Roles of Confined Placental Mosaicism (CPM) and H19/IGF2 imprinting in pregnancies derived from intracytoplasmic sperm injection (ICSI)

In contrast to the success of ICSI in treating male infertility, concerns have been raised about the health outcomes of the children conceived through this procedure. Cohort studies have shown that the ICSI population has an increase in low birth weight (LBW), birth defects, chromosomal abnormalities, and imprinting disorders. However, the underlying causes remain unknown. Two potential risk factors for these negative pregnancy outcomes, particularly for LBW, were investigated in this study - Confined Placental Mosaicism (CPM) and epigenetic defects at the differentially methylated region (DMR) of H19/IGF2. CPM was examined in villi from thirty post-delivery placentas derived from ICSI after confirming a normal karyotype in cord blood. Subsequently, the parental origin was determined in detected CPM as well as in non-mosaic chromosomal abnormalities ascertained through spontaneous abortions. When a paternal origin was confirmed, aneuploidy in sperm from the father was investigated. Finally, methylation pattern at two CpG sites from the DMR of H19/IGF2 was quantitatively analyzed in placentas from ICSI pregnancies with LBW (n=10) and with normal BW (n=12). Placentas from natural conceptions (n=14) served as controls. Among the thirty placentas, one monosomy X case was detected from a conceptus with a normal blood karyotype and pregnancy outcomes. Thus, the incidence of CPM was 3.3% in the study population, which is not significantly different from the rate observed in the general population (6.0%). A paternal origin was revealed in one out of four cases, which include chromosome abnormalities derived from CPM (n=2) and spontaneous abortions (n=2). In the paternally inherited t(13;21) case, 88.39% of the sperm were normal or balanced, and 7.29% were nullisomic or disomic for chromosome 13 and 21. In methylation analysis, differences were not found among the three groups; however, hypomethylation (