However, ICSI is also increasingly used in patients without male factor infertility where the procedure has not been shown to improve clinical outcomes. Findings from some but not all studies suggest that ICSI is associated with an increased risk for chromosomal abnormalities, autism, intellectual disabilities, and birth defects compared with conventional IVF.
These increased risks may also be due to the effects of subfertility. Reproductive outcomes for cycles using conventional IVF and those using ICSI among patients with male factor infertility and among patients with non-male factor infertility during were also compared. These findings provide important information on the benefits and risks of ICSI.
Section Navigation. Facebook Twitter LinkedIn Syndicate. This process was initially developed for men whose sperm had low motility , and could not penetrate the zona pellucida. The process that leads up to the insemination of eggs with sperm is called controlled ovarian hyperstimulation. Once the eggs have been retrieved during an in-office procedure called an egg oocyte retrieval, it is time for the true IVF to begin.
Eggs can be fertilized via ICSI or conventional insemination. Conventional IVF was developed to circumvent female fertility problems such as blockages in the Fallopian tubes, endometriosis, or when previous IUI cycles were not successful. If using conventional fertilization, eggs are placed in media drops and sperm is then added to those drops.
ICSI is a more recent technology developed with male factor infertility in mind, allowing men with low sperm count oligozoospermia or immotile sperm asthenozoospermia to father a child. During traditional IVF, many sperm are placed together with an egg in hopes that one of the sperm will enter and fertilize the egg on its own. With ICSI, the embryologist takes a single sperm and injects it directly into an egg.
But fertilization rates are different than clinical pregnancy or live birth rates. ICSI has the ability to achieve good reproductive outcomes in cases where traditional IVF would not, however in cases where male infertility is not an issue, multiple studies have demonstrated fertilization and pregnancy success rates with ICSI are equivalent to standard insemination by IVF.
The success rates of each method are highly dependent on the skill of the embryologist, egg and sperm quality, and the overall health and causes of infertility in both partners. Furthermore, correlation is not the same thing as causation," said Prof Van Steirteghem.
For instance, paired analysis of samples from fathers and sons should be carried out, and we need to look at larger numbers of offspring. This remains a challenging project for the VUB. However, health authorities and funding agencies should provide the means to answer questions concerning the effects of genetics, mode of conception, foetal growth patterns and birth weights on the fertility of ICSI men," he said. Since the early days of ICSI, the technique has been used increasingly to treat infertility, even when male infertility is not suspected.
Therefore, the authors warn that the findings from this study cannot be extrapolated to all offspring born after ICSI since nowadays ICSI is increasingly used even when there is no evidence that a couple's infertility is due to abnormal semen measurements in the man. Note: Content may be edited for style and length.
Science News. Journal Reference : F. Belva, M. Bonduelle, M. Artificial reproductive techniques are currently responsible for 1. Despite being an invaluable tool for infertile couples, the technique bypasses several biological barriers that naturally select the gametes to achieve an optimal embryonic and fetal development. In this perspective, ICSI has been associated with an increased risk for diverse health problems, ranging from premature births and diverse metabolic disorders in the offspring to more severe complications such as abortions, congenital malformations, and imprinting disorders.
In this review, we discuss the possible implications of the technique per se on these adverse outcomes and highlight the importance of several experiments using mammalian models to truthfully test these implications and to uncover the molecular base that origins these health problems.
We also dissect the specific hazards associated to ICSI and describe some strategies that have been developed to mimic the gamete selection occurring in natural conception in order to improve the safety of the procedure.
The great advances in artificial reproductive techniques ART over the last decades have fulfilled the dreams of millions of infertile couples. An estimated 3. The use of ICSI may pose a risk for the health of the mother and child. ARTs are considered a risk factor for different pregnancy complications such as high blood pressure, preeclampsia, growth retardation, bleeding or even premature births, and intrauterine death [reviewed in Ref. The health of the assisted-conception children may be also compromised.
An analysis of 19 publications selected by a quality score based on sample size and appropriateness of control group observed that major malformation rates ranged from 0 to 9. A particularly sizeable study conducted in Israel, where the national insurance policy covers all IVF procedures for the first two children, reported an adjusted odd ratio for congenital malformations of 1.
The odd ratio of this study was adjusted for other significant interacting factors such as maternal age or gender of the child, limiting the chance of spurious relation. Genomic imprinting is an epigenetic mechanism based on DNA methylation at imprinting control regions ICR that determines the monoparental expression of a subset of genes. These methylation marks are established during gametogenesis in a sex-specific manner and remain unaltered after syngamia, evading the global demethylation taking place during preimplantation development However, ART may alter this special protection resulting into abnormal imprinting patterns that lead to transcriptional dysregulation of imprinting genes.
The altered transcriptional patterns of the imprinting genes leads to aberrant embryonic and placental development, ultimately manifested as imprinting syndromes in the offspring One comprehensive meta-analysis suggested that only three imprinting disorders BWS, AS, and maternal hypomethylation syndrome, all of which associated with hypomethylation at different maternal ICRs, have been consistently linked to the use of ART BWS and AS may have a genetic i.
In a similar context, a lower DNA methylation has been reported in the placenta of children conceived in vitro compared to the control, although the reduction in CpG methylation affected equally imprinted and non-imprinted regions Some of the adverse outcomes observed following ART may be due to the increased risk for health problems in couples pursuing ART, rather than the ART per se 9 , 17 , The contribution of this parental factor to the health problems associated to the ART is difficult to dissect from the risk derived from the technique itself in human studies, as the appropriate control group to establish a possible relation between ICSI and risk of pregnancy complications or birth defects should be babies naturally conceived by infertile couples.
Also, the rarity of the some of the diseases associated to ART such as congenital malformations or imprinting disorders result in a very low statistical power Unfertile couples often show an increased risk factor for pregnancy disorders. Furthermore, other potential risk factors such as cycle irregularities, uterine anomalies, or obesity — with mixed effects on oocyte quality or uterine receptivity 21 — are also more common in these patients 4.
The higher occurrence of multiple pregnancies resulting from the transfer of more than one embryo constitutes another risk factor for pregnancy complications 4. On the paternal side, the spermatozoa from infertile male have been shown to display genetic and epigenetic alterations that can be linked to a reduced embryo development and the appearance of abnormal phenotypes in their offspring.
The assisted reproduction treatment for ICSI is not limited to the injection of a sperm head into an oocyte. It also involves the hormonal induction to achieve supernumerary oocyte production, in vitro maturation IVM of the oocytes retrieved, in vitro culture IVC of the zygotes produced by ICSI, and cryopreservation of gametes and embryos, all of which may play a role in hampering optimal embryo development 25 , 26 Figure 1.
The possible differential risk for adverse outcomes between both procedures remains controversial. Experiments conducted in animal models have observed several developmental alterations exclusively attributed to ICSI, as detailed below. Besides, an epidemiologic study reported a higher major malformation rate in babies obtained by ICSI with cryopreserved sperm compared with IVF 8. However, large meta-analyses of a mix of selected publications using fresh or frozen spermatozoa under different conditions did not observe a differential risk for birth defects between ICSI and IVF 8 , 9.
Figure 1. Mammalian models constitute a valuable tool to study the adverse outcomes associated with ART. Studies in animal models provide a proper control group of healthy and fertile animals, reduce the environmental variations, and provide a pre-set experimental frame that avoids selective reporting.
Furthermore, the molecular mechanisms behind the phenotypic alterations caused by ART are shared between mammalian species. Due to practical and technical limitations in ruminants or pigs, the rodents have been the most frequently used models to study the long-term effects of ICSI in the health of the offspring.
In rodent models, ICSI has been reported to alter DNA decondensation 29 and calcium oscillation 30 in mouse zygotes compared with IVF, and to impair the active demethylation of the male pronucleus in rat zygotes ICSI performed with fresh sperm has been reported to increase the appearance of abnormal chromosome segregation ACS at the first mitotic division in mouse Half of these ACS embryos developed into morphologically normal blastocysts able to implant, but unable to develop to term, resulting in spontaneous abortions at E7.
However, less severely impaired, yet abnormal embryos produced by ICSI may be able to survive through pregnancy, resulting in long-term effects on the adult life in the context of the Developmental Origins of Adult Health and Disease DOHaD. In this perspective, several alterations have been described in the offspring, such as aberrant transcriptional aberrations spanning to the neonatal stage 33 , alterations in glucose parameters in adult mice 34 , and decreased testis weight, abnormal testicular tubule morphology, and increased testicular apoptosis These long-term effects are usually manifested in a sex-specific manner, which can be explained by the widespread epigenetic sexual dimorphism observed in preimplantation embryos 36 — The study of DFS-ICSI effects in animal models is particularly relevant because a significant proportion of infertile men have elevated levels of DNA damage in their ejaculated spermatozoa, which may be morphologically normal and thereby inadvertently used for ICSI Sperm DNA fragmentation has been reported to affect embryo post-implantation development in ICSI procedures in humans, resulting in pregnancy loss On preimplantation mouse embryos, DFS-ICSI has been observed to delay male pronucleus demethylation, alter blastocyst gene expression, and modify the expression of imprinting genes These early alterations may result in embryonic death or in aberrant phenotypes in the offspring, such as aberrant growth, premature aging, abnormal behavior, and a higher incidence of mesenchymal tumors The same study also observed that the offspring derived from DFS-ICSI displayed an increased chance for the appearance of abnormal phenotypes kinky-tail in the Axin Fu mouse model of metastable epiallele, suggesting a transgenerational inheritance of the epigenetic alterations generated by DFS-ICSI However, the heritability of other epigenetic changes has not been observed in other studies 43 , so the transgenerational epigenetic inheritance may depend on the specific epigenetic alteration.
While dissecting the ICSI-specific hazards, two are exclusive from this technique: the injection of the sperm head into the oocyte and the bypass of the natural spermatozoa selection mechanisms, which is partly shared with IVF. The micromanipulation itself may harm the oocyte and the resulting embryo. The injection of a sperm head that has not undergone acrosome reaction increases the risk of vacuole formation in the oocyte.
Although this effect, observed in mice, only happened when three or more intact spermatozoa were injected 44 , removal of sperm plasma membrane improved embryo development in mice 45 and selection for spermatozoa with reacted acrosome improved implantation rates in humans 46 and mouse Although a large number of spermatozoa are present in the ejaculate, only a minority reach the fertilization place.
On the journey of the sperm from the site of deposition to the site of fertilization, spermatozoa should pass through different barriers that ensure that only those with normal morphology and vigorous motility will have chances to fertilize the oocyte forming a healthy embryo 47 , Spermatozoa selection under natural circumstances is based on three different steps: 1 the female reproductive tract microenvironment, 2 the sperm—oviduct interactions at the caudal isthmus, and 3 the sperm—zone pellucida interaction 48 Figure 2.
ICSI bypasses this natural selection process of the fertilizing sperm 49 , as it does not allow the sperm—oviduct interaction and other spermatozoa selection processes including ZP binding-penetration.
Figure 2. Spermatozoa selection barriers bypassed by ICSI: 1 the female reproductive tract microenvironment, including immune cells 2 the sperm—oviduct interactions at the caudal isthmus, and 3 the sperm—zone pellucida interaction.
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