Motor behaviour in infancy is associated with neurological, cognitive, and behavioural function of children born to parents with reduced fertility.

AIM: To evaluate the associations between motor development in infancy and developmental outcomes at school age. METHOD: Participants were 195 children (99 males, 96 females; mean age [SD] 9y 3mo [3mo], range 8y 4mo-10y 11mo) born to couples whose reduced fertility was or was not treated with assisted reproductive technologies. Motor behaviour was assessed at 4, 10, and 18 months with the Infant Motor Profile (IMP). IQ, neurological optimality score (NOS), and behavioural problem scores were measured at 9 years with the Wechsler Abbreviated Scale of Intelligence, minor neurological dysfunction assessment, and the Child Behavior Checklist respectively. RESULTS: Children with a slow developmental trajectory in the IMP-domain adaptability had an IQ 12.6 points lower (95% confidence interval [CI] 4.7-20.4) and an NOS 3.4 points lower (95% CI 0.7-6.2) at 9 years of age than children with typical adaptability development. Children with a slow developmental trajectory in the IMP-domain performance had an IQ 5.0 points lower (95% CI 0.7-9.3) than children with typical performance development. A non-optimal trajectory in IMP-variation and a fluctuating trajectory in IMP-fluency were associated with higher internalizing scores of 3.6 and 5.8 points respectively, than infants with optimal IMP-domain trajectories. INTERPRETATION: In relatively low-risk children, motor behaviour in infancy was associated with neurological, cognitive, and behavioural function at school age.

IVF procedures are not, but subfertility is associated with neurological condition of 9-year-old offspring.

In vitro fertilization (IVF) is not associated with neurological abnormalities in offspring's early childhood. Yet, it is unclear whether this is also true for school age. Neither do we know the role of parental subfertility in offspring's neurological development. The present study examined neurological condition at 9 years of 57 singletons born after controlled ovarian hyperstimulation IVF (COH-IVF), 46 singletons born after modified natural cycle IVF (MNC-IVF) and 66 singletons born to subfertile parents after natural conception (Sub-NC). To assess the effect of subfertility, the groups were pooled to form a subfertile group, and compared with a prospectively followed fertile reference group (n = 282). The sensitive Minor Neurological Dysfunction (MND) examination was used, resulting in the detailed Neurological Optimality Score (NOS) and the prevalence of the clinically relevant complex MND. Neurological condition of the three subfertile groups did not differ significantly: median NOS was 53 in each subfertile group and the prevalence of complex MND in the three subfertile groups was 30%, 37% and 36%, respectively. However, the NOS was lower and the prevalence of complex MND higher in children born to subfertile couples than in children of fertile couples (adjusted mean difference [95% CI]: -4.48 [-5.53 to -3.42]) and adjusted OR [95% CI]: 5.13 [2.60-10.16], respectively). We conclude that ovarian hyperstimulation, in vitro procedures, and the combination of both were not associated with a less favourable neurological outcome of 9-year-old singletons. However, the presence of parental subfertility was associated with less favourable neurological outcome of offspring at 9 years follow up.

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

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

Cardiovascular health of 9-year-old IVF offspring: no association with ovarian hyperstimulation and the in vitro procedure.

STUDY QUESTION: Are the in vitro procedure, ovarian hyperstimulation or a combination of these two associated with blood pressure (BP) of 9-year-old IVF children born to subfertile couples? SUMMARY ANSWER: Our study demonstrates that ovarian hyperstimulation and the in vitro procedure are not associated with BP values in 9-year-old children born to subfertile couples. WHAT IS KNOWN ALREADY: Possible long-term effects of IVF on child health and development have been studied relatively little. This is surprising, as it is known that environmental conditions may influence embryonic and foetal development which may result in health related problems in later life. Some studies suggested that IVF is associated with higher BP at pre-school age. Yet, it is unclear whether this may be also true for older children and if so, which component of IVF, i.e. the ovarian hyperstimulation, the embryo culture or a combination of these, attributes to this potentially less favourable BP. STUDY DESIGN, SIZE, DURATION: The Groningen Assisted Reproductive Technology cohort-study is a prospective assessor-blinded study of children followed from before birth onwards. In total, 170 children were assessed at the age of 9 years. The attrition rate up until the 9-year-old assessment was 21%. PARTICIPANTS/MATERIALS, SETTING, METHODS: We evaluated cardiovascular health, focusing on BP (in mmHg and the internationally recognized percentiles of the US National High BP Education Program), heart rate and anthropometrics of 57 children born following controlled ovarian hyperstimulation-IVF/ICSI (COH-IVF/ICSI); 47 children born after modified natural cycle-IVF/ICSI (MNC-IVF/ICSI); and 66 children who were conceived naturally by subfertile couples (Sub-NC). Cardiovascular parameters were measured multiple times on one day. In addition, anthropometric data, including BMI and skinfold thickness, were collected. MAIN RESULTS AND THE ROLE OF CHANCE: Systolic BP in mmHg did not differ between the COH-IVF/ICSI (mean 106.9, SD 6.7), MNC-IVF/ICSI (mean 104.8, SD 5.9) and Sub-NC (mean 106.3, SD 5.3) groups. In addition, systolic BP percentiles did not differ between the groups: COH-IVF/ICSI (mean 62.4, SD 20.2); MNC-IVF/ICSI (mean 56.3, SD 19.3); and Sub-NC (mean 62.3, SD17.8). Also, after adjustment for confounders BP in the three groups was similar. Heart rate and anthropometric values in the three groups did not differ. For instance, BMI values in the COH-IVF/ICSI-children were 16.3 (median value, range 13.0-24.7), in MNC-IVF/ICSI-children 16.1 (range 12.7-22.5) and in Sub-NC children 16.3 (range 12.7-24.0). LIMITATIONS, REASONS FOR CAUTION: The size of our study groups does not allow for pertinent conclusions on the effect of ovarian hyperstimulation and the in vitro procedure. The lack of a fertile control group may be regarded as another limitation. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that ovarian hyperstimulation and in vitro procedures are not associated with cardiovascular health in 9-year-old. Yet, BP percentiles of the three groups were higher than the expected 50th percentile. This might indicate that children of subfertile couples have a higher BP than naturally conceived children. STUDY FUNDING/COMPETING INTEREST(S): The study was financially supported by the University Medical Center Groningen (UMCG), the two graduate schools of the UMCG, BCN, SHARE and the Cornelia Stichting. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. The authors have no conflicts of interest to declare.

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

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

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.