference was observed between males and females (Tables 2 and 4). In the group of RPL, a higher percentage of male POCs were euploid in comparison to the female POCs (50% vs. 39.85%), but the difference was not significant (p=0.1).
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