Human Reproduction Update Advance Access originally published online on March 26, 2008
Human Reproduction Update 2008 14(3):219-231; doi:10.1093/humupd/dmn005
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Neuromotor, cognitive, language and behavioural outcome in children born following IVF or ICSI–a systematic review
1 Department of Paediatrics, Division of Developmental Neurology, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands 2 Department of Obstetrics and Gynaecology, University Medical Center Groningen, Groningen, The Netherlands 3 Department of Obstetrics and Gynaecology, Academic Medical Center, Amsterdam, The Netherlands 4 Department of Paediatrics, Division of Neonatology, University Medical Center Groningen, Groningen, The Netherlands
5 Correspondence address. Tel: +31-50-3614247; Fax: +31-50-3615918; E-mail: k.j.middelburg{at}developmentalneurology.com
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Abstract |
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BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
Key words: children / follow-up / ICSI / IVF / neurodevelopmental outcome
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Introduction |
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The effect of assisted conception on the developing human brain is still not clear, notwithstanding the fact that in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) have been introduced more than 25 and 15 years ago, respectively (Steptoe and Edwards, 1978
; Palermo et al., 1992). Since then many studies have been conducted on neurodevelopmental outcome (an umbrella term covering neuromotor, cognitive, speech/ language and behavioural outcome) of children born following these techniques but hitherto uncertainties persist. For instance, contradicting results have been reported considering the association between assisted conception and cerebral palsy (CP), which is a neuromotor disorder that is attributed to non-progressive disturbances in the developing brain (Bax et al., 2005). Some studies report an association between assisted conception and CP (Ericson et al., 2002; Lidegaard et al., 2005; Strömberg et al., 2002), whereas others could not demonstrate such association (Pinborg et al., 2004; Källén et al., 2005; Hvidtjørn et al., 2006; Klemetti et al., 2006). The lack of clarity on potential neurodevelopmental risk after IVF/ICSI is worrying for multiple reasons. First, the number of pregnancies obtained by an assisted reproductive technology (ART) is steadily increasing. In Europe, up to 3.9% of national births are infants born after ART (Nyboe Andersen et al., 2007). Moreover, new and more invasive techniques are introduced at a rapid pace and are not always accompanied by extensive follow-up programmes.
Furthermore, there might be reasons to suppose that IVF/ICSI is associated with an increase in neurodevelopmental problems. Early development of the human nervous system is a complex and neatly orchestrated process which can be affected easily by external influences (De Graaf-Peters and Hadders-Algra, 2006). It has already been established that perinatal outcome of singletons born after assisted conception is worse than that of naturally conceived singletons. Artificially conceived singleton pregnancies end significantly more often preterm and with low birth weight (Schieve et al., 2002; Helmerhorst et al., 2004; Jackson et al., 2004) and perinatal mortality and neonatal intensive care admission are increased (Helmerhorst et al., 2004; Jackson et al., 2004).
The lack of consensus about neurodevelopmental risk after IVF/ICSI largely stems from the fact that the results of the various follow-up studies often are difficult to interpret because of methodological shortcomings. Previous reviews mentioned methodological drawbacks but lacked a thorough methodological evaluation (Van Balen, 1998; Buitendijk, 1999; Tarlatzis and Grimbizis, 1999; Olivennes et al., 2002; Ludwig and Diedrich, 2002; Ludwig et al., 2006; Sutcliffe and Ludwig, 2007). Others focused on subgroups of children, e.g. twins (Pinborg, 2005), children born following ICSI (Van Steirteghem et al., 2002; Leslie, 2004), or children born following cryopreservation of embryos (Sutcliffe, 2000; Wennerholm, 2000), or took into account only a part of neurodevelopmental outcome, such as psychosocial well being (Hahn, 2001; Colpin, 2002; Golombok and MacCallum, 2003; Gibson and McMahon, 2004). Therefore, the aim of the present review is to evaluate in a systematic manner studies on neurodevelopmental outcome of children born following IVF or ICSI compared to naturally conceived children. We restricted ourselves to the techniques of IVF and ICSI as the character of these procedures is invasive and a substantial number of follow-up studies have been reported. For the still more invasive techniques, such as preimplantation genetic screening and in vitro maturation, follow-up information is almost completely lacking. We first evaluated the methodological quality of the studies in a strict and standardized way. The identified studies of good methodological quality are summarized and the results are presented and discussed in an age-specific manner.
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Methodology |
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Literature search
An extensive literature search was performed for relevant studies on neurodevelopmental outcome of children born following IVF or ICSI. We searched for articles published between 1978 and 5 December 2007 in Medline, Embase (since its first coverage year: 1989), PsycINFO and the Cochrane library. A computer based search strategy with multiple combinations of terms was entered into the databases. This search strategy consisted of all combinations of (i) IVF OR ICSI OR reproductive techniques, assisted OR fertilization in vitro AND (ii) child development OR abnormalities OR morbidity OR psychomotor performance OR motor skills OR intelligence OR child psychology OR child behaviour OR developmental disabilities OR nervous system diseases OR CP AND (iii) infant(s) OR child(ren) OR adolescent(s) OR twins OR triplets. Note that the terms were adapted to terminology used in the various databases. In addition, the reference lists of all identified studies and review articles were reviewed for additional articles.
Inclusion and exclusion criteria
We searched for all studies which assessed neurodevelopmental outcome, i.e. neuromotor development, cognition, speech/language and behaviour as a primary outcome measure in IVF or ICSI children and a naturally conceived comparison group. Excluded from the study were studies (i) which did not include a naturally conceived control group, (ii) with a study group size of less than 25 children, (iii) in which the follow-up did not extend beyond the neonatal period, (iv) in which the study group included more than 10% of children born following ovulation induction only (without IVF or ICSI), (v) which compared outcome of children born following IVF or ICSI to children born from donor gametes, adopted children or children born from surrogate mothers and (vi) not published in English. The decision to exclude studies with a group size of less than 25 children was based on preliminary results which revealed that a small group size virtually always was associated with a poor methodological quality. Family studies were only included when a substantial part of the study was devoted to the child’s neurodevelopmental outcome.
The search strategy yielded 1131 publications in Medline and Embase, 213 in PsycINFO and 181 in the Cochrane library. These were supplemented with articles found in reference lists. On the basis of abstract and title, 115 potentially relevant articles were identified and screened for retrieval. Fig. 1 shows a flow-diagram of the in and excluded studies, with reasons for exclusion. The manuscripts of the studies included in the systematic review were read in full by two independent reviewers (M.H-A. and K.J.M.). Study characteristics, data qualifying methodology and data on outcome were extracted and discussed until consensus was met.
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Methodological hierarchy
Studies evaluating outcome after IVF/ICSI do not allow for a randomized clinical trial (Buck Louis et al., 2005). The best option for a clinical trial is the design which evaluates outcome in prospective cohorts of consecutively born IVF/ICSI children and naturally conceived controls, both recruited pre- or perinatally. Next best approaches are studies in which IVF/ICSI children are studied prospectively as a cohort, but the naturally conceived controls are matched retrospectively at nursery- or school age. In order to enhance the ability to fine grade the quality of IVF/ICSI studies, we therefore made the differentiation between prospective- and retrospective-cohort studies (respectively, PC and RC) according to the enrollment of the control children. Studies, which included IVF/ICSI children whose selection was not clearly defined, i.e. studies in which it was not clear whether the children studied represented the entire population of a region or a centre, were classified as retrospective cohort. Studies which included children with a disorder or disease (e.g. CP) and evaluated the mode of conception of children in the diseased and non-diseased groups were classified as case–control (CC).
The effect of IVF/ICSI has not only been studied in clinical trials, but also in studies based on nation-wide registers. These register-based (RB) studies are in particular valuable to detect disorders of low incidence, like CP. Hierarchically, RB studies were considered as having the same level of evidence as the PC studies.
Attrition is an important problem in follow-up studies. We classified studies according to their degree of post-natal attrition. This means that attrition due to perinatal mortality is not taken into account. A low rate of attrition indicates that the chance of selection bias will be kept to a minimum. Blind evaluation of outcome is another important criterion for validity. We only considered a study blind if this was explicitly mentioned in the paper or if data were collected for a purpose other than the evaluation of the effect of IVF/ICSI treatment. A case in point is data collected in Child Welfare Clinics or in habilitation centres.
Neurodevelopmental outcome is affected by multiple factors. Studies dealing with the effect of IVF/ICSI should take into account these confounding factors, either by matching study- and control groups or by including the confounders in multivariate statistics evaluating outcome. We evaluated whether studies took the following confounding variables into account: plurality, gestational age or low birthweight, parity, maternal age, parental education, parental profession or other indicators of social–economical class and the age at which the child had been tested. We did not list gender amongst the confounders, as we were interested in particular whether boys or girls might have a specific vulnerability for sequelae after ART. It is well known that the prevalence of neurodevelopmental disorders is higher in boys than in girls (Hadders-Algra et al., 1988a,b). Therefore, we chose to explicitly report the results if studies did stratify for gender.
Quality assessment was performed by the two independent reviewers and took into account internal validity (quality of the study) and external validity (generalizability of the study; Moher et al., 1999). Internal validity was based on (i) design of the study, (ii) attrition, (iii) blinding at evaluation, (iv) validity of the neurodevelopmental tests applied in the study and (v) the degree to which confounders were taken into account. External validity was based on internal validity, the size of the samples studied and/or the presence of a power calculation. When results of a study had been reported in two different papers, only the paper which described the study most extensively was taken into account for the review. Criteria for classification of methodological quality of controlled studies, i.e. internal and external validity, are listed in Table I.
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Presentation of the results
We first report the methodological quality of the retrieved studies (Table II). Thereafter, we present the data of the studies with a good methodological quality (
++ external validity). A differentiation was made between RB (Table III) and controlled studies (Tables IV, V, VI). For the controlled studies, infants, pre-school children and school-age children are reported separately as neurological dysfunction in these age groups is expressed differently. This is for instance reflected by the existence of specific neurological assessments for infants, pre-schoolers and school-age children (Hadders-Algra, 2005). Owing to the plasticity of the brain dysfunctions that exist at a young age may disappear when the child grows older. But the reverse may also occur: with increasing age increasingly complex brain functions become functionally expressed, which may be accompanied by the emergence of dysfunctions in the novel functions. A case in point is the development of dyslexia at school age (Hadders-Algra, 2005).
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In the different age-groups, neuromotor development (including neuromotor handicaps), cognition, language and behaviour are reported separately. Ages of the infants at evaluation, neurodevelopmental tests used and study outcome were recorded. Owing to the heterogeneity in tests used and child age a meta-analysis on the effect of IVF/ICSI could not be performed.
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Results |
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Methodological quality of the studies
Fifty-nine studies fulfiled the selection criteria, including 9 RB studies and 50 controlled studies. Study characteristics are summarized in Table II. Sample size of the study groups ranged from 26 to 16 280 children. There was a considerable amount of overlap of children between studies. We decided to report the studies separately as they in general used different developmental outcome parameters. Most studies included children born following conventional IVF or a mixture of IVF and ICSI (denoted by S; 33 out of 59 studies, i.e. 56%). Twenty-four studies reported results of children born following ICSI only (S1; 41%) and two studies reported on children born following cryopreservation as embryos (S2; 3%).
Twenty-three of the controlled studies used a prospective study design for both study and control group. In these studies, the control group was formed as a cohort either prenatally, neonatally or from a hospital delivery register. Twenty-seven cohort studies were performed retrospectively. This always meant that at least a part of the control group had been recruited retrospectively, e.g. via nurseries or schools. A CC design was not used in the controlled studies. Information on attrition was available in 97% of the studies; it varied from 0 to 88%.
Thirty-three of the identified studies had good (++ or +++) internal validity and 23 studies had good external validity. Only outcome of studies with good external validity are reported in detail, separately for RB studies (9; 100%) and controlled studies (14; 28%).
In some Scandinavian countries, national registers of fertility treatment have been linked to national registers of hospital diagnoses or registers of psychiatric disorders to calculate the odds for adverse outcome in children born following fertility treatment. Nine of these RB studies focused on neurodevelopmental outcome (Table III). Three studies included only children aged at least 1
or 2 years to ensure accurate neurological diagnosis (Strömberg et al., 2002; Pinborg et al., 2004; Klemetti et al., 2006). With respect to risk for CP, this is very appropriate as the diagnosis CP cannot be established prior to the age of 1–2 years of age (Bax et al., 2006). Strömberg et al. (2002) identified IVF as an independent risk factor for development of CP, but the effect disappeared when only singletons were taken into account. Pinborg et al. (2004) reported that twins born following IVF/ICSI had a similar risk of CP as naturally conceived twins and singletons born following IVF/ICSI. Klemetti et al. (2006) reported an increased risk of CP for children born after IVF/ICSI when all pluralities were taken into account, but not for singletons only. Studies that included also younger children (Ericson et al., 2002; Källén et al., 2005; Lidegaard et al., 2005; Hvidtjørn et al., 2006) showed that IVF/ICSI might be associated with a higher prevalence of CP, but when the results had been adjusted for important confounders such as preterm birth and plurality the increased risk usually disappeared. Interestingly, epilepsy and/or the occurrence of convulsions remained associated with IVF/ICSI in some studies even after correction for confounders (Ericson et al., 2002; Kallén et al., 2005).
The association of IVF/ICSI and mental retardation was investigated in five papers. These studies reported a consistent absence of a relationship between IVF/ICSI and mental retardation. Speech/language retardation was only investigated by Lidegaard et al. (2005); no differences between IVF/ICSI children and naturally conceived children were demonstrated. Four studies reported on behaviour, three of them found no differences and one—the CC study of Maimburg and Væth (2007)—surprisingly reported that children born after assisted conception had a lower risk of developing infantile autism.
None of the RB studies reported different outcomes after IVF/ICSI for boys and girls.
Controlled studies with follow-up in infancy
Nine studies with good external validity (41%) investigated neurodevelopmental outcome of infants born following assisted conception (Table IV). Five evaluated children born following routine IVF (or a combination of IVF and ICSI) and four studies focused on infants conceived by ICSI. The age of the infants at the time of assessment varied from 4 months to two and a half years. In four studies, the same group of infants was examined (McMahon et al., 1997; Gibson et al., 1998, 2000; McMahon and Gibson, 2002).
Neuromotor development was assessed in six studies either with the help of the Bayley Scales of Infant Development (second edition: BSID-II; Bayley, 1993) or with the Griffiths mental development scales (Griffiths, 1996). Four studies found no differences between infants born following assisted and natural conception. One study reported that children born after ICSI had significantly worse eye–hand coordination than naturally conceived infants (Sutcliffe et al., 1999). Another study indicated that children born after IVF had a better psychomotor development than naturally conceived controls (Morin et al., 1989). Two studies provided information on neurological handicap. They found similar rates of handicap in children born following IVF/ICSI and controls.
Cognition was assessed in six studies: four used the Bayley scales and two the Griffiths scales. Five out of the six studies reported no differences between the study and the control group in mental development. Only the study of Bowen et al. (1998) reported significantly lower mental scores in 1-year-old infants born after ICSI than in age matched infants born after IVF and naturally conceived infants. Stratification for gender revealed that lower mental development index scores were only found in boys but not in girls (Table IV).
Speech and language were tested in three studies. The results were inconsistent: two studies showed no differences between study and control group and one study found lower scores on receptive language development in infants born following IVF, but no differences in expressive language skills (Gibson et al., 1998).
Behaviour was assessed in six studies. It is good to realize that many different inventories are available to test behaviour. Most objective evaluation procedures are observational measures in which scores are based on observed behaviour during testing. Four of the six studies evaluated behaviour of the same group of infants, be it at different ages (McMahon et al., 1997; Gibson et al., 1998, 2000; McMahon and Gibson, 2002). These four studies in general showed little difference between study and control infants, but on some inventories the IVF-infants were rated as having a more difficult temperament than naturally conceived infants (McMahon et al., 1997; Gibson et al., 1998; McMahon and Gibson, 2002). Two of the six studies reported no differences in behaviour and one of the six studies reported higher energy levels and vocalization in infants born after IVF (Morin et al., 1989).
In summary, the controlled studies with follow-up in infancy do not indicate that neuromotor or cognitive development, including handicapping neurological conditions, of infants born after IVF/ICSI differs from that of non-IVF/ICSI controls. Nor do these studies indicate that infants born following IVF/ICSI show a higher prevalence of language- or behaviour problems than naturally conceived controls.
Controlled studies with follow-up of pre-school children
Only two studies on neurodevelopmental outcome at pre-school age had a good external validity (Brandes et al., 1992; Leslie et al., 2003; Table V). The other 13 studies with follow-up at pre-school age did not fulfil the criteria for good external validity, mainly because of a retrospective design, high attrition and non-blinded testing. The study of Leslie et al. (2003) was a follow-up of the children described by Bowen et al. (1998). It revealed that the previously reported difference in cognitive development at 18 months between children born after ICSI compared to those born after IVF or after natural conception had disappeared at 5 years. The other study with follow-up at pre-school age did not find a difference in neurological handicap and cognition between children born after IVF and controls (Brandes et al., 1992). Neither of the studies stratified for gender.
Controlled studies with follow-up of school-age children
Three studies with good external validity reported on neurodevelopmental outcome of school-age children (Levy-Shiff et al., 1998; Knoester et al., 2007a, 2008; Table VI). Major reasons for insufficient external validity of the other 10 studies were high attrition—a generally recognized problem in long term follow-up studies—and the use of non-validated outcome measures. The study of Levy-Shiff et al. (1998) reported that children born after IVF/ICSI in general do not differ from their naturally conceived peers. Nevertheless, the data indicated that children born after IVF had more socioemotional problems, aggression, anxiety and depression than naturally conceived peers. This was especially true for boys. The studies performed by Knoester et al. (2007a,2008) could not identify a difference in neuromotor outcome between ICSI and either IVF or naturally conceived children, but cognitive development was slightly worse, i.e. IQ was lower, in singletons born after ICSI than in naturally conceived singletons; this was true for boys and girls.
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Discussion |
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In general, the follow-up studies of good methodological quality showed no consistent differences in neuromotor, cognitive, language and behavioural development between children born following IVF/ICSI and natural conception. We made a great effort to assess methodological quality as a good methodological quality is a prerequisite for generalization of the results of a study. Only 23 papers (39%) met our predefined criteria for good external validity. Thus, our study stresses the need for research with a high methodological quality, i.e. RB studies or truly prospective studies in which all consecutive pregnancies of a hospital or fertility clinic and their naturally conceived controls are followed carefully.
The data from RB studies indicate that IVF/ICSI per se does not increase the risk for CP, but that an increased risk for CP is induced by the association of assisted conception with other risk factors, like preterm birth. Children born following assisted conception are more likely to be born premature and with low birthweight. The increased risk for adverse perinatal outcome cannot solely be attributed to the higher rate of multiplicity following assisted conception. For singletons, the relative risk for preterm and very preterm birth is also found to be increased (Helmerhorst et al., 2004; Jackson et al., 2004). Prematurity and multiple gestations are both strongly associated with the risk of CP (Strömberg et al., 2002; Hvidtjørn et al., 2006). Therefore, these strong risk factors might hide a potential additionally milder effect of IVF/ICSI as causative factor for CP (Dahlquist et al., 2002), if present at all.
It is reassuring that the RB studies did not report an increase in mental retardation or clinically relevant behaviour problems. Since this information is based on large nation-wide registers the chance of a possible non-detected association probably is small. However, a matter of concern is the contradictory findings in the association between IVF/ICSI and epilepsy or convulsions.
To study more subtle differences between IVF/ICSI children and naturally conceived children, such as a minor reduction in IQ, minor neurological or behavioural dysfunction, the controlled studies are most appropriate. In general, these studies did not report an excess of neuromotor, cognitive, language and behavioural disorders in children born following IVF/ICSI. However, two points should be taken into consideration. First, in the case of neuromotor and cognitive development, most studies used evaluation tools such as the Bayley Scales of Infant Development. These tests have been well standardized and validated as tools for clinical assessment. This means that these instruments are reliable in detecting gross pathology, but they do not evaluate neuromotor and cognitive outcome in a detailed sense. Second, the number of studies of high methodological quality that continued follow-up after infancy is rather limited, while most so-called ‘minor’ neurodevelopmental disorders are first diagnosed beyond that age.
The procedure of ICSI is more invasive in nature than IVF only; natural sperm selection is passed by and spermatozoa with impaired mobility, morphology or genetic abnormalities may be used (Bowen et al., 1998; Sutcliffe et al., 1999, 2001; Knoester et al., 2007a, 2008). In addition, the origin of infertility preceding the fertility therapy is usually different for IVF and ICSI and we do not know how this may affect neurodevelopmental outcome. Overall, the controlled studies included in this review which focused explicitly on follow-up after ICSI showed similar neuromotor, cognitive, language and behavioural outcome after ICSI and natural conception. However, two studies reported a mild IQ reduction in children born after ICSI. The study of Bowen et al. (1998) reported significantly lower mental scores in ICSI-boys than IVF- and naturally conceived boys. However, for the generalizability of this study it has to be taken into account that a substantial proportion of infants included in this study were born after the transfer of cryopreserved embryos (Sutcliffe et al., 1998). Recently, Knoester et al. (2008) reported lower IQ-scores in 5- to 8-year-old ICSI children when compared to naturally conceived children. This blinded study used a validated test instrument and extensively adjusted for confounders, however, response rate and reasons for non-participation were unclear in the naturally conceived control group. Therefore, ascertainment bias could have emerged: parents who believe that their child is intelligent are probably more willing to let their child cooperate in an intelligence-test, which could have resulted in relatively high IQ-scores in the naturally conceived group. Nevertheless, the results of these two studies warrant more research of high methodological quality and long-term follow-up.
Some studies compared children born following IVF only to children born following IVF with ICSI (Bowen et al., 1998, Leslie et al., 2003; Pinborg et al., 2004; Källén et al., 2005; Hvidtjørn et al., 2006; Knoester et al., 2007a, 2008). The risk of CP between the two treatments did not differ (Pinborg et al., 2004; Källén et al., 2005; Hvidtjørn et al., 2006). The limited data available from controlled studies also did not suggest that other neurodevelopmental outcome parameters differed for the two treatments (Bowen et al., 1998; Leslie et al., 2003; Knoester et al., 2007a, 2008).
Perspectives for future research
This review demonstrated a clear need for follow-up studies of good methodological quality and with continuation of follow-up after infancy, ideally continuing into adulthood. So far only few studies with solid methodology addressed gender specific vulnerability for neurodevelopmental disorders after IVF or ICSI (Bowen et al., 1998; Levy-Shiff et al., 1998; Knoester et al., 2008). As two of these studies suggest a larger risk for cognitive and emotional problems in boys, we suggest that future studies continue to pay attention to the gender issue.
Another issue which needs evaluation in future research is the long-term effect of cryopreservation of embryos on developmental outcome. Until now very few studies have addressed this problem, while this technique has already been applied on routine base for years. Similar careful and long-term follow-up is warranted for other technologies, such as preimplantation genetic screening or in vitro maturation. We underline the ESHRE Task Force recommendation that with the introduction of new technologies a plan for follow-up should accompany the clinical trial, as the interests of future offspring should be emphasized (ESHRE Task Force on Ethics and Law, 2007).
The majority of studies on neurodevelopmental outcome after IVF/ICSI did not have a robust methodological quality. The exception to this rule was formed by the RB studies. The latter studies suggest that IVF/ICSI per se does not increase the risk for mental retardation or CP. However, the association of assisted conception with risk factors such as multiple gestation and preterm birth does result in an indirect association of IVF/ICSI with CP. The controlled studies which met the criteria of good methodological quality did not show an increase in neuromotor, cognitive, language and behavioural problems in children born after IVF/ICSI. It should be realized that the majority of these studies evaluated outcome in infancy, which precludes a conclusion about the risk of minor neurodevelopmental disorders, which in general first become expressed after infancy.
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The study is financially supported by the University Medical Center Groningen.
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The authors wish to thank Sjoukje van der Werf for her help in conducting the literature search.
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References |
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