Motor development in infancy is related to cognitive function at 4 years of age.

AIM: Evidence is accumulating that motor and cognitive development are interrelated. This study investigates associations between motor development in infancy and cognitive function at 4 years of age. METHOD: This study is part of the Groningen prospective cohort study on the development of children born after assisted reproductive techniques such as in vitro fertilization. The study group consisted of 223 children (119 males, 104 females) born to subfertile couples (median gestational age 39.6wks, range 30-43wks). Motor behaviour was assessed with the Infant Motor Profile (IMP) at 4 months, 10 months, and 18 months. IQ was evaluated at 4 years with the Kaufman Assessment Battery for Children, Second Edition. Latent class growth modelling was used to analyse relations between IMP and IQ scores. RESULTS: Infants with low total IMP scores had an IQ that was 8.9 points lower at 4 years than infants with typical IMP scores (95% confidence interval 3.6-14.1). Also, low scores in the domains of variation and performance were associated with a lower IQ at 4 years of age, by 6.1 points and 13.2 points respectively. INTERPRETATION: Motor development in relatively low-risk infants is associated with cognition at 4 years of age. In particular, low motor variation and performance are associated with a lower IQ at 4 years of age. WHAT THIS PAPER ADDS: Motor development in infancy is directly related to cognitive function at 4 years of age. This relationship is most pronounced for infant motor variation and performance. The size of the differences in IQ is clinically relevant.

Developmental outcome of 9-year-old children born after PGS: follow-up of a randomized trial.

STUDY QUESTION: Does Day-3 cleavage-stage PGS affect neurodevelopment of 9-year-old IVF offspring? SUMMARY ANSWER: We did not find evidence of adverse consequences of Day-3 cleavage-stage PGS on neurodevelopment of 9-year-old IVF offspring, although children born after IVF with or without PGS often had a non-optimal neurological condition. WHAT IS KNOWN ALREADY: Knowledge on long-term sequelae for development and health of children born following PGS is lacking. This is striking as evidence accumulates that IVF itself is associated with increased risk for impaired health and development in the offspring. STUDY DESIGN SIZE, DURATION: This prospective, assessor-blinded, multicentre, follow-up study evaluated development and health of 9-year-old IVF children born to women who were randomly assigned to IVF with PGS (PGS group) or without PGS (control group). The follow-up examination at 9 years took place between March 2014 and May 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 408 women were included and randomly assigned to IVF with or without Day-3 cleavage-stage PGS. This resulted in 52 ongoing pregnancies in the PGS group and 74 in the control group. In the PGS group, 59 children were born alive; in the control group, 85 children were born alive. At the age of 9 years, 43 children born after PGS and 56 control children participated in the study. Our primary outcome was the neurological optimality score, a sensitive measure of neurological condition assessed with a standardized, age-specific test (Touwen test). Secondary outcomes were adverse neurological condition (neurologically abnormal and the complex form of minor neurological dysfunction), cognitive development (intelligence quotient and specific domains), behaviour (parental and teacher's questionnaires), blood pressure and anthropometrics. MAIN RESULTS AND THE ROLE OF CHANCE: Neurodevelopmental outcome of PGS children did not differ from that of controls; the neurological optimality scores (mean values [(95% CI]: PGS children 51.5 [49.3; 53.7], control children 53.1 [50.5; 55.7]) were not significantly different. The prevalences of adverse neurological outcome (in all but one child implying the presence of the complex form of minor neurological dysfunction) did not differ between the groups (PGS group 17/43 [40%], control group 19/56 [34%]), although the prevalence of complex minor neurological dysfunction in both groups was rather high. Also intelligence quotient scores of the two groups were not significantly different (PGS group 114 [108; 120]); control group 117 [109; 125]), and the behaviour, blood pressure and anthropometrics of both groups did not differ. Mean blood pressures of both groups were above the 60th percentile. LIMITATIONS REASONS FOR CAUTION: The power analysis of the study was not based on the number of children needed for the follow-up study, but on the number of women who were needed to detect an increase in ongoing pregnancy rates after PGS. In addition, our study evaluated embryo biopsy in the form of PGS at cleavage stage (Day-3 embryo biopsy), while currently PGS at blastocyst stage (Day-5 embryo biopsy) is recommended and increasingly being used. WIDER IMPLICATIONS OF THE FINDINGS: Our findings indicate that PGS in cleavage stage embryos is not associated with adverse effects on neurological, cognitive and behavioural development, blood pressure and anthropometrics of offspring at 9 years. This is a reassuring finding as embryo biopsy in the forms of PGS and PGD is increasingly applied. However, both groups of IVF offspring showed high prevalences of the clinically relevant form of minor neurological dysfunction, which is a point of concern for the IVF community. In addition, our study confirms findings of others that IVF offspring may be at risk of an unfavourable cardiovascular outcome. These findings are alarming and highlight the importance of research on the underlying mechanisms of unfavourable neurodevelopmental and cardiovascular outcomes in IVF offspring. STUDY FUNDING/COMPETING INTEREST(S): The randomized controlled trial was financially supported by the Organization for Health Research and Development (ZonMw), The Netherlands (Grant number 945-03-013). The follow-up was financially supported by the University Medical Center Groningen (Grant number: 754510), the Cornelia Foundation, and the graduate schools BCN and Share, Groningen, The Netherlands. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: ISRCTN76355836.

Neurological condition assessed with the Hempel examination and cognition and behaviour at 4years.

AIM: To investigate associations between neurological condition, assessed with the Hempel examination, in terms of minor neurological dysfunction (MND) and neurological optimality, and cognition and behaviour at 4years. STUDY DESIGN: Cross-sectional analyses within a prospective, assessor-blinded follow-up study. SUBJECTS: Four-year-old singletons born to subfertile parents (n=235; 120 boys). OUTCOME MEASURES: Outcome parameters were complex minor neurological dysfunction (complex MND) and the neurological optimality score (NOS). Cognitive outcome was evaluated with the Kaufman Assessment Battery for Children, resulting in a total intelligence quotient (IQ). Behavioural outcome was evaluated with the Child Behavior Checklist, resulting in a total problem T-score. RESULTS: Fifty-seven (24.3%) children had complex MND. None of the children showed fine motor dysfunction, suggesting a ceiling effect of the Hempel assessment. Complex MND was not correlated with IQ or total problem T-score. Nevertheless, a higher NOS was correlated with a higher IQ and a lower total problem T-score (adjusted mean estimate [95% confidence interval]: cognition: 0.445 [0.026; 0.865], p=0.038; behaviour: -0.458 [-0.830; -0.087], p=0.016). INTERPRETATION: At age 4, complex MND assessed with the Hempel assessment was not associated with cognition and behaviour, presumably due to a ceiling effect in the Hempel domain of fine motor function. A more optimal neurological condition was associated with higher IQ and better behaviour.

Neurodevelopmental and cardiometabolic outcome in 4-year-old twins and singletons born after IVF.

This prospective cohort study evaluated whether the cognitive development, neurological condition, anthropometrics and blood pressure of 4-year-old IVF twins differed from those of 4-year-old IVF singletons; 103 IVF singletons and 48 IVF twins born after conventional IVF treatment were included. Primary outcome was total intelligence quotient (IQ). Secondary outcomes were minor neurological dysfunction, anthropometrics and blood pressure. Unadjusted analyses found that the total IQ score of twins was lower than that of singletons, with a mean difference of -5.4 (-9.7 to -1.0). Weight (singletons: 18.6 [18.1 to 19.1] kg; twins: 16.9 [16.0 to 17.9] kg) and height (singletons: 108.8 [107.9 to 109.8] cm; twins: 105.9 [104.0 to 107.7] cm) of twins were lower than those of singletons (mean values [95% CI]). All differences disappeared after adjusting for mediators and confounders. Neurological outcome, systolic and diastolic blood pressure of twins and singletons were similar. Four-year-old IVF twins had a lower total IQ (-5.4 points), lowerbodyweight (-1.7 kg) and were shorter (-2.9 cm) than 4-year-old IVF singletons. After adjustment, the adverse twin effect disappeared, implying that increased risk for impaired health and development in twins also holds true for IVF twins, and is not altered by IVF.

Subfertility factors rather than assisted conception factors affect cognitive and behavioural development of 4-year-old singletons.

Research on cognitive and behavioural development of children born after assisted conception is inconsistent. This prospective study aimed to explore underlying causal relationships between ovarian stimulation, in-vitro procedures, subfertility components and child cognition and behaviour. Participants were singletons born to subfertile couples after ovarian stimulation IVF (n = 63), modified natural cycle IVF (n = 53), natural conception (n = 79) and singletons born to fertile couples (reference group) (n = 98). At 4 years, cognition (Kaufmann-ABC-II; total IQ) and behaviour (Child Behavior Checklist; total problem T-score) were assessed. Causal inference search algorithms and structural equation modelling was applied to unravel causal mechanisms. Most children had typical cognitive and behavioural scores. No underlying causal effect was found between ovarian stimulation and the in-vitro procedure and outcome. Direct negative causal effects were found between severity of subfertility (time to pregnancy) and cognition and presence of subfertility and behaviour. Maternal age and maternal education acted as confounders. The study concludes that no causal effects were found between ovarian stimulation or in-vitro procedures and cognition and behaviour in childrenaged 4 years born to subfertile couples. Subfertility, especially severe subfertility, however, was associated with worse cognition and behaviour.

A 15-year-old Girl with an Asymmetric Hemitruncal Fat Distribution: Hemihyperthrophy or Hemiatrophy?

A 15-year-old girl presented to the pediatrician with complaints of excessive fat distribution on the right side and breast asymmetry. At age 2, she had undergone a left-sided nephrectomy because of a stage III Wilms tumor using a transverse cut supraumbilical approach, followed by systemic chemotherapy and local radiotherapy. In the case of trunk asymmetry, it is questionable which side is deviant. The asymmetry may be an expression of isolated hemihyperthrophy, syndromal hemihypertrophy related to the Wilms tumor, or an expression of left-sided hemiatrophy as a late consequence of radiotherapy, chemotherapy, or surgery. Late clinical manifestations of childhood cancer treatment are difficult to distinguish from other independent diseases but must be considered as explanations for new onset of symptoms in adolescents.

Predictive value of general movements' quality in low-risk infants for minor neurological dysfunction and behavioural problems at preschool age.

BACKGROUND: General movement (GM) assessment is a well-established tool to predict cerebral palsy in high-risk infants. Little is known on the predictive value of GM assessment in low-risk populations. AIMS: To assess the predictive value of GM quality in early infancy for the development of the clinically relevant form of minor neurological dysfunction (complex MND) and behavioral problems at preschool age. STUDY DESIGN: Prospective cohort study. SUBJECTS: A total of 216 members of the prospective Groningen Assisted Reproductive Techniques (ART) cohort study were included in this study. ART did not affect neurodevelopmental outcome of these relatively low-risk infants born to subfertile parents. OUTCOME MEASURES: GM quality was determined at 2 weeks and 3 months. At 18 months and 4 years, the Hempel neurological examination was used to assess MND. At 4 years, parents completed the Child Behavior Checklist; this resulted in the total problem score (TPS), internalizing problem score (IPS), and externalizing problem score (EPS). Predictive values of definitely (DA) and mildly (MA) abnormal GMs were calculated. RESULTS: DA GMs at 2 weeks were associated with complex MND at 18 months and atypical TPS and IPS at 4 years (all p<0.05). Sensitivity and positive predictive value of DA GMs at 2 weeks were rather low (13%-60%); specificity and negative predictive value were excellent (92%-99%). DA GMs at 3 months occurred too infrequently to calculate prediction. MA GMs were not associated with outcome. CONCLUSIONS: GM quality as a single predictor for complex MND and behavioral problems at preschool age has limited clinical value in children at low risk for developmental disorders.

Asthma and asthma medication use among 4-year-old offspring of subfertile couples--association with IVF?

This study evaluated the prevalence of asthma and asthma medication use in 213 4-year-old singletons followed from birth onwards, including three groups of children born following: (i) controlled ovarian hyperstimulation IVF/intracytoplasmic sperm injection (ICSI); (ii) modified natural cycle IVF/ICSI; and (iii) natural conception in subfertile couples. The rate of asthma medication was higher in the ovarian hyperstimulation-IVF/ICSI than in the subfertile group (adjusted odds ratios [aOR]: 1.96 [1.00-3.84]). Time to pregnancy, a proxy for the severity of subfertility, was not associated with asthma and asthma medication. In conclusion, controlled ovarian hyperstimulation-IVF/ICSI is associated with the use of asthma medication in 4-year-old offspring of subfertile couples.

Is ovarian hyperstimulation associated with higher blood pressure in 4-year-old IVF offspring? Part I: multivariable regression analysis.

STUDY QUESTION: Does ovarian hyperstimulation, the in vitro procedure, or a combination of these two negatively influence blood pressure (BP) and anthropometrics of 4-year-old children born following IVF? SUMMARY ANSWER: Higher systolic blood pressure (SBP) percentiles were found in 4-year-old children born following conventional IVF with ovarian hyperstimulation compared with children born following IVF without ovarian hyperstimulation. WHAT IS KNOWN ALREADY: Increasing evidence suggests that IVF, which has an increased incidence of preterm birth and low birthweight, is associated with higher BP and altered body fat distribution in offspring but the underlying mechanisms are largely unknown. STUDY DESIGN, SIZE, DURATION: We performed a prospective, assessor-blinded follow-up study in which 194 children were assessed. The attrition rate up until the 4-year-old assessment was 10%. PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured BP and anthropometrics of 4-year-old singletons born following conventional IVF with controlled ovarian hyperstimulation (COH-IVF, n = 63), or born following modified natural cycle IV (MNC-IVF, n = 52), or born to subfertile couples who conceived naturally (Sub-NC, n = 79). Both IVF and ICSI were performed. Primary outcome measures were the SBP percentiles and diastolic BP (DBP) percentiles. Anthropometric measures included triceps and subscapular skinfold thickness. Several multivariable regression analyses were applied in order to correct for subsets of confounders. The value 'B' is the unstandardized regression coefficient. MAIN RESULTS AND THE ROLE OF CHANCE: SBP percentiles were significantly lower in the MNC-IVF group (mean 59, SD 24) than in the COH-IVF (mean 68, SD 22) and Sub-NC groups (mean 70, SD 16). The difference in SBP between COH-IVF and MNC-IVF remained significant after correction for current, early life and parental characteristics (B: 14.09; 95% confidence interval (CI): 5.39-22.79), whereas the difference between MNC-IVF and Sub-NC did not. DBP percentiles did not differ between groups. After correction for early life factors, subscapular skinfold thickness was thicker in the COH-IVF group than in the Sub-NC group (B: 0.28; 95% CI: 0.03-0.53). LIMITATIONS, REASONS FOR CAUTION: Larger study groups are necessary to draw firm conclusions. An effect of gender or ICSI could not be properly investigated as stratifying would further reduce the sample size. We corrected for the known differences between MNC-IVF and COH-IVF but it is possible that the groups differ in additional, more subtle parental characteristics. In addition, we measured BP on 1 day only, had no control group of children born to fertile couples (precluding investigating effects of the underlying subfertility) and included singletons only. As COH-IVF is associated with multiple births we may have underestimated cardiometabolic problems after COH-IVF. Finally, multivariable regression analysis does not provide clear insight in the causal mechanisms and we have performed further explorative analyses. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are in line with other studies describing adverse effects of IVF on cardiometabolic outcome but this is the first study suggesting that ovarian hyperstimulation, as used in IVF treatments, could be a causative mechanism. Perhaps ovarian hyperstimulation negatively influences cardiometabolic outcome via changes in the early environment of the oocyte and/or embryo that result in epigenetic modifications of key metabolic systems that are involved in BP regulation. Future research needs to assess further the role of ovarian hyperstimulation in poorer cardiometabolic outcome and investigate the underlying mechanisms. The findings emphasize the importance of cardiometabolic monitoring of the growing number of children born following IVF. STUDY FUNDING/COMPETING INTEREST(S): The authors have no conflicts of interest to declare. The study was supported by the University Medical Center Groningen, the Cornelia Foundation and the school for Behavioral- and Cognitive Neurosciences. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report.

Is ovarian hyperstimulation associated with higher blood pressure in 4-year-old IVF offspring? Part II: an explorative causal inference approach.

STUDY QUESTION: What causal relationships underlie the associations between ovarian stimulation, the IVF procedure, parental-, fertility- and child characteristics, and blood pressure (BP) and anthropometrics of 4-year-old IVF children? SUMMARY ANSWER: Causal models compatible with the data suggest the presence of positive direct effects of controlled ovarian hyperstimulation as applied in IVF (COH-IVF) on systolic blood pressure (SBP) percentiles and subscapular skinfold thickness. WHAT IS KNOWN ALREADY: Increasing evidence suggests that IVF is associated with higher blood pressure and altered body fat distribution in offspring, but underlying mechanisms describing the causal relationships between the variables are largely unknown. STUDY DESIGN, SIZE, DURATION: In this assessor-blinded follow-up study, 194 children were assessed. The attrition rate until the 4-year-old assessment was 10%. PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured blood pressure and anthropometrics of 4-year-old singletons born following COH-IVF (n = 63), or born following modified natural cycle IVF (MNC-IVF, n = 52) or born to subfertile couples who conceived naturally (Sub-NC, n = 79). Primary outcome measures were the SBP and diastolic blood pressure (DBP) percentiles. Anthropometrics included triceps and subscapular skinfold thickness. Causal inference search algorithms and structural equation modeling were applied. MAIN RESULTS AND THE ROLE OF CHANCE: Explorative analyses suggested a direct effect of COH on SBP percentiles and on subscapular skinfold thickness. This hypothesis needs confirmation with additional, preferably larger, studies. LIMITATIONS, REASONS FOR CAUTION: Search algorithms were used as explorative tools to generate hypotheses on the causal mechanisms underlying fertility treatment, blood pressure, anthropometrics and other variables. More studies using larger groups are needed to draw firm conclusions. WIDER IMPLICATIONS OF THE FINDINGS: Our findings are in line with other studies describing adverse effects of IVF on cardiometabolic outcome, but this is the first study suggesting a causal mechanism underlying this association. Perhaps ovarian hyperstimulation negatively influences cardiometabolic outcome via changes in the early environment of the oocyte and/or embryo, possibly resulting in epigenetic modifications of key metabolic systems that are involved in BP regulation. Future research needs to confirm the role of ovarian stimulation in poorer cardiometabolic outcome and should investigate the underlying mechanisms. Our proposed causal models provide research hypotheses to be tested with new data from preferably larger studies. STUDY FUNDING/COMPETING INTEREST(S): The authors have no conflicts of interest to declare. The study was supported by the University Medical Center Groningen, the Cornelia Foundation and the school for Behavioral- and Cognitive Neurosciences. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report.

Blood pressure and anthropometrics of 4-y-old children born after preimplantation genetic screening: follow-up of a unique, moderately sized, randomized controlled trial.

BACKGROUND: Recent studies suggest that in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are associated with suboptimal cardiometabolic outcome in offspring. It is unknown whether preimplantation genetic screening (PGS), which involves embryo biopsy, affects blood pressure (BP), anthropometrics, and the frequency of received medical care. METHODS: In this prospective multicenter follow-up study, we assessed BP, anthropometrics, and received medical care of 4-y-old children born to women who were randomly assigned to IVF/ICSI with PGS (n = 49) or without PGS (controls; n = 64). We applied linear and generalized linear mixed-effects models to investigate possible effects of PGS. RESULTS: BP in the PGS and control groups was similar: 102/64 and 100/64 mm Hg, respectively. Main anthropometric outcomes in the PGS vs. control group were: BMI: 16.1 vs. 15.8; triceps skinfold: 108 vs. 98 mm; and subscapular skinfold: 54 vs. 53 mm (all P values > 0.05). More PGS children than controls had received paramedical care (speech, physical, or occupational therapy: 14 (29%) vs. 9 (14%); P = 0.03 in multivariable analysis). The frequency of medicial treatment was comparable. CONCLUSION: PGS does not seem to affect BP or anthropometrics in 4-y-old children. The higher frequency of received paramedical care after PGS may suggest an effect of PGS on subtle developmental parameters.

Movement variation in infants born following IVF/ICSI with and without ovarian hyperstimulation.

BACKGROUND: The effect of in vitro fertilisation (IVF) on neurodevelopment is not fully understood. Probably, IVF does not affect traditional measures of neurodevelopment in infancy. Recently, an instrument, the Infant Motor Profile (IMP), was developed that evaluates the quality of motor behaviour. It includes the evaluation of movement variation (i.e. movement repertoire size), a parameter reflecting the integrity of cortical connectivity. AIM: To evaluate the effect of ovarian hyperstimulation and the in vitro procedure on movement variation during infancy. STUDY DESIGN: Prospective cohort study. SUBJECTS: Singletons born following IVF or intracytoplasmic sperm injection (ICSI) with conventional controlled ovarian hyperstimulation (COH-IVF/ICSI, n=68), in a modified natural cycle (MNC-IVF/ICSI, n=57) and natural conception born to subfertile couples (Sub-NC, n=90). OUTCOME MEASURES: Children were assessed with the IMP at 4, 10 and 18 months, resulting in a total IMP score and five domain scores: variation, variability, symmetry, fluency and performance. Primary outcome was the domain score variation. RESULTS: A significant effect of study group was observed for the variation score up until 18 months of age (p=0.039). COH-IVF/ICSI children had a significantly lower mean variation score than MNC-IVF/ICSI children (mean difference [95% confidence interval] -1.010 [-1.766; -0.254]). Mean variation scores of COH-IVF/ICSI and Sub-NC children were similar; the same held true for the comparison between MNC-IVF/ICSI and Sub-NC. Total IMP scores and other domain scores of the three groups were similar. CONCLUSION: The present study did not demonstrate a clear effect of ovarian hyperstimulation and the in vitro procedure on movement variation throughout infancy.

Increased time to pregnancy is associated with suboptimal neurological condition of 2-year-olds.

OBJECTIVE: To evaluate whether time to pregnancy (TTP) is associated with neurological condition of 2-year-old children born to subfertile parents. DESIGN: Data collected in a prospective, assessor-blinded follow-up study were used for cross-sectional analyses. PATIENTS: Participants were the singletons of the Groningen assisted reproductive technique cohort study: all children were born to subfertile couples (n=209). The active waiting TTP of the couples obtained from fertility charts was recorded in years and months, and was converted to decimal years. MAIN OUTCOME MEASURE: The presence of minor neurological dysfunction (MND), assessed with the Hempel examination. RESULTS: MND was present in 16 (7.7%) children. TTP of children with MND (median 4.1, range 1.6-13.2) was significantly longer than that of children without MND (median 2.8, range 0.1-13.3; Mann-Whitney U test p=0.014). Logistic regression analysis on the contribution of TTP to MND resulted in a crude OR of 1.27 (95% CI 1.06 to 1.54). After correction for gestational age, parental age and parental level of education, the association remained statistically significant: OR=1.30 (95% CI 1.05 to 1.61). CONCLUSIONS: Increased TTP was associated with suboptimal neurological development in 2-year-old children. This suggests that subfertility and its determinants are involved in the genesis of neurodevelopmental problems.