Abstract
STUDY QUESTION: Do ovarian stimulation (OS) and the in vitro laboratory procedures affect offsprings' cognitive and behavioural outcome at 9 years? SUMMARY ANSWER: OS and the in vitro laboratory procedures or the combination of both were not associated with cognitive and behavioural outcome at age 9 years. WHAT IS KNOWN ALREADY: ART is not associated with an adverse short-term developmental outcome of the offspring, but limited knowledge is available on the offspring's long-term neurodevelopmental condition. STUDY DESIGN, SIZE, DURATION: A 9-year longitudinal, assessor-blinded, prospective follow-up study of 169 out of 215 singletons (79%) born between March 2005 and December 2006 was performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Singletons born following IVF or ICSI with OS (n = 57), born after modified natural cycle IVF/ICSI (MNC-IVF/ICSI; n = 46) and born after natural conception to subfertile couples (Sub-NC; n = 66), were assessed at 9 years. This study design, with two ART groups and a subfertile reference group, allows for disentangling the effects of OS and ART procedures on developmental outcome. Cognitive outcome was evaluated with the Wechsler abbreviated scale of intelligence and the NEPSY-II. Behaviour was assessed with the child behaviour checklist (CBCL) and teacher report form (TRF). Univariable analyses and multiple linear regression models were used. MAIN RESULTS AND THE ROLE OF CHANCE: There was no significant difference in intelligence quotient (IQ) scores between ART groups (mean IQ (95% CI): OS 114.8 (83.2-142.6); MNC 114.0 (90.2-140.8); Sub-NC 115.4 (87.9-141.2), P = 0.746). Multivariable analyses did not reveal a statistically significant association between ART group and total, verbal and performance IQ. CBCL and TRF scores did not differ significantly between ART groups (P = 0.090 and 0.507, respectively). Multivariable analyses did not demonstrate a statistically significant association between ART group and CBCL and TRF total, or internalising and externalising T-scores. No significant correlations between time to pregnancy (TTP)-a proxy for the severity of parental subfertility-and outcome measures were found (Spearman rho between -0.050 and 0.049, NS), which was confirmed with multivariable analyses. LIMITATIONS, REASONS FOR CAUTION: The attrition rate of 21% may be considered as a limitation of the study; however, after a follow-up period of 9 years, this rate is generally considered acceptable, and there were no significant differences in background characteristics between children with and without follow-up, making an attrition-related selection bias less likely. Another limitation of the study is the relatively small sample size, which could contribute to selection bias, hamper generalizability to the ART population and lead to false negative findings as a result of underpowering. An a priori power analysis on total IQ indicated that the OS-IVF/ICSI and Sub-NC groups should contain 64 children, confirming that our study including 57 and 66 children, respectively, was slightly underpowered. WIDER IMPLICATIONS OF THE FINDINGS: Our study indicated that OS and the in vitro laboratory procedures or the combination of both and TTP were not associated with cognitive and behavioural outcome at 9 years. These are reassuring results for both parents and clinicians involved in ART. STUDY FUNDING/COMPETING INTEREST(S): The study was financially supported by the University Medical Center Groningen (UMCG), two graduate schools of the UMCG (BCN and 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.