Pamela Schendelaar

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

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

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

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

Is 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.

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.

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.

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

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

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

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

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.

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

Evidence is accumulating that motor and cognitive development are interrelated. This study investigates associations between motor development in infancy and cognitive function at 4 years of age.