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Infertile couples, assisted reproduction and increased risks to the children
RBMOnline - Vol 15. No 2. 2007 245-246 Reproductive BioMedicine Online; www.rbmonline.com/Article/ 2895 on web 15 June 2007
Jean Cohen’s Corner Infertile couples, assisted reproduction and increased risks to the children Jean Cohen Clinique Marignan, 8 rue de Marignan, Paris 75008, France e-mail: [email protected]
Abstract Among possible causes of increased risks of health problems in babies resulting from assisted reproduction treatment, the main one is infertility itself. Epidemiological investigations aimed at assessing assisted reproduction and child health are difficult ones. Large multicentric international studies are necessary. Keywords: ART, assisted reproduction, infertility, risks to children Assisted reproductive technology has become a routine treatment for infertile couples. Nearly 2 million babies have been born worldwide. In France, 2% of births are obtained after treatment using assisted reproductive technology as compared with >4% in Finland. Risks of birth defects in infants born after assisted reproduction remain a controversial question since significant degrees of confusion emerge in most publications, because information about factors, such as mother’s age, male factors, single or multiple pregnancies, technique used, specific parental situations, is not available. Also, most publications are concerned with the prevalence of birth defects in intracytoplasmic sperm injection (ICSI) or IVF infants and compare them with spontaneously conceived infants, despite the former’s serious methodological limitations. In spite of this, most recent publications have concluded that there is an increased risk of birth defects. Many reports studied the maternal and perinatal risks. Most complications have been attributed to the higher number of multiple pregnancies after infertility treatment. This is now well known and may be avoided by the single embryo transfer technique. But even singleton pregnancies have been shown to be associated with increased rates of vaginal bleeding, placenta praevia, pregnancy-induced hypertension and Caesarean section. Higher perinatal risks, including prematurity, intrauterine growth retardation and low birth weight have also been highlighted in these pregnancies, although in the absence of multiple pregnancies the cause for this phenomenon has yet to be identified (Pandian et al., 2001). Evidence concerning birth defects is less clear. Many authors have been reassuring, and consider that increased risk estimates were not statistically significant (Sutcliffe et al., 1995; Verlaenen et al., 1995; Isaksson et al., 2002; Zadori et al., 2003; Ponjaert-Kristoffersen et al., 2005). On the contrary, Buckett and Tan (2005) and Schieve et al. (2005), for example, consider that there is an increased risk of congenital abnormalities in children born after assisted reproductive technology. Hansen et al. (2005) assessed an extensive literature search to identify all papers with data relating to the prevalence of birth defects
in infants conceived following IVF and/or ICSI as compared with spontaneously conceived children. A total of 25 studies were identified for review, and two-thirds of these showed a 25% or greater increased risk of birth defects associated with assisted reproduction treatment. In seven reviewer-selected studies, results suggested a greater and statistically significant increased of 30–40% birth defects in infants born after assisted reproduction treatment. Pooled results from all suitable published studies suggest that children born following assisted reproductive treatment are at increased risk of birth defects compared with spontaneous conception. The possible causes of increased risks of health problems in babies born after assisted reproductive technology are numerous. If we exclude multiple pregnancies, there are three possible sources: (i) the IVF procedure, e.g. ICSI (Gekas et al., 2001; Schieve et al., 2005); (ii) ovarian stimulating drugs (Hack et al. 1970; Adashi et al. 1979); and (iii) infertility itself. This cause has recently been suspected on either the male or the female side. Zhu et al. (2007) studied the Danish National Birth Cohort and concluded that singletons born from infertile couples had an increased prevalence of genital congenital malformations when compared with babies conceived naturally. Edwards and Ludwig (2001) suggested that higher frequencies of abnormal births after assisted reproduction treatment could be partly explained by factors independent of assisted conception (e.g. uterine factors, high steroids levels, culture media). (Meschede, 2000) published a review suggesting there was a genetic basis to male infertility. Numerical and structural chromosomal abnormalities ranked first, followed by microdeletions in the long arm of the Y chromosome. Other well-established genetic causes of male factor infertility include mutations in the cystic fibrosis gene CFTR, some rare syndromes, (e.g. Aarskog, Bardet Biedl, Boucher Neuhauser, Kalmann’s syndromes) and monomorphic sperm defects such as globozoospermia. Even among relatives of infertile men in whom none of the known genetic aberrations can be detected, male factor infertility displays a distinct pattern of familial aggregation. This and other findings point to a possible role of non-Mendelian multifactorial inheritance in the pathogenesis of male reproductive failure.
245
Risks of assisted reproduction treatment - J Cohen Recently Dieterich et al. (2007) published a study about infertile men with normal somatic karyotype but abnormal spermatozoa. He identified a common region of homozygosity harbouring the aurora kinase C gene (AURKC) with a single nucleotide deletion in the AURKC coding sequence. In addition, he showed that this founder mutation results in premature termination of translation, yielding a truncated protein that lacks the kinase domain, and concluded that the absence of AURKC causes male infertility due to the production of large-headed multiflagellar polypoid spermatozoa. Gekas et al. (2001) studied 3208 patients and found an equal risk of constitutional alterations in woman and men. Lambert (2003) conducted a literature review on premature birth, low birth weight, and perinatal mortality with major birth defects in children conceived from different infertility treatments. Only 39 publications were selected when comparing the outcome of pregnancy in an infertile group of patients to a matched control group. Analyses of the outcome of singleton pregnancies resulting from IVF as compared with artificial insemination, each obtained with or without the use of ovarian stimulatory agents and with or without the use of a semen donor, indicates the responsibility of IVF procedure, of stimulating drugs and of infertility. It suggests that female infertility per se is the most important risk factor. At the present time, most infertile men and women at risk of birth defects in children have not been identified. Most of infertile couples are unaware of the possible risks in having babies utilising assisted reproductive technology. Research in this field and extensive counselling of parents is needed because the birth of a handicapped child provokes more suffering than infertility itself. More attention is already given to patients with a family history of abnormalities. However such a research is very difficult since national registers are not adapted to such a study because they lack information. The major methodological difficulty is the lack of appropriate control groups so that effects of assisted reproduction treatment can be differentiated from those of underlying infertility. Also, there are various definitions of infertility (especially concerning duration) and so many different treatments and techniques, while the definition of major congenital anomalies varies from one country to another. Other difficulties concerning the definition of pregnancy include the importance of drop-outs so that huge sample sizes are required. Buck Louis et al. (2004) identified those aspects of fecundity and the nuances of medical practice that need to be considered and understood when designing epidemiological investigations aimed at assessing assisted reproductive treatment and child health. These aspects include: (i) the use of prospective study designs in which the unit of analysis is defined (i.e. cycle versus individual versus couple); (ii) data collection on relevant timevarying covariates at, before and during treatment; and (iii) the use of statistical techniques appropriate for hierarchical data and correlated exposures.
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I know through experience that such a methodology is quite impossible to carry on in one country due to the huge sample size required. It has also to be carried out in a short period of time, because the results might be out-of-date due to rapid changes in techniques. Only large multicentric randomized international studies could cover the necessary rigour of the methodology. It
seems that the International Federation of Fertility Societies, European Society for Human Reproduction and Embryology, or American Society for Reproductive Medicine could promote such ideal studies. Let us hope they do!
References Adashi EY, Rock JA, Sapp KC et al. 1979 Gestational outcome of clomiphene related conceptions. Fertility and Sterility 31, 620–626. Buck Louis GM, Schisterman EF, Dukic VM, Schieve LA 2004 Research hurdles complicating the analysis of infertility treatment and child health. Human Reproduction 20, 12–18. Buckett WM, Tan SL 2005 Congenital abnormalities in children born after assisted reproductive techniques: how much is associated with the presence of infertility and how much with its treatment? Fertility and Sterility 84, 1318–1319. Dieterich K, Soto Rifo R, Karen Faure A et al. 2007 Homozygous mutation of AURKC yields large headed polyploid spermatozoa and causes male infertility. Nature Genetics 39, 661–665. Edwards RG, Ludwig M 2001 Are major defects in children conceived in vitro due to innate problems in patients or to induced genetic damage? Reproductive BioMedicine Online 7, 131–138. Gekas J, Thepot F, Thorleau C et al. 2001 Chromosomal factors of infertility in candidate couples for ICSI. Human Reproduction 16, 82–90. Hack M, Brih M, Serr D et al. 1970 Outcome of pregnancies and children born after induced ovulation. Journal of the American Medical Association 220, 1329–1333. Hansen M, Bower C, Milne E et al. 2005 Assisted reproduction technologies and the risk of birth defects, a systematic review. Human Reproduction 20, 328–338. Isaksson R, Gissler M, Titinen A 2002 Obstetric outcome among women with unexplained infertility after IVF: a matched case– control study. Human Reproduction 17, 1755–1761. Lambert RD 2003 Safety issues in ART, aetiology of health problems in singleton ART babies. Human Reproduction 18, 1987–1991. Meschede D 2000 Male infertility as a heritable disorder. Reproductive Technologies 10, 189–196. Pandian Z, Bhattacharya S, Templeton A 2001 Review of unexplained infertility and obstetric outcome: a 10 year review. Human Reproduction 16, 2593–2597. Ponjaert-Kristoffersen I, Bonduelle M, Barnes J et al. 2005 International collaborative study of intracytoplasmic sperm injection-conceived, in vitro fertilization-conceived, and naturally conceived 5-year-old child outcomes: cognitive and motor assessments. Pediatrics 115, 283–289. Schieve L-A Rasmussen SA, Reefhuis J 2005 Risk of birth defects among children conceived with reproductive technology; providing an epidemiologic context to the data. Fertility and Sterility 84, 1320–1324. Sutcliffe AG, D’Souza SW, Cadman J et al. 1995 Minor congenital anomalies, major congenital malformations and development in children conceived from cryopreserved embryos. Human Reproduction 10, 3332–3337. Verlaenen H, Cammu H, Derde MP, Amy JJ 1995 Singleton pregnancy after in-vitro fertilization; expectations and outcome. Obstetrics and Gynecology 86, 906–910. Zadori ZJ, Kozinsky Z, Orvos H et al. 2003 The incidence of major birth defects following in-vitro fertilization. Journal of Assisted Reproduction and Genetics 20, 131–132. Zhu J, Basso O, Obel C et al. 2007 Infertility, infertility treatment, and congenital malformations: Danish national birth cohort. British Medical Journal 333, 665–666. Received 23 April 2007; accepted 6 June 2007.
RBMOnline®
Jean Cohen’s Corner Infertile couples, assisted reproduction and increased risks to the children Jean Cohen Clinique Marignan, 8 rue de Marignan, Paris 75008, France e-mail: [email protected]
Abstract Among possible causes of increased risks of health problems in babies resulting from assisted reproduction treatment, the main one is infertility itself. Epidemiological investigations aimed at assessing assisted reproduction and child health are difficult ones. Large multicentric international studies are necessary. Keywords: ART, assisted reproduction, infertility, risks to children Assisted reproductive technology has become a routine treatment for infertile couples. Nearly 2 million babies have been born worldwide. In France, 2% of births are obtained after treatment using assisted reproductive technology as compared with >4% in Finland. Risks of birth defects in infants born after assisted reproduction remain a controversial question since significant degrees of confusion emerge in most publications, because information about factors, such as mother’s age, male factors, single or multiple pregnancies, technique used, specific parental situations, is not available. Also, most publications are concerned with the prevalence of birth defects in intracytoplasmic sperm injection (ICSI) or IVF infants and compare them with spontaneously conceived infants, despite the former’s serious methodological limitations. In spite of this, most recent publications have concluded that there is an increased risk of birth defects. Many reports studied the maternal and perinatal risks. Most complications have been attributed to the higher number of multiple pregnancies after infertility treatment. This is now well known and may be avoided by the single embryo transfer technique. But even singleton pregnancies have been shown to be associated with increased rates of vaginal bleeding, placenta praevia, pregnancy-induced hypertension and Caesarean section. Higher perinatal risks, including prematurity, intrauterine growth retardation and low birth weight have also been highlighted in these pregnancies, although in the absence of multiple pregnancies the cause for this phenomenon has yet to be identified (Pandian et al., 2001). Evidence concerning birth defects is less clear. Many authors have been reassuring, and consider that increased risk estimates were not statistically significant (Sutcliffe et al., 1995; Verlaenen et al., 1995; Isaksson et al., 2002; Zadori et al., 2003; Ponjaert-Kristoffersen et al., 2005). On the contrary, Buckett and Tan (2005) and Schieve et al. (2005), for example, consider that there is an increased risk of congenital abnormalities in children born after assisted reproductive technology. Hansen et al. (2005) assessed an extensive literature search to identify all papers with data relating to the prevalence of birth defects
in infants conceived following IVF and/or ICSI as compared with spontaneously conceived children. A total of 25 studies were identified for review, and two-thirds of these showed a 25% or greater increased risk of birth defects associated with assisted reproduction treatment. In seven reviewer-selected studies, results suggested a greater and statistically significant increased of 30–40% birth defects in infants born after assisted reproduction treatment. Pooled results from all suitable published studies suggest that children born following assisted reproductive treatment are at increased risk of birth defects compared with spontaneous conception. The possible causes of increased risks of health problems in babies born after assisted reproductive technology are numerous. If we exclude multiple pregnancies, there are three possible sources: (i) the IVF procedure, e.g. ICSI (Gekas et al., 2001; Schieve et al., 2005); (ii) ovarian stimulating drugs (Hack et al. 1970; Adashi et al. 1979); and (iii) infertility itself. This cause has recently been suspected on either the male or the female side. Zhu et al. (2007) studied the Danish National Birth Cohort and concluded that singletons born from infertile couples had an increased prevalence of genital congenital malformations when compared with babies conceived naturally. Edwards and Ludwig (2001) suggested that higher frequencies of abnormal births after assisted reproduction treatment could be partly explained by factors independent of assisted conception (e.g. uterine factors, high steroids levels, culture media). (Meschede, 2000) published a review suggesting there was a genetic basis to male infertility. Numerical and structural chromosomal abnormalities ranked first, followed by microdeletions in the long arm of the Y chromosome. Other well-established genetic causes of male factor infertility include mutations in the cystic fibrosis gene CFTR, some rare syndromes, (e.g. Aarskog, Bardet Biedl, Boucher Neuhauser, Kalmann’s syndromes) and monomorphic sperm defects such as globozoospermia. Even among relatives of infertile men in whom none of the known genetic aberrations can be detected, male factor infertility displays a distinct pattern of familial aggregation. This and other findings point to a possible role of non-Mendelian multifactorial inheritance in the pathogenesis of male reproductive failure.
245
Risks of assisted reproduction treatment - J Cohen Recently Dieterich et al. (2007) published a study about infertile men with normal somatic karyotype but abnormal spermatozoa. He identified a common region of homozygosity harbouring the aurora kinase C gene (AURKC) with a single nucleotide deletion in the AURKC coding sequence. In addition, he showed that this founder mutation results in premature termination of translation, yielding a truncated protein that lacks the kinase domain, and concluded that the absence of AURKC causes male infertility due to the production of large-headed multiflagellar polypoid spermatozoa. Gekas et al. (2001) studied 3208 patients and found an equal risk of constitutional alterations in woman and men. Lambert (2003) conducted a literature review on premature birth, low birth weight, and perinatal mortality with major birth defects in children conceived from different infertility treatments. Only 39 publications were selected when comparing the outcome of pregnancy in an infertile group of patients to a matched control group. Analyses of the outcome of singleton pregnancies resulting from IVF as compared with artificial insemination, each obtained with or without the use of ovarian stimulatory agents and with or without the use of a semen donor, indicates the responsibility of IVF procedure, of stimulating drugs and of infertility. It suggests that female infertility per se is the most important risk factor. At the present time, most infertile men and women at risk of birth defects in children have not been identified. Most of infertile couples are unaware of the possible risks in having babies utilising assisted reproductive technology. Research in this field and extensive counselling of parents is needed because the birth of a handicapped child provokes more suffering than infertility itself. More attention is already given to patients with a family history of abnormalities. However such a research is very difficult since national registers are not adapted to such a study because they lack information. The major methodological difficulty is the lack of appropriate control groups so that effects of assisted reproduction treatment can be differentiated from those of underlying infertility. Also, there are various definitions of infertility (especially concerning duration) and so many different treatments and techniques, while the definition of major congenital anomalies varies from one country to another. Other difficulties concerning the definition of pregnancy include the importance of drop-outs so that huge sample sizes are required. Buck Louis et al. (2004) identified those aspects of fecundity and the nuances of medical practice that need to be considered and understood when designing epidemiological investigations aimed at assessing assisted reproductive treatment and child health. These aspects include: (i) the use of prospective study designs in which the unit of analysis is defined (i.e. cycle versus individual versus couple); (ii) data collection on relevant timevarying covariates at, before and during treatment; and (iii) the use of statistical techniques appropriate for hierarchical data and correlated exposures.
246
I know through experience that such a methodology is quite impossible to carry on in one country due to the huge sample size required. It has also to be carried out in a short period of time, because the results might be out-of-date due to rapid changes in techniques. Only large multicentric randomized international studies could cover the necessary rigour of the methodology. It
seems that the International Federation of Fertility Societies, European Society for Human Reproduction and Embryology, or American Society for Reproductive Medicine could promote such ideal studies. Let us hope they do!
References Adashi EY, Rock JA, Sapp KC et al. 1979 Gestational outcome of clomiphene related conceptions. Fertility and Sterility 31, 620–626. Buck Louis GM, Schisterman EF, Dukic VM, Schieve LA 2004 Research hurdles complicating the analysis of infertility treatment and child health. Human Reproduction 20, 12–18. Buckett WM, Tan SL 2005 Congenital abnormalities in children born after assisted reproductive techniques: how much is associated with the presence of infertility and how much with its treatment? Fertility and Sterility 84, 1318–1319. Dieterich K, Soto Rifo R, Karen Faure A et al. 2007 Homozygous mutation of AURKC yields large headed polyploid spermatozoa and causes male infertility. Nature Genetics 39, 661–665. Edwards RG, Ludwig M 2001 Are major defects in children conceived in vitro due to innate problems in patients or to induced genetic damage? Reproductive BioMedicine Online 7, 131–138. Gekas J, Thepot F, Thorleau C et al. 2001 Chromosomal factors of infertility in candidate couples for ICSI. Human Reproduction 16, 82–90. Hack M, Brih M, Serr D et al. 1970 Outcome of pregnancies and children born after induced ovulation. Journal of the American Medical Association 220, 1329–1333. Hansen M, Bower C, Milne E et al. 2005 Assisted reproduction technologies and the risk of birth defects, a systematic review. Human Reproduction 20, 328–338. Isaksson R, Gissler M, Titinen A 2002 Obstetric outcome among women with unexplained infertility after IVF: a matched case– control study. Human Reproduction 17, 1755–1761. Lambert RD 2003 Safety issues in ART, aetiology of health problems in singleton ART babies. Human Reproduction 18, 1987–1991. Meschede D 2000 Male infertility as a heritable disorder. Reproductive Technologies 10, 189–196. Pandian Z, Bhattacharya S, Templeton A 2001 Review of unexplained infertility and obstetric outcome: a 10 year review. Human Reproduction 16, 2593–2597. Ponjaert-Kristoffersen I, Bonduelle M, Barnes J et al. 2005 International collaborative study of intracytoplasmic sperm injection-conceived, in vitro fertilization-conceived, and naturally conceived 5-year-old child outcomes: cognitive and motor assessments. Pediatrics 115, 283–289. Schieve L-A Rasmussen SA, Reefhuis J 2005 Risk of birth defects among children conceived with reproductive technology; providing an epidemiologic context to the data. Fertility and Sterility 84, 1320–1324. Sutcliffe AG, D’Souza SW, Cadman J et al. 1995 Minor congenital anomalies, major congenital malformations and development in children conceived from cryopreserved embryos. Human Reproduction 10, 3332–3337. Verlaenen H, Cammu H, Derde MP, Amy JJ 1995 Singleton pregnancy after in-vitro fertilization; expectations and outcome. Obstetrics and Gynecology 86, 906–910. Zadori ZJ, Kozinsky Z, Orvos H et al. 2003 The incidence of major birth defects following in-vitro fertilization. Journal of Assisted Reproduction and Genetics 20, 131–132. Zhu J, Basso O, Obel C et al. 2007 Infertility, infertility treatment, and congenital malformations: Danish national birth cohort. British Medical Journal 333, 665–666. Received 23 April 2007; accepted 6 June 2007.
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