OUP accepted manuscript

Study question Does In vitro maturation (IVM) of immature oocytes affect health, including growth at 2 years of age, in singletons born to mothers with polycystic ovary syndrome (PCOS)? Summary answer This study of 92 singletons born after IVM in mothers with PCOS showed no significant differences in anthropometry and health outcome parameters in comparison with a cohort of 74 peers born after intracytoplasmic sperm injection (ICSI) and conventional controlled ovarian stimulation (COS) in mothers with PCOS. What is known already IVM has been used worldwide in women with PCOS. However, the paucity of available data related to children's health following IVM is an important impediment to a more widespread use of the technology. Although previous reports on the neonatal outcome after IVM are generally reassuring, these studies have flaws that hamper the interpretation of outcomes. Moreover, few studies have reported on health outcomes after IVM beyond infancy, and particularly growth data in children born after IVM of immature oocytes from mothers with PCOS are lacking. Study design size duration This single-center cohort study compared anthropometry and health outcomes in 92 singletons born after ICSI of in vitro matured oocytes with 74 singletons born after ICSI without IVM (COS). All participants were born to mothers who were diagnosed with PCOS phenotype A, B, C or D and reached the age of 2 years between November 2012 and June 2019. Singletons born after COS were randomly selected for follow-up until young adulthood. Participants/materials setting methods Anthropometric parameters and health status data were prospectively collected at birth, 4 months and 2 years in cohorts of singletons followed since birth. Results were adjusted for neonatal (birthweight z-score, birth order), treatment (day of transfer, number of embryos transferred, mode of transfer) and parental (maternal smoking, age, body mass index (BMI), anti-Mullerian hormone level, PCOS phenotype, gestational diabetes, hypertensive disorder and paternal BMI) characteristics. Main results and the role of chance Overall, no differences were found for bodyweight, height and head circumference z-score between IVM and COS children at birth, at 4 months or at 2 years (all P > 0.05). In addition, z-scores of waist and mid-upper arm circumference at 2 years were comparable in IVM and COS children. Adjustment for covariates did not change the conclusion. Surgical intervention rate as well as the hospital admission rate were comparable between the IVM and COS group (all P > 0.05). The proportion of children born to mothers with metabolically unfavorable PCOS phenotypes (A and C) was comparable in the two groups (52.1% in IVM and 45.9% in COS). Mothers giving birth to a child conceived using IVM were younger than mothers in the COS group but their BMI was comparable. Limitations reasons for caution Although our study describes the largest cohort to date of singletons born after IVM applied in mothers with well-defined PCOS phenotypes, the current sample size only allowed us to detect moderate differences in anthropometry. Also, follow-up of children born after IVM for indications other than PCOS, for example fertililty preservation after cancer diagnosis, is highly recommended. Wider implications of the findings We did not observe adverse effects of IVM on growth parameters in offspring ~2 years of age compared to COS, but future studies should focus on cardiovascular and metabolic outcomes in these children and adolescents given their mother's PCOS condition. Study funding/competing interests This study was supported by Methusalem grants and by grants from Wetenschappelijk Fonds Willy Gepts; all issued by the Vrije Universiteit Brussel (VUB). All co-authors, except M.B., M.D.V. and H.T. declared no conflict of interest. M.B. has received consultancy fees from MSD, Serono Symposia and Merck. M.D.V. has received fees for lectures from MSD, Ferring, Gedeon Richter and Cook Medical. H.T. has received consultancy fees from Gedeon Richter, Merck, Ferring, Abbott and ObsEva. The Universitair Ziekenhuis Brussel (UZ Brussel) and the Center for Medical Genetics have received several educational grants from IBSA, Ferring, MSD and Merck for establishing the database for follow-up research and organizing the data collection.