Committee Paper Committee: Scientific and Clinical Advances Advisory Committee Meeting Date: 12 May 2009 Agenda Item: 4 Paper Number: SCAAC(05/09)01 Paper Title: ICSI guidance Author: Hannah Darby and Rachel Fowler For Information or Decision? Decision Resource Implications: None Implementation: Communication: Organisational Risk: Recommendation to the Committee: Evaluation: N/A SCAAC s advice will be passed onto the Authority when deciding on the content of the 8 th edition of the Code of Practice Low Members are asked to advise the Authority on whether, in light of the latest research, guidance on the risks of ICSI should be revised. N/A Lay summary: Intra cytoplasmic sperm injection (ICSI) is the process of injecting a single sperm into an egg. The HFEA issues guidance to licensed fertility centres regarding information which they should provide to patients about the risks involved with ICSI eg, risks of eggs being damaged in the procedure and risk of embryos/children having genetic abnormalities. The latest research regarding these risks has been summarised and committee members are asked to advise whether guidance subsequently needs to be updated. 1 Introduction 1.1 The draft 8 th edition of the Code of Practice outlines the following guidance to centres regarding information which they should provide to patients about ICSI: Before treatment is offered, the centre should give the woman seeking treatment and her partner, if applicable, information about ICSI. This should include information on the risks of ICSI which might lead to: 1
a) damage to eggs b) embryos with abnormal numbers or structures of chromosomes c) embryos with novel chromosomal abnormalities d) children conceived having inherited genetic and chromosomal abnormalities, including cystic fibrosis gene mutations, sex chromosome defects and heritable sub-fertility, and e) difficulties for the woman during pregnancy, including miscarriage. 1.2 This guidance is based on information from a Chair s letter regarding risks involved with ICSI (Annex A), which was issued to centres in 1998. The production of a new edition of the Code of Practice presents an opportunity to review this guidance and ensure it reflects the latest studies in the field. 1.3 At the last meeting (27 January 2009) members discussed the latest research regarding developmental and birth defects following assisted reproduction and advised that information on this issue should be provided to all patients, not just patients undergoing ICSI cycles. This paper considers further risks which apply more specifically to ICSI. 2 Risk of damage to eggs 2.1 The ICSI procedure is typically associated with degeneration of approximately 10% of the treated eggs 1. The cause of this degeneration is unclear. 2.2 The possibility that compression of the egg when the needle is inserted damages the zona pellucida and oolemma (plasma membrane) of the egg has been investigated. The technique of drilling of a small hole through the zona pellucida using a laser has been developed to avoid compression of the egg during ICSI (laser-assisted ICSI). Although some studies have shown a decrease in egg degeneration using this technique, 2 3 a larger, randomised controlled trial 1 showed no evidence that laser-assisted ICSI decreased the rate of egg degeneration. 2.3 The possibility that degeneration is technician-dependent has also been investigated, but no connection was found. It has been suggested that egg degeneration is in fact a marker of the inherent egg quality. 4 3 Risk of embryos having novel chromosomal abnormalities, an abnormal number or structure of chromosomes and risk of children conceived having inherited and genetic chromosomal abnormalities Procedure-related aneuploidy and chromosomal anomalies 3.1 As outlined in a review by Verpost and Tournaye 5, it is possible that the injection of sperm into eggs may lead to aneuploidy or chromosomes anomalies. Sperm injection may cause 2
physical and biochemical disturbance and dislocation of ooplasm, or disturbance of the meiotic spindle, which may lead to aneuploidy and an increased risk of chromosomal anomalies. This may be due to the ICSI procedure itself, because of errors in the second meiotic division or in mitosis during early cleavage divisions. However, there is conflicting evidence on this issue. De novo chromosomal anomalies 3.2 It is commonly recognised that the rate of de novo chromosomal anomalies, such as sex chromosome anomalies, in children conceived via ICSI is higher than observed in the general IVF population 6 7. 3.3 A Dutch group 8 investigated the incidence of sections of chromosomes being deleted or duplicated (genomic copy number variations) in a group of 12 ICSI children, compared with a control group of 30 naturally conceived children. In six of the 12 ICSI children, they found that 10 apparently de novo changes (simultaneous copy number gain, or loss, with respect to both biological parents), 9 of which were losses. In statistically significant contrast, similar observations were encountered only six times in the control group in five of the 30 children. These genomic changes were not observed to have a phenotypic consequence in the children. However, their study group was small, so a larger group is needed to confirm these findings. 3.4 A group from the Brussels Free University have reported results from prenatal testing of ICSI pregnancies 9. They reported a significantly higher rate of de novo chromosomal anomalies in ICSI offspring (1.6% versus 0.5% in the general population), relating mainly to a higher number of sex chromosomal anomalies and partly to a higher number of autosomal (chromosomes other than sex chromosomes) structural anomalies. The group concluded that this finding was related to sperm concentration and motility (see 3.8 for the group s recommendation). Imprinting disorders 3.5 A review of 10 years experience of ICSI 10, published in 2004, highlighted that recent publications mention that a few children are affected by diseases caused by imprinting disorders (eg, Angelman syndrome and Beckwith-Wiedemann syndrome). They explain that in reports of Angelman syndrome and Beckwith-Wiedermann syndrome it is the maternal allele that is affected (unmethylated). This makes it unlikely that the problem is related to sperm differentiation and more likely that ICSI or some other aspects of the assisted reproductive technology used disturbs methylation in the maternal genome or early embryo. Further studies are needed to assess the association between assisted reproductive technologies and imprinting disorders. The absolute risk of imprinting disorders after IVF/ICSI is still small (estimated at 1/20,000 for Angelman s syndrome compared to 1/200,000-1/400,000 in the general population) 5. Inherited chromosomal abnormalities 3.6 As outlined in the ASRM Committee opinion paper, 7 the prevalence of sex chromosome abnormalities in children conceived via ICSI is higher than observed in the general IVF population. It is unclear whether this is due to the ICSI procedure itself or if it reflects a direct 3
paternal effect. Men with abnormal semen parameters often have an increased level of sperm aneuploidy, especially aneuploidy of the sex chromosomes (X and Y). 3.7 As summarised in the ASRM Committee opinion paper, one relatively common cause of male infertility, amongst men which are selected for ICSI, is congenital bilateral absence of the vas deferens (CBAVD). It is a condition associated with certain cases of cystic fibrosis, so there is an increased risk that men with CBAVD are cystic fibrosis carriers. In addition, Y chromosome microdeletions, in the azoospermia factors region, have been observed in between 3% and 15% of men with severe oligozoospermia and non-obstructive azoospermia. There is a risk that male offspring, conceived by ICSI, may inherit these abnormalities. The ultimate impact they may have on their phenotype is not yet clear. 3.8 The ASRM Committee recommends that when specific abnormalities such as these are identified, affected couples should receive appropriate genetic counselling before proceeding with treatment. Only those who fully understand the risk of transmitting a genetic abnormality and its potential effect on their offspring should be offered ICSI. 3.9 A group from the Brussels Free University observed a significantly higher rate of inherited anomalies in ICSI offspring (1.4 versus 0.3-0.4% in the general population). The group concluded that that this was related to a higher rate of chromosomal anomalies, mainly in the fathers. The group recommend that couples should be informed of the risks of an abnormal result related to sperm quality, and of the risk linked to a prenatal procedure as well as about the relatively benign character of some chromosomal anomalies such as de novo structural anomalies or sex chromosomal anomalies in order to be able to make a choice for prenatal testing, or not. 3.10 In addition, in a debate about whether ICSI patients should have genetic testing before treatment 11, a Scandinavian group recommend that men with very low sperm counts considering ICSI should always be informed of the possibility of genetic testing. The information should include a precise statement of the implications of the results for the patient, his family and his offspring, and reassurance that a decision to test or not to test, or the subsequent test results, will not be used as a reason for withholding treatment. If an abnormality is identified, patients should be referred to specialist genetic counselling. 4. Risk of difficulties during pregnancy, including miscarriage 4.1 The miscarriage rate in pregnancies resulting from ICSI and IVF is 17.6% and 16.7% respectively 12. The miscarriage rate may be affected by the procedure of ICSI allowing abnormal gametes to produce viable embryos that they would otherwise not be able to. 4.2 For example, there is substantial evidence that infertile men have higher levels of sperm DNA damage 13. However, it is unclear whether the rate of miscarriage in pregnancies resulting from ICSI is linked to the opportunity ICSI provides for sperm with higher than normal levels of DNA damage to produce an embryo 14. 4
4.3 Postnatal outcomes, such as prematurity and very low birth weight, have also been shown to differ only slightly between IVF and ICSI. The rate of premature births in children born as a result of ICSI and IVF is 31.8% and 29.3% respectively and the rate of very low birth weight is 4.4% and 5.6% respectively. These figures are based on 2889 ICSI and 2995 IVF pregnancies 15. 5. Conclusion 5.1 The summary of evidence highlights that: the ICSI procedure is typically associated with degeneration of approximately 10% of the treated eggs compared to the general population, there is an increased risk of chromosome abnormalities (both inherited and de novo) in ICSI embryos/children, some of which have unknown consequences and many of which are known not to have phenotypic consequences there have been reports of children conceived from ICSI being affected by imprinting disorders, and the risk of imprinting disorders is slightly higher for IVF/ICSI conceived children compared to the general population the risk of miscarriage, premature birth and low birth weight following IVF and ICSI is very similar men providing sperm for ICSI may wish to consider genetic testing 5.2 Therefore the Executive recommends that the guidance in the Code of Practice, as outlined in section 1, should be amended to state the following: Before treatment is offered, the centre should give the woman seeking treatment and her partner, if applicable, information about ICSI. This should include information on the risks of ICSI which might lead to: a) damage to eggs b) embryos with abnormal numbers or structures of chromosomes c) embryos with novel chromosomal abnormalities d) children conceived having inherited genetic and chromosomal abnormalities, including cystic fibrosis gene mutations, sex chromosome defects and heritable sub-fertility, and e) difficulties for the woman during pregnancy, including miscarriage Where appropriate centres should also provide patients with information about the possibility of genetic testing of the sperm provider. 5
References 1 Richter KS et a) (2006). No advantage of laser-assisted over conventional intracytoplasmic sperm injection: a randomized controlled trial [NCT00114725] J Exp Clin Assist Reprod. (3) 5. 2 Abdelmassih S et al (2002) Laser-assisted ICSI: a novel approach to obtain higher oocyte survival and embryo quality rates. Hum Reprod. (17) 2694-2699 3 Rienzi L et al (2004) Clinical application of laser-assisted ICSI: a pilot study. Eur J Obstet Gynecol Reprod Biol. (115) Suppl 1:S77 9. 4 Rosen MP et al (2006) Oocyte degeneration after intracytoplasmic sperm injection: a multivariate analysis to assess its importance as a laboratory or clinical marker. Fertil Steril. Jun;85(6):1736-43. 5 Verpost and Tournaye. ICSI: Hype or hazard? (2006) Human Fertility, 9(2):81-92. 6 Bonduelle et al. (2002) Prenatal testing in ICSI pregnancies: incidence of chromosomal anomalies in 1586 karyotypes and relation to sperm parameters. Human Reprodcution 17:2600-2614. 7 The Practice Committee of the American Society for Reproductive Medicine and the Practice Committee of the Society for Assisted Reproductive Technology (2008). Genetic considerations related to intracytoplasmic sperm injection (ICSI) Fertility and Sterility, 90:S182-4. 8 Woldringh et al. (2009) Constitutional DNA copy number changes in ICSI children. Human Reproduction, 24(1): 233-240. 9 Bonduelle et al. (2002) Prenatal testing in ICSI pregnancies: incidence of chromosomal anomalies in 1586 karyotypes and relation to sperm parameters. Human Reproduction, 17(10):2600-2614. 10 Devroey and Steirteghem (2004) A review of ten years experience of ICSI. Human Reproduction Update, 10(1): 19-28. 11 Aittomaki et al. (2004) Safety issues in assisted reproductive technology: Should ICSI patients have genetic testing before treatment? A practical proposition to help patient information. Human Reproduction 19(3):472-476. 12 Verpoest et al (2006). ICSI: Hype or hazard? Human Fertility 9(2) 81-92. 13 Morris et al (2002). The spectrum of DNA damage in human sperm assessed by single cell gel electrophoresis (Comet assay) and its relationship to fertilization and embryo development. Human Reproduction 17(4):990-998. 14 Zini et al (2008). Sperm DNA damage is associated with an increased risk of pregnancy loss after IVF and ICSI: systematic review and meta-analysis. Human Reproduction 23(12) 2663-2668. 15 Devroey and Steirteghem (2004). A review of ten years experience of ICSI. Human Reproduction Update 10(1) 19-28. 6