A multi-centre cohort study of the physical health of 5-year-old children conceived after intracytoplasmic sperm injection, in vitro fertilization and natural conception

BACKGROUND: Over a million children have been born from assisted conception worldwide. Newer techniques being introduced appear less and less 'natural', such as intracytoplasmic sperm injection (ICSI), but there is little information on these children beyond the neonatal period. METHODS: 540 ICSI conceived 5-year-old children from five European countries were comprehensively assessed, along with 538 matched naturally conceived children and 437 children conceived with standard IVF. RESULTS: Of the 540 ICSI children examined, 63 (4.2%) had experienced a major congenital malformation. Compared with naturally conceived children, the odds of a major malformation were 2.77 (95% CI 1.41-5.46) for ICSI children and 1.80 (95% CI 0.85-3.81) for IVF children; these estimates were little affected by adjustment for socio-demographic factors. The higher rate observed in the ICSI group was due partially to an excess of malformations in the (boys') urogenital system. In addition, ICSI and IVF children were more likely than naturally conceived children to have had a significant childhood illness, to have had a surgical operation, to require medical therapy and to be admitted to hospital. A detailed physical examination revealed no further substantial differences between the groups, however. CONCLUSIONS: Singleton ICSI and IVF 5-year-olds are more likely to need health care resources than naturally conceived children. Assessment of singleton ICSI and IVF children at 5 years of age was generally reassuring, however, we found that ICSI children presented with more major congenital malformations and both ICSI and IVF children were more likely to need health care resources than naturally conceived children. Ongoing monitoring of these children is therefore required.     

Assisted reproduction: the epigenetic perspective

Developmental pathways in humans and other organisms are buffered against changes in genotype and environment. Therefore, it should not come as a surprise that most of the children conceived by assisted reproduction technology (ART) are healthy, although ART bypasses a lot of biological filters and subjects the gametes and the early embryo to environmental stress. If, however, the buffer breaks down, the development of certain tissues or organs may follow abnormal trajectories. We argue that both normal and abnormal development in children conceived by ART can be explained by epigenetic mechanisms, which control the establishment and maintenance of gene expression patterns in the placenta and fetus. Imprinted genes are of special importance in this respect. There is increasing evidence that genetic factors in infertile couples as well as environmental factors (hormones and culture media) can have adverse effects on epigenetic processes controlling implantation, placentation, organ formation and fetal growth. In addition, loss of epigenetic control may expose hidden genetic variation.     

Perinatal complications of assisted reproduction

The main perinatal complications of assisted reproduction include congenital malformation, chromosomal aberrations, multiple pregnancy, and prematurity. Earlier studies and in vitro fertilization (IVF) registries showed that there was no increased incidence of congenital malformations in children conceived by IVF/intracytoplasmic sperm injection (ICSI). However, a large Australian study has found that by one year of age, the incidence of congenital malformations in IVF/ICSI children is increased in comparison with those naturally conceived. Several investigators found a slight but increased risk of chromosomal aberrations in ICSI children. Multiple pregnancy is a major cause of increased perinatal mortality due to increased incidence of both prematurity and congenital malformations. Even in singleton pregnancies conceived by assisted reproductive technologies, the risk of prematurity and newborns small for gestational age is increased. In this article, recently published work on perinatal complications associated with assisted reproductive technologies is reviewed.     

Comparative birth weights of singletons born after assisted reproduction and natural conception in previously infertile women

BACKGROUND: The possible interference of assisted reproduction techniques (ART) with epigenetic reprogramming during early embryo development has recently sparked renewed interest about the reported lower birth weight among infants born as a consequence of infertility treatments. However, the latter finding so far has relied on the comparison of the birth weight of infants conceived with ART to general population data. A more appropriate comparison group should involve pregnancies in infertile women after natural conception. Therefore, we compared neonatal birth weight data of infants born after various ART treatments, including intrauterine insemination (IUI), with those of previously infertile women achieving pregnancy after sexual intercourse. METHODS: Between August 1996 and March 2004 the data of all infertile women presenting in the infertility unit of the University Women's Hospital of Basel, Switzerland, were collected prospectively, adding up to 995 intact pregnancies and deliveries. The birth weight of all infants resulting from 741 singleton pregnancies were analysed with regard to the patients' characteristics, the occurrence of complications during pregnancy and the type of infertility treatment with which the pregnancies were achieved. RESULTS: Comparison of duration of pregnancy and birth weight of infants born after infertility treatment confirms a shorter pregnancy span and a lower mean birth weight in infants born after IVF and ICSI. If women with pregnancies after ART deliver before term, neonatal birth weight is significantly lower. CONCLUSIONS: There is a specific effect of ART, mainly IVF and ICSI, on both shortening the duration of pregnancy and lowering neonatal birth weight. Both these parameters seem to be interrelated consequences of some modification in the gestational process induced by the infertility treatment. Freezing and thawing of oocytes in the pronucleate stage had a lesser impact on pregnancy span and on neonatal birth weight.     

Perinatal outcome and developmental studies on children born after IVF

Since the first birth after IVF, many scientific papers have been published on the technical aspects of the IVF procedure, but few studies have addressed the issue of the perinatal outcome of IVF pregnancies and of the children's development and well-being. A high rate of adverse outcome has been demonstrated in a large group of IVF pregnancies. Prematurity, low birth weight and perinatal mortality are higher than in the general population. The majority of these complications are related to multiple births, but they are also found in singleton pregnancies. An analysis of the multiple risk factors involved in these complications is needed. The infertile status of IVF patients clearly plays a role in the risk of adverse outcome. Age and parity may be important factors. The role of IVF itself has not been demonstrated convincingly. The effect of ovarian stimulation deserves further study. Most of the studies published on the follow-up of IVF children are reassuring, but it is clear that these studies are not sufficient to eliminate without doubt any adverse effects on the well-being of IVF children. All IVF pregnancies should be followed with great care, not because they are more precious than spontaneous pregnancies, but because they are exposed to an increased risk of complications. The main problem of IVF remains the high rate of multiple pregnancies, including twins.     

Single embryo transfer and IVF/ICSI outcome: a balanced appraisal

This review considers the value of single embryo transfer (SET) to prevent multiple pregnancies (MP) after IVF/ICSI. The incidence of MP (twins and higher order pregnancies) after IVF/ICSI is much higher (approximately 30%) than after natural conception (approximately 1%). Approximately half of all the neonates are multiples. The obstetric, neonatal and long-term consequences for the health of these children are enormous and costs incurred extremely high. Judicious SET is the only method to decrease this epidemic of iatrogenic multiple gestations. Clinical trials have shown that programmes with >50% of SET maintain high overall ongoing pregnancy rates ( approximately 30% per started cycle) while reducing the MP rate to <10%. Experience with SET remains largely European although the need to reduce MP is accepted worldwide. An important issue is how to select patients suitable for SET and embryos with a high putative implantation potential. The typical patient suitable for SET is young (aged <36 years) and in her first or second IVF/ICSI trial. Embryo selection is performed using one or a combination of embryo characteristics. Available evidence suggests that, for the overall population, day 3 and day 5 selection yield similar results but better than zygote selection results. Prospective studies correlating embryo characteristics with documented implantation potential, utilizing databases of individual embryos, are needed. The application of SET should be supported by other measures: reimbursement of IVF/ICSI (earned back by reducing costs), optimized cryopreservation to augment cumulative pregnancy rates per oocyte harvest and a standardized format for reporting results. To make SET the standard of care in the appropriate target group, there is a need for more clinical studies, for intensive counselling of patients, and for an increased sense of responsibility in patients, health care providers and health insurers.     

Perinatal outcome of 12,021 singleton and 3108 twin births after non-IVF-assisted reproduction: a cohort study

Perinatal outcome of pregnancies caused by assisted reproduction technique (ART) is substantially worse when compared with pregnancies following natural conception. We investigated the possible risks of non-IVF ART on perinatal health. We conducted a retrospective cohort study with two exposure groups: a study group of pregnancies after controlled ovarian stimulation (COS), with or without artificial insemination (AI), and a naturally conceived comparison group. We used the data from the regional registry of all hospital deliveries in the Dutch-speaking part of Belgium during the period from January 1993 until December 2003 to investigate differences in perinatal outcome of singleton and twin pregnancies. 12 021 singleton and 3108 twin births could be selected. Naturally conceived subjects were matched for maternal age, parity, fetal sex and year of birth. The main outcome measures were duration of pregnancy, birth weight, perinatal morbidity and perinatal mortality. Our overall results showed a significantly higher incidence of prematurity (<32 and <37 weeks), low and very low birth weight, transfer to the neonatal intensive care unit and most neonatal morbidity parameters for COS/AI singletons. Twin pregnancies resulting from COS/AI showed an increased rate of neonatal mortality, assisted ventilation and respiratory distress syndrome. After excluding same-sex twin sets, COS/AI twin pregnancies were at increased risk for extreme prematurity and very low birth weight. In conclusion, COS/AI singleton and twin pregnancies are significantly disadvantaged compared to naturally conceived children.     

Follow-up studies of children born after frozen sperm donation

The need to assess the health of children born after assisted reproductive technologies (ART) using frozen donor spermatozoa has been a major concern for the last decade. Most available published studies are confusing (since they are retrospective) and refer to small numbers of cases or involve a bias. Two prospective and large population-based studies have been published, one in France and the other in Australia. The general characteristics of children born after ART using frozen spermatozoa was unchanged in comparison with the general population (weight, prematurity, stillbirths, sex ratio). However, the rate of multiple pregnancy was increased, first in artificial insemination with donor semen (AID), where the use of hormonal treatment may be too heavily prescribed, and second in IVF with donor semen (IVF/D) where both the ovulation induction treatments and embryo transfer policy increase the rate of multiple pregnancies. As far as birth defects or chromosomal abnormalities are concerned, no difference has been observed from the general population. Finally, the use of frozen spermatozoa does not seem to affect the health of children conceived by AID or IVF/D. The psychosocial development of such infants is not as well known because of the confidentiality in many countries concerning sperm donation. However, the available information on the psychosocial development of these children up to the age of 8-10 years appears to be reassuring. Larger and longer studies are needed to answer such questions, particularly with regard to adulthood.     

Neonatal data on a cohort of 2889 infants born after ICSI (1991-1999) and of 2995 infants born after IVF (1983-1999)

BACKGROUND: To evaluate the safety of ICSI, this study compared data of IVF and ICSI children by collecting data on neonatal outcome and congenital malformations during pregnancy and at birth. METHODS: The follow-up study included agreement to genetic counselling and eventual prenatal diagnosis, followed by a physical examination of the children after 2 months, after 1 year and after 2 years. 2840 ICSI children (1991-1999) and 2955 IVF children (1983-1999) were liveborn after replacement of fresh embryos. ICSI was carried out using ejaculated, epididymal or testicular sperm. RESULTS: In the two cohorts, similar rates of multiple pregnancies were observed. ICSI and IVF maternal characteristics were comparable for medication taken during pregnancy, pregnancy duration and maternal educational level, whereas maternal age was higher in ICSI and a higher percentage of first pregnancies and first children born was observed in the ICSI mothers. Birthweight, number of neonatal complications, low birthweight, stillbirth rate and perinatal death rate were compared between the ICSI and the IVF groups and were similar for ICSI and IVF. Prematurity was slightly higher in the ICSI children (31.8%) than in the IVF children (29.3%). Very low birthweight was higher in the IVF pregnancies (5.7%) compared with ICSI pregnancies (4.4%). Major malformations (defined as those causing functional impairment or requiring surgical correction), were observed at birth in 3.4% of the ICSI liveborn children and in 3.8% of the IVF children (P = 0.538). Malformation rate in ICSI was not related to sperm origin or sperm quality. The number of stillbirths (born > or =20 weeks of pregnancy) was 1.69% in the ICSI group and 1.31% in the IVF group. Total malformation rate taking into account major malformations in stillborns, in terminations and in liveborns was 4.2% in ICSI and 4.6% in IVF (P = 0.482). CONCLUSIONS: The comparison of ICSI and IVF children taking part in an identical follow-up study did not show any increased risk of major malformations and neonatal complications in the ICSI group.     

IVF/ICSI twin pregnancies: risks and prevention

Since the 1970s, the national twin birth rates have been increasing worldwide. Apart from the increasing childbearing age, the main cause is the use of assisted reproductive technologies (ART). To explore the overall consequences of dual embryo transfer (DET), the literature has been reviewed systematically regarding short- and long-term outcomes of IVF/ICSI twin pregnancies i.e. pregnancy complications, maternal risks, obstetric outcome and long-term morbidity including neurological sequelae, cognitive development and family implications. Another consequence of DET is vanishing twins, which seems to be a possible cause of adverse outcome in IVF singletons. The sparse literature on vanishing twins in IVF pregnancies and the influence on the surviving co-twin were also addressed. Finally, to determine the effects of implementing elective single embryo transfer (eSET), trials concerning eSET versus DET were analysed. In the light of the steadily increasing twin birth rates and the findings in this overview, where IVF/ICSI twins carry adverse outcome, it should be emphasized that the major obstacle in IVF remains the high twin birth rate. Furthermore vanishing twins account for another hazard of DET. These problems can be resolved by implementing eSET, diminishing the twin birth rate without affecting the overall goal of achieving a healthy infant.     

Neuromotor, cognitive, language and behavioural outcome in children born following IVF or ICSI-a systematic review

BACKGROUND: The effect of in vitro fertilization (IVF) or intracytoplasmicsperm injection (ICSI) on the developing human brain is unclear.The objective of this study is to evaluate neurodevelopmental(ND) outcome of children born following these techniques. METHODS: This systematic review includes studies which compare a groupof children born following IVF/ICSI to children born after naturalconception by assessing outcome in terms of neuromotor development,cognition, speech/language and behaviour. Specific attentionis paid to the studies’ methodological quality based onstudy design, attrition, blinding of the assessor, validityof ND tests used, confounders included and group size or poweranalysis. RESULTS: Twenty-three out of 59 studies had a good methodological qualityincluding 9 register-based (RB) and 14 controlled studies. RBstudies suggested that IVF/ICSI per se does not increase therisk for severe cognitive impairment (i.e. mental retardation)or neuromotor handicaps such as cerebral palsy (CP), the associationof IVF/ICSI and CP being brought about by the association ofassisted conception with risk factors, like preterm birth. Ingeneral, controlled studies of good quality did not report anexcess of ND disorders in IVF/ICSI-children. However, the majorityof studies followed the children during infancy only, therebyprecluding pertinent conclusions on the risk of ND disordersthat come to the expression at older ages, such as fine manipulativedisability or dyslexia. CONCLUSIONS: A negative effect of assisted conception on the developing humanbrain is not identified; however, further research of high methodologicalquality in children beyond pre-school age is needed.     

Globozoospermia revisited

Globozoospermia is a rare (incidence <0.1%) but severe disorder in male infertility. Total globozoospermia is diagnosed by the presence of 100% round-headed spermatozoa lacking an acrosome. It is still unclear whether patients whose ejaculate contains both normal and globozoospermic cells (partial globozoospermia) suffer from a variation of the same syndrome. Apart from the fact that affected males suffer from reduced fertility or even infertility, no other physical characteristics can be associated with the syndrome. ICSI is a treatment option for these patients, although low fertilization rates after ICSI show a reduced ability to activate the oocyte. In globozoospermic cells, the use of acrosome markers has demonstrated an absent or severely malformed acrosome. Chromatin compaction appears to be disturbed but is not consistently over- or undercondensed. In some cases, an increased number of cells with DNA fragmentation have been observed. The analysis of the cytogenetic composition revealed an increased aneuploidy rate in some cases. Nonetheless, no increased number of spontaneous abortions or congenital defects has been reported in pregnancies conceived after ICSI. The pathogenesis of globozoospermia most probably originates in spermiogenesis, more specifically in acrosome formation and sperm head elongation. In several knockout mouse models, a phenotype similar to that in humans was found. Together with the occurrence of affected siblings, these findings indicate a genetic origin, which makes globozoospermia a good candidate for genetic analysis. More research is needed to elucidate the pathogenesis of human globozoospermia to further understand globozoospermia as well as (abnormalities in) spermiogenesis and spermatogenesis in general.     

Androgen receptor CAG polymorphism (Xq11-12) status and human spermatogenesis: a prospective analysis of infertile males and their offspring conceived by intracytoplasmic sperm injection

We determined the association of androgen receptor (AR) (CAG)n lengths among fertile and infertile males and offspring conceived by intracytoplasmic sperm injection (ICSI). Assessment of (CAG)n repeats in the AR was performed in a Caucasian population by gene sequencing in fertile men (n=13), infertile men (n=64), boys conceived after ICSI (n=21), and boys conceived naturally (n=11). In the AZF region of the Y chromosome, a total of 22 STSs were analyzed by multiplex PCR; selected spermatozoa were also analyzed by fluorescent in situ hybridization (FISH) for chromosomes 18, 21, X, and Y. The average age was 43.7+/-7 yr for infertile, 44.8+/-7 yr for fertile men, and 5.0+/-0.5 yr for the children. The mean (CAG)n was 22.2+/-3 for the infertile men and 19.3+/-5 for fertile controls. There was a significant difference in CAG repeat length in the severely oligo-/azoo-spermic men vs. controls (p=0.02). An inverse correlation was evident between CAG length and semen parameters. For ICSI male children, the AR (CAG)n lengths were 21.4+/-3.2 vs. 20.8+/-3.4 for boys conceived naturally. While all peripheral karyotypes of fertile and infertile men were normal, de novo gonosomal abnormalities were observed in the ICSI offspring. The incidence of Y microdeletions was 1.6% in infertile men; all the ICSI sons had an intact Y chromosome. In conclusion, severely oligo- and azoospermic men had longer CAG repeat length than fertile controls, suggesting that certain AR gene mutations may have a negative effect on spermatogenesis. An increased incidence of de novo gonosomal abnormalities was found in the ICSI offspring when compared to children conceived naturally. Our assessment of the polymorphic region of the AR gene, in the absence of other specific genomic abnormalities, suggests that the fertility of children conceived by ICSI may be conserved.     

Maternal serum alpha-fetoprotein and human chorionic gonadotrophin in pregnancies conceived after intracytoplasmic sperm injection and conventional in-vitro fertilization.

Data in the Caucasian population suggest that maternal serum alpha-fetoprotein (AFP) and unconjugated oestriol concentrations are reduced and human chorionic gonadotrophin (HCG) concentrations are elevated in pregnancies conceived after in-vitro fertilization (IVF), leading to a higher than expected Down's syndrome screen-positive rate. There are no previous reports on the serum marker values in pregnancies conceived after intracytoplasmic injection (ICSI). Between 1996 and 1998, we measured maternal serum total HCG and AFP concentrations between 15 and 20 weeks gestation in 42 in-vitro fertilization (IVF) pregnancies and 23 ICSI pregnancies with known normal outcome. The results were compared with that of 2799 naturally occurring singleton pregnancies who were known to have a normal outcome. Median AFP multiple of the median (MOM) in ICSI pregnancies was significantly reduced to 0.76 compared with both that of the controls and that of the IVF pregnancies. For the IVF pregnancies, median HCG MOM was elevated to 1.15, and median AFP MOM was reduced to 0.88 compared with the controls, but these differences were not statistically significant. In both the IVF and ICSI pregnancies the changes might result in a falsely high Down's syndrome risk. In particular, the reduced AFP concentration in ICSI pregnancies was substantial. If this preliminary finding is substantiated by other series, the appropriate adjustment needs to be made to allow for valid interpretation of the screen result and to avoid an unnecessarily high false positive rate.     

Transmission of male infertility to future generations: lessons from the Y chromosome

The introduction of ICSI and testicular sperm extraction (TESE) has allowed many infertile men to father children. The biggest concern about the wide use of these techniques is the health of the resulting offspring, in particular their fertility status. If the spermatogenic defect is genetic in origin, there is potential risk of transmitting this defect to future offspring. The most frequently documented genetic cause of male infertility is a Y chromosome deletion. The Y chromosome has acquired a large number of testis-specific genes during recent evolution, and deletions causing infertility take out a number of these genes. These deletions have been shown to be transmitted to 100% of male offspring. Also, absence of an aberration on the Y chromosome does not rule out a genetic cause of the infertility phenotype, as there are many other genes involved in spermatogenesis elsewhere in the genome, and current mapping techniques--especially on the Y chromosome--can miss many aberrations. More detailed studies of these spermatogenesis genes, which are now possible because of more precise sequence-based mapping, will lead to improved understanding of the genetic basis of male infertility and enable proper counselling of patients undergoing ICSI in the future.     

The present and future state of hormonal treatment for male infertility

Although male factors contribute to over half of all cases of infertility, most infertile men are described as 'idiopathic oligo/asthenozoospermic' rather than diagnosed precisely; hence, specific medical treatment is not possible. One uncommon but treatable cause of male infertility is gonadotrophin deficiency in which gonadotrophin replacement therapy is highly effective at inducing spermatogenesis and fertility. Hormonal therapy is a logical approach for empirical drug therapy given the fundamental role of hormonal regulation in spermatogenesis. However, treatment with GnRH analogues, gonadotrophins, androgens, anti-estrogens, aromatase inhibitors, growth hormone- and prolactin-suppressing drugs is ineffective in unselected infertile men. Prolonged high-dose glucocorticoid therapy for sperm autoimmunity may improve pregnancy rates modestly, but the risks are generally unacceptable compared with IVF or ICSI. For these reasons, modern reproductive technologies, notably ICSI/IVF, have become the de-facto standard empirical treatment of male infertility, despite involving significant though infrequent risks to the fetus and mother. There remains a potential for hormonal methods to improve sperm quality or ultrastructure in subgroups of infertile men more responsive to hormonal manipulation or using novel protein or gene-targeted therapies or biochemical approaches based on post-hormonal receptor mechanisms that stimulate spermatogenesis. How such novel hormonal methods will develop in conjunction with improved ICSI/IVF or cloning technologies, and the potential role of adjunctive hormonal therapy remains to be clarified.     

Clinical implications of uterine malformations and hysteroscopic treatment results

Uterine malformations consist of a group of miscellaneous congenital anomalies of the female genital system. Their mean prevalence in the general population and in the population of fertile women is approximately 4.3%, in infertile patients approximately 3.5% and in patients with recurrent pregnancy losses approximately 13%. Septate uterus is the commonest uterine anomaly with a mean incidence of approximately 35% followed by bicornuate uterus (approximately 25%) and arcuate uterus (approximately 20%). It seems that malformed uterus and especially septate uterus is not an infertility factor in itself. However, it may have a part in the delayed natural conception of women with mainly secondary infertility. On the other hand, patients with uterine malformations seem to have an impaired pregnancy outcome even as early as their first pregnancy. Overall term delivery rates in patients with untreated uterine malformations are only approximately 50% and obstetric complications are more frequent. Unicornuate and didelphys uterus have term delivery rates of approximately 45%, and the pregnancy outcome of patients with untreated bicornuate and septate uterus is also poor with term delivery rates of only approximately 40%. Arcuate uterus is associated with a slightly better but still impaired pregnancy outcome with term delivery rates of approximately 65%. Women who have undergone hysteroscopic septum resection and have been reported in the different series comprise a highly selected group of symptomatic patients with term delivery and live birth rates of only approximately 5%. Hysteroscopic treatment seems to restore an almost normal prognosis for the outcome of their pregnancies with term delivery rates of approximately 75% and live birth rates of approximately 85%. It seems, therefore, that hysteroscopic septum resection can be applied as a therapeutic procedure in cases of symptomatic patients but also as a prophylactic procedure in asymptomatic patients in order to improve their chances for a successful delivery.     

PGD in 47,XXY Klinefelter's syndrome patients

The use of ICSI has been a major breakthrough in the treatment of male infertility. Even azoospermic patients with focal spermatogenesis in the testis, may benefit from the ICSI technique in order to father a child. As ICSI use has become more common, centres have introduced infertility treatment for Klinefelter patients. To date, 34 healthy children have been born using ICSI without PGD, and the conception of one 47,XXY fetus has been reported. In view of the possible risk of an increased gonosome number in the spermatozoa of Klinefelter patients, a safer approach--offering these couples ICSI combined with PGD--has been used, and has resulted in the birth of three healthy children. Couples in which the male suffered from Klinefelter's syndrome were first treated in 1995; these patients were offered ICSI + PGD using FISH technology, notably to enumerate the X and Y chromosomes. ICSI + PGD was performed in 32 cycles of 20 couples with spermatozoa originating from a fresh ejaculate (n = 1), testicular biopsy (n = 21) or frozen-thawed testicular biopsy (n = 10). Normal fertilization occurred in 56.0 +/- 22.4% of the successfully injected oocytes. On day 3 of development, 119 embryos from 29 cycles were of sufficient quality to undergo biopsy and subsequent PGD; a positive result was obtained in 113 embryos. Embryos were available for transfer in 26 cycles, with a mean of 1.6 +/- 0.6 embryos per transfer. Eight pregnancies were obtained, and five resulted in a delivery. A total of 113 embryos from couples with Klinefelter's syndrome was compared with 578 embryos from control couples with X-linked disease where PGD was used to determine gender. A significant fall occurred in the rate of normal embryos for couples with Klinefelter's syndrome (54.0%) compared with controls (77.2%). Moreover, a significantly increased risk of abnormalities was observed for sex chromosomes and autosomes; for each autosome separately, this reached significance level for chromosomes 18 and 21 only. Hence, a cautious approach is warranted in advising couples with non-mosaic Klinefelter's syndrome. Moreover, the use of ICSI + PGD or prenatal diagnosis should be carefully considered.     

Intracytoplasmic sperm injection (ICSI) in 2006: evidence and evolution

The introduction of intracytoplasmic sperm injection (ICSI)in 1992 has dramatically changed the management of severe maleinfertility. In severe male infertility, live birth rates withICSI are superior to those with other non-donor treatments.In non-male infertility, however, pregnancy rates are not betterwith ICSI than with in vitro fertilization (IVF). With obstructiveor non-obstructive azoospermia, reasonable pregnancy rates arenow possible with ICSI after recovery of sperm from the testesfollowed by ICSI. Genetic counselling is indicated for severemale infertility, whether or not ICSI is considered. ICSI isindicated in preimplantation genetic diagnosis (PGD) to avoidcontamination by extraneous DNA in the case of PCR-based testingand to increase the number of embryos available for testing.In turn, PGD may be indicated in pregnancies that are at highrisk of aneuploidy because of genetic factors associated withazoospermia. As with IVF, not all couples succeed, but 2% ofcouples with failed ICSI cycles will conceive without treatment.ICSI outcome studies indicate that there is a significant increasein prematurity, low birthweight, and perinatal mortality associatedwith single and multiple births, similar to the outcomes ofconventional IVF. However, as evidenced in long-term follow-upstudies, the higher rates of urogenital abnormalities and increaseduse of healthcare may be associated with paternal characteristics.     

Fertility after hysteroscopic myomectomy

The available data concerning hysteroscopic myomec-tomy forsubmucous myomas has been reviewed with the aim of evaluatingthe safety and efficacy of this technique in infertile womenwho wish to preserve or to enhance their fertility potential.A total of 134 infertile patients undergoing hysteroscopic myomectomyby resectoscope or by Nd:YAG laser or by scissors have beencollectively recorded. Of these, 79 (58.9%) patients conceived.This clinical outcome is similar to that occurring after laparotomicsubmucous myomectomy. Moreover, the hysteroscopic approach hasseveral advantages over its abdominal counterpart, such as reductionof length of time of hospitalization, less morbidity and nohysterotomy. The operative risk of hysteroscopic myomectomyis 3%. Uterine perforation, distension system hazard, infectionand haemorrhage are the commonest complications. Hysteroscopicmyomectomy is a safe, effective and relatively simple surgicalprocedure for the restoration of fertility.