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

Department of Paediatrics, Division of Developmental Neurology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Human Reproduction Update (Impact Factor: 10.17). 02/2008; 14(3):219-31. DOI: 10.1093/humupd/dmn005
Source: PubMed


The effect of in vitro fertilization (IVF) or intracytoplasmic sperm 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.
This systematic review includes studies which compare a group of children born following IVF/ICSI to children born after natural conception by assessing outcome in terms of neuromotor development, cognition, speech/language and behaviour. Specific attention is paid to the studies' methodological quality based on study design, attrition, blinding of the assessor, validity of ND tests used, confounders included and group size or power analysis.
Twenty-three out of 59 studies had a good methodological quality including 9 register-based (RB) and 14 controlled studies. RB studies suggested that IVF/ICSI per se does not increase the risk for severe cognitive impairment (i.e. mental retardation) or neuromotor handicaps such as cerebral palsy (CP), the association of IVF/ICSI and CP being brought about by the association of assisted conception with risk factors, like preterm birth. In general, controlled studies of good quality did not report an excess of ND disorders in IVF/ICSI-children. However, the majority of studies followed the children during infancy only, thereby precluding pertinent conclusions on the risk of ND disorders that come to the expression at older ages, such as fine manipulative disability or dyslexia.
A negative effect of assisted conception on the developing human brain is not identified; however, further research of high methodological quality in children beyond pre-school age is needed.

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    • "For example, decreased birthweights are reported after the transfer of a fresh embryo (Belva et al., 2008; Shih et al., 2008; McDonald et al., 2009; Pelkonen et al., 2010; Pinborg et al., 2010) and recent data suggests an increased risk of being born large for gestational age after the transfer of a thawed embryo (Pinborg et al., 2014). Despite over 5 million IVF children being born, relatively few studies have investigated phenotypic characteristics of IVF children beyond birth (see reviews: Middelburg et al., 2008; Savage et al., 2011; Hart and Norman, 2013a,b). An increasing number of these studies have identified distinct phenotypic differences in growth rate, weight gain, height and blood pressure in later (pre-pubertal) assessments of IVF children when compared with naturally conceived children (Miles et al., 2007; Ceelen et al., 2009; Seggers et al., 2014). "
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    ABSTRACT: STUDY QUESTION Are childhood measures of phenotype associated with peri-conception parental, IVF treatment and/or embryonic characteristics of IVF children?
    Full-text · Article · Sep 2014 · Human Reproduction
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    • "In a systematic review by Middelburg et al. (2008) on neuromotor and cognitive differences between children born after ICSI and spontaneous conception (SC), two studies are mentioned which showed lower intelligence quotient (IQ) scores after ICSI conception as opposed to SC (Bouwen et al., 1998; Knoester et al., 2008). "
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    ABSTRACT: STUDY QUESTION Do preschool preimplantation genetic diagnosis (PGD) children differ in their cognitive and psychomotor development from children born after ICSI and spontaneous conception (SC)?
    Full-text · Article · Jul 2014 · Human Reproduction
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    • "Prader–Willi and Angelman syndromes are also characterized by mental impairment (Driscoll et al., 1998; Horsthemke and Buiting, 2008; Owen and Segars, 2009) and there has been a long-standing interest in cognitive development in the offspring of fertility treatment. Many studies have reported no detectable effect of ICSI on neurodevelopmental/cognitive outcomes, or only modest delays in achieving milestones (Bowen et al., 1998; Sutcliffe et al., 2001; Bonduelle et al., 2003; Leslie et al., 2003; Ponjaert-Kristoffersen et al., 2005; Knoester et al., 2008; Leunens et al., 2008; Middelburg et al., 2008; Zhu et al., 2009; Sanchez-Albisua et al., 2011). However, a recent study of 2.5 million children in Sweden concluded that IVF treatment overall was associated with a small increased risk of mental retardation and that ICSI for paternal infertility was associated with a small increase in the risk of autistic disorder and mental retardation compared with IVF without ICSI (Sandin et al., 2013). "
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    ABSTRACT: Is DNA methylation in buccal cell DNA from children born following IVF (in vitro fertilization) and ICSI (intra-cytoplasmic sperm injection) different from that of spontaneously conceived children? DNA methylation in the imprinted gene, small nuclear ribonucleoprotein polypeptide N (SNRPN), was higher in children conceived by ICSI and in those born to women with the longest duration of infertility regardless of the method of conception. Fertility treatment is associated with a small but significant increase in the risk of a range of adverse obstetric outcomes, birth defects and longer term sequelae, but the biological basis for this is unknown. A growing evidence base suggests that epigenetics may play a role in subfertility and the link between fertility and health. In this retrospective cohort study of children born between 2002 and 2008, we measured DNA methylation in paternally expressed gene 3 (PEG3), insulin-like growth factor II (IGF2), SNRPN, long interspersed nuclear element 1 (LINE1) and the insulin gene (INS) in buccal cell DNA from children born following IVF (n = 49) and ICSI (n = 20) and compared them with a matched spontaneous conception group (n = 86). Participants were identified from the Aberdeen Maternity and Neonatal Databank and IVF and ICSI pregnancies were matched to spontaneous conception pregnancies on year of birth and maternal age at delivery. Only singleton pregnancies following fresh embryo transfer were included. DNA methylation was determined by pyrosequencing. Regression with adjustment for covariates was used to determine the effect of infertility on offspring DNA methylation. SNRPN methylation in the offspring was linked to fertility treatment in the parents. This effect was specific to children conceived using ICSI and was apparent in the comparison of ICSI versus spontaneous conception (1.03%; 95% CI 0.10, 1.97; P = 0.031), ICSI versus standard IVF (1.13%; 95% CI 0.04, 2.23; P = 0.043) and ICSI versus standard IVF and spontaneous conception (1.05; 95% CI 0.15, 1.94; P = 0.023). In all comparisons, the use of ICSI was associated with a higher level of SNRPN methylation in the offspring. A higher level of SNRPN methylation in the offspring was also associated with a longer duration of infertility in the parents. This was observed in all cases of infertility (0.18% per year of infertility; 95% CI 0.02, 0.33; P = 0.026) and after excluding ICSI cases (0.21% per year of infertility; 95% CI 0.04, 0.37; P = 0.017). There was a significant increase in the level of LINE1 methylation with age between birth and 7 years (0.77% per year; 95% CI 0.49, 1.05; P < 0.001). Methylation in the INS gene decreased significantly over the same period (-0.46% per year; 95% CI -0.89, -0.03; P = 0.035). There was no evidence from this cross-sectional data that methylation within the imprinted genes changed over the first 7 years of life. The ICSI sample size was limited but the groups were carefully selected and well matched and the SNRPN findings were consistent across different outcomes. The results of this study provide support for a role for epigenetics, and imprinting in particular, in fertility. The specific changes point to possible long-term consequences of fertility treatment for the health and fertility of future generations. The authors report no conflict of interest in relation to this work. Funding was provided by the University of Aberdeen and the Scottish Government. Not applicable.
    Preview · Article · May 2014 · Human Reproduction
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