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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.

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 subfertilitymay 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 INTEREST(S): 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.

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.

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? 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. 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. 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%. 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. 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). 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. 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. 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

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.

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.STUDY FUNDING/COMPETING INTEREST(S): The RCT was financially supported by the Organization for Health Research and Development (ZonMw), The Netherlands (grant number 945-03-013). The follow-up at 4 years was financially supported by the University Medical Center Groningen (grant number: 754510), the Cornelia Foundation, the Junior Scientific Master Class and the Postgraduate School of Behavioural and Cognitive Neurosciences, 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.

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.)

Aim 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. Method A longitudinal prospective study was performed in a group of 30 term infants (12 females, 18 males; median gestational age 40.1wks, range 37.6–42wks) and 59 preterm infants (25 females, 34 males; median gestational age 29.7wks, range 25–34.7wks). 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. Results Gestational age, socio-economic status, and 5-minute Apgar scores were significant determinants of IMP scores in the total group of infants (p

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.

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.)

Objective: Singletons born after IVF treatment are at risk for adverse pregnancy outcome, the cause of which is unknown. The aim of the present study was to investigate the influence of ovarian stimulation on perinatal outcome.Study design: In this single-centre retrospective study, perinatal outcome of singleton pregnancies resulting from IVF treatment with (n = 106) and without ovarian stimulation (n = 84) were compared. For IVF without ovarian stimulation, a modified natural cycle protocol was used.Results: No differences were found in pregnancy duration, proportion of prematurity and proportion of low birth weight. Mean birth weight of modified natural cycle vs standard IVF singletons was 3485 (+/-527) vs 3218 (+/-670) g; P = 0.003. After adjustment for prognostic factors by linear regression analysis, the difference in birth weight remaining was 134 g; P = 0.045.Conclusions: Birth weights of modified natural cycle IVF singletons found in this study are higher than standard IVF singletons, suggesting that ovarian stimulation may be a causative factor in the occurrence of low birth weight in standard IVF. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

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.

Aim of this study was to evaluate the effect of preimplantation genetic screening (PGS) on neurodevelopmental outcome in children. We conducted a prospective follow-up Study of children born to women randomly assigned to in vitro fertilization with or without PGS. Primary outcome was adverse neurologic outcome at 18 mo; secondary outcomes were types of minor neurologic dysfunction (MND), neurologic outcome before 18 mo, neonatal intensive care admission, and congenital malformations. Twenty women in the PGS group participated with 25 children and 26 women in the control group participated with 31 children. Five PGS pregnancies (25%) and four control pregnancies (15%) resulted in birth of at least one child with an adverse neurologic Outcome (adjusted odds ratio: 2.3 [0.4-12.0]). Dysfunction in fine motor abilities and posture and muscle tone dysregulation tended to be present more frequently after PGS. Neurologic outcome before 19 mo, neonatal intensive care admission, and prevalence of congenital malformations were similar in study and control pregnancies. Nevertheless, at child level, rates of adverse outcome were higher after PGS. In conclusion, outcome in pregnancies after in vitro fertilization (IVF) with and without PGS was similar. The small sample size precludes the conclusion that PGS is not associated with less favorable neurologic outcome. Safety of new assisted reproductive techniques should be evaluated before large-scale implementation. (Pediatr Res 67: 430-434, 2010)

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. (C) 2010, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

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.

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.

Background and aims: Increased risk for chromosomal abnormalities in embryos is considered as a cause of low pregnancy rate with advanced maternal age. PGS has been suggested to improve pregnancy outcome. Since PGS includes extensive embryo manipulation, PGS could have an effect on morphological outcome in children. A follow-up study of a RCT comparing IVF/ICSI with PGS (PGS+) and without (PGS-) was performed to evaluate morphological abnormalities of live born children at 2 years of age. Methods: 408 women were included in a multicenter RCT on the efficacy of PGS. There were 120 women with ≥1 live births, 119 mothers with 142 children alive (57 PGS+; 85 PGS-) were available for follow-up. A reference group of 67 children conceived naturally was formed. At 2 years of age a body-surface examination and anthropometry was performed. Morphological abnormalities were classified as major abnormalities, minor anomalies or common variants according to Merks (Am J Med Genet 2003;123A:211-230). Results: No significant association was found between PGS and any specific minor anomaly or major abnormality. The proportions [95% CI] of children with ≥1 minor anomalies and ≥1 major abnormalities for PGS+ versus PGS- were 64 % [50 -76] vs 67 % [55 - 77] and 28 % [18 - 42] vs 35 % [25 - 46], respectively. No significant differences were found between the randomized and reference groups. Conclusions: This study found no differences in morphological abnormalities between children conceived after IVF/ICSI with PGS and children conceived after regular treatment.