ICSI and Genetic Mutations: Does IVF Leave a Trace in a Child’s DNA?

ART singletons carried an average of 2.48 additional de novo mutations compared with naturally conceived children.

An observational genome study examined treatment-specific patterns and early health associations—not proof that IVF causes disease.

Do IVF procedures leave a different pattern of new DNA mutations in children? Whole-genome analysis of 7,851 families found associations involving ICSI, ovarian stimulation and embryo culture, with some mutation types also linked statistically to birth and infant-development outcomes.

Published online in Nature Medicine on August 7, 2026, the study analyzed 24,030 people from the Jiangsu birth cohort in China.

Rather than treating assisted reproduction as a single exposure, the researchers examined different treatment stages and approaches. The results identify questions for further safety research, not a basis for changing treatment independently.

An average of 2.48 additional new mutations in ART singletons

De novo mutations are DNA changes not detected in the parents that arise during sperm or egg formation or after fertilization in early development.

They also occur after natural conception. Most have no clear health effect, although some can contribute to genetic or congenital conditions.

Across the dataset, researchers identified 390,924 new single-nucleotide variants, changes in an individual DNA letter.

After accounting for factors including parental age and child sex, ART-conceived singletons had an average of 2.48 more new DNA mutations than naturally conceived children.

The increase in single-nucleotide variants averaged 2.38: 0.74 paternal-origin, 0.62 maternal-origin and 1.02 arising during early post-fertilization development.

Approximately 42.9% of the ART-associated increase in single-nucleotide variants arose after fertilization. This points to the importance of investigating both parental reproductive cells and the environment of early embryo development.

ICSI was associated with more paternal-origin variants

ICSI places a selected sperm directly inside an egg and is used in settings such as low sperm counts, poor motility or previous fertilization difficulties.

Within the ART group, after accounting for several treatment factors, ICSI was associated with an average increase of 1.01 paternal-origin single-nucleotide variants.

Conventional IVF, in which eggs and sperm are cultured together, did not show a statistically significant paternal-origin difference compared with natural conception.

The researchers considered the possibility that ICSI bypasses some natural sperm-selection steps. However, the procedure itself cannot be identified as the cause from these data. Underlying male infertility and sperm characteristics influencing the choice of ICSI may also contribute.

GnRH antagonist use was associated with maternal-origin variants

GnRH antagonists are used during ovarian stimulation to help prevent premature ovulation.

Their use was associated with an average increase of 1.69 maternal-origin single-nucleotide variants after adjustment. Drug exposure and variant numbers were also related.

The investigators proposed possible links involving egg maturation, cellular stress or DNA repair. These are potential explanations, not established mechanisms.

The findings do not prove that antagonists cause genetic damage. These medicines have important roles in stimulation protocols, including approaches that help manage ovarian hyperstimulation risk. The study is not evidence that patients should avoid a particular stimulation method.

Frozen blastocyst transfer and early mosaic variants

The researchers examined early post-zygotic mosaic mutations, or EPZMs, arising during early divisions after fertilization. Such changes may be present in some, rather than all, cells of the resulting child.

Compared with fresh day-2–3 embryo transfer, frozen day-5–6 blastocyst transfer was associated with an average of 0.81 additional EPZMs. Compared with natural conception, the difference was 1.23.

The proportion of cytosine-to-adenine, or C→A, substitutions was also higher after blastocyst transfer. This mutation pattern can be associated with oxidative DNA damage.

The researchers considered oxidative stress during laboratory culture as one possible explanation. The analysis cannot fully separate culture duration, freezing and thawing, laboratory conditions and embryo selection. Longer culture should not automatically be equated with greater genetic damage.

Associations with preterm birth and infant development

Among 7,374 singletons, more paternal-origin single-nucleotide variants were associated with shorter gestation and higher risks of preterm birth and low birth weight.

The estimated contribution was limited. These variants statistically mediated approximately 2.95% of the association between ART and preterm birth, and approximately 8.32% of the difference in the ICSI-versus-natural-conception analysis.

Pregnancy outcomes involve many other factors, including maternal health, underlying infertility and pregnancy complications.

Each additional early C→A mosaic variant was also associated with approximately 14% higher risk of cognitive developmental delay at one year.

This is not a finding that IVF increases developmental-disorder risk by 14%. It describes an association between a particular mutation count and an infant assessment, rather than established long-term developmental disability.

Mutation counts are not the same as disease risk

This observational comparison of genomes and treatment records cannot demonstrate that a specific procedure directly generated a mutation.

A newly identified variant does not necessarily cause disease. Its biological importance depends on its location and function, and most variants have no clear health consequence.

The findings do not justify independently avoiding ICSI, changing stimulation medication or stopping frozen blastocyst transfer. Treatment decisions depend on the cause of infertility, individual circumstances, effectiveness and safety.

The research instead calls for closer investigation of sperm selection, stimulation and embryo-culture conditions, together with long-term offspring follow-up.

Assessing ART safety requires more than counting variants or measuring pregnancy rates: researchers must determine which changes, if any, have meaningful consequences for health and development.

Study source

Qin, N. and colleagues: “Large-scale whole-genome sequencing reveals the landscape and health implications of de novo mutations.” Nature Medicine, published online August 7, 2026. The study analyzed whole genomes from 24,030 people in 7,851 Jiangsu birth-cohort families. DOI: 10.1038/s41591-026-04585-2.

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