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Re: Male Reproductive Tract Abnormalities: More Common After Assisted Reproduction?
EUROPEAN UROLOGY 59 (2011) 879–884
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Words of Wisdom Re: Male Reproductive Tract Abnormalities: More Common After Assisted Reproduction? Funke S, Flach E, Kiss I, et al Early Hum Dev 2010;86:547–50 Expert’s summary: In a cohort of 7870 boys born in the period 1999 to 2008 in Pe´cs, Hungary, 165 (2.1%) were born after in vitro fertilization (IVF) and 263 (3.3%) after intracytoplasmic sperm injection (ICSI). These groups were examined for the incidence of hypospadias and cryptorchidism at birth or in prematurely born children at the expected date of delivery and compared with boys born after spontaneous conception. Infants conceived with an assisted reproduction technique (ART) were more often twins (odds ratio [OR]: 4.9), preterms (OR: 3.4), or low birthweight infants (OR: 2.5). Hypospadias were found in 2.7% (ICSI) and 1.8% (IVF) versus 1.1% (spontaneous), and cryptorchidism was diagnosed in 1.9% (ICSI) and 1.2% (IVF) versus 1.0% (spontaneous). Low birthweight and preterm births were found to be significant risk factors for hypospadias (ORs: 9.1 and 8.1) and cryptorchidism (ORs: 4.3 and 3.5). Twins (OR: 4.2), singletons (OR: 3.2), and newborns with normal weight (OR: 4.0) showed a significant risk for hypospadias after ICSI. Nonsignificant trends were seen for cryptorchidism. Expert’s comments: Since 1978 more than a million children worldwide have been conceived artificially. This paper reported on the largest series regarding hypospadias and cryptorchidism in boys after ART. Although ART is considered a safe and effective therapy for male factor infertility, it may carry an increased risk for the transmission of genetic abnormalities to offspring, either through the procedure itself or through the increased risk of such abnormalities due to the bypassing of normal biologic sperm selection. Y-chromosome microdeletions at Yq11 may represent the etiologic factor in 10–20% of cases with idiopathic azoospermia [1]. Hypospadias and cryptorchidism are part of the testicular dysgenesis syndrome (TDS) together with infertility and testicular cancer. But these are not the only possible disorders associated with ART. There is evidence that IVF 0302-2838/$ – see back matter
and ICSI increase the rate of birth defects with a variety of otherwise rare syndromes such as the BeckwithWiedemann syndrome (BWS) of visceromegaly, polycystic kidney disease, hydronephrosis, and embryonal tumours such as neuroblastoma of the adrenal gland. BWS and all other syndromes are associated with epigenetic phenomenon such as genomic imprinting or lack of maintenance DNA methylation. Approximately 14% of BWS patients develop tumours; two thirds of these are Wilms’ tumours associated with dysregulation at the telomeric domain of 11p15 showing ORs up to 4 [2]. These imprinting disorders have also been correlated with ovarian stimulation in ART. The risk for the development of testicular cancer in patients with cryptorchidism and hypospadias was recently calculated as 2.1–3.7 [3]. The gr/gr deletion, associated with infertility, was found to be associated with a twofold increased risk of testicular cancer and even a threefold increased risk among patients with a positive family history [4]. TDS seems to reflect a possible interaction between genetic and environmental/lifestyle-related factors, with certain genotypes making individuals more susceptible to adverse exogenous exposures. The present knowledge of birth defects with ART warrants meticulous follow-up for these offspring as suggested by the guidelines of the Society of Obstetricians and Gynaecologists of Canada [5]. A worldwide registry would be helpful to gain solid data on the long-term consequences of ART that should be discussed with infertile couples. Conflicts of interest: The author has nothing to disclose.
References [1] Foresta C, et al. Endocr Rev 2001;22:226–39. [2] Rump P, et al. Am J Med Genet A 2005;136:95–104. [3] Schnack TH, et al. J Natl Cancer Inst 2010;102:187–92. [4] Nathanson KL, et al. Am J Hum Genet 2005;77:1034–43. [5] Allen VM, et al. J Obstet Gynaecol Can 2006;28:220–50. Walter Albrecht Department of Urology, Landesklinikum Weinviertel Mistelbach, Mistelbach, Austria E-mail address: [email protected]
DOI: 10.1016/j.eururo.2011.02.011
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Words of Wisdom Re: Male Reproductive Tract Abnormalities: More Common After Assisted Reproduction? Funke S, Flach E, Kiss I, et al Early Hum Dev 2010;86:547–50 Expert’s summary: In a cohort of 7870 boys born in the period 1999 to 2008 in Pe´cs, Hungary, 165 (2.1%) were born after in vitro fertilization (IVF) and 263 (3.3%) after intracytoplasmic sperm injection (ICSI). These groups were examined for the incidence of hypospadias and cryptorchidism at birth or in prematurely born children at the expected date of delivery and compared with boys born after spontaneous conception. Infants conceived with an assisted reproduction technique (ART) were more often twins (odds ratio [OR]: 4.9), preterms (OR: 3.4), or low birthweight infants (OR: 2.5). Hypospadias were found in 2.7% (ICSI) and 1.8% (IVF) versus 1.1% (spontaneous), and cryptorchidism was diagnosed in 1.9% (ICSI) and 1.2% (IVF) versus 1.0% (spontaneous). Low birthweight and preterm births were found to be significant risk factors for hypospadias (ORs: 9.1 and 8.1) and cryptorchidism (ORs: 4.3 and 3.5). Twins (OR: 4.2), singletons (OR: 3.2), and newborns with normal weight (OR: 4.0) showed a significant risk for hypospadias after ICSI. Nonsignificant trends were seen for cryptorchidism. Expert’s comments: Since 1978 more than a million children worldwide have been conceived artificially. This paper reported on the largest series regarding hypospadias and cryptorchidism in boys after ART. Although ART is considered a safe and effective therapy for male factor infertility, it may carry an increased risk for the transmission of genetic abnormalities to offspring, either through the procedure itself or through the increased risk of such abnormalities due to the bypassing of normal biologic sperm selection. Y-chromosome microdeletions at Yq11 may represent the etiologic factor in 10–20% of cases with idiopathic azoospermia [1]. Hypospadias and cryptorchidism are part of the testicular dysgenesis syndrome (TDS) together with infertility and testicular cancer. But these are not the only possible disorders associated with ART. There is evidence that IVF 0302-2838/$ – see back matter
and ICSI increase the rate of birth defects with a variety of otherwise rare syndromes such as the BeckwithWiedemann syndrome (BWS) of visceromegaly, polycystic kidney disease, hydronephrosis, and embryonal tumours such as neuroblastoma of the adrenal gland. BWS and all other syndromes are associated with epigenetic phenomenon such as genomic imprinting or lack of maintenance DNA methylation. Approximately 14% of BWS patients develop tumours; two thirds of these are Wilms’ tumours associated with dysregulation at the telomeric domain of 11p15 showing ORs up to 4 [2]. These imprinting disorders have also been correlated with ovarian stimulation in ART. The risk for the development of testicular cancer in patients with cryptorchidism and hypospadias was recently calculated as 2.1–3.7 [3]. The gr/gr deletion, associated with infertility, was found to be associated with a twofold increased risk of testicular cancer and even a threefold increased risk among patients with a positive family history [4]. TDS seems to reflect a possible interaction between genetic and environmental/lifestyle-related factors, with certain genotypes making individuals more susceptible to adverse exogenous exposures. The present knowledge of birth defects with ART warrants meticulous follow-up for these offspring as suggested by the guidelines of the Society of Obstetricians and Gynaecologists of Canada [5]. A worldwide registry would be helpful to gain solid data on the long-term consequences of ART that should be discussed with infertile couples. Conflicts of interest: The author has nothing to disclose.
References [1] Foresta C, et al. Endocr Rev 2001;22:226–39. [2] Rump P, et al. Am J Med Genet A 2005;136:95–104. [3] Schnack TH, et al. J Natl Cancer Inst 2010;102:187–92. [4] Nathanson KL, et al. Am J Hum Genet 2005;77:1034–43. [5] Allen VM, et al. J Obstet Gynaecol Can 2006;28:220–50. Walter Albrecht Department of Urology, Landesklinikum Weinviertel Mistelbach, Mistelbach, Austria E-mail address: [email protected]
DOI: 10.1016/j.eururo.2011.02.011