Article Application of intracytoplasmic sperm injection in assisted reproductive technologies

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1 RBMOnline - Vol 6. No Reproductive BioMedicine Online; on web 26 February 2003 Article Application of intracytoplasmic sperm injection in assisted reproductive technologies Dr Gianpiero Palermo Gianpiero D Palermo developed ICSI, the revolutionary procedure that alleviates male infertility. He established the ICSI programmes with André Van Steirteghem at the Brussels Free University in Belgium and later with Zev Rosenwaks at Cornell University in New York. ICSI is progressively superseding standard in-vitro insemination: over 40,000 babies have been born from this procedure worldwide. Dr Palermo completed his clinical training in Obstetrics and Gynaecology at the University of Bari in Italy, attended the Masters and PhD programmes at the Brussels Free University and is currently completing additional postdoctoral training in New York and Melbourne. Dr Palermo has won many prestigious prizes and awards for his pioneer work in Reproductive Biology and has delivered over 100 lectures before international audiences on topics of mammalian fertilization. He is also a prolific author. Since 1993 he has been Director of the ICSI Program at the Cornell Institute for Reproductive Medicine and Associate Professor at the Weill Medical College of Cornell University. He leads a team of talented researchers actively involved in molecular and genetic aspects of fertilization, follow-up of ICSI babies, genetic aspects of male infertility as well as devising new procedures to treat age-related female infertility. GD Palermo 1, T Takeuchi, QV Neri, Y Katagiri, LL Veeck, Z Rosenwaks Cornell Institute for Reproductive Medicine, Weill Medical College of Cornell University, New York, NY, USA Correspondence: gdpalerm@med.cornell.edu Abstract Intracytoplasmic sperm injection (ICSI) entails the mechanical insertion of a chosen spermatozoon directly into the cytoplasm of an oocyte. Due to the consistent fertilization and pregnancy outcome, ICSI is routinely used to treat azoospermic patients where spermatozoa are retrieved by epididymal aspiration or testicular biopsy. Since male subfertility has been associated with a higher incidence of genomic defects, ranging from numerical chromosomal abnormalities to Yq microdeletions, concerns have been raised as to the risk of transmitting genetic defects to the offspring. Screening for such defects can provide invaluable information for appropriate counselling prior to ICSI treatment. In order to address these concerns, a follow-up of the children born after ICSI treatment was conducted. Keywords: azoospermia, genetic defects, ICSI, male subfertility, screening 456 Introduction IVF was developed initially as a treatment for female factor infertility, particularly that caused by tubal occlusion. Soon after its introduction, the treatment options of IVF were extended to male factor infertility. For the latter, different approaches, ranging from microdrop insemination to partial zona dissection and subzonal insemination, were employed at first. However, these gave poor and unpredictable results until the development of intracytoplasmic sperm injection (ICSI). ICSI is now the most successful micromanipulation technique used for treatment of male factor infertility. It entails the insertion of a selected spermatozoon directly into the cytoplasm of a human oocyte. This procedure was first applied to human gametes in 1988 (Lanzendorf et al., 1988) and human pregnancies were reported 4 years later (Palermo et al., 1992). Since that time, ICSI has confirmed itself as the best technique through which to achieve a consistently high fertilization rate and pregnancy outcome, in couples with suboptimal spermatozoa (Palermo et al., 1992, 1993, 1995, 1998, 1999; Van Steirteghem et al., 1993; Colombero et al., 1999). The success of this procedure appears not to be influenced by the collection method or origin of the semen sample, by various semen parameters, or by the presence of anti-sperm antibodies. In addition, although in-vitro insemination with putatively normal spermatozoa generally brings excellent fertilization rates, unpredictable fertilization failure can still occur. Thus, in choosing between standard insemination and/or ICSI it is very difficult to identify factors that might predict a poor fertilization outcome. Several studies comparing the outcome of ICSI versus standard IVF in nonmale factor infertility, reported comparable results for both, although conventional insemination did result in unexpected fertilization failure (Aboulgahr et al., 1995; Calderon et al., 1995; Palermo et al., 1995; Staessen et al., 1999; Verheyen et al., 1999; Fishel et al., 2000; Poehl et al., 2001). In fact, the large majority of such couples are successfully treated with ICSI in subsequent cycles. Nevertheless, fertilization failure can still occur sometimes even after the ICSI procedure (Liu et al., 1995; Flaherty et al., 1998; Moomjy et al., 1998). The ability of virtually any spermatozoon to induce oocyte activation and pronucleus formation has resulted in the application of ICSI for the treatment of azoospermic patients.

2 Azoospermia has been considered to be a poorly treatable form of infertility, the fertilization rate being only 10 13% using male germ cells obtained in such cases for standard in-vitro insemination. However, it then became apparent that ICSI with testicular spermatozoa could be used to successfully treat azoospermia (Schoysman et al., 1993). Soon thereafter, the first case series of ICSI was performed with epididymal spermatozoa (Tournaye et al., 1994). Nonetheless, although the fertilization rates obtained with them were satisfactory, these were significantly lower than the rates observed with freshly ejaculated sperm cells. The reason for this was attributed possibly to a different constitution of the sperm membrane, presumably related to a higher lipid content, since the results improved following a more aggressive sperm immobilization procedure (Palermo et al., 1996a). It may be that this facilitates the release of a sperm cytosolic factor required for activation of the oocyte (Dozortsev et al., 1995; Palermo et al., 1997). Complete azoospermia underlies approximately 10% of cases of male factor infertility, and this can be classified as obstructive and non-obstructive. For instance, obstructive azoospermia is characterized by a normal sperm production and is often caused by a congenital bilateral absence of the vas deferens (CBAVD), a condition associated with a cystic fibrosis gene mutation. In such cases, spermatozoa are often retrieved by microsurgical epididymal sperm aspiration (MESA) or by percutaneous epididymal sperm aspiration (PESA), and only where they cannot be recovered does testicular sampling become appropriate. The latter situation, non-obstructive azoospermia, is characterized by a varying degree of spermatogenic failure, often by chromosomal abnormalities (Reijo et al., 1996; Girardi et al., 1997), and direct tissue sampling from the testis is the only method of retrieval (Schlegel et al., 1997). More recently, the testicular fine needle aspiration (TEFNA) technique has been introduced as an alternative to open testicular biopsy (Friedler et al., 1997). Submicroscopic deletions in the Y chromosome are also associated with male infertility. Assessment of such deletions provides important information for counselling when the male partner has compromised spermatogenesis, and therefore could transmit the cause to the male offspring (Kent-First et al., 1996). Thus, screening for such defects can provide invaluable information for such potential ICSI cases. Notwithstanding the large number of babies born from the ICSI procedure worldwide, concerns still exist because of the use of suboptimal spermatozoa that have a higher incidence of genomic abnormalities (Ludwig and Katalinic, 2002). Although initial worries related to ICSI have been eased by the reassuring condition of the babies born, concerns still exist about their later development. Therefore, follow-up of the ICSI children during their development is highly recommended. The use of parent-administered questionnaires has been proposed as a way of monitoring the development of ICSI offspring, since assessment of psychological and physical development is costly and time consuming. In this study, fertilization, pregnancy, and delivery rates are reported in couples treated by ICSI with ejaculated and surgically retrieved spermatozoa. Aspects of the assessment of ICSI children as well as the genetic status of their parents have also been analysed. Since October 1999, a follow-up study of the psychological and motor development of 3-year-old ICSI compared with IVF children has also been performed. Materials and methods From September 1993 through June 2002, 6269 ICSI cycles were performed with ejaculated spermatozoa on female patients and in 865 cycles with surgically retrieved spermatozoa (35.4 ± 5 years). All couples undergoing surgical retrieval of spermatozoa were genetically screened and counselled. Oocyte retrieval was performed after downregulation with gonadotrophin-releasing hormone agonist (GnRHa) and superovulation with gonadotrophins. After removal of the cumulus, a single immobilized spermatozoon was injected directly into the cytoplasm of a metaphase II oocyte, as previously described (Palermo et al., 1995). Morphologically good quality 8-cell embryos were transferred on day 3 after ICSI. In about 10% of cases, the replacement of early embryo blastocyst was performed on day 5. Clinical pregnancy was defined as the presence of a gestational sac as well as at least a fetal heartbeat on ultrasonographic screening starting on day 49. In cases of miscarriage, pathological and, when possible, genetic assessments were carried out on the expelled embryonic trophoblastic material. Amniocentesis was suggested for patients over 35 years old, and for those with abnormal or equivocal triple screening, abnormal or equivocal ultrasound, a history of previous miscarriages, high order gestation or parental chromosomal abnormality. Prenatal diagnosis performed in pregnant patients was carried out on amniotic fluid. Neonatal information and reports were obtained from obstetricians and/or paediatricians. Yq microdeletion assessment Samples were obtained from 96 consenting families with 95 mothers (38 ± 4 years), 66 fathers (44 ± 6 years) and 91 children (5 ± 0.5 years) providing at least one of the following: blood, semen and/or cheek cells (IRB no ). Peripheral lymphocytes were assessed for numerical chromosomal abnormalities by an external laboratory through standard G- band karyotyping. Cells were collected from the cheek mucosa. DNA was isolated from blood cells using the Wizard Genomic DNA Purification Kit (Promega), from semen pretreated with dithiothreitol (DTT) and proteinase K followed by protein precipitation, and from cheek cells by the phenol/chloroform method or the silica-coated magnetic particles method. In the AZF region of the Y chromosome, a total of 22 sequence tagged sites (STS) were analysed by multiplex PCR (Katagiri et al., 2002a,b). The products of PCR underwent electrophoresis in Tris/borate/EDTA buffer (TBE) in 4% NuSieve 3:1 agarose gel, and these were analysed under UV light. ICSI children follow-up study Consenting parents (IRB no ) of children aged 3 years (±6 months) completed the Ages and Stages Questionnaires (ASQ), a series of parent-completed developmental questionnaires spanning the birth to 5 years age range (76 ICSI and 34 IVF children). The ASQ is an illustrated 30-item questionnaire for assessing child development in their natural environment. Five key developmental areas, communication, 457

3 Table 1. Fertilization and pregnancy rates according to the origin of spermatozoa. Spermatozoa Ejaculated Surgically retrieved No. of cycles Maternal age 36.4 ± 5 a 34.4 ± 5 a (mean years ± SD) Fertilization (%) 39,775/52,827 (75.3) 5518/8282 (66.6) b Clinical 2665 (42.5) c 421 (48.7) c pregnancies (%) a Student s t-test, two independent samples; difference in maternal age, P < b χ 2, 2 2, 1 df, effect of sperm source on fertilization rate, P = c χ 2, 2 2, 1 df, effect of sperm source on clinical pregnancy rate, P < gross motor, fine motor, problem solving and personal social, were evaluated in addition to an overall section addressing specific parental concerns. According to the child s score, questionnaires were ranked as typical development or as needing further evaluation (i.e. at risk, clinical range). Data analysis Statistical analysis was performed using Statview 512+ (Brain Power Inc., Calabasas, CA, USA) and Microsoft Excel 2000 (Microsoft Corporation, Redmond, WA, USA). A comparison of the means in continuous data was conducted using Student s unpaired t-test. The χ 2 test was used for discrete univariate and bivariate data except where test assumptions were violated, necessitating the use of Fisher s exact test. Statistical procedures were carried out by two-tailed tests using a 5% level of significance to evaluate all hypotheses. Significant differences are noted in the text and/or tables. Results ICSI was performed in 7134 consecutive cycles of assisted fertilization where spermatozoa were ejaculated, or were surgically retrieved from the epididymis or the testis. To evaluate any eventual difference in fertilization and pregnancy rates, ICSI cycles were grouped according to the collection method and/or whether the spermatozoa were fresh or cryopreserved (Table 1). ICSI with ejaculated spermatozoa Of 6269 ICSI cycles performed with ejaculated spermatozoa, the semen parameters were normal in 851, and were abnormal in 5418, according to the World Health Organization and Kruger criteria. A total of 52,827 mature oocytes were obtained, of which 91.0% (48,052/52,827) survived ICSI, and 75.3% (39,775) developed two pronuclei. When mature spermatozoa were used (i.e. fresh or cryopreserved ejaculated spermatozoa, or those obtained by electroejaculation or bladder catheterization), the origin of the sperm sample did not influence fertilization but influenced pregnancy rate (P = ). When these mature spermatozoa were compared with the surgically retrieved, they had superior fertilization rate (P = ) and a lower pregnancy rate (P < 0.001) as expected from the higher maternal age. ICSI with spermatozoa retrieved surgically The fertilization and the pregnancy characteristics were compared in 473 cycles using epididymal spermatozoa against 392 cycles with testicular spermatozoa. Cryopreservation of epididymal spermatozoa clearly impaired the motility on thawing (P < ), and the pregnancy rate was also lower (P = ), although the fertilization rate was unaffected. On the other hand, when testicular samples were used for ICSI, only the fertilization rate was impaired with cryopreservation (Table 2). When the ICSI outcome with epididymal Table 2. Outcome of ICSI cycles according to the origin and treatment of spermatozoa. Spermatozoa Epididymal Testicular Fresh Frozen/thawed Fresh Frozen/thawed Cycles Maternal age 33.3 ± 5 a 35.5 ± 5 a 34.0 ± 5 b 35.3 ± 5 b (mean years ± SD) Density ( 10 6 /ml SD) 31.6 ± ± ± ± 0.4 Motility (% ± SD) 19.1 ± 17 c 3.1 ± 7 c 5.2 ± ± 4 Morphology (% ± SD) 1.8 ± ± Fertilization (%) 1476/ / / /776 (73.4) (71.5) (60.4) d (55.5) d Clinical pregnancies (%) 126 (65.3) e 127 (45.3) e 136 (44.1) 32 (38.1) a,b Student s t-test, two independent samples; difference in maternal age, P < c Student s t-test, two independent samples; effect of cryopreservation of epididymal spermatozoa on sperm motility, P < d 2 χ, 2 2, 1 df, Effect of cryopreserved testicular spermatozoa on fertilization rate, P < e 2 χ, 2 2, 1 df, Effect of cryopreserved epididymal spermatozoa on clinical pregnancy rate, P =

4 Table 3. ICSI outcome with epididymal spermatozoa in relation to the cause of the obstruction. Obstruction Congenital Acquired Cycles Maternal age 33.4 ± ± 5 (mean years ± SD) Density ( 10 6 /ml ± SD) 31.7 ± ± 26 Motility (mean ± SD) 9.7 ± ± 15 Morphology 1.7 ± ± 2 (mean ± SD) Fertilization (%) 2012/2775 (72.5) 1349/1872 (72.1) Clinical pregnancies 152 (56.3) 101 (49.7) (%) Table 4. ICSI outcome with testicular spermatozoa in relation to the cause of the azoospermia. Table 5. Pregnancy characteristics of 7134 ICSI cycles. n Rate of positive outcomes: % (number) ICSI cycles 7134 a Embryo replacements 6729 Positive βhcg (3807/7134) Biochemical pregnancies 501 Blighted ova 158 Ectopic pregnancies 39 Patients with positive b (3109/7134) fetal heartbeats Miscarriages/therapeutic 288 abortions Deliveries and ongoing (2821/7134) pregnancies a Not applicable. b Clinical pregnancies. Azoospermia Obstructive Non-obstructive Cycles Maternal age 34.8 ± ± 5 (mean years ± SD) Density ( 10 6 /ml ± SD) 0.4 ± ± 3 Motility (mean ± SD) 5.2 ± ± 11 Morphology 0.2 ± (mean ± SD) Fertilization (%) 603/877 (68.7) a 1554/2758 (56.3) a Clinical pregnancies 49 (47.6) 119 (41.2) (%) a χ 2, 2 2, 1 df, effect of aetiology of azoospermia on fertilization rate, P = spermatozoa was observed in relation to the origin of the obstruction, no differences were found in fertilization and pregnancy rates (Table 3), while with testicular spermatozoa, the aetiology of azoospermia appeared to influence only fertilization (P = 0.001) (Table 4). Pregnancy and delivery characteristics Of 7134 ICSI cycles, 3807 resulted in a positive β-human chorionic gonadotrophin (βhcg) (53.4%) (Table 5). Of these, 501 (7.0%) were biochemical pregnancies, 158 (2.2%) were blighted ova, and 39 had an ectopic pregnancy. Among 3109 patients in whom a viable fetal heart was observed by ultrasound, 288 miscarried or aborted. The ongoing pregnancy rate was 39.5% per retrieval (2821/7134) and 41.9% per replacement procedure (2821/6729). Of 3451 neonates born from 2403 deliveries, 1719 were males and 1666 were females (ratio 1.03:1), with 2.8% (97) exhibiting congenital abnormalities at birth. Among the latter, 50 (1.4%) were major and 47 (1.4%) were minor. These ICSI babies experienced a similar rate of congenital malformations to that in offspring born after standard IVF. In a patient population from September 1993 to June 2001, ICSI outcomes were compared in relation to maternal age. In 6356 ICSI cycles with at least one embryo replaced, there was a progressive decrease in pregnancy (P = ) (Table 6) and delivery rates with increasing maternal age (Figure 1), while a direct relationship was observed between the occurrence of miscarriages and therapeutic abortions with maternal age (P = ) (Table 6). Over 48% of the 5286 ICSI cycles in this study population developed a viable fetal heart, with nearly 40% resulting in deliveries and over 56% of live births. Pregnancy wastage was similar to that after conventional in-vitro insemination, as well as that reported by other centres that master ICSI. Cytogenetic information from 362 patients revealed that a chromosomal trisomy was responsible for 40 cases of arrested embryo growth among the 97 who experienced a pregnancy loss (Table 7). Few patients accepted amniocentesis simply because ICSI had been used to conceive their child. Notably, in this cohort the mean maternal age was 38.3 years (range: 31 43). Similarly, in 44 patients with a mean maternal age of 38.3 ± 4 years, pregnancies were terminated due to chromosomal abnormalities (mainly trisomies) evident at prenatal diagnosis, supporting the premise that aneuploidy increases with advancing maternal age. Due to this higher rate of chromosomal abnormalities with increasing age, pregnancy loss was three times greater in women 40 years when compared with those 35 years. In addition, the rates of clinical pregnancy and delivery were drastically reduced in patients older than 36 years. Chromosomal status and incidence of Y deletion A total of 237 blood samples were subjected to chromosomal analysis. Cytogenetic analyses were performed on mothers (n = 93), fathers (n = 65), daughters (n = 47) and sons (n = 35). All the adults and children had normal karyotypes except for one child with a mosaic Klinefelter syndrome, another with a complete Klinefelter syndrome form, and a third with an XYY 459

5 Figure 1. Effect of maternal age on delivery rate. Table 6. Relationship of maternal age to ICSI outcome. No. of cycles with (%) Maternal age (years) < Embryo replacement (ER) Positive βhcg (% of ER) 1623 (67.5) a 1351 (55.7) a 644 (42.2) a Clinical pregnancy (CP) 1366 (56.8) b 1124 (46.3) b 444 (29.1) b (+FHB) (% of ER) Miscarriage (% of CP) 66 (4.8) c 97 (8.6) c 103 (23.2) c Therapeutic abortion 6 (0.43) d 14 (1.2) d 8 (1.8) d (% of CP) Delivery and ongoing 1057 (44.0) e 798 (32.9) e 234 (15.3) e pregnancy (% of ER) FHB = fetal heart beat. a,b,c,e χ 2, 3 2, 2 df, effect of maternal age on pregnancy outcome, P = d χ 2, 3 2, 2 df, effect of maternal age on the frequency of therapeutic abortion, P = syndrome (3.6%, 3/82). The father of the child with the mosaic Klinefelter, the only family member willing to provide a blood sample, had a normal male karyotype. All DNA extraction and PCR amplifications were successful in a total of 98 blood samples, 101 cheek cell specimens and 26 semen samples, analysed for Y chromosome microdeletions. The mean sperm concentration in ejaculates was 39.0 ± /ml (mean ± SD) (n = 40) and 0.9 ± /ml for those retrieved surgically (n = 2). Microdeletions in the AZFb, AZFd and AZFc regions were detected in three fathers (4.5%, 3/66), two of whom had a daughter and one a son with an identical Yq deletion. ICSI children follow-up study Of those invited to take part in a follow-up, only 21.8% (76/348) of ICSI families and only 14.0% (34/242) of IVF families completed the questionnaires. Based on ASQ screening cut-off points, 85.5% of 76 ICSI children displayed normal development, quite comparable to the 88.2% of 34 IVF children. On the other hand, 11 (14.5%) ICSI children were considered at risk, five coming from multiple pregnancies, compared with the four (11.8%) children in the IVF group, of which two were from a high order gestation. There were no differences between boys versus girls in respect of the five developmental areas. Discussion and conclusions Currently, micromanipulation involving ICSI is the most effective means of treating couples with male factor infertility, and also previous fertilization failures following IVF. The high fertilization and pregnancy rates were comparable to those obtained with standard IVF in non-male factor patients regardless of the semen characteristics and/or origin. In addition, the successes with spermatozoa collected from the epididymis and from the testis demonstrate that ICSI can bring about fertilization regardless of the maturational stage of the spermatozoa. Although a difference in fertilization rate was observed with ejaculated spermatozoa, the pregnancy rate was higher, however, in the surgically retrieved groups. Today, the consistency of the results and its relative independence from the quality of the spermatozoa has brought ICSI a wide following. Moreover, concerns related to its invasiveness have been eased by finding a normal incidence of malformations and normal infant development. In order to minimize unpredictable fertilization failure and to maximize the number of available embryos, ICSI has even been proposed as the preferred mode of insemination (Aboulghar et al., 1996a,b). On the other hand, although ICSI has been used occasionally after fertilization failure in standard IVF, direct approach to fertilization of ageing eggs has resulted in an

6 Table 7. Outcome of amniocentesis in ICSI pregnancies from September 1993 to June No. of ICSI IVF Clinical pregnancies Pregnancies analysed (%) 1119(38.1) 809 (40.7) Fetuses karyotyped Abnormalities (%) 33 (2.9) 27 (3.3) Trisomy 2 1 Trisomy 7 1 Trisomy 13 1 Trisomy Trisomy Cystic fibrosis carrier 1 46,XY,inv(9)(p11;q13) ,XX,inv(9)(p11;q13) 1 46,XX,inv(9) 1 46,XY,inv(2) 1 46,XX,t(5:18)(p13;p11.2) 1 46,XY,t(5,7) balanced 1 Unknown translocation ,XY,9qh+ or 46,XX,9qh ,XY,16qh+ 2 46,XY,qs 1 46,XY,22ps+ 1 46,XY,22pss 2 (double satellites) 46,XX,15p+ or 46,XY,15p+ 2/1 46,XX,add(13)(p12)/46,XX 1 46,XY/47,XY,+mar 1 46,XXX 1 Klinefelter full 2/1 form/mosaic Turner syndrome full 1/1 1/ form/mosaic increase incidence of sex chromosome abnormalities (Nagy et al., 1995; Morton et al., 1997; Park et al., 2000; Yuzpe et al., 2000), and in countries such as the UK, this repeat insemination approach using ICSI has been banned (HFEA, 1996; Fishel et al., 2000). Since most of the occasional fertilization failures after ICSI are due to a lower number of eggs retrieved, such cases can be treated by repeating the ICSI procedure in a subsequent cycle with, hopefully, more eggs (Moomjy et al., 1998). In the few isolated cases of fertilization failure after ICSI with adequate number of oocytes, assisted oocyte activation may be particularly helpful (Rybouchikin et al., 1997; Yanagida et al., 1999). The occasional association of severe oligo- or azoospermia with certain genetic defects (Y chromosome microdeletions and karyotypic anomalies) has raised concerns as to whether the defects will be transmitted to the offspring. While such worries have been eased by the outcome and follow-up of ICSI newborns (Bonduelle et al., 1995, 1997, 1998a,b, 2002; Palermo et al., 1996b, 2000), nonetheless, genetic screening, evaluation and counselling of such couples is strongly encouraged. In 1998, an Australian study reported an increased risk for mild developmental delay in 1-year-old ICSI children compared with standard IVF and naturally conceived children (Bowen et al., 1998). While a subsequent reassuring report (Bonduelle et al., 1998b) demonstrated that ICSI and IVF children at 2 years of age have no delayed mental development in comparison with controls, a yet more recent report suggests that infants conceived using either ICSI or standard IVF appear to have a 2-fold increase in risk of having a major birth defect compared with control children (Hansen et al., 2002). However, the study by Hansen et al. appears to suffer from methodological problems such as failure to match maternal age between mothers receiving assisted reproductive treatment and controls, in addition to parity, ethnic background, history of infertility and paternal age (Steinkampf and Grifo, 2002). Furthermore, Hansen et al. did not properly classify the neonatal abnormalities presented and failed to exclude the severe male factor patients, a category linked to higher incidence of abnormalities of the sex chromosomes in their offspring (Sills and Palermo, 2002). Sutcliffe et al. suggested that a possible reason for the discrepancies in Hansen s report may stem from their use of the utilization of the International Classification of Diseases (9th revision), which does not distinguish between major and minor defects, thereby elevating 2-fold the incidence of malformations (Sutcliffe et al., 2002). Therefore the debate is still open and further studies need to be conducted for definitive conclusion. In the present study, the great majority of the 3-year-old children analysed in the ICSI and IVF groups, have developed well in regard to their cognitive abilities, socio-emotional development, and motor skills. According to the ASQ, both ICSI and IVF offspring scored within the normal ranges. This study indicates that the ASQ is a cost-effective method, and currently, a study is being conducted to compare the development of 5-year-old ICSI children with the general population in regard to their psychological and physical development. While further evaluation is still needed since the response rate among both ICSI and IVF parents was relatively low, these preliminary data argue for the safety of the ICSI procedure. In a genetic follow-up of ICSI offspring, these children had a higher incidence of gonosomal abnormalities (3.6%), compared with the general population, possibly arising de novo. However, sex chromosomal abnormalities are increased in offspring of infertile men and the incidence of Yq deletion was within the expected range for an azoo-/oligospermic population. Acknowledgments The authors thank the clinical and scientific staff of The Center for Reproductive Medicine and Infertility and Professor J Michael Bedford for his critical review of the manuscript. References Aboulghar MA, Mansour RT, Serour GI et al The role of intracytoplasmic sperm injection (ICSI) in the treatment of patients with borderline semen. Human Reproduction 10, Aboulghar MA, Mansour RT, Serour GI et al. 1996a 461

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New England Journal of Medicine 338, Palermo GD, Schlegel PN, Hariprashad JJ et al Fertilization and pregnancy outcome with intracytoplasmic sperm injection for azoospermic men. Human Reproduction 14, Palermo GD, Neri QV, Hariprashad JJ et al ICSI and its outcome. Seminars for Reproductive Medicine 18, Park KS, Song HB, Chun SS 2000 Late fertilization of unfertilized human oocytes in in vitro fertilization and intracytoplasmic sperm injection cycles: conventional insemination versus ICSI. Journal of Assisted Reproduction and Genetics 17, Poehl M, Holagschwandtner M, Bichler K 2001 IVF-patients with nonmale factor To ICSI or Not to ICSI That is the question? Journal of Assisted Reproduction and Genetics 18, Reijo R, Alagappan RK, Patrizio P et al Severe oligospermia resulting from deletions of azoospermia factor gene on Y chromosome. 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8 reproduction. New England Journal of Medicine 347, Staessen C, Camus M, Clasen K et al Conventional in-vitro fertilization versus intracytoplasmic sperm injection in sibling oocytes from couples with tubal infertility and normozoospermic semen. Human Reproduction 14, Steinkampf MP, Grifo J 2002 Major birth defects after assisted reproduction. New England Journal of Medicine 347, Sutcliffe AG, Bonduelle M, Taylor BW 2002 Major birth defects after assisted reproduction. New England Journal of Medicine 347, Tournaye H, Devroey P, Liu J et al Microsurgical epididymal sperm aspiration and intracytoplasmic sperm injection: a new effective approach to infertility as a result of congenital bilateral absence of the vas deferens. Fertility and Sterility 61, Van Steirteghem AC, Liu J, Joris H et al Higher success rate by intracytoplasmic sperm injection than by subzonal insemination. Report of a second series of 300 consecutive treatment cycles. Human Reproduction 8, Verheyen G, Tournaye H, Staessen C 1999 Controlled comparison of conventional in-vitro fertilization and intracytoplasmic sperm injection in patients with asthenozoospermia. Human Reproduction 14, Yanagida K, Katayose H, Yazawa H et al Successful fertilization and pregnancy following ICSI and electrical oocyte activation. Human Reproduction 14, Yuzpe AA, Liu Z, Fluker MR 2000 Rescue intracytoplasmic sperm injection (ICSI)-salvaging in vitro fertilization (IVF) cycles after total or near-total fertilization failure. Fertility and Sterility 73, Paper based on contribution presented at the Serono Symposium Toward Optimizing ART: a Tribute to Howard and Georgeanna Jones in Williamsburg, VA, USA, April Received 10 October 2002; refereed 31 October 2002; accepted 17 January

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