ICSI and ovarian stimulation linked to different patterns in children's DNA

Parental age and various procedures used during fertility treatment have been linked to different patterns of changes in the DNA of offspring.

Researchers from Nanjing Medical University, China, investigated how delayed parenthood and the use of fertility treatment influence the frequency of de novo mutations (DNMs). These genetic changes, which can have neutral, positive or negative effects on health, are present in a child but not his parents as they can spontaneously arise in parental gametes or during early development. The study, published in Nature Medicine, found that paternal and maternal age, as well as various fertility treatment procedures, were associated with different patterns of DNMs.

Commenting on the findings in a Nature Medicine briefing, Dr Beth Dumont, an associate professor at the Jackson Laboratory in Bar Harbor, Maine, who was not involved in the study, said: 'Although earlier studies have suggested that [fertility treatments] can influence DNM accumulation, this work takes an important next step by identifying the specific procedures that contribute to that increased mutation burden. Its scale provides a powerful and detailed view of the genetic consequences of widely used infertility treatments while highlighting opportunities to refine clinical protocols and further minimise genetic risk.'

The researchers performed whole genome sequencing in 8328 live-born infants from 7851 families, including 5619 families who conceived naturally and 2232 who had fertility treatment. They identified 390,924 de novo single-nucleotide variants (dnSNVs), which are changes to a single DNA base. Paternal age showed the strongest association with DNM burden, with the number of paternal DNMs increasing as fathers became older. Maternal DNMs showed a different pattern, increasing more rapidly around 29–32 years.

The researchers also found that some fertility procedures were associated with DNMs, independently of parental age. Specifically, the use of intracytoplasmic sperm injection (ICSI), where a single sperm is injected directly into an egg, was linked to an increase in paternal dnSNVs. Ovarian stimulation was associated with maternal dnSNVs, while embryo culture was linked to mutations arising during very early embryo development, leading to mosaicism.

The study also investigated whether these mutations were associated with health and developmental outcomes in children. Increased paternal dnSNVs partly accounted for the association between older parental age and ICSI on shorter gestational duration and preterm birth. However, the team could not detect any links between parental dnSNVs and defects at birth or after one year.

The findings shed light on the different mutational patterns associated with parental age and specific treatments. However, the study was observational and therefore cannot establish that parental age or fertility procedures directly cause these mutations or any associated health outcomes. Further work is needed to explore these associations and determine whether they are underpinned by biological mechanisms.