Karin J. Middelburg

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.

Perinatal outcome in singletons after modified natural cycle IVF and standard IVF with ovarian stimulation

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.

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.

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.

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 childrens 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.

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.

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.

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.

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.

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.