Cognitive and behavioural outcome of children born after IVF at age 9 years.

STUDY QUESTION: Do ovarian stimulation (OS) and the in vitro laboratory procedures affect offsprings' cognitive and behavioural outcome at 9 years? SUMMARY ANSWER: OS and the in vitro laboratory procedures or the combination of both were not associated with cognitive and behavioural outcome at age 9 years. WHAT IS KNOWN ALREADY: ART is not associated with an adverse short-term developmental outcome of the offspring, but limited knowledge is available on the offspring's long-term neurodevelopmental condition. STUDY DESIGN, SIZE, DURATION: A 9-year longitudinal, assessor-blinded, prospective follow-up study of 169 out of 215 singletons (79%) born between March 2005 and December 2006 was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Singletons born following IVF or ICSI with OS (n = 57), born after modified natural cycle IVF/ICSI (MNC-IVF/ICSI; n = 46) and born after natural conception to subfertile couples (Sub-NC; n = 66), were assessed at 9 years. This study design, with two ART groups and a subfertile reference group, allows for disentangling the effects of OS and ART procedures on developmental outcome. Cognitive outcome was evaluated with the Wechsler abbreviated scale of intelligence and the NEPSY-II. Behaviour was assessed with the child behaviour checklist (CBCL) and teacher report form (TRF). Univariable analyses and multiple linear regression models were used. MAIN RESULTS AND THE ROLE OF CHANCE: There was no significant difference in intelligence quotient (IQ) scores between ART groups (mean IQ (95% CI): OS 114.8 (83.2-142.6); MNC 114.0 (90.2-140.8); Sub-NC 115.4 (87.9-141.2), P = 0.746). Multivariable analyses did not reveal a statistically significant association between ART group and total, verbal and performance IQ. CBCL and TRF scores did not differ significantly between ART groups (P = 0.090 and 0.507, respectively). Multivariable analyses did not demonstrate a statistically significant association between ART group and CBCL and TRF total, or internalising and externalising T-scores. No significant correlations between time to pregnancy (TTP)-a proxy for the severity of parental subfertility-and outcome measures were found (Spearman rho between -0.050 and 0.049, NS), which was confirmed with multivariable analyses. LIMITATIONS, REASONS FOR CAUTION: The attrition rate of 21% may be considered as a limitation of the study; however, after a follow-up period of 9 years, this rate is generally considered acceptable, and there were no significant differences in background characteristics between children with and without follow-up, making an attrition-related selection bias less likely. Another limitation of the study is the relatively small sample size, which could contribute to selection bias, hamper generalizability to the ART population and lead to false negative findings as a result of underpowering. An a priori power analysis on total IQ indicated that the OS-IVF/ICSI and Sub-NC groups should contain 64 children, confirming that our study including 57 and 66 children, respectively, was slightly underpowered. WIDER IMPLICATIONS OF THE FINDINGS: Our study indicated that OS and the in vitro laboratory procedures or the combination of both and TTP were not associated with cognitive and behavioural outcome at 9 years. These are reassuring results for both parents and clinicians involved in ART. STUDY FUNDING/COMPETING INTEREST(S): The study was financially supported by the University Medical Center Groningen (UMCG), two graduate schools of the UMCG (BCN and SHARE) and the Cornelia Stichting. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The authors have no conflicts of interest to declare.

Early vibration assisted physiotherapy in toddlers with cerebral palsy - a randomized controlled pilot trial.

OBJECTIVES: to investigate feasibility, safety and efficacy of home-based side-alternating whole body vibration (sWBV) to improve motor function in toddlers with cerebral palsy (CP). METHODS: Randomized controlled trial including 24 toddlers with CP (mean age 19 months (SD±3.1); 13 boys). INTERVENTION: 14 weeks sWBV with ten 9-minute sessions weekly (non-individualized). Group A started with sWBV, followed by 14 weeks without; in group B this order was reversed. Feasibility (≥70% adherence) and adverse events were recorded; efficacy evaluated with the Gross Motor Function Measure (GMFM-66), Pediatric Evaluation of Disability Inventory (PEDI), at baseline (T0), 14 (T1) and 28 weeks (T2). RESULTS: Developmental change between T0 and T1 was similar in both groups; change scores in group A and B: GMFM-66 2.4 (SD±2.1) and 3.3 (SD±2.9) (p=0.412); PEDI mobility 8.4 (SD±6.6) and 3.5 (SD±9.2) (p=0.148), respectively. In two children muscle tone increased post-sWBV. 24 children received between 67 and 140 sWBV sessions, rate of completed sessions ranged from 48 to 100% and no dropouts were observed. CONCLUSION: A 14-week home-based sWBV intervention was feasible and safe in toddlers with CP, but was not associated with improvement in gross motor function.

Increased time to pregnancy is associated with less optimal neurological condition in 4-year-old singletons, in vitro fertilization itself is not.

STUDY QUESTION: Does ovarian hyperstimulation, the in vitro procedures required for in vitro fertilization (IVF)/ intracytoplasmic sperm injection or the combination of both, affect the neurological outcome of 4-year-old singletons? SUMMARY ANSWER: Ovarian hyperstimulation, the in vitro procedure and the combination of both, were not associated with the worse neurological outcome in 4-year-old singletons. WHAT IS KNOWN ALREADY: Assisted reproduction techniques (ARTs) are not associated with neurological dysfunction during the first post-natal years; however, effects on the long-term neurological outcome are still inconclusive. An increased time to pregnancy (TTP, a proxy for the severity of subfertility) has been associated with a less optimal neurological condition at age 2. The present study focuses on the neurodevelopmental outcome of 4-year-old ART-offspring. STUDY DESIGN, SIZE, DURATION: Longitudinal, prospective follow-up study. PARTICIPANTS, SETTING, METHODS: Four-year-old singletons born to subfertile parents (subfertile group, n = 195), including singletons born after controlled ovarian hyperstimulation IVF (COH-IVF, n = 63), modified natural cycle IVF (MNC-IVF, n = 53) and natural conception (Sub-NC, n = 79). Data on underlying cause of subfertility and TTP were present. In addition, we assessed newly recruited 4-year-old singletons born to fertile parents after natural conception (reference group, n = 98). Neurological development was evaluated with the neurological examination according to Hempel, resulting in a neurological optimality score (NOS), a fluency score and the occurrence of the clinically relevant form of minor neurological dysfunction (complex MND). The primary outcome was the fluency score, as fluency of movements is easily reduced by subtle brain dysfunction. Data were analysed with univariable and multivariable regression analyses, in which special attention was paid to sex differences in the neurological outcome. MAIN RESULTS AND THE ROLE OF CHANCE: The fluency score, NOS and the prevalence of complex MND were similar in COH-IVF, MNC-IVF and Sub-NC children. The neurological condition of children born to subfertile parents was similar to that of children of fertile parents and was independent of the underlying cause of subfertility. No statistically significant associations were found between TTP and the fluency score and NOS. However, a positive correlation was found between TTP and the prevalence of complex MND (TTP in years, adjusted odds ratio [OR] [95% confidence interval, CI]: 1.207 [1.038 to 1.404], P = 0.014); a correlation which could be attributed to girls, in whom an evident positive correlation was present (adjusted OR [95% CI]: 1.542 [1.161 to 2.047], P = 0.003). A similar association was absent in boys. LIMITATIONS, REASONS FOR CAUTION: The prospective design of our study and small post-natal attrition rate (9.3%) reduced potential selection bias based on the child's development or health. The assessors were blind to the mode of conception, except for the group of children born to fertile parents, which was newly recruited. The study lacks sufficient power to conclude firmly that increased TTP is associated with a higher prevalence of complex MND. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that the severity of subfertility, rather than its simple presence or components of IVF treatment, affects the neurological outcome. Moreover, girls may be neurologically more vulnerable for the effect of severity of subfertility. The finding that the severity of subfertility may be the decisive factor rather than the presence of a history of subfertility per se corroborates previous reports. Our results cannot be generalized to multiples, as we studied singletons only. STUDY FUNDING/COMPETING INTERESTS: The study was financially supported by the University Medical Center Groningen, grant number: 754510, the Junior Scientific Masterclass, the Postgraduate School Behavioural and Cognitive Neurosciences and the Cornelia Foundation, Groningen, The Netherlands. The authors have no conflicts of interest to declare.

Treadmill interventions with partial body weight support in children under six years of age at risk of neuromotor delay: a report of a Cochrane systematic review and meta-analysis.

UNLABELLED: Delayed motor development may occur in children with Down syndrome, cerebral palsy or children born preterm, which in turn may limit the child's opportunities to explore the environment. Neurophysiologic and early intervention literature suggests that task-specific training facilitates motor development. Treadmill intervention is a good example of locomotor task-specific training. AIM: The aim of this paper was to assess the effectiveness of treadmill intervention on locomotor motor development in pre-ambulatory infants and children under six years of age who are at risk for neuromotor delay. DESIGN: A Cochrane systematic review with meta-analysis. METHODS: We employed a comprehensive search strategy. We included randomised, quasi-randomised and controlled clinical trials that evaluated the effect of treadmill intervention in children up to six years of age with delays in gait development or the attainment of independent walking or who were at risk of neuromotor delay. We searched CENTRAL, MEDLINE, EMBASE, PsycINFO, CINAHL, Science Citation Index, PEDro, CPCI-S and LILACS; and also ICTRP, ClinicalTrials.gov, mRCT and CenterWatch. Four authors independently extracted the data using standardized forms. RESULTS: We included five studies, which reported on treadmill intervention in 139 children. Of the 139 children, 73 were allocated to treadmill intervention groups. The studies varied in the type of population studied, the type of comparison, the time of evaluation and the parameters assessed. Due to the diversity of the studies, we were only able to use data from three studies in meta-analyses and these were limited to two outcomes: age of onset of independent walking and gross motor function. Evidence suggested that treadmill intervention could lead to earlier onset of independent walking when compared to no treadmill intervention (effect estimate -1.47; 95% CI: -2.97, 0.03), though these trials studied two different populations: Down syndrome and children at risk of neuromotor disabilities. Children with Down syndrome seemed to benefit while it was not clear if this was the case for children at high risk of neuromotor disabilities. Two other studies, both in children with Down syndrome, compared different types of treadmill intervention (high versus low intensity training). Both were inconclusive regarding the impact of these different protocols on the age at which children started to walk. There is insufficient evidence to determine whether treadmill intervention improves gross motor function (effect estimate 0.88; 95% CI: -4.54, 6.30). CONCLUSION: The current review provided only limited evidence of the efficacy of treadmill intervention in children up to six years of age. Few studies have assessed treadmill interventions in young children using an appropriate control group. The available evidence indicates that treadmill intervention may accelerate the development of independent walking in children with Down syndrome. Further research is needed to confirm this and should also address whether intensive treadmill intervention can accelerate walking onset in young children with cerebral palsy and high risk infants, and whether treadmill intervention has a general effect on gross motor development in the various subgroups of young children at risk for developmental delay.

The effect of preimplantation genetic screening on neurological, cognitive and behavioural development in 4-year-old children: follow-up of a RCT.

STUDY QUESTION: Does embryo biopsy inherent to preimplantation genetic screening (PGS) affect neurological, cognitive and behavioural development of 4-year-old children? SUMMARY ANSWER: PGS does not seem to affect neurological, cognitive and behavioural development of 4-year-old singletons; however, our data suggest that it may be associated with altered neurodevelopment in twins. WHAT IS KNOWN ALREADY: Evidence concerning the safety of PGS on neurodevelopmental outcome in offspring is scarce. The present study provides information on neurodevelopmental, cognitive and behavioural outcome of 4-year-old PGS offspring. STUDY DESIGN, SIZE, DURATION: A prospective, assessor-blinded follow-up study of children born to women who participated in a multi-centre RCT on the effect of IVF with or without PGS. PARTICIPANTS/MATERIALS, SETTING, METHODS: At 4 years, 49 children (31 singletons, 9 sets of twins) born following IVF with PGS and 64 children (42 singletons, 11 sets of twins) born following IVF without PGS (controls) were assessed (post-natal attrition 18%). Neurological development was evaluated with the standardized, age-specific and sensitive neurological examination according to Hempel, resulting in a neurological optimality score (NOS), a fluency score and the rate of adverse neurological outcome. Primary outcome was the fluency score, as fluency of movements is easily reduced by subtle dysfunction of the brain. Cognitive development was evaluated with the Kaufman Assessment Battery for Children; behavioural development was evaluated with the Child Behavior Checklist. The effect of PGS was analysed with a mixed effects model. MAIN RESULTS AND THE ROLE OF CHANCE: Based on the intention to treat analysis, neurodevelopmental outcome of PGS children was similar to that of controls. However, additional analyses indicated that PGS affected neurodevelopmental outcome of twins in a different way than that of singletons. The fluency score of singletons born following PGS was similar to that of control singletons [mean values, 95% confidence intervals (CIs): 12.2 (11.5;12.8) and 12.2 (11.6;12.8)], respectively, P = 0.977) that was also true for the other neurodevelopmental parameters. The fluency score of PGS twins was significantly lower than that of control twins [mean values, 95% CIs: 10.6 (9.8;11.3) and 12.3 (11.5;13.1)], respectively, P = 0.001); the same was true for the NOS. In addition, PGS in twins was associated with a higher sequential intelligence quotient score. On the other hand, other neurodevelopmental parameters were similar for PGS twins and control twins. Post hoc sample size calculation for the primary outcome parameter, the fluency score, indicated that the study groups, including the subgroups of singletons and twins, were adequately powered. LIMITATIONS, REASONS FOR CAUTION: We assessed singletons and twins who contributed to the generalizability of the study. A limitation of our study is the relative small size of our study groups and the selective dropout in both groups (dropouts PGS group: higher gestational age; control group: less well-educated parents). These preclude the conclusion that PGS per se is not associated with neurodevelopmental, cognitive and behavioural problems in singletons and the conclusion that PGS is associated with altered neurodevelopmental outcome in twins. WIDER IMPLICATIONS OF THE FINDINGS: The need for careful long-term monitoring of children born following embryo biopsy remains, as it is still applied in the form of PGD and it is still unknown whether embryo biopsy affects long-term neurodevelopmental outcome.

Increase in impaired motor coordination in six-year-old German children between 1990 and 2007.

AIM: To evaluate changes in prevalence of impaired motor coordination among 6-year-olds of a geographically defined area in Germany between the years 1990 and 2007. METHODS: Data from the obligatory school entrance examinations in the German state of North Rhine Westphalia between the years 1990 and 2007 were used. The number of children assessed per year varied from 81 517 to 124 086. The classification of impaired motor coordination was based on the combination of standardized screening and physicians' clinical impression of need of treatment. Logistic regression modelling was performed to evaluate the changes in prevalence of impaired motor coordination. RESULTS: Between 1990 and 2007, the prevalence of impaired motor coordination rose from 2.5% to 8.9% in boys and from 0.8% to 3.6% in girls. As the standard error of these percentages is below 0.15%, the changes are highly statistically significant. CONCLUSION: The prevalence of impaired motor coordination tripled during the last decades in North Rhine Westphalia. This may imply that the prevalence of Developmental Coordination Disorder also increased. Factors that may explain the increasing prevalence include the increase in surviving preterm infants, increasing parental age at child birth, maternal and child obesity and decreasing child mobility.

The impact of IVF/ICSI on parental well-being and anxiety 1 year after childbirth.

BACKGROUND: More couples are delaying childbirth resulting in an increase of age-related subfertility in women. Subfertility and assisted reproductive technology (ART) treatments may affect couples' psychological well-being. The aim of the present study was to investigate whether factors related to IVF/ICSI affect anxiety and mental health in couples 1 year after childbirth. METHOD: In this cohort study, we included couples with a singleton pregnancy following IVF/ICSI treatment (n=113) and subfertile couples who naturally conceived (NC; n=83). Parental trait anxiety (Dutch version of the Spielberger State-Trait Anxiety Inventory) and mental health (Dutch version of General Health Questionnaire) were assessed 1 year after childbirth. The influence of fertility-related factors was analyzed with logistic regression analyses. RESULTS: One hundred and ninety-six couples participated, 93% of those eligible. Trait anxiety and mental health were similar in IVF/ICSI and NC groups. However, NC fathers had more often mental health scores in the clinical range (21%) than fathers in the IVF/ICSI group (9%). The risk of having a trait anxiety or mental health score in the clinical range was reduced by the presence of one of the following factors: for females a higher number of IVF/ICSI treatment cycles, and a maternal cause of subfertility, for males having been treated by IVF/ICSI and a longer time to pregnancy. CONCLUSIONS: The present study indicates (i) that IVF/ICSI treatment is not associated with an increase in clinically relevant Spielberger State-Trait Anxiety Inventory and General Health Questionnaire scores in parents 1 year after childbirth and (ii) a higher number of IVF/ICSI treatment cycles and a longer time to pregnancy were associated with less trait anxiety and better mental health. A limitation of the study is the absence of mental health and trait anxiety data at baseline.

Parental psychological distress and anxiety after a successful IVF/ICSI procedure with and without preimplantation genetic screening: follow-up of a randomised controlled trial.

BACKGROUND: Infertility treatment has an acknowledged psychological impact on women and their partners; however, information about the development of parental well-being after child birth is inconclusive. Preimplantation genetic screening (PGS) has been suggested to increase the efficacy of infertility treatments, but the effect it may have on parental well-being is unknown. AIM: To evaluate parental distress and anxiety at one and two years after successful infertility treatment and to explore variables that might affect parental outcome, including PGS and child behaviour. STUDY DESIGN: Follow-up of a randomised controlled trial (RCT) on the efficacy of PGS. SUBJECTS: Parents (n=101) that successfully underwent IVF/ICSI with or without PGS. OUTCOME MEASURES: At one and two years, parental distress and anxiety were assessed with the General Health Questionnaire 30 and State Trait Anxiety Inventory, respectively. At two years, child development and behaviour were assessed with the Dutch Bayley Scales of Infant Development-II and the Child Behaviour Checklist 1½-5, respectively. RESULTS: PGS had no effect on parental distress or anxiety. Child behaviour problems were associated with parental distress and anxiety. There was a main effect of time on parental distress, with distress levels decreasing over time. CONCLUSIONS: We found no objection to PGS related to parental psychological distress and anxiety. When parental psychological problems are present after infertility treatment, the results of this study could be useful to support counselling.

The Groningen ART cohort study: the effects of ovarian hyperstimulation and the IVF laboratory procedures on neurological condition at 2 years.

BACKGROUND: Up to 4% of children are born following assisted reproduction techniques (ART) yet relatively little is known on neurodevelopmental outcome of these children after 18 months of age. Only a limited number of long-term follow-up studies with adequate methodological quality have been reported. Our aim was to evaluate the effects of ovarian hyperstimulation, IVF laboratory procedures and a history of subfertility on neurological condition at 2 years. METHODS: Singletons born after controlled ovarian hyperstimulation IVF (COH-IVF, n = 66), modified natural cycle IVF (MNC-IVF, n = 56), natural conception in subfertile couples (Sub-NC, n = 87) and in fertile couples (reference group, n = 101) were assessed (using Hempel approach) by neurological examination at 2 years of age. This resulted in a neurological optimality score (NOS), a fluency score and the prevalence of minor neurological dysfunction (MND). Primary outcome was the fluency score, as fluency of movements is easily affected by subtle dysfunction of the nervous system. RESULTS: Fluency score, NOS and prevalence of MND were similar in COH-IVF, MNC-IVF and Sub-NC children. However, the fluency score (P < 0.01) and NOS (P < 0.001) of the three subfertile groups were higher, and the prevalence of MND was lower (P = 0.045), than those in the reference group. CONCLUSIONS: Neurological condition of 2 year olds born after ART is similar to that of children of subfertile couples conceived naturally. Moreover, subfertility does not seem to be associated with a worse neurological outcome. These findings are reassuring, but we have to keep in mind that subtle neurodevelopmental disorders may emerge as children grow older.

Is the birthweight of singletons born after IVF reduced by ovarian stimulation or by IVF laboratory procedures?

Singletons born after IVF are at risk of adverse pregnancy outcome, the cause of which is unknown. The present study investigated the influence of ovarian stimulation and IVF laboratory procedure on birthweight. Birthweight of singleton pregnancies resulting from IVF treatment with (n=161) and without ovarian stimulation (using a modified natural cycle (MNC) protocol; n=158), and spontaneous conceptions in subfertile patients (n=132) were compared. Mean+/-SD birthweight of singletons after conventional IVF with ovarian stimulation, MNC-IVF and natural conception were 3271+/-655, 3472+/-548 and 3527+/-582 g (P=0.001). After adjustment for biological and social confounders, the difference in birthweight between conventional IVF and MNC-IVF was reduced to 88 g and the differences between conventional IVF and MNC-IVF versus spontaneous conceptions to 123 and 23 g, respectively. The results lead to three conclusions. First, a major part of the crude differences in birthweight between the three groups is related to patient and pregnancy characteristics. Second, the IVF laboratory procedure has no influence on birthweight. Third, although a trend towards lower birthweight after ovarian stimulation was found, an adverse effect of ovarian stimulation on birthweight was not substantiated.

Quantitative score for the evaluation of kinematic recordings in neuropediatric diagnostics. Detection of complex patterns in spontaneous limb movements.

OBJECTIVE: Evaluation of spontaneous infant movements is an important tool for the detection of neurological impairments. One important aspect of this evaluation is the observation of movements which exhibit certain complex properties. This article presents a method to automatically extract segments which contain such complex patterns in order to quantitatively assess them. METHODS: Expert knowledge is represented in a principal component model which captures the term complexity as the multivariate interactions in the kinematic chains of the upper and the lower limb. A complexity score is introduced which is used to quantify the similarity of new movements to this model. It was applied to the recordings of 53 infants which were diagnosed by physicians as normal or pathologic. RESULTS: Time segments marked as complex (from five infants) by physicians could be detected with a mean accuracy of 0.77 by the automated approach. The median of the best complexity scores of the pathologic group (n = 21) is significantly lower (p = 0.001) than the median of the normal group (n = 27). CONCLUSION: Using the complexity score we were able to quantify movement complexity in regard of the understanding of physicians. This could be useful for clinical applications.

Development of adaptive motor behaviour in typically developing infants.

AIM: During motor development, infants learn to select adaptive motor strategies out of their motor repertoire. The aim of this study is twofold: first, to investigate whether the presence of adaptive motor behaviour can be observed reliably, and second, to explore the ages at which clinically observable transition to adaptive motility emerges for four specific motor functions: abdominal progression, sitting motility, reaching and grasping. METHODS: The reliability part of the study included 38 assessments of term and preterm infants in the age range of 4-18 months. The longitudinal prospective study included 30 term born typically developing infants with nine assessments between 3 and 18 months. On the basis of standardized video-recordings of spontaneous motor behaviour, the presence of adaptive motor strategies was scored. RESULTS: Intra- and interobserver reliability were good. Clinically observable transitions to adaptive selection started to emerge from 6 months onwards and peaked between 8 and 15 months. Transitions developed gradually and occurred at specific ages for different motor functions. CONCLUSION: Transition to adaptive motor behaviour can be observed reliably. Adaptive motor behaviour develops gradually from 6 months onwards at function-specific ages. Comparison of our results to literature showed that changes measured by neurophysiologic methods precede clinically observed transitions.

The Groningen ART cohort study: ovarian hyperstimulation and the in vitro procedure do not affect neurological outcome in infancy.

BACKGROUND: Due to the growing number of children born following assisted reproduction technology, even subtle changes in the children's health and development are of importance to society at large. The aim of the present study was to evaluate the specific effects of ovarian hyperstimulation and the in vitro procedure on neurological outcome in 4-18-month-old children. METHODS: In this prospective assessor-blinded cohort study, we included singletons born following controlled ovarian hyperstimulation in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) (COH-IVF; n = 68) or modified natural cycle-IVF/ICSI (MNC-IVF; n = 57) or naturally conceived singletons of subfertile couples (NC; n = 90). Children were assessed with standardized, age-specific and sensitive neurological assessments (TINE and Hempel assessment) at 4, 10 and 18 months. Neurological examination resulted in a neurological optimality score (NOS), a fluency score and a clinical neurological classification. Fluency of movements is easily affected by neurological dysfunction and is therefore a sensitive measure for minimal changes in neuromotor development. RESULTS: The NOS and the fluency score were similar in COH-IVF, MNC-IVF and NC children. None of the children showed major neurological dysfunction and rates of minor neurological dysfunction at the three ages were not different between the three conception groups. CONCLUSIONS: We found no effects of ovarian hyperstimulation or the in vitro procedure itself on neurological outcome in children aged 4-18 months. The findings of our study are reassuring, nevertheless it should be kept in mind that subtle neurodevelopmental disorders may emerge when children grow older. Continuation of follow-up in older and larger groups of children is therefore still needed.

Sulphonylurea therapy improves cognition in a patient with the V59M KCNJ11 mutation.

BACKGROUND: KCNJ11 mutations are a common cause of diabetes diagnosed in the first 6 months of life, and approximately 25% of patients have neurological features. Sulphonylureas have been shown to improve glycaemic control and also motor function, but the impact on cognitive function has not been extensively addressed previously. METHODS: The patient had a low birth weight and was found to have diabetes at the age of 2 days. The patient was treated with insulin from diagnosis. The child also had marked developmental delay so that his average functional age was 2.5 years when he was 12 years old. A V59M mutation in KCNJ11 was found on sequencing, resulting in a diagnosis of intermediate developmental delay, epilepsy, neonatal diabetes (DEND) syndrome. Identification of a Kir6.2 mutation allowed insulin injections to be replaced by glibenclamide tablets. RESULTS: This resulted not only in improved glycaemic control (HbA(1c) fell from 8.1 to 6.5%), but also an impressive improvement in many aspects of cognitive function, with the functional age increasing to 4 years within 6 months of treatment change. CONCLUSIONS: This is the first clear report of cognitive function improving in a patient with the neurological features associated with a K(ATP) channel mutation following transfer to sulphonylureas. The finding of cognitive improvement suggests that glibenclamide is likely to be acting directly on the brain and not just on nerve and muscle, improving muscle strength.

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

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.

Does early intervention in infants at high risk for a developmental motor disorder improve motor and cognitive development?

Infants at high risk for developmental motor disorders are in general referred to early intervention (EI) services. It is a matter of debate to which extent EI may facilitate outcome in various developmental domains. We reviewed the effects of EI programmes aiming at promoting motor and cognitive development. With respect to motor development the data indicated that EI prior to term age probably is most effective when it aims at mimicking the intrauterine environment; after term age general developmental programmes probably are most effective. Some evidence was provided that EI prior to term age has a beneficial effect on cognitive development regardless the type of intervention which is applied. After term age only general developmental programmes seemed to have an effect on cognitive development. The review concludes with preliminary data on the effect a new intervention programme, COPCA, applied between 3 and 6 months corrected age on developmental outcome till 18 months. The results indicated that COPCA was more beneficial for the development of sitting behaviour and cognition than traditional paediatric physiotherapy.

Posture and movement in healthy preterm infants in supine position in and outside the nest.

OBJECTIVE: To evaluate whether lying in a nest affects the posture and spontaneous movements of healthy preterm infants. METHOD: 10 healthy preterm infants underwent serial video recording in the supine position, when lying in a nest and outside it, at three ages: 30-33 weeks postmenstrual age (PMA) (early preterm), 34-36 weeks PMA (late preterm) and 37-40 weeks PMA (term). The nest was shell-shaped, made by putting two rolled blankets in a form of an oval. Posture was assessed both before and after general movements by scoring the predominant postural pattern. Movements towards and across the midline, elegant wrist movements, abrupt hand and/or limb movements, rolling to side, and frozen postures of the arms and legs were assessed during four general movements. All data relating to motor and postural items were normalised into frequencies of events per minute because the general movements varied in duration. RESULTS: When lying in the nest, the infants more often displayed a flexed posture with shoulder adduction and elbow, and hip and knee flexion, and the head was frequently in the midline. The nest was also associated with an increase in elegant wrist movements and movements towards and across the midline and a reduction in abrupt movements and frozen postures of the limbs. The nest did not affect the occurrence of asymmetrical tonic neck posture. CONCLUSIONS: A nest promotes a flexed posture of the limbs with adduction of shoulders, facilitates elegant wrist movements and movements towards and across the midline and reduces abrupt movements and frozen postures of the arms and legs.

Improved motor development and good long-term glycaemic control with sulfonylurea treatment in a patient with the syndrome of intermediate developmental delay, early-onset generalised epilepsy and neonatal diabetes associated with the V59M mutation in the KCNJ11 gene.

AIMS/HYPOTHESIS: Activating mutations in the KCNJ11 gene encoding the Kir6.2 subunit of the K(ATP) channels in pancreatic beta cells are a common cause of neonatal diabetes. One-third of patients also have developmental delay, which probably results from mutated K(ATP) channels in muscle, nerve and brain. Sulfonylureas, which bind to the sulfonylurea receptor 1 subunit of the K(ATP) channel, can replace insulin injections in patients with KCNJ11 mutations. The aim of this study was to investigate the long-term outcome and impact on neurological features of sulfonylurea treatment. METHODS: We report the response to sulfonylurea treatment in a boy with neonatal diabetes and marked developmental delay resulting from the KCNJ11 mutation V59M. RESULTS: Glibenclamide (glyburide) treatment was started at 23 months and resulted in insulin being discontinued, lower overall glycaemia, reduced glucose fluctuations and reduced hypoglycaemia. Good control (HbA(1c) 6.5%) was maintained 2 years after discontinuing insulin, despite a reduction in the glibenclamide dose (from 0.41 to 0.11 mg.kg(-1).day(-1)). Within 1 month of starting glibenclamide there was marked improvement in motor function, resulting in the patient progressing from being unable to stand unaided to walking independently, but there was no improvement in mental function. CONCLUSIONS/INTERPRETATION: This 2-year follow-up of a patient highlights that sulfonylurea treatment can result in prolonged, excellent glycaemic control and may improve motor features, but not mental features, associated with KCNJ11 mutations. This suggests that the neurological actions of sulfonylurea are initially principally on peripheral (nerve or muscle) rather than on central (brain) K(ATP) channels. Early molecular diagnosis is important in patients with neonatal diabetes and neurological features.

Prescription of the first prosthesis and later use in children with congenital unilateral upper limb deficiency: A systematic review.

BACKGROUND: The prosthetic rejection rates in children with an upper limb transversal reduction deficiency are considerable. It is unclear whether the timing of the first prescription of the prosthesis contributes to the rejection rates. OBJECTIVE: To reveal whether scientific evidence is available in literature to confirm the hypothesis that the first prosthesis of children with an upper limb deficiency should be prescribed before two years of age. We expect lower rejection rates and better functional outcomes in children fitted at young age. METHODS: A computerized search was performed in several databases (Medline, Embase, Cinahl, Amed, Psycinfo, PiCarta and the Cochrane database). A combination of the following keywords and their synonyms was used: "prostheses, upper limb, upper extremity, arm and congenital". Furthermore, references of conference reports, references of most relevant studies, citations of most relevant studies and related articles were checked for relevancy. RESULTS: The search yielded 285 publications, of which four studies met the selection criteria. The methodological quality of the studies was low. All studies showed a trend of lower rejection rates in children who were provided with their first prosthesis at less than two years of age. The pooled odds ratio of two studies showed a higher rejection rate in children who were fitted over two years of age (pooled OR = 3.6, 95% CI 1.6 - 8.0). No scientific evidence was found concerning the relation between the age at which a prosthesis was prescribed for the first time and functional outcomes. CONCLUSION: In literature only little evidence was found for a relationship between the fitting of a first prosthesis in children with a congenital upper limb deficiency and rejection rates or functional outcomes. As such, clinical practice of the introduction of a prosthesis is guided by clinical experience rather than by evidence-based medicine.