Increased time to pregnancy is associated with less optimal neurological condition in 4-year-old singletons, in vitro fertilization itself is not.

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 subfertility may 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 INTERESTS: 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.

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 impact of IVF/ICSI on parental well-being and anxiety 1 year after childbirth.

BACKGROUND: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

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 the birthweight of singletons born after IVF reduced by ovarian stimulation or by IVF laboratory procedures?

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.

Development of adaptive motor behaviour in typically developing infants.

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.

The Groningen ART cohort study: ovarian hyperstimulation and the in vitro procedure do not affect neurological outcome in infancy.

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

Parental psychological distress and anxiety after a successful IVF/ICSI procedure with and without preimplantation genetic screening: follow-up of a randomised controlled trial.

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 1½-5, 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.

Neuromotor, cognitive, language and behavioural outcome in children born following IVF or ICSI-a systematic review.

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.