As indicated by Ludwig (89), factors may be involved at different steps of the ART treatment that may lead to an increased risk of adverse outcome.
The genetics of the male and female partners may influence the outcome. It has been well established that there are more constitutional abnormal karyotypes in infertile males and females. Several studies also indicated that abnormal sperm have more chromosomal abnormalities. In a cohort of 1298 ICSI parents seen for genetic counseling, it was concluded that there was an increased genetic risk for 557 of these children (45). This increased risk was due to maternal or paternal age, chromosomal aberrations, monogenic or multifactorial disease, and consanguinity. Slightly less than 5% of infertile males and 1.5% of tested females had an abnormal karyotype. With regard to fetal karyotypes after ART, there are only systematic data available for ICSI (90). Results on 1586 fetal karyotypes indicated an increased risk related to the chromosomal anomalies in the parents. The majority of cases (17 out of 22) were paternally inherited. There were significantly more de novo anomalies (1.6%), but the absolute risk is low. More anomalies were observed when sperm concentration was <20x106 sperm per ml and when sperm motility was impaired. Although the ICSI procedure is much more invasive than conventional IVF, there is no difference in outcome between ICSI and IVF (83-85,91). This contrasts with the observations of the abnormalities in the fertilization process after ICSI as compared to IVF in rhesus monkeys (92). In theory, all manipulations of gametes and embryos such as gamete preparation and manipulation, in vitro culture, blastomere biopsy, and assisted hatching could influence the constitution of the embryo and ultimately the health of fetuses and children. Efforts should be pursued to establish multinational registries to collect data on the offspring, as has been done by the ESHRE Consortium on Preimplanta-tion Genetic Diagnosis (93). Strict quality management in the IVF laboratory (such as strict temperature control) is indicated because of its influence on outcome. In recent literature, case reports and case-control studies have been published on the occurrence of imprinting disorders in ART children. There are cases of Angelman syndrome (94) and Beckwith-Wiedeman syndrome (95,96). The absolute risk for these imprinting disorders in ART remains low, and so far the reason for an increased risk of imprinting errors remains unknown. As outlined by Buck Louis et al.(80), a major drawback of all outcome studies is that the control group is fertile, and the study group is unfertile. It would therefore be indicated that a comparison should be made between ART conceptions and spontaneous conceptions in a subfertile population. With regard to pregnancy complications, a study from the United Kingdom (97) indicated that there is an increased incidence of abruptio placentae, pre-eclampsia, and Caesarean section in couples with idiopathic infertility compared to fertile couples whether conception was spontaneous or after infertility treatment. Similar observations were made in the United States, Denmark, and Sweden (98-101). The question of why the risks are increased remains unanswered: is it due to in vitro conditions or to the infertility status per se? To assess the contribution of in vitro handling, risk assessment for malformations may be done comparing ovarian stimulation alone or in combination with intrauterine insemination.
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