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.

Dysmorphic features and developmental outcome of 2-year-old children.

AIM: The 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. METHOD: In our cross-sectional study, 272 generally healthy 2-year-olds (143 males, 129 females; median gestational age 39 weeks, [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. RESULTS: Of 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. INTERPRETATION: As 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.

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.

Reliability and concurrent validity of the Infant Motor Profile.

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<0.001 at all ages). INTERPRETATION: Interobserver reliability of the IMP is good. Concurrent validity with the AIMS is best for the IMP performance domain. Concurrent validity with age-specific neurological examination is very good.

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.

Morphologic abnormalities in 2-year-old children born after in vitro fertilization/intracytoplasmic sperm injection with preimplantation genetic screening: follow-up of a randomized controlled trial.

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 < 2.5% chance of ≥ 10% more major abnormalities in children born after PGS.

Dysmorphic features in 2-year-old IVF/ICSI offspring.

BACKGROUND: An increased risk of major congenital abnormalities after IVF and ICSI has been described, but underlying mechanisms are unclear. This study evaluates the effects of ovarian hyperstimulation, the in vitro procedure and time to pregnancy (TTP) - as proxy for the severity of subfertility - on the prevalence of dysmorphic features. DESIGN/METHODS: Participants were singletons born following controlled ovarian hyperstimulation-IVF/ICSI (COH-IVF/ICSI; n=66), or modified natural cycle-IVF/ICSI (MNC-IVF/ICSI; n=56), or to subfertile couples who conceived naturally (Sub-NC; n=86). Dysmorphic features were assessed according to the method of Merks et al., and are classified into 'minor variants' (minor anomalies or common variants) and 'abnormalities' (clinically relevant or irrelevant abnormalities). We focussed on minor anomalies as they indicate altered embryonic development and because they have the advantage of a higher prevalence. RESULTS: The prevalences of any of the outcome measures were similar in the three groups. One or more minor anomalies, our primary outcome measure, occurred in 50% of COH-IVF/ICSI, 54% of MNC-IVF/ICSI and 53% of Sub-NC children. TTP in years was significantly associated with abnormalities (adjustedOR=1.20; 95%CI=1.02-1.40), especially with clinically relevant abnormalities (adjustedOR=1.22; 95%CI=1.01-1.48). CONCLUSIONS: The study indicates that ovarian hyperstimulation and the in vitro procedure are not associated with an increase in dysmorphic features. The positive association between TTP and clinically relevant abnormalities suggests a role of the underlying subfertility and its determinants in the genesis of dysmorphic features.

Mental, psychomotor, neurologic, and behavioral outcomes of 2-year-old children born after preimplantation genetic screening: follow-up of a randomized controlled trial.

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.

The Groningen assisted reproductive technologies cohort study: developmental status and behavior at 2 years.

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.

Construct validity of the Infant Motor Profile: relation with prenatal, perinatal, and neonatal risk factors.

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 40.1 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. RESULTS: Gestational age, socio-economic status, and 5-minute Apgar scores were significant determinants of IMP scores in the total group of infants (p<0.001, <0.002, and <0.042 respectively). In the subgroup of preterm infants, IMP scores were significantly affected by brain lesions on neonatal ultrasound (p<0.001) and by socio-economic status (p=0.001). INTERPRETATION: The findings support the construct validity of the IMP: IMP scores are clearly associated with relevant determinants of neuromotor function.

Maternal anxiety is related to infant neurological condition, paternal anxiety is not.

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<0.01) of the infant. This association persisted after adjusting for confounders and results were confirmed by the outcome of the developmental questionnaire. Paternal trait anxiety and parental well-being were not related to the infant's neurodevelopmental outcome. 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.

Neurological condition of infants born after in vitro fertilization with preimplantation genetic screening.

UNLABELLED: 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 18 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. ABBREVIATIONS: :

The assessment of minor neurological dysfunction in infancy using the Touwen Infant Neurological Examination: strengths and limitations.

AIM: Little 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. METHOD: Inter-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 <35 weeks' gestation (gestational age 25-34wks, median 29) participated in the validity study. They were neurologically assessed with the TINE at the corrected ages of 4, 6, 10, and 12 months and with the Hempel assessment at 18 months. RESULTS: The 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. INTERPRETATION: We 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.

Ovarian hyperstimulation and the in vitro fertilization procedure do not influence early neuromotor development; a history of subfertility does.

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.