A US-UK Collaborative Study of the Health of Children Born From In Vitro Fertilization: From Conception Through Young Adulthood

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PROJECT SUMMARY Since the birth of the first child from in vitro fertilization (IVF) in the UK in 1978 and in the US in 1981, more than ten million babies have been born from this technology, including more than 1.37 million babies annually worldwide. In 2018, IVF births accounted for 2.24% of all US births and 3.1% of all UK births. Consistent research findings indicate that IVF-conceived pregnancies and IVF-conceived children are at greater risk for a spectrum of adverse perinatal outcomes. A persistent, unresolved issue remains what proportion of the adverse perinatal and child health outcomes after IVF is due to parental factors and what proportion is due to the IVF procedures. In the US, the national IVF database, the Society for Assisted Reproductive Technology Clinic Outcome Reporting System is left-censored at 2004; it is not feasible to obtain data on earlier cycles. In addition, the US has few national databases to facilitate tracking children’s health over time. To overcome these limitations, we are partnering with researchers in the UK in this proposed study. The UK system, under the Human Fertilisation and Embryology Authority, can track individuals treated as early as 1991, linking all adults treated and all children conceived with IVF to a number of national databases. Through this collaboration, we seek to draw upon the strengths of each country: in the UK, longer follow-up and more linked health databases; in the US, more annual IVF cycles and births; and more racial and ethnic diversity. The long-term health of children conceived with IVF is still not clearly understood. Follow-up studies of the growth and health of IVF-conceived children have been limited by small sample sizes, high drop-out rates, and methodological issues, with many knowledge gaps remaining. In this proposed renewal, we are seeking to overcome these limitations using an early life-course approach to evaluate the growth and health of children born from IVF, from conception through childhood, and for the UK component, through adulthood. The two primary aims of this proposed renewal are (1) comprehensively evaluate the role of IVF conception on birth defects, cancer, and the co-occurrence of these conditions through large-scale registry linkages and analysis of the neonatal methylome and (2) to evaluate the effect of IVF treatment parameters, specifically the use of ICSI, number of embryos transferred (embryonic and/or fetal loss as plurality at conception versus at birth), oocyte source/state-embryo state combinations, on child growth (size at birth, and height and weight at ages 4-5 and 10-11) and health (birth defects, cancer, acute and chronic illness, and premature mortality), accounting for parental, socioeconomic, and environmental factors. This proposed study will include a total of more than 4.75 million children, including more than 458,000 IVF- conceived children born 1991-2018, 88,000 naturally-conceived siblings, and 4.2 million naturally-conceived control children, with 80.6 million person-years of follow-up, averaging 14.4 years in the US (ranging from birth to age 22) and 18.3 years in the UK (ranging from birth to age 36), and will provide a comprehensive contemporary picture of child health after conception by in vitro fertilization.