The Groningen ART cohort study: Does ovarian hyperstimulation, the in vitro procedure or a combination of both influence cognitive and behavioural development of 4-year-old IVF-offspring?

Study question: Evaluating the effects and underlying causal relationships of ovarian hyperstimulation, the in vitro procedure and the combination of both on cognitive and behavioural development in 4-year-olds. Summary answer: Our preliminary results suggest that ovarian hyperstimulation, the in vitro procedure and the combination of both are not associated with cognitive and behavioural development in 4-year-olds. The child's cognitive and behavioural development largely depend on parental characteristics such as level of education and maternal age. What is known already: Long-term follow-up of health and development of IVFoffspring is important since the use of assisted reproduction techniques (ART) is steadily increasing. Results of long-term studies on cognitive and behavioural development in IVF-children vary, partly due to difficulties in interpretation of direct and indirect underlying causal relationships between ART, subfertility- and parental- and child aspects. The present study focuses on cognitive and behavioural development of 4-year-old IVF-offspring and underlying causal relationships. Study design, size, duration: A prospective follow-up study, in which 195 4-year-old singletons were assessed. They were born to subfertile couples (n = 195) following IVF with controlled ovarian hyperstimulation (COH-IVF, n = 63), IVF in the modified natural cycle (MNC-IVF, n = 53) and natural conception (Sub-NC, n = 79). The attrition rate since birth was 9.3%. Participants/materials, setting, methods: Cognitive development was evaluated with the Kaufman Assessment Battery for Children; behavioural development was evaluated with the Child Behavior Checklist. Primary cognitive outcome parameter was the total intelligence quotient (IQ); behavioural outcome parameter was the total problem T-score. Regression analyses, causal inference search algorithms and structural equation modelling were applied. Main results and the role of chance: The total IQ score [mean (sd)] for COH-IVF, MNC-IVF and Sub-NC children was 106.1 (11.8), 105.2 (13.3) and 108.9 (10.7), respectively and did not differ significantly between the three groups. Similarly, behavioural scores did not differ between the three groups. The causal models suggested that ovarian hyperstimulation and the in vitro procedure did not affect cognitive and behavioural outcome. Rather, cognitive and behavioural outcome were associated with parental characteristics such as maternal age and educational level. Limitations, reason for caution: The prospective design of our study and small post-natal attrition rate reduced potential selection bias based on the child's development or health. The assessors were blind to the mode of conception. However, our results cannot be generalized to multiples, as we studied singletons only. Wider implications of the findings: Our study contributes to the understanding of the relation between ART-aspects and cognitive and behavioural development. Long-term monitoring of development and growth of children born after ART remains of importance, especially since in society maternal age at child birth, and with that subfertility and the use of ART are steadily increasing.