Seminars in Fetal & Neonatal Medicine 19 (2014) 245e249
Contents lists available at ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Review
I was born following ART: how will I get on at school? Omar Abdel-Mannan*, Alastair Sutcliffe General and Adolescent Paediatric Unit, Institute of Child Health, London, UK
s u m m a r y Keywords: Assisted reproductive techniques Children Intracytoplasmic sperm injection In-vitro fertilisation Neurodevelopmental outcome
With an ever-expanding population of children born after in-vitro fertilisation (IVF), the widespread use of assisted reproductive techniques (ART) has placed a great emphasis on the need to study their longterm outcomes. Indeed, there has been concern that mechanisms used in ART may have a detrimental effect on the neurocognitive development of these children. Reassuringly, most neurocognitive and motor development studies using various assessment scales have generally found no differences between intracytoplasmic sperm injection, IVF and naturally conceived children. Only a few studies have reported concerns. In terms of predictors of intelligence in children, ART appears to have a minimal effect in comparison to birth weight, gestational age, socio-economic status, and parental educational levels. Nevertheless, further research of higher methodological quality in children beyond pre-school age and on newer ART procedures is needed. Ó 2014 Published by Elsevier Ltd.
1. Introduction The population of children born after in-vitro fertilisation (IVF) has grown over the last two decades; since 1978, more than five million children have been conceived through assisted reproductive techniques (ART). Whereas the techniques are generally considered safe, their widespread use has culminated in greater emphasis on the need to study the long-term outcomes of ART. Evidence from a number of studies has shown that IVF pregnancies carry a higher risk for genetic imprinting disorders, preterm birth, low birthweight, and small for gestational age, mainly due to the resulting high proportion of multi-fetal pregnancies [1,2]. The prevalence of congenital malformations in different studies has ranged from 5.6% to 9.0% in comparison to 4.2% to 5% in the general population [3,4]. The majority of studies on IVF children’s outlook focus on medical outcomes and, in particular, there is now increasing attention being given to the neurocognitive and developmental follow-up of these children. Given that the human brain is the most complex of organs, it is the most prone to any insult, whether gross or minor. Previous studies have yielded mixed to reassuring
* Corresponding author. Address: General and Adolescent Paediatric Unit, Institute of Child Health, 43 Great Ormond Street, London WC1N 3HZ, UK. Tel.: þ44 07717 747012. E-mail address: [email protected] (O. Abdel-Mannan). http://dx.doi.org/10.1016/j.siny.2014.04.003 1744-165X/Ó 2014 Published by Elsevier Ltd.
findings regarding very young to school-aged ART children’s motor and cognitive development. Studies following children ranging from 1 year to 13 years of age have not given rise to concerns regarding growth and physical development of IVF children [5,6], and cognitive and behavioural development have also been reported to be normal among this subgroup [7,8]. Herein is a synopsis of studies subdividing them into different categories. 2. Neurodevelopmental outcomes Almost all studies of neurodevelopmental outcomes have shown reassuring outcomes for ART children. As demonstrated in the studies discussed in this review, the tests used to assess neurocognitive outcomes are limited by a number of recurrent problems, including:
lack of blinding of study assessors underpowered non-standardised assessment tools inter-observer error (more than one assessor used) bilingual children perform less well on the tests twins perform less well and there are no studies on triplets low participation rates selection bias e participants’ parents may have an agenda.
In this synopsis, we have sought to focus on the largest studies on this topic, mainly including more than 100 subjects.
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3. Studies reporting no neurocognitive outcome concerns Leslie et al. [9] determined the developmental outcomes of children using intelligence quotients (IQ) obtained from the Wechsler Preschool and Primary Scale of Intelligence e Revised (WPPSI-R [10]). The study looked at the mental development of 97 intracytoplasmic sperm injection (ICSI), 80 IVF and 110 naturally conceived (NC) singleton or twin children at 5 years of age. ICSI is an effective treatment for severe male-factor infertility. Whereas in conventional IVF, 50,000e100,0000 sperm are incubated with an oocyte in a culture medium, in ICSI a single sperm is injected directly into the oocyte’s vitellus, thus bypassing natural sperm selection barriers. The fact that less mature sperm are used in this technique has raised hypothetical concerns regarding increased risk of genetic abnormalities and structural defects. Early reports suggested possible developmental or other problems [11,12]; however, these studies were limited by small sample sizes, unstandardised assessment systems, poor rates of follow-up, multiple observers and other methodological problems. In this study, the mean Bayley Scales mental development index (MDI) of the ICSI group was found to be significantly lower than both IVF and NC control groups at 1 year of age. This is in contrast to other studies that found the mean Griffiths Mental Development Scales General Quotient (GQ) of ICSI children not to be significantly different from that of NC controls. Many of the previous studies were performed on children aged 2 years, and tests of cognitive ability may not reliably predict long-term intelligence at that stage [13,14]. It is therefore essential to evaluate children further at an age when long-term intellectual ability can be predicted with more reliability. Indeed, the authors highlighted that if differences seen at 1 year of age were maintained at school age, this would raise the likelihood of ICSI children needing additional assistance at school in comparison to their NC or IVF peers. The mean values for all three IQ scales used for all three groups were nevertheless within the normal range. ICSI group mean values, reassuringly for parents, were not significantly different from either the IVF or NC control groups. Interestingly, at 1 year of age, a higher percentage of children in the ICSI group had delayed cognitive development in comparison to the other two groups. However, at 5 years of age, the percentage of ICSI children with cognitive delay had fallen (from 17% to 5%) and ICSI itself was no longer an independent predictor of delay in cognitive development. In keeping with results of other population-based studies of nonART children [15,16], the study showed that parental education and other demographic factors are the strongest predictors of cognitive ability at 5 years of age. Potential bias may have been introduced by some group differences in the recruitment of children assessed at 5 years of age. For instance, whereas IVF children were recruited prospectively during pregnancy, additional NC controls were enrolled from pre-schools selected to match ICSI cohort demographics. Only 12% of potentially eligible children were enrolled from the pre-schools, which may have led to parental motivation in child participation affecting the results. On the one hand, parents with concerns about their child’s educational performance may have agreed to participate, thus lowering the mean IQ for the natural conception group; on the other hand, parents may have sought confirmation of above-average IQ in their children through this study. Sutcliffe et al. [17] undertook a study comparing 208 ICSI singleton children and 221 NC singleton children. The primary outcome was neurodevelopmental scoring using the Griffiths Mental Development Scales (re-standardised for the UK in 1996 to reflect the child-rearing practices, social habits, racial groupings, and other socio-demographic factors). Secondary measures included perinatal morbidity, postnatal health, and congenital
abnormalities. With a follow-up rate of 90% in the ICSI group, no difference was found between the study children and the NC children in mean (SD) neurodevelopmental scores [98.08 (10.93) vs 98.69 (9.99), respectively] or any subscales on the Griffiths’ scales of mental development. The use of a single observer, involvement of the major UK ICSI centres and selection of a similar comparison group in terms of baseline characteristics strengthen this study’s reliability. However, observers were not blinded from the mode of conception. The study also used a recent revision of the Griffiths Mental Development Scales General Quotient (GQ) and there is a decrease in the range of maximum scores achievable for infants aged >20 months, which may have affected this study’s results, where some of the study participants were aged 21 22 months. The group scores may have been dampened, reducing the likelihood of finding significant differences between groups. Notably, the findings of Sutcliffe et al. are in conflict with results from Bowen et al. [11], who suggested that children born after ICSI are developmentally less able than NC children at 1 year of age. The latter study was, however, marred by several methodological limitations, discussed in more detail below. Large-scale multi-centre collaborative studies have also investigated the long-term effects of ICSI in terms of development of preschool to school-aged children. In a study by Ponjaert-Kristoffersen et al. [18], no significant differences were found in intelligence quotient (IQ) on the WPPSI-R between 5-year-old ICSI and spontaneously NC children from Belgium, Sweden, and the USA. However, on further subtest score analysis, ICSI children appeared more likely to perform better on general factual/acquired knowledge information and worse on some visualespatial abilities (mazes, block design and object assembly). A collaborative follow-up study by the same authors compared 5-year-old singleton ICSI-born children with IVF and NC controls recruited across various European countries and matched according to age, sex, birth order, maternal education, parental socio-economic status and mother’s age at birth [19]. No significant inter-group differences on intelligence were evident. However, lower full-scale and verbal IQ in ICSI/ IVF children were linked with older maternal age at birth. Higher maternal education was associated with better object assembly in ICSI/IVF children, and a lower educational level was associated with worse spatial visualisation and block design. These findings suggest that factors such as maternal age and educational level have a greater effect on the long-term cognitive development of ICSI children than the mode of conception. A proportion of the Belgian children in the study by PonjaertKristoffersen et al. study were followed up and assessed at 8 years of age [20]. A total of 151 ICSI and 153 NC children were assessed by means of the Wechsler Intelligence Scale for Children e Revised (WISC-R) and the Movement Assessment Battery for Children along with an extensive paediatric-neurological evaluation and a family-relational assessment. The intelligence outcome was favourable for ICSI children, although the effect was not clinically significant. It was hypothesised that a higher degree of child stimulation due to higher maternal educational levels explained this phenomenon in the ICSI group. Other research has also shown a higher average achievement in developmental examination among IVF children (with 12 30 month follow-up) [21]. The explanation given was exceptional parental motivation, and it would be interesting to look further into how much family functioning and environmental stimuli can enhance an IVF child’s development. Follow-up of the children in the 2006 Leunens et al. [22] study examined the second-wave study findings for the cognitive and motor development of ICSI children at 10 years of age, comparing them to the first-wave results at 8 years of age. The study was designed to investigate the possible pathways of influence of ICSI
O. Abdel-Mannan, A. Sutcliffe / Seminars in Fetal & Neonatal Medicine 19 (2014) 245e249
on child development. Therefore, different developmental dimensions and socio-cognitive factors of influence were assessed through a multi-method multi-informant approach. A single trained psychologist individually tested all the children, applying testing conditions similar to those in the first-wave study. Most significantly, 10-year-old ICSI children did not display any significant developmental delays compared with NC children at age 8 or 10 years, in terms of cognitive or motor functioning. Nevertheless caution is needed when generalising these findings due to the study’s limitations. Whereas the follow-up rate for first study wave was 72%, more than half of the initial birth cohort were not assessed in the second study wave, raising questions regarding participation bias. Another potential limitation of these findings is the fact that only children born after 32 weeks of gestation were included. Whilst the findings of this study are interesting, replication of these results with later cohorts and longer-term follow-up are needed. Several studies have assessed the neurological or developmental outcome of children at 5 or 8 years of age [23e25]. In some of these, pre-term children or multiples were included but most include fewer than 100 children in each group. A large cohort study with a comparison group of NC children by Ludwig et al. [26] was the first to exclude the influence of prematurity and was well powered to detect an equivalent mental development. The aim of the study was to assess the neurodevelopmental health at 5.5 years in 276 ICSI children compared to 273 NC controls. Neuromotor development was assessed by a detailed neurological examination, including the standardised motor test MOT 4e6, and emotional/behavioural development and intelligence were assessed with the Kaufman Assessment Battery for Children (K-ABC). There were no significant differences between ICSI and NC children with regard to the neurological findings, motor skills, emotional/behavioural development, or intelligence. A sensitivity analysis with adjustment for maternal age and social status also showed equivalent results for all subscales of the K-ABC. It is important to note that in both groups the mean social status and parental education level was above the national average. Thus when interpreting the data, we cannot assume that this represents the average in society. In addition, parental education and other environmental factors play a crucial role. This was previously shown by Place and Englert [23], who found that the difference in IQ in ICSI/IVF children compared to NC children disappeared after adjusting for parental education. Whereas the study by Ludwig et al. was well powered for the primary outcome and large in size, four different paediatricians examined the children and a lower response rate was achieved for the NC children. The results are also only applicable to term-born singletons, and multiples or children born preterm will need further investigation.
247
(P < 0.0001). The authors proposed that possible reasons for the poorer performance among the ICSI children include factors relating to genetic abnormalities in the sperm as well as ICSI procedural factors. We know from the literature that cytogenetic studies of subfertile men have shown increased risk of chromosomal abnormalities including balanced rearrangements and meiotic abnormalities [25,26]. The study has, however, been since criticised for using an unstandardised testing system, insufficient adjustment for demographic differences between groups, and inclusion of cryopregnancies and multiple pregnancies.1 Minor developmental deficits have been noted in children after replacement of cryopreserved embryos [27]. Other factors in this study, which may have influenced the outcome, include a lack of blinding and demographic differences between the groups. Notably, the IVF and natural conception controls were originally recruited as part of a separate study to compare IVF parents and children, so the investigators were already aware of the children’s status. No information was provided regarding comparability of the NC children and the IVF/ICSI study groups with respect to ethnic background and social class e all factors that are potential confounders for birth defects. In line with these findings, a study by Knoester et al. found a difference in cognitive development between ICSI and IVF children [28]. This particular Dutch study compared the cognitive development of 5e8-year-old ICSI singletons (n ¼ 86) with two control groups: children born after IVF (n ¼ 83) and NC controls (n ¼ 85). At the time of the study, Dutch norms for the WISC-III had not yet been approved and so the Revised Amsterdam Intelligence Test (RAKIT) was used instead, applicable to 4e11-year-old children [29]. ICSI children had significantly lower scores on three subsets in comparison to NC children and their IQ distribution was shifted to lower end. Potential weaknesses of this study include the small sample size and the use of multiple observers, although they were blinded to the mode of conception and the researchers distributed them at random across the groups studied. The clinical significance of the observed differences in IQ is debatable, given that the mean IQ in ICSI children was still within the normal range. A response of 79% in ICSI children and 73% in IVF children was achieved at this centre, but in the NC group the response rate and reasons for nonparticipation were unclear. Selection bias, a recurrent limitation of studies of cognitive development, may have occurred. In summary, the study authors cautiously state that in their limited sample, the lower cognitive development in ICSI singletons compared to IVF and NC children may be due to selection bias and unmeasured confounders, although the effect of ICSI per se cannot be excluded.
4. Studies reporting neurocognitive outcome concerns Bowen et al. [11] published worrying results on the mental development of ICSI children at 13 months, which initially drew attention to this area. The study compared the medical and developmental outcome at 1 year of 89 ICSI children with 84 routine IVF children and 80 NC children in an early prospective study. Formal developmental assessment was done with Bayley Scales of Infant Development, 2nd edition (BSID-II) from which an MDI was derived. Whereas the results of this small study showed no significant difference in the incidence of major congenital malformations in the first year of life, the Bayley MDI was significantly lower for ICSI children than for IVF or NC children [95.9 (SD 10.7), 101.8 (8.5), and 102.5 (7.6), respectively, P < 0.0001]. Seventeen percent of ICSI children experienced mild or significant developmental delay at 1 year, compared with 2% of IVF children and 1% of NC children
5. Other recent studies: autism, attention deficit/ hyperactivity disorder and assisted conception In infants born after IVF, an increased risk of neuropsychiatric disturbances has been suggested and a higher risk of cerebral palsy has been demonstrated [30,31]. A Swedish study by Kallén et al. [32] investigated the risk of attention deficit/hyperactivity disorder (ADHD) in children conceived following IVF; 28,158 IVF children were compared to 2,417,886 children in the population. After adjustment for potential confounders, a weak but statistically significant association was found with an odds ratio of 1.18 [95%
1 ‘Cryopregnancy’ refers to the process of preserving an embryo at sub-zero temperature at an embryogenesis stage corresponding to pre-implantation. It is useful for leftover embryos after a cycle of IVF.
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confidence interval (CI): 1.03e1.36]. This weak increase in odds of drug-treated ADHD after IVF is in contrast to a previous study in the USA of 173 individuals that found a ten-fold increase in the risk of ADHD [33]. Clearly, the aetiology of ADHD is very complex and many variables can appear as confounders in a study of the association between IVF and ADHD. In fact the results of the Swedish study were no longer statistically significant when adjusted for length of childlessness, and the authors themselves admitted that the moderate association was unlikely to be clinically significant. Autism spectrum disorders (ASD) are a group of disorders defined by communication and social deficiencies in addition to stereotyped behaviours. There is a wide variability in intensity and presence of core symptoms, and in cognitive and language skills. Only a few studies have assessed the association between ASD and assisted conception, and thus far they show conflicting results. Often they have methodological limitations including a lack of statistical power [34] and evaluation of a combined group of psychiatric disorders [35,36] disorders. Associations between ASD and assisted conception may be predicted due to at least three potential risk factors: high parental age, high maternal educational level, and hormonal disturbances. In addition, as assisted conception leads to a higher rate of preterm delivery and low birth weight, which have been associated with ASD, a higher risk may be expected in IVF or ICSI children. In a population-based follow-up study in Denmark, 599,967 children born between 1995 and 2003 were investigated [37]. Children exposed to IVF or ovulation induction (OI) were identified in the IVF Register and in the Danish Drug Prescription Register. The crude analysis showed an increased risk of ASD diagnosis in assisted conception [hazard rate ratio (HRR): 1.25; 95% CI: 1.09e 1.43], but after adjusting for maternal age, educational level, parity, smoking, birth weight and plurality the risk disappeared (adjusted HRR: 1.13; 95% CI: 0.97e1.31). However, subgroup analysis suggested a possible association between OI treatment and exposure to FSH with increased ASD risk. A caseecontrol study by Zachor et al. [38] focused on the association between ART and ASD in a large Israeli population diagnosed with ASD using stringent criteria based on standardised tests. The study included 624 participants, 507 of whom were diagnosed with ASD. The proportion born following ART treatment in the ASD group was significantly higher (10.7%) than in a large Israeli population (3.06%). In both ASD groups, with and without ART, parental age distribution did not differ and the frequency of ART in young mothers (aged
Contents lists available at ScienceDirect
Seminars in Fetal & Neonatal Medicine journal homepage: www.elsevier.com/locate/siny
Review
I was born following ART: how will I get on at school? Omar Abdel-Mannan*, Alastair Sutcliffe General and Adolescent Paediatric Unit, Institute of Child Health, London, UK
s u m m a r y Keywords: Assisted reproductive techniques Children Intracytoplasmic sperm injection In-vitro fertilisation Neurodevelopmental outcome
With an ever-expanding population of children born after in-vitro fertilisation (IVF), the widespread use of assisted reproductive techniques (ART) has placed a great emphasis on the need to study their longterm outcomes. Indeed, there has been concern that mechanisms used in ART may have a detrimental effect on the neurocognitive development of these children. Reassuringly, most neurocognitive and motor development studies using various assessment scales have generally found no differences between intracytoplasmic sperm injection, IVF and naturally conceived children. Only a few studies have reported concerns. In terms of predictors of intelligence in children, ART appears to have a minimal effect in comparison to birth weight, gestational age, socio-economic status, and parental educational levels. Nevertheless, further research of higher methodological quality in children beyond pre-school age and on newer ART procedures is needed. Ó 2014 Published by Elsevier Ltd.
1. Introduction The population of children born after in-vitro fertilisation (IVF) has grown over the last two decades; since 1978, more than five million children have been conceived through assisted reproductive techniques (ART). Whereas the techniques are generally considered safe, their widespread use has culminated in greater emphasis on the need to study the long-term outcomes of ART. Evidence from a number of studies has shown that IVF pregnancies carry a higher risk for genetic imprinting disorders, preterm birth, low birthweight, and small for gestational age, mainly due to the resulting high proportion of multi-fetal pregnancies [1,2]. The prevalence of congenital malformations in different studies has ranged from 5.6% to 9.0% in comparison to 4.2% to 5% in the general population [3,4]. The majority of studies on IVF children’s outlook focus on medical outcomes and, in particular, there is now increasing attention being given to the neurocognitive and developmental follow-up of these children. Given that the human brain is the most complex of organs, it is the most prone to any insult, whether gross or minor. Previous studies have yielded mixed to reassuring
* Corresponding author. Address: General and Adolescent Paediatric Unit, Institute of Child Health, 43 Great Ormond Street, London WC1N 3HZ, UK. Tel.: þ44 07717 747012. E-mail address: [email protected] (O. Abdel-Mannan). http://dx.doi.org/10.1016/j.siny.2014.04.003 1744-165X/Ó 2014 Published by Elsevier Ltd.
findings regarding very young to school-aged ART children’s motor and cognitive development. Studies following children ranging from 1 year to 13 years of age have not given rise to concerns regarding growth and physical development of IVF children [5,6], and cognitive and behavioural development have also been reported to be normal among this subgroup [7,8]. Herein is a synopsis of studies subdividing them into different categories. 2. Neurodevelopmental outcomes Almost all studies of neurodevelopmental outcomes have shown reassuring outcomes for ART children. As demonstrated in the studies discussed in this review, the tests used to assess neurocognitive outcomes are limited by a number of recurrent problems, including:
lack of blinding of study assessors underpowered non-standardised assessment tools inter-observer error (more than one assessor used) bilingual children perform less well on the tests twins perform less well and there are no studies on triplets low participation rates selection bias e participants’ parents may have an agenda.
In this synopsis, we have sought to focus on the largest studies on this topic, mainly including more than 100 subjects.
246
O. Abdel-Mannan, A. Sutcliffe / Seminars in Fetal & Neonatal Medicine 19 (2014) 245e249
3. Studies reporting no neurocognitive outcome concerns Leslie et al. [9] determined the developmental outcomes of children using intelligence quotients (IQ) obtained from the Wechsler Preschool and Primary Scale of Intelligence e Revised (WPPSI-R [10]). The study looked at the mental development of 97 intracytoplasmic sperm injection (ICSI), 80 IVF and 110 naturally conceived (NC) singleton or twin children at 5 years of age. ICSI is an effective treatment for severe male-factor infertility. Whereas in conventional IVF, 50,000e100,0000 sperm are incubated with an oocyte in a culture medium, in ICSI a single sperm is injected directly into the oocyte’s vitellus, thus bypassing natural sperm selection barriers. The fact that less mature sperm are used in this technique has raised hypothetical concerns regarding increased risk of genetic abnormalities and structural defects. Early reports suggested possible developmental or other problems [11,12]; however, these studies were limited by small sample sizes, unstandardised assessment systems, poor rates of follow-up, multiple observers and other methodological problems. In this study, the mean Bayley Scales mental development index (MDI) of the ICSI group was found to be significantly lower than both IVF and NC control groups at 1 year of age. This is in contrast to other studies that found the mean Griffiths Mental Development Scales General Quotient (GQ) of ICSI children not to be significantly different from that of NC controls. Many of the previous studies were performed on children aged 2 years, and tests of cognitive ability may not reliably predict long-term intelligence at that stage [13,14]. It is therefore essential to evaluate children further at an age when long-term intellectual ability can be predicted with more reliability. Indeed, the authors highlighted that if differences seen at 1 year of age were maintained at school age, this would raise the likelihood of ICSI children needing additional assistance at school in comparison to their NC or IVF peers. The mean values for all three IQ scales used for all three groups were nevertheless within the normal range. ICSI group mean values, reassuringly for parents, were not significantly different from either the IVF or NC control groups. Interestingly, at 1 year of age, a higher percentage of children in the ICSI group had delayed cognitive development in comparison to the other two groups. However, at 5 years of age, the percentage of ICSI children with cognitive delay had fallen (from 17% to 5%) and ICSI itself was no longer an independent predictor of delay in cognitive development. In keeping with results of other population-based studies of nonART children [15,16], the study showed that parental education and other demographic factors are the strongest predictors of cognitive ability at 5 years of age. Potential bias may have been introduced by some group differences in the recruitment of children assessed at 5 years of age. For instance, whereas IVF children were recruited prospectively during pregnancy, additional NC controls were enrolled from pre-schools selected to match ICSI cohort demographics. Only 12% of potentially eligible children were enrolled from the pre-schools, which may have led to parental motivation in child participation affecting the results. On the one hand, parents with concerns about their child’s educational performance may have agreed to participate, thus lowering the mean IQ for the natural conception group; on the other hand, parents may have sought confirmation of above-average IQ in their children through this study. Sutcliffe et al. [17] undertook a study comparing 208 ICSI singleton children and 221 NC singleton children. The primary outcome was neurodevelopmental scoring using the Griffiths Mental Development Scales (re-standardised for the UK in 1996 to reflect the child-rearing practices, social habits, racial groupings, and other socio-demographic factors). Secondary measures included perinatal morbidity, postnatal health, and congenital
abnormalities. With a follow-up rate of 90% in the ICSI group, no difference was found between the study children and the NC children in mean (SD) neurodevelopmental scores [98.08 (10.93) vs 98.69 (9.99), respectively] or any subscales on the Griffiths’ scales of mental development. The use of a single observer, involvement of the major UK ICSI centres and selection of a similar comparison group in terms of baseline characteristics strengthen this study’s reliability. However, observers were not blinded from the mode of conception. The study also used a recent revision of the Griffiths Mental Development Scales General Quotient (GQ) and there is a decrease in the range of maximum scores achievable for infants aged >20 months, which may have affected this study’s results, where some of the study participants were aged 21 22 months. The group scores may have been dampened, reducing the likelihood of finding significant differences between groups. Notably, the findings of Sutcliffe et al. are in conflict with results from Bowen et al. [11], who suggested that children born after ICSI are developmentally less able than NC children at 1 year of age. The latter study was, however, marred by several methodological limitations, discussed in more detail below. Large-scale multi-centre collaborative studies have also investigated the long-term effects of ICSI in terms of development of preschool to school-aged children. In a study by Ponjaert-Kristoffersen et al. [18], no significant differences were found in intelligence quotient (IQ) on the WPPSI-R between 5-year-old ICSI and spontaneously NC children from Belgium, Sweden, and the USA. However, on further subtest score analysis, ICSI children appeared more likely to perform better on general factual/acquired knowledge information and worse on some visualespatial abilities (mazes, block design and object assembly). A collaborative follow-up study by the same authors compared 5-year-old singleton ICSI-born children with IVF and NC controls recruited across various European countries and matched according to age, sex, birth order, maternal education, parental socio-economic status and mother’s age at birth [19]. No significant inter-group differences on intelligence were evident. However, lower full-scale and verbal IQ in ICSI/ IVF children were linked with older maternal age at birth. Higher maternal education was associated with better object assembly in ICSI/IVF children, and a lower educational level was associated with worse spatial visualisation and block design. These findings suggest that factors such as maternal age and educational level have a greater effect on the long-term cognitive development of ICSI children than the mode of conception. A proportion of the Belgian children in the study by PonjaertKristoffersen et al. study were followed up and assessed at 8 years of age [20]. A total of 151 ICSI and 153 NC children were assessed by means of the Wechsler Intelligence Scale for Children e Revised (WISC-R) and the Movement Assessment Battery for Children along with an extensive paediatric-neurological evaluation and a family-relational assessment. The intelligence outcome was favourable for ICSI children, although the effect was not clinically significant. It was hypothesised that a higher degree of child stimulation due to higher maternal educational levels explained this phenomenon in the ICSI group. Other research has also shown a higher average achievement in developmental examination among IVF children (with 12 30 month follow-up) [21]. The explanation given was exceptional parental motivation, and it would be interesting to look further into how much family functioning and environmental stimuli can enhance an IVF child’s development. Follow-up of the children in the 2006 Leunens et al. [22] study examined the second-wave study findings for the cognitive and motor development of ICSI children at 10 years of age, comparing them to the first-wave results at 8 years of age. The study was designed to investigate the possible pathways of influence of ICSI
O. Abdel-Mannan, A. Sutcliffe / Seminars in Fetal & Neonatal Medicine 19 (2014) 245e249
on child development. Therefore, different developmental dimensions and socio-cognitive factors of influence were assessed through a multi-method multi-informant approach. A single trained psychologist individually tested all the children, applying testing conditions similar to those in the first-wave study. Most significantly, 10-year-old ICSI children did not display any significant developmental delays compared with NC children at age 8 or 10 years, in terms of cognitive or motor functioning. Nevertheless caution is needed when generalising these findings due to the study’s limitations. Whereas the follow-up rate for first study wave was 72%, more than half of the initial birth cohort were not assessed in the second study wave, raising questions regarding participation bias. Another potential limitation of these findings is the fact that only children born after 32 weeks of gestation were included. Whilst the findings of this study are interesting, replication of these results with later cohorts and longer-term follow-up are needed. Several studies have assessed the neurological or developmental outcome of children at 5 or 8 years of age [23e25]. In some of these, pre-term children or multiples were included but most include fewer than 100 children in each group. A large cohort study with a comparison group of NC children by Ludwig et al. [26] was the first to exclude the influence of prematurity and was well powered to detect an equivalent mental development. The aim of the study was to assess the neurodevelopmental health at 5.5 years in 276 ICSI children compared to 273 NC controls. Neuromotor development was assessed by a detailed neurological examination, including the standardised motor test MOT 4e6, and emotional/behavioural development and intelligence were assessed with the Kaufman Assessment Battery for Children (K-ABC). There were no significant differences between ICSI and NC children with regard to the neurological findings, motor skills, emotional/behavioural development, or intelligence. A sensitivity analysis with adjustment for maternal age and social status also showed equivalent results for all subscales of the K-ABC. It is important to note that in both groups the mean social status and parental education level was above the national average. Thus when interpreting the data, we cannot assume that this represents the average in society. In addition, parental education and other environmental factors play a crucial role. This was previously shown by Place and Englert [23], who found that the difference in IQ in ICSI/IVF children compared to NC children disappeared after adjusting for parental education. Whereas the study by Ludwig et al. was well powered for the primary outcome and large in size, four different paediatricians examined the children and a lower response rate was achieved for the NC children. The results are also only applicable to term-born singletons, and multiples or children born preterm will need further investigation.
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(P < 0.0001). The authors proposed that possible reasons for the poorer performance among the ICSI children include factors relating to genetic abnormalities in the sperm as well as ICSI procedural factors. We know from the literature that cytogenetic studies of subfertile men have shown increased risk of chromosomal abnormalities including balanced rearrangements and meiotic abnormalities [25,26]. The study has, however, been since criticised for using an unstandardised testing system, insufficient adjustment for demographic differences between groups, and inclusion of cryopregnancies and multiple pregnancies.1 Minor developmental deficits have been noted in children after replacement of cryopreserved embryos [27]. Other factors in this study, which may have influenced the outcome, include a lack of blinding and demographic differences between the groups. Notably, the IVF and natural conception controls were originally recruited as part of a separate study to compare IVF parents and children, so the investigators were already aware of the children’s status. No information was provided regarding comparability of the NC children and the IVF/ICSI study groups with respect to ethnic background and social class e all factors that are potential confounders for birth defects. In line with these findings, a study by Knoester et al. found a difference in cognitive development between ICSI and IVF children [28]. This particular Dutch study compared the cognitive development of 5e8-year-old ICSI singletons (n ¼ 86) with two control groups: children born after IVF (n ¼ 83) and NC controls (n ¼ 85). At the time of the study, Dutch norms for the WISC-III had not yet been approved and so the Revised Amsterdam Intelligence Test (RAKIT) was used instead, applicable to 4e11-year-old children [29]. ICSI children had significantly lower scores on three subsets in comparison to NC children and their IQ distribution was shifted to lower end. Potential weaknesses of this study include the small sample size and the use of multiple observers, although they were blinded to the mode of conception and the researchers distributed them at random across the groups studied. The clinical significance of the observed differences in IQ is debatable, given that the mean IQ in ICSI children was still within the normal range. A response of 79% in ICSI children and 73% in IVF children was achieved at this centre, but in the NC group the response rate and reasons for nonparticipation were unclear. Selection bias, a recurrent limitation of studies of cognitive development, may have occurred. In summary, the study authors cautiously state that in their limited sample, the lower cognitive development in ICSI singletons compared to IVF and NC children may be due to selection bias and unmeasured confounders, although the effect of ICSI per se cannot be excluded.
4. Studies reporting neurocognitive outcome concerns Bowen et al. [11] published worrying results on the mental development of ICSI children at 13 months, which initially drew attention to this area. The study compared the medical and developmental outcome at 1 year of 89 ICSI children with 84 routine IVF children and 80 NC children in an early prospective study. Formal developmental assessment was done with Bayley Scales of Infant Development, 2nd edition (BSID-II) from which an MDI was derived. Whereas the results of this small study showed no significant difference in the incidence of major congenital malformations in the first year of life, the Bayley MDI was significantly lower for ICSI children than for IVF or NC children [95.9 (SD 10.7), 101.8 (8.5), and 102.5 (7.6), respectively, P < 0.0001]. Seventeen percent of ICSI children experienced mild or significant developmental delay at 1 year, compared with 2% of IVF children and 1% of NC children
5. Other recent studies: autism, attention deficit/ hyperactivity disorder and assisted conception In infants born after IVF, an increased risk of neuropsychiatric disturbances has been suggested and a higher risk of cerebral palsy has been demonstrated [30,31]. A Swedish study by Kallén et al. [32] investigated the risk of attention deficit/hyperactivity disorder (ADHD) in children conceived following IVF; 28,158 IVF children were compared to 2,417,886 children in the population. After adjustment for potential confounders, a weak but statistically significant association was found with an odds ratio of 1.18 [95%
1 ‘Cryopregnancy’ refers to the process of preserving an embryo at sub-zero temperature at an embryogenesis stage corresponding to pre-implantation. It is useful for leftover embryos after a cycle of IVF.
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confidence interval (CI): 1.03e1.36]. This weak increase in odds of drug-treated ADHD after IVF is in contrast to a previous study in the USA of 173 individuals that found a ten-fold increase in the risk of ADHD [33]. Clearly, the aetiology of ADHD is very complex and many variables can appear as confounders in a study of the association between IVF and ADHD. In fact the results of the Swedish study were no longer statistically significant when adjusted for length of childlessness, and the authors themselves admitted that the moderate association was unlikely to be clinically significant. Autism spectrum disorders (ASD) are a group of disorders defined by communication and social deficiencies in addition to stereotyped behaviours. There is a wide variability in intensity and presence of core symptoms, and in cognitive and language skills. Only a few studies have assessed the association between ASD and assisted conception, and thus far they show conflicting results. Often they have methodological limitations including a lack of statistical power [34] and evaluation of a combined group of psychiatric disorders [35,36] disorders. Associations between ASD and assisted conception may be predicted due to at least three potential risk factors: high parental age, high maternal educational level, and hormonal disturbances. In addition, as assisted conception leads to a higher rate of preterm delivery and low birth weight, which have been associated with ASD, a higher risk may be expected in IVF or ICSI children. In a population-based follow-up study in Denmark, 599,967 children born between 1995 and 2003 were investigated [37]. Children exposed to IVF or ovulation induction (OI) were identified in the IVF Register and in the Danish Drug Prescription Register. The crude analysis showed an increased risk of ASD diagnosis in assisted conception [hazard rate ratio (HRR): 1.25; 95% CI: 1.09e 1.43], but after adjusting for maternal age, educational level, parity, smoking, birth weight and plurality the risk disappeared (adjusted HRR: 1.13; 95% CI: 0.97e1.31). However, subgroup analysis suggested a possible association between OI treatment and exposure to FSH with increased ASD risk. A caseecontrol study by Zachor et al. [38] focused on the association between ART and ASD in a large Israeli population diagnosed with ASD using stringent criteria based on standardised tests. The study included 624 participants, 507 of whom were diagnosed with ASD. The proportion born following ART treatment in the ASD group was significantly higher (10.7%) than in a large Israeli population (3.06%). In both ASD groups, with and without ART, parental age distribution did not differ and the frequency of ART in young mothers (aged
