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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 children aged 4 years born to subfertile couples. Subfertility, especially severe subfertility, however, was associated with worse cognition and behaviour. (C) 2016 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

AimThe aim of this study was to assess the associations between dysmorphic features and neurological, mental, psychomotor, and behavioural development in order to improve our understanding of aetiological pathways leading to minor developmental problems.MethodIn our cross-sectional study, 272 generally healthy 2-year-olds (143 males, 129 females; median gestational age 39weeks, [range 30-43wks]), born after a parental history of subfertility either with or without fertility treatment, were examined. Dysmorphic features were classified as abnormalities (clinically relevant or not), minor anomalies, or common variants according to Merks' classification system. Hempel's neurological assessment resulted in a neurological optimality score (NOS) and fluency score. Mental and psychomotor development were assessed with the Dutch version of the Bayley Scales of Infant Development and behavioural development with the Achenbach Child Behaviour Checklist.ResultsOf the different types of dysmorphic feature, clinically relevant abnormalities were most strongly associated with a lower NOS (difference -2.53, 95% confidence interval [CI] -4.23 to -0.83) and fluency score (difference -0.62, 95% CI -1.1 to -0.15). The presence of one or more abnormalities (clinically relevant or not) or one or more common variants was significantly associated with a lower NOS, and the presence of three or more minor anomalies was associated with lower fluency scores. Dysmorphic features were not associated with mental, psychomotor, or behavioural development.InterpretationAs dysmorphic features originate during the first trimester of pregnancy, the association between dysmorphic features and minor alterations in neurodevelopment may suggest an early ontogenetic origin of subtle neurological deviations.What this paper addsWe found that dysmorphic features are associated with minor alterations in neurological development.This finding suggests an early ontogenetic origin of subtle neurological deviations.

Objective: To evaluate the effect of preimplantation genetic screening (PGS) on morphologic outcome in children.Design: Follow-up of a randomized controlled trial (RCT).Setting: University hospital.Patient(s): Two-year-old children born to mothers who participated in an RCT on the efficacy of PGS: 50 children born after in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) with PGS (intervention group; PGS+) and 72 children born after IVF/ICSI only (control group; PGS-). Sixty-six age-matched children conceived without any form of assisted reproduction were recruited separately in a local public health service center (reference group).Intervention(s): PGS.Main Outcome Measure(s): Body surface examination and anthropometry. The evaluation of morphologic abnormalities allowed assessment of children's phenotype in detail. Morphologic abnormalities were classified as major abnormalities (abnormal development in organogenesis, deformations, disruptions, or dysplasia) and minor anomalies (deviations in phenogenesis).Result(s): The percentage of children with >= 1 major abnormality was 28% in the PGS+ and 35% in the PGS - group [difference - 7%, 95% CI - 23% to 10%]. The percentage of children with >= 1 minor anomaly was 64% in the PGS+ and 67% in the PGS - group [difference - 3%, 95% CI - 15% to 20%]. In the reference group 30% of the children had >= 1 major abnormality [95% CI 20% to 43%] and 74% had >= 1 minor anomaly [95% CI 62% to 84%].Conclusion(s): No statistically significant differences were found in minor anomalies between children conceived after IVF/ICSI with or without PGS. There is = 10% more major abnormalities in children born after PGS. (Fertil Steril (R) 2013;99:408-13. (C) 2013 by American Society for Reproductive Medicine.)

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 11/2-5, 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. (c) 2012 Elsevier Ireland Ltd. All rights reserved.

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

Objective: To evaluate whether children's cognitive and psychomotor development and behavior at 2 years are affected by ovarian hyperstimulation and the IVF laboratory procedures or subfertility.Design: Prospective longitudinal cohort study.Setting: University Medical Center Groningen, the Netherlands.Patient(s): Singletons born after controlled ovarian hyperstimulation (COH)-IVF (n = 66) and modified natural cycle-IVF (n = 56), singletons born to subfertile couples who conceived naturally (subfertile-naturally conceived, n 87), and a reference group of 101 2-year-old singletons born to fertile couples.Intervention(s): None.Main Outcome Measure(s): Bayley Scales of Infant Development and Achenbach Child Behavior Checklist.Result(s): Mental and psychomotor development and behavioral outcome in COH-IVF, modified natural cycle-IVF, and subfertile-natural cycle groups was not different. Developmental outcome and behavior of the subfertile groups were largely similar to those of the fertile reference group. Nevertheless, the subfertile groups scored higher on the scale of anxious-depressed behavior than the reference group.Conclusion(s): This present relatively small study found no differences in cognitive and psychomotor development and behavior at 2 years in children born after COH-IVF or modified natural cycle-IVF or naturally conceived children of subfertile parents. Replication of the study is needed before firm conclusions can be drawn. Furthermore, long-term follow-up is needed to confirm these findings in older children. (Fertil Steril (R) 2011; 95: 2283-9. (C) 2011 by American Society for Reproductive Medicine.)

Background: Parental anxiety and stress may have consequences for infant neurological development.Aims: To study relationships between parental anxiety or well-being and infant neurological development approximately one year after birth.Study design: Longitudinal study of a birth cohort of infants born to subfertile couples. Subjects: 206 parent-child dyads.Outcome measures: Infant neurology was assessed with the Touwen Infant Neurological Examination (TINE) at 10 months and a developmental questionnaire at 12 months. Parental measures included trait anxiety measured by the State-Trait Anxiety Inventory (STAI) and well-being measured by the General Health Questionnaire (GHQ).Results: Maternal trait anxiety was associated with a less optimal neurological condition (r(s) = -0.19, p Conclusions: Infants of mothers with high trait anxiety have an increased vulnerability to develop a non-optimal nervous system. The association may be mediated in part by early programming of monoaminergic systems. Future research should include an exploration of specific windows of vulnerability to maternal anxiety. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

Objective: To evaluate specific effects of ovarian hyperstimulation, the in vitro procedure, and a history of subfertility on neuromotor development at 3 months of age.Design: Prospective, cohort study.Setting: University Medical Center Groningen, The Netherlands.Patient(s): Singletons conceived after controlled ovarian hyperstimulation-IVF/intracytoplasmic sperm injection (COH-IVF: n = 68) or modified natural cycle-IVF/intracytoplasmic sperm injection (MNC-IVF; n = 57), and naturally conceived singletons of subfertile couples (NC; n = 90). Data from a reference population were available (n = 450).Intervention(S): None.Main Outcome Measure(s): Quality of general movements (GMs), classified as normal-optimal, normal-suboptimal, mildly abnormal, or definitely abnormal. Definitely abnormal GMs indicate brain dysfunction, mildly abnormal GMs normal but non-optimal brain function.Result(s): Mildly abnormal and definitely abnormal GMs were observed equally frequently in COH-IVF, MNC-IVF, and NC singletons. The three subfertile groups showed a reduction in GM quality, in particular more mildly abnormal GMs, in comparison with the reference population.Conclusion(s): Singletons born after IVF (with or without ovarian hyperstimulation) are not at increased risk for abnormal GMs compared with naturally conceived peers of subfertile parents. Mildly abnormal GMs occur more often in infants of subfertile parents than in the general population, suggesting that factors associated with subfertility rather than those related to IVF procedures may be associated with less-optimal early neurodevelopmental outcome. These results need confirmation through replication and follow-up at older ages. (Fertil Steril(R) 2010;93:544-53. (C)2010 by American Society for Reproductive Medicine.)

AimLittle is known of minor neurological dysfunction (MND) in infancy. This study aimed to evaluate the inter-assessor reliability of the assessment of MND with the Touwen Infant Neurological Examination (TINE) and the construct and predictive validity of MND in infancy.MethodInter-assessor agreement was determined in a sample of 40 infants (24 males, 16 females) aged 3 to 12 months (25 born at term: gestational age 37-41wks, median 39; and 15 born preterm, gestational age 24-35wks, median 32). Thirty typically developing term infants (18 males, 12 females; gestational age 37-42wks, median 40) and 59 preterm infants (34 males, 25 females) born at ResultsThe findings indicated that MND can be assessed reliably (inter-assessor agreement: kappa=0.83). MND during infancy was related to prenatal, perinatal, and social factors, and in particular to preterm birth. Neurological condition during infancy was prone to change, but was related to neurological condition at 18 months at all ages tested.InterpretationWe conclude that MND can be determined reliably in infancy. Important considerations in the construct of MND in infancy are its relation to prenatal and perinatal factors, its limited stability, and its moderate predictive value.

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? 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. 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. In this assessor-blinded follow-up study, 194 children were assessed. The attrition rate until the 4-year-old assessment was 10%. 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. 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. 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. 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. 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

ObjectiveTo evaluate whether time to pregnancy (TTP) is associated with neurological condition of 2-year-old children born to subfertile parents.DesignData collected in a prospective, assessor-blinded follow-up study were used for cross-sectional analyses.PatientsParticipants 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 measureThe presence of minor neurological dysfunction (MND), assessed with the Hempel examination.ResultsMND 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).ConclusionsIncreased 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.

Aim The Infant Motor Profile (IMP) is a qualitative assessment of motor behaviour in infancy. It consists of five domains: movement variation, variability, fluency, symmetry, and performance. The aim of this study was to assess interobserver reliability and concurrent validity of the IMP with the Alberta Infant Motor Scale (AIMS) and an age-specific neurological examination. Method Fifty-nine preterm infants (25 females, 34 males; median gestational age 29.7wks, median birthweight 1285g) and 146 term infants (74 females, 72 males; median gestational age 40.1wks, birthweight 3500g) were included. Assessments were performed at corrected ages of 4, 6, 10, 12, and 18 months and consisted of the IMP, AIMS, and an age-specific neurological examination. Interobserver reliability was investigated on a sample of 25 video recordings. Non-parametric statistics were used to analyse the data. Results Interobserver reliability was high (intraclass correlation coefficient 0.95). At all ages, AIMS scores correlated weakly to fairly with total IMP scores (Spearman's ρ 0.36–0.55), but moderately to strongly with scores on the performance domain of the IMP (Spearman's ρ 0.47–0.84). A clear relation was found between total IMP score and outcome of the neurological examination (Kruskal–Wallis p

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.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.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.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.

Objective: To evaluate the effect of preimplantation genetic screening (PGS) on neurodevelopmental outcomes in children.Design: Prospective, assessor-blinded, follow-up study of children born to women randomly assigned to in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI) with or without PGS.Setting: University Medical Center, Groningen, and Academic Medical Center, Amsterdam, the Netherlands.Patient(s): Fifty-four PGS children and 77 controls.Intervention(s): PGS.Main Outcome Measure(s): Mental, psychomotor, neurologic, and behavioral outcomes in 2-year-old children as measured with the Bayley Scales of Infant Development, the Hempel neurologic examination, and the Child Behavior Check List.Result(s): The mental, psychomotor, and behavioral outcomes at 2 years in children born after IVF with and without PGS were similar overall. The PGS children showed lower neurologic optimality scores than the control children. Scores on all tests were within the normal range.Conclusion(s): Conception with PGS does not seem to be associated with impaired mental, psychomotor, or behavioral outcomes by age 2. However, the lower neurologic optimality scores found in the PGS children may signal less favorable long-term neurologic outcomes in PGS children. Our findings stress the need for safety evaluations with new assisted reproductive techniques before large-scale implementation. (Fertil Steril (R) 2011;96:165-9. (C) 2011 by American Society for Reproductive Medicine.)

The Infant Motor Profile (IMP) is a qualitative assessment of motor behaviour of infants aged 3 to 18 months. The aim of this study was to investigate construct validity of the IMP through the relation of IMP scores with prenatal, perinatal, and neonatal variables, including the presence of brain pathology indicated by neonatal ultrasound imaging of the brain.A longitudinal prospective study was performed in a group of 30 term infants (12 females, 18 males; median gestational age 40.1 wks, range 37.6-42 wks) and 59 preterm infants (25 females, 34 males; median gestational age 29.7 wks, range 25-34.7 wks). IMP assessments were performed at (corrected) ages of 4, 6, 10, 12, and 18 months. Socio-economic and perinatal data were collected, which, in the case of preterm infants, included information on periventricular leukomalacia and intraventricular haemorrhage based on neonatal cranial ultrasound. Data were analysed by fitting mixed-effects models.Gestational age, socio-economic status, and 5-minute Apgar scores were significant determinants of IMP scores in the total group of infants (p0.001,0.002, and0.042 respectively). In the subgroup of preterm infants, IMP scores were significantly affected by brain lesions on neonatal ultrasound (p0.001) and by socio-economic status (p=0.001).The findings support the construct validity of the IMP: IMP scores are clearly associated with relevant determinants of neuromotor function.

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 ¼ 68) or modified natural cycle-IVF/ICSI (MNC-IVF; n ¼ 57) or naturally conceived singletons of subfertile couples (NC; n ¼ 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.