Impact of male factor infertility on offspring health and development

Monitoring the safety of intracytoplasmic sperm injection (ICSI) has been impeded by uncertainties regarding the extent to which offspring health is influenced by paternal characteristics linked to male infertility or the processes that ICSI treatment entails. Few studies examining long-term health and developmental outcomes in children conceived with ICSI have considered the influence of paternal infertility adequately. In the available literature, large population-based studies suggest underlying male factors, and the severity of male factor infertility, increase the risk of mental retardation and autism in offspring, as does the ICSI procedure itself, but these findings have not been replicated consistently. Robust evidence of the influence of male factors on other health outcomes is lacking, with many studies limited by sample size. Nevertheless, emerging evidence suggests children conceived with ICSI have increased adiposity, particularly girls. Further, young men conceived with ICSI may have impaired spermatogenesis; the mechanisms underlying this remain unclear, with inconclusive evidence of inheritance of Y chromosome microdeletions. The current inconsistent and often sparse literature concerning the long-term health of children conceived with ICSI, and the specific influence of male infertility factors, underscore the need for concerted monitoring of children conceived with this technique across the lifespan. With the rapid expansion of use of ICSI for non-male factors, sufficiently large studies that compare outcomes between groups conceived with this technique for male factors versus non-male factors will provide critical evidence to elucidate the intergenerational impact of male infertility. Monitoring the safety of intracytoplasmic sperm injection (ICSI) has been impeded by uncertainties regarding the extent to which offspring health is influenced by paternal characteristics linked to male infertility or the processes that ICSI treatment entails. Few studies examining long-term health and developmental outcomes in children conceived with ICSI have considered the influence of paternal infertility adequately. In the available literature, large population-based studies suggest underlying male factors, and the severity of male factor infertility, increase the risk of mental retardation and autism in offspring, as does the ICSI procedure itself, but these findings have not been replicated consistently. Robust evidence of the influence of male factors on other health outcomes is lacking, with many studies limited by sample size. Nevertheless, emerging evidence suggests children conceived with ICSI have increased adiposity, particularly girls. Further, young men conceived with ICSI may have impaired spermatogenesis; the mechanisms underlying this remain unclear, with inconclusive evidence of inheritance of Y chromosome microdeletions. The current inconsistent and often sparse literature concerning the long-term health of children conceived with ICSI, and the specific influence of male infertility factors, underscore the need for concerted monitoring of children conceived with this technique across the lifespan. With the rapid expansion of use of ICSI for non-male factors, sufficiently large studies that compare outcomes between groups conceived with this technique for male factors versus non-male factors will provide critical evidence to elucidate the intergenerational impact of male infertility. Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/48580-28218 Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/48580-28218 Male factor infertility is defined as one or more abnormal semen parameters detected on semen analysis or the presence of inadequate sexual or ejaculatory function (1Rowe P.J. Comhaire F.H. Hargreave T.B. Mahmoud A.M.A. WHO manual for the standardized investigation and diagnosis of the infertile male. Cambridge University Press, Cambridge, UK2000Google Scholar). Among couples seeking treatment for infertility, male factors are the sole cause in approximately 20% of cases and implicated in a further 30% to 40% in combination with female factors (2Hull M.G. Glazener C.M. Kelly N.J. Conway D.I. Foster P.A. Hinton R.A. et al.Population study of causes, treatment, and outcome of infertility.Br Med J (Clin Res Ed). 1985; 291: 1693-1697Google Scholar, 3Thonneau P. Marchand S. Tallec A. Ferial M.L. Ducot B. Lansac J. et al.Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988-1989).Hum Reprod. 1991; 6: 811-816Google Scholar, 4Anderson J.E. Farr S.L. Jamieson D.J. Warner L. Macaluso M. Infertility services reported by men in the United States: national survey data.Fertil Steril. 2009; 91: 2466-2470Google Scholar, 5Leung A.K. Henry M.A. Mehta A. Gaps in male infertility health services research.Transl Androl Urol. 2018; 7: S303-S309Google Scholar). Common semen abnormalities include low semen volume (oligospermia, ≤1.5 ml), low sperm concentration (oligozoospermia, ≤15 million spermatozoa/ml), decreased sperm motility (asthenozoospermia, total motility ≤40% or <32% progressive motile spermatozoa), and abnormal sperm morphology (teratozoospermia, ≤4% normal forms) (6Cooper T.G. Noonan E. Von Eckardstein S. Auger J. Baker H.W.G. Behre H.M. et al.World Health Organization reference values for human semen characteristics.Hum Reprod Update. 2010; 16: 231-245Google Scholar). The degree of male infertility is typically classified as severe when there is a sperm concentration less than 5 million per milliliter (severe oligozoospermia) or no sperm in the ejaculate (azoospermia) (7Practice Committee of the American Society for Reproductive MedicineDiagnostic evaluation of the infertile male: a committee opinion.Fertil Steril. 2015; 103: e18-e25Google Scholar). The introduction of intracytoplasmic sperm injection (ICSI) into assisted reproductive technology (ART) in 1992 heralded a breakthrough in the treatment of severe male factor infertility. Prior to that, couples with this type of infertility often faced a poor prognosis with conventional in vitro fertilization (IVF), which is reliant on optimal numbers and functioning of sperm for fertilization. In contrast, ICSI involves the direct injection of a single spermatozoon into the oocyte via micromanipulation techniques, using either ejaculated sperm or, in the case of azoospermia, microsurgically extracted sperm from the epididymis or testis. The use of ICSI has enabled many couples worldwide to achieve their desire for a biological child. Nevertheless, there have been ongoing concerns about the health and developmental outcomes of children conceived by this technique, as the use of a single spermatozoon bypasses the processes of natural sperm selection occurring in normal fertilization. A primary concern is the potential for transmission of genetic disorders to the child. Men with severe oligozoospermia or azoospermia have an increased risk of genetic abnormalities including karyotypic chromosomal abnormalities, Y-chromosome microdeletions and cystic fibrosis gene mutations, and can also have sperm that are chromosomally abnormal even when there is no detectable genetic defect (7Practice Committee of the American Society for Reproductive MedicineDiagnostic evaluation of the infertile male: a committee opinion.Fertil Steril. 2015; 103: e18-e25Google Scholar, 8Katagiri Y. Neri Q.V. Takeuchi T. Schlegel P.N. Megid W.A. Kent-First M. et al.Y chromosome assessment and its implications for the development of ICSI children.Reprod Biomed Online. 2004; 8: 307-318Google Scholar, 9Foresta C. Garolla A. Bartoloni L. Bettella A. Ferlin A. Genetic Abnormalities among Severely Oligospermic Men Who Are Candidates for Intracytoplasmic Sperm Injection.J Clin Endocrinol Metab. 2005; 90: 152-156Google Scholar). Genetic factors have also recently been linked to abnormalities in sperm morphology and function (10Ray P.F. Toure A. Metzler-Guillemain C. Mitchell M.J. Arnoult C. Coutton C. Genetic abnormalities leading to qualitative defects of sperm morphology or function.Clin Genet. 2017; 91: 217-232Google Scholar). A second concern is the potential introduction of epigenetic modifications, with diverse consequences for offspring health and development (11Thompson J.G. Kind K.L. Roberts C.T. Robertson S.A. Robinson J.S. Epigenetic risks related to assisted reproductive technologies: short- and long-term consequences for the health of children conceived through assisted reproduction technology: more reason for caution?.Hum Reprod. 2002; 17: 2783-2786Google Scholar, 12Chen M. Heilbronn L.K. The health outcomes of human offspring conceived by assisted reproductive technologies (ART).J Dev Orig Health Dis. 2017; 8: 388-402Google Scholar). Epigenetic alterations may occur because of parental characteristics related to infertility or directly from the laboratory processes involved in ICSI required to create and manipulate embryos (13Whitelaw N. Bhattacharya S. Hoad G. Horgan G.W. Hamilton M. Haggarty P. Epigenetic status in the offspring of spontaneous and assisted conception.Hum Reprod. 2014; 29: 1452-1458Google Scholar). Several reviews of the literature pertaining to long-term health and developmental outcomes of children conceived with ICSI have now been undertaken (14Rumbold A.R. Moore V.M. Whitrow M.J. Oswald T.K. Moran L.J. Fernandez R.C. et al.The impact of specific fertility treatments on cognitive development in childhood and adolescence: a systematic review.Hum Reprod. 2017; 32: 1489-1507Google Scholar, 15Catford S.R. McLachlan R.I. O'Bryan M.K. Halliday J.L. Long-term follow-up of intra-cytoplasmic sperm injection-conceived offspring compared with in vitro fertilization-conceived offspring: a systematic review of health outcomes beyond the neonatal period.Andrology. 2017; 5: 610-621Google Scholar, 16Catford S.R. McLachlan R.I. O'Bryan M.K. Halliday J.L. Long-term follow-up of ICSI-conceived offspring compared with spontaneously conceived offspring: a systematic review of health outcomes beyond the neonatal period.Andrology. 2018; 6: 635-653Google Scholar, 17Bay B. Lyngsø J. Hohwü L. Kesmodel U. Childhood growth of singletons conceived following in vitro fertilisation or intracytoplasmic sperm injection: a systematic review and meta-analysis.BJOG. 2019; 126: 158-166Google Scholar). These reviews identify possible increased risks of certain neurodevelopmental disorders, as well as impaired cardiometabolic and reproductive health profiles among children conceived with ICSI. However, the pattern of elevated risks is not consistent across all studies. In addition, uncertainties remain about whether any increases in risk are due to infertility itself or to aspects of the treatment. Discerning the impact of these various factors has been difficult in historical cohorts of ICSI-conceived children, where the use of ICSI has occurred exclusively for severe male infertility. Typically, children in these cohorts have been compared with either children conceived spontaneously or those conceived with conventional IVF; in both instances, the parental health profiles of the comparison groups are considerably different to the ICSI group, and the treatment modality tends to be inextricably linked to the type of infertility experienced. However, the past two decades have witnessed a rapid rise in the use of ICSI for mild male factor infertility, non-male factors, and fertilization failures (18Boulet S.L. Mehta A. Kissin D.M. Warner L. Kawwass J.F. Jamieson D.J. Trends in use of and reproductive outcomes associated with intracytoplasmic sperm injection.JAMA. 2015; 313: 255Google Scholar), such that it is now the predominant mode of ART conception in many countries. While this may not be prudent given the unknown risks (19Evers J.L. Santa Claus in the fertility clinic.Hum Reprod. 2016; 31: 1381-1382Google Scholar), it does mean that it is now possible to examine outcomes among children conceived with ICSI with stratification for type and severity of infertility, including specific sperm parameters. This is important not only for counselling individual couples about long-term risks associated with an infertility diagnosis, but also for identifying the treatment factors that could be modified to promote offspring health. Here we review the literature concerning the long-term outcomes of children conceived with ICSI, where attempts have been made to distinguish the specific influence of male factor infertility (and severity) from ICSI treatment-related factors. We focus on outcomes related to cognitive development, neurodevelopmental disorders, growth and metabolic health, and male infertility (Table 1).Table 1Summary of research examining paternal infertility requiring treatment with ICSI on long-term health and developmental outcomes in offspring.OutcomeSummaryCognitive outcomesThe severity of male factor infertility does not appear to influence cognitive development in early childhood among children conceived with ICSI, however, many studies are limited by sample size and the potential for ICSI by itself to influence cognitive outcomes requires clarification.Neurodevelopmental disordersSeveral large population-based studies report modest increases in risks of mental retardation and autism in children conceived with ICSI. There are conflicting findings concerning the specific contribution of male factor infertility to these elevated risks.Growth, adiposity, and cardiometabolic healthThere is evidence that children conceived with ICSI have accelerated postnatal growth and may be at risk of increased adiposity, particularly girls. The specific influence of male factor infertility on these outcomes remains unknown, and studies are limited by small sample size.Male infertilityMen conceived with ICSI may have impaired spermatogenesis, which could be due to either inherited or non-inherited factors. This requires confirmation in larger studies.Note: ICSI = intracytoplasmic sperm injection. Open table in a new tab Note: ICSI = intracytoplasmic sperm injection. There is now a substantial pool of studies examining cognitive outcomes in children conceived with ICSI. A recent systematic review of this literature (14Rumbold A.R. Moore V.M. Whitrow M.J. Oswald T.K. Moran L.J. Fernandez R.C. et al.The impact of specific fertility treatments on cognitive development in childhood and adolescence: a systematic review.Hum Reprod. 2017; 32: 1489-1507Google Scholar) found that most studies were subject to methodological limitations, with less than a third of studies rated as high quality. Among high quality studies the results were conflicting, with some evidence of lower intelligence quotient (IQ) scores among children conceived with ICSI relative to spontaneously conceived children and IVF children, while other studies reported comparable outcomes between these groups. We identified seven studies that examined cognitive outcomes among children conceived with ICSI with stratification for specific paternal sperm parameters. In a study of 208 singleton children aged 1 to 2 years of age, Sutcliffe and colleagues (20Sutcliffe A.G. Taylor B. Saunders K. Thornton S. Lieberman B.A. Grudzinskas J.G. Outcome in the second year of life after in-vitro fertilisation by intracytoplasmic sperm injection: a UK case-control study.Lancet. 2001; 357: 2080-2084Google Scholar) reported no differences in mean scores on the Griffiths Mental Development Scales between children conceived to oligozoospermic men and those conceived to men with other sperm abnormalities or other indications for ICSI. The findings were replicated by the same group in a study of 58 singleton ICSI children of the same age (21Sutcliffe A.G. Saunders K. McLachlan R. Taylor B. Edwards P. Grudzinskas G. et al.A retrospective case-control study of developmental and other outcomes in a cohort of Australian children conceived by intracytoplasmic sperm injection compared with a similar group in the United Kingdom.Fertil Steril. 2003; 79: 512-516Google Scholar), with the authors concluding that the severity of the father's sperm defect did not significantly influence infant neurodevelopmental outcomes. Similarly, in a subset of 439 ICSI children (including twins) aged 24 to 28 months, Bonduelle et al. (22Bonduelle M. Ponjaert I. Steirteghem A.V. Derde M.P. Devroey P. Liebaers I. Developmental outcome at 2 years of age for children born after ICSI compared with children born after IVF.Hum Reprod. 2003; 18: 342-350Google Scholar) found no difference in the mean scores on the Bayley Scales of Infant Development when stratified by sperm parameters, including severe oligozoospermia, as well as indicators of sperm motility and morphology. In a study of older children by Leslie and colleagues (23Leslie G.I. Gibson F.L. McMahon C. Cohen J. Saunders D.M. Tennant C. Children conceived using ICSI do not have an increased risk of delayed mental development at 5 years of age.Hum Reprod. 2003; 18: 2067-2072Google Scholar), including 97 ICSI-conceived children aged 5 years of age, comparisons were made with peers conceived with conventional IVF or spontaneously. There were no overall differences in mean IQ between these groups, however, the distribution of IQ was shifted to the left among ICSI children, such that 5.2% had an IQ <85 compared with 2.5% and 0.9% of IVF and spontaneous conception groups. Although this was not statistically significant, the findings raise concern about possible intellectual impairment in the ICSI group. Most relevant to the focus of this review, within the subgroup of ICSI-conceived children, mean IQ was not different between children stratified by the type of paternal defect, and the IQ of children whose father had a triple sperm defect was not significantly different from that of children whose fathers had normal sperm. These findings are in agreement with Wennerholm and colleagues (24Wennerholm U.B. Paternal sperm concentration and growth and cognitive development in children born with a gestational age more than 32 weeks after assisted reproductive.therapy. 2006; 21: 1514-1520Google Scholar) who examined cognitive outcomes in five year-old singleton children born after 32 weeks and conceived with ICSI (n=492) and IVF (n=265) in five European countries. Within the ICSI group, mean IQ scores were similar across all sperm concentration levels, and when the source of sperm was epididymal or testicular compared with ejaculated sperm. Similarly, in the IVF group, IQ scores were similar between children of fathers with a sperm count <20 and ≥20 million per ml. Two further studies examining the influence of the source of sperm reported that cognitive outcomes were superior in the group of children conceived with surgically extracted sperm. In a Dutch study, mental development scores on the Bayley scales were higher in 148 singleton children aged 2 years and conceived from epididymal sperm in comparison with Dutch age matched reference scores (25Woldringh G.H. Horvers M. Janssen A.J.W.M. Reuser J.J.C.M. De Groot S.A.F. Steiner K. et al.Follow-up of children born after ICSI with epididymal spermatozoa.Hum Reprod. 2011; 26: 1759-1767Google Scholar). However, this could be due to confounding as the authors did not adjust for maternal education, which was higher in the ICSI group. Further, in a study of three year-old children, Palermo and colleagues (26Palermo G.D. Neri Q.V. Takeuchi T. Squires J. Moy F. Rosenwaks Z. Genetic and epigenetic characteristics of ICSI children.Reprod Biomed Online. 2008; 17: 820-833Google Scholar) found offspring conceived with surgically extracted sperm were less likely to be classified as developmentally at risk than those conceived from ejaculated sperm using the Ages and Stages Questionnaire (2.8% vs. 11.5%, P<.001). These anomalous findings warrant further exploration, and may be subject to bias, as few details were provided about the establishment of this cohort. Collectively these studies suggest that among children conceived with ICSI, the severity of male factor infertility does not appear to influence cognitive development in early childhood. However, studies of cognitive outcome in adolescents and adulthood are lacking. A key limitation of the existing literature is the small sample size of the ICSI group overall (<500 across all studies), and in each strata of sperm parameter, including the ‘normal’ sperm comparison group. Therefore, these studies only have adequate statistical power to detect large differences between groups and null findings cannot be viewed as reassuring. Existing studies are also subject to bias arising from incomplete follow up arising from attrition, and selection bias due to exclusion of multiple births and preterm infants, as identified in previous systematic reviews (14Rumbold A.R. Moore V.M. Whitrow M.J. Oswald T.K. Moran L.J. Fernandez R.C. et al.The impact of specific fertility treatments on cognitive development in childhood and adolescence: a systematic review.Hum Reprod. 2017; 32: 1489-1507Google Scholar, 15Catford S.R. McLachlan R.I. O'Bryan M.K. Halliday J.L. Long-term follow-up of intra-cytoplasmic sperm injection-conceived offspring compared with in vitro fertilization-conceived offspring: a systematic review of health outcomes beyond the neonatal period.Andrology. 2017; 5: 610-621Google Scholar, 16Catford S.R. McLachlan R.I. O'Bryan M.K. Halliday J.L. Long-term follow-up of ICSI-conceived offspring compared with spontaneously conceived offspring: a systematic review of health outcomes beyond the neonatal period.Andrology. 2018; 6: 635-653Google Scholar). In addition, while these studies suggest cognitive outcomes are comparable between children conceived by ICSI for severe and less severe sperm defects, the inconsistent findings in the general literature concerning outcomes of ICSI children means that the potential for ICSI by itself to influence cognitive outcomes still requires clarification. In summary, large appropriately designed population-based studies, for whom the indications for infertility treatment are well characterized, and with a sufficiently sized comparison group of children conceived with ICSI for non-male factor indications are needed to clarify both the influence of male factor infertility and ICSI on cognitive outcomes. A recent systematic review examined the influence of ICSI on neurodevelopmental disorders and found conflicting findings with regard to the risks of mental retardation and autism among children conceived with ICSI relative to those conceived with conventional IVF (15Catford S.R. McLachlan R.I. O'Bryan M.K. Halliday J.L. Long-term follow-up of intra-cytoplasmic sperm injection-conceived offspring compared with in vitro fertilization-conceived offspring: a systematic review of health outcomes beyond the neonatal period.Andrology. 2017; 5: 610-621Google Scholar). We identified four large population registry studies that specifically examined the contribution of male factor infertility to neurodevelopmental disorders in these groups. The largest of these studies, undertaken by Sandin and colleagues (27Sandin S. Nygren K.G. Iliadou A. Hultman C.M. Reichenberg A. Autism and mental retardation among offspring born after in vitro fertilization.JAMA. 2013; 310: 75-84Google Scholar) in Sweden, involved 10,718 children conceived with ICSI, 19,445 children conceived with IVF, and 2,510,166 spontaneously conceived children born between 1982 and 2007 and followed for an average of 10 years. In this study, the risk of mental retardation was heightened in children conceived with any ART (relative risk [RR] 1.18, 95% confidence interval [CI] 1.01–1.36), and particularly elevated in those conceived with ICSI relative to IVF (RR 1.51, 95% CI 1.10–2.09). When the source of sperm was examined, relative to conventional IVF (with fresh embryo transfer cycles), the risk of mental retardation was greatest in those conceived with ICSI using surgically extracted sperm and fresh embryo transfer cycles (RR 2.35, 95% CI 1.01–5.45, P=.05) and remained elevated in those conceived with ICSI using ejaculated sperm and fresh embryo cycles (RR 1.47, 95% CI 1.03–2.09). Further, children conceived with ICSI using ejaculated sperm and frozen embryo cycles also had an elevated risk (RR 2.36, 95% CI 1.04–5.36). The findings were robust to adjustment for parental age, parental psychiatric history, child age, and birth year. However, when confined to singletons, the association for ICSI and surgically extracted sperm lost statistical significance, most likely reflecting a loss of statistical power. Irrespective of mode of conception, the overall comparison of use of surgically extracted versus ejaculated sperm revealed an elevated risk of mental retardation in the surgical group although this was not statistically significant (RR 1.67, 95% CI 0.73–3.79), except in the subgroup born preterm (RR 3.31 95% CI 1.18–9.31). While risks are elevated, the absolute frequency of mental retardation in these groups was low. Nevertheless, the findings suggest that severe male infertility, requiring surgical sperm extraction, contributes to an increased risk of mental retardation in offspring. Importantly, treatment factors, including ICSI and embryo cryopreservation, also appear to influence this risk. In the same study, the risk of autism was examined and found to be increased in children conceived with ICSI using surgically extracted sperm and fresh embryo cycles relative to conventional IVF (RR 4.60, 95% CI 2.14–9.88). These findings were not significant in the sub analyses of singleton births, again, possibly reflecting a loss of statistical power. Comparing children conceived with surgically extracted sperm with those conceived with ejaculated sperm (using either conventional IVF or ICSI), there was an increase in risk associated with surgical extraction (RR 3.29 95% CI 1.58–6.87), suggesting the severity of paternal infertility is an important contributor to risk of autism. Kissin and colleagues (28Kissin D.M. Zhang Y. Boulet S.L. Fountain C. Bearman P. Schieve L. et al.Association of assisted reproductive technology (ART) treatment and parental infertility diagnosis with autism in ART-conceived children.Hum Reprod. 2015; 30: 454-465Google Scholar) examined diagnosis of autism within the first five years of life in 42,383 children conceived with ART (1997–2006), and reported an overall increase in risk of autism when ICSI was used over conventional IVF, which was present in both singletons (hazard ratio [HR] 1.65, 95% CI 1.08–2.52) and multiple births (HR 1.71, 1.10–2.66), after adjusting for parental age, infant sex, and pregnancy and birth outcomes. Importantly, a diagnosis of male infertility was not associated with an increased risk of autism, when results were stratified by type of infertility (male/non-male) and method of semen collection. For example, relative to children conceived with IVF (without ICSI), the association between autism and ICSI was stronger among children conceived with ICSI for non-male factors (HR 1.57, 95% CI 1.18–2.09) and using ejaculated sperm (HR 1.41, 95% CI 1.06–1.81), and attenuated and no longer statistically significant in children conceived with ICSI for male factor infertility (HR 1.23, 95% CI 0.92–1.64) and using surgically collected semen (HR 1.22, 95% CI 0.65–2.31). A diagnosis of male factor infertility thus appears to be a very broad classification, lacking precision as an exposure variable. This should be borne in mind throughout this review. Two further studies contrast with the findings of both of these prospective cohorts. In a large Danish study of mental disorders (autism, mental retardation, and conduct disorders) in over 33,000 children conceived with fertility treatment born between 1995 and 2003, there was no increased risk of any disorder in children conceived with ICSI, or separately for children conceived with either IVF or ICSI for male factor infertility, when compared with spontaneously conceived controls (29Bay B. Mortensen E.L. Hvidtjorn D. Kesmodel U.S. Fertility treatment and risk of childhood and adolescent mental disorders: register based cohort study.BMJ. 2013; 347: f3978Google Scholar). In addition, Hvidtjorn and colleagues (30Hvidtjorn D. Grove J. Schendel D. Schieve L.A. Svaerke C. Ernst E. et al.Risk of autism spectrum disorders in children born after assisted conception: a population-based follow-up study.J Epidemiol Community Health. 2011; 65: 497-502Google Scholar) found no increased risk of autism in children conceived with either IVF or ICSI with a male infertility diagnosis, relative to spontaneously conceived controls. In relation to other neurodevelopmental disorders, several studies have now examined the risk of cerebral palsy in ART children (31Hvidtjorn D. Schieve L. Schendel D. Jacobsson B. Svaerke C. Thorsen P. Cerebral palsy, autism spectrum disorders, and developmental delay in children born after assisted conception: a systematic review and meta-analysis.Arch Pediatr Adolesc Med. 2009; 163: 72-83Google Scholar), however, we identified only one study that stratified outcomes according to the type of infertility. In that study, the risk of cerebral palsy was not elevated in those conceived with IVF or ICSI for male factor infertility relative to other causes, nor when ICSI was compared with conventional IVF, however the number of cases of cerebral palsy was small (32Hvidtjorn D. Grove J. Schendel D.E. Vaeth M. Ernst E. Nielsen L.F. et al.Cerebral palsy among children born after in vitro fertilization: the role of preterm delivery–a population-based, cohort study.Pediatrics. 2006; 118: 475-482Google Scholar). In summa