ICSI and Birth Defect Risks: What 30+ Years of Medical Evidence Shows

Key Takeaways

Observational studies have reported a small association between ICSI and birth defects, but they do not establish that the microinjection itself is the cause. Underlying infertility and parental factors may contribute, and the absolute risk remains low. ASRM 2026 does not recommend routine ICSI without male-factor infertility or previous poor fertilization with conventional IVF.

Key evidence: ASRM Committee Opinion: ICSI for Non-Male Factor Indications (2026) · Davies et al.: Reproductive Technologies and the Risk of Birth Defects (NEJM 2012) · Belva et al.: Semen Quality in Young Adult ICSI Offspring (Human Reproduction)

ICSI and Child Health: What Over 30 Years of Follow-Up Shows

Intracytoplasmic sperm injection (ICSI) was introduced clinically in 1992 to improve fertilization when sperm parameters are severely impaired or when conventional IVF has previously resulted in poor or absent fertilization. It is a way to overcome a fertilization barrier; it is not a treatment for the genetic or biological cause of male infertility.

Because ICSI bypasses natural sperm selection barriers and directly penetrates the oocyte membrane, pediatric and genetic health outcomes of children conceived through this technique have been monitored closely for over three decades.

Long-term cohort studies and national registry data are reassuring for many outcomes, but they do not show that every health outcome is identical to that of naturally conceived children. The evidence also highlights specific genetic factors that require tailored clinical attention.

Major Birth Defect Rates: What Do the Numbers Show?

Published estimates are not interchangeable: studies use different definitions of a birth defect, follow-up periods, and comparator groups. In the large South Australian cohort by Davies et al., 308,974 births were followed through the child’s fifth birthday. Any birth defect was recorded in 8.3% of assisted-conception pregnancies and 5.8% of pregnancies without assisted conception; after multivariable adjustment, the odds ratio was 1.28 for assisted conception overall, 1.07 for IVF, and 1.57 for ICSI (95% CI 1.30–1.90).1 These are study-specific associations, not a universal individual risk for every ICSI pregnancy.

The Critical Role of Parental Subfertility (Confounding by Indication)

A central question in reproductive epidemiology is whether this modest risk elevation stems from the micromanipulation procedure itself or from the biological characteristics of couples requiring treatment.

A landmark population study by Davies et al. (New England Journal of Medicine, 2012), evaluating over 300,000 births in South Australia, showed both an ICSI association and important uncertainty about its cause:

1. The adjusted association remained statistically significant for ICSI, while the adjusted association for IVF was not statistically significant.
2. A history of infertility without assisted conception was also associated with birth defects, so underlying parental factors may contribute. The study was observational and could not determine how much of the ICSI association was caused by the procedure itself.1

The safest interpretation is therefore conditional: parental subfertility and pregnancy characteristics may explain part of the association, but the available evidence does not justify saying that they explain the entire signal or that the micromanipulation is biologically neutral.

Male Factor and Genetics: 4 Key Clinical Considerations

The procedure and the reason it is being used should be considered separately. Severe male-factor infertility can itself have genetic implications, while observational studies have not fully isolated any independent effect of the micromanipulation.

1. Transmission of Y-Chromosome Microdeletions

In men with severe oligozoospermia or non-obstructive azoospermia, microdeletions on the long arm of the Y chromosome (AZFa, AZFb, or AZFc regions) may be identified. The frequency varies by sperm concentration and study population; the EAU guideline reports the highest frequency in azoospermia and severe oligozoospermia.2

• Clinical Reality: If sperm harboring an AZFc deletion fertilizes an egg, this exact deletion is transmitted to 100% of male offspring, who will likely face similar fertility challenges in adulthood.
• Best Practice: The EAU guideline recommends Y-chromosome microdeletion testing at sperm concentrations of ≤1 million/mL and says it should be considered below 5 million/mL. Results should be discussed with genetic counseling before ICSI.2

2. Sex Chromosome Aneuploidies

Some ICSI cohorts have reported more sex-chromosome abnormalities, such as Klinefelter syndrome (47,XXY) or 47,XYY, than general-population comparisons (Bonduelle et al., 2002). The estimates vary by cohort, ascertainment, and the underlying male-factor diagnosis, so a single universal percentage should not be applied to every ICSI pregnancy.

3. Genomic Imprinting and Epigenetic Disorders

Rare imprinting disorders, including Beckwith-Wiedemann, Angelman, Prader-Willi, and Silver-Russell syndromes, have been studied after ART. The evidence remains mixed and the absolute risk is very low. In a Nordic register study, the absolute risk of Beckwith-Wiedemann syndrome after ART was 10.7 per 100,000 newborns; the risks of Angelman, Prader-Willi, and Silver-Russell syndromes were not increased (Henningsen et al., 2020).

4. Long-Term Health and Adult Development

Longitudinal cohorts (notably from the Vrije Universiteit Brussel led by Bonduelle et al. and Belva et al.) have followed ICSI offspring from infancy into early adulthood (ages 18–22+):

• Cognitive & Neurological Outcomes: Neurodevelopment and growth generally appear similar in available studies, but the evidence is not proof that every outcome is identical.4
• Cardiometabolic Health: Studies have reported mostly small or uncertain differences; longer follow-up is still needed rather than assuming uniformly normal cardiometabolic results.4
• Young Adult Male Fertility: In one cohort of 54 young adult men conceived by ICSI for male infertility, median sperm concentration and total sperm count were lower than in spontaneously conceived peers. This supports careful counseling about possible paternal transmission of impaired spermatogenesis; it does not establish the same outcome for every ICSI son.5

Dr. Aksoy’s Approach

Dr. Senai Aksoy’s Perspective: Diagnostic Precision Over Routine Overuse

“The modest excess risk of anomalies reported after ICSI cannot be attributed with certainty to the micromanipulation procedure itself. The studies are observational, and couples requiring ICSI more often have severe male-factor or other parental infertility characteristics that may contribute to the association. At the same time, the evidence does not justify saying that the technique has no independent effect.

I explain this without alarmism: the absolute risk remains low, but ICSI should not be presented as a harmless precaution without costs or clinical implications. In the absence of an established male factor or a history of total or near-total fertilization failure in conventional IVF, I do not recommend routine ICSI: it has demonstrated no improvement in live birth rates, including in cases of advanced maternal age or low oocyte yield (ASRM Committee Opinion, 2026).

Conversely, in severe sperm impairment, ICSI is often an appropriate route to achieve fertilization, but it must be paired with a comprehensive andrological workup—including karyotyping, Y-chromosome microdeletion testing, or CFTR analysis where indicated—along with genetic counseling. ICSI bypasses a fertilization barrier; it does not correct the underlying genetic cause, and when a genetic defect is present, part of the fertility impairment may be transmitted to male offspring.”

— Dr. Senai Aksoy

Recommended Pre-ICSI Medical Workup

The workup should be tailored to semen parameters and the clinical phenotype:

1. Standard Semen Analysis: Thorough assessment of count, motility, and strict morphology according to WHO standards.
2. Peripheral Blood Karyotyping: The EAU guideline recommends standard karyotyping and genetic counseling in azoospermia or when sperm concentration is below 5 million/mL. Its background text also discusses the broader current indication below 10 million/mL; this is not the same as the strong recommendation threshold.2
3. Y-Chromosome Microdeletion Analysis (AZF): The EAU guideline recommends testing at ≤1 million/mL and says it should be considered below 5 million/mL. A positive result has implications for sperm retrieval and transmission to sons.2
4. CFTR Gene Mutation Screening: Considered when congenital bilateral absence of the vas deferens (CBAVD) or another obstructive-azoospermia phenotype suggests CFTR-related disease; the couple should receive genetic counseling and partner testing.2

Frequently Asked Questions

Does ICSI increase the risk of birth defects in children?

Studies have reported an association between ICSI and birth defects, but the absolute figures depend on the study definition and comparator. Davies et al. found an adjusted odds ratio of 1.57 for ICSI in one South Australian cohort, while also noting that infertility without ART was associated with birth defects.1 This does not prove that ICSI itself caused the association.

Why is routine ICSI discouraged when male parameters are normal?

The ASRM Committee Opinion (2026) concludes that routine ICSI without a male-factor indication or a history of poor or failed fertilization has not been shown to improve live birth outcomes, including in older women or low-oocyte cycles.

Will a boy conceived via ICSI have fertility problems as an adult?

Most girls and boys conceived by ICSI do not have a known fertility problem because of ICSI alone. When a father has a documented Y-chromosome microdeletion, however, any biological son who inherits his Y chromosome will inherit that deletion and may face fertility impairment in adulthood.2

Do children born after ICSI develop normally?

Many follow-up studies are reassuring for neurodevelopment and growth, but the evidence does not establish that every long-term outcome is identical to natural conception. Metabolic and reproductive outcomes remain areas of active follow-up.4

Related Articles

• IMSI, PICSI, and MACS in IVF: What Clinical Evidence Shows
• Azoospermia and Micro-TESE: When a Second Attempt is Considered
• Standard IVF, ICSI, and Natural Cycle IVF: Key Differences
• Improving Sperm Quality: Evidence-Based Medical Guidance

Sources

• Practice Committee of the American Society for Reproductive Medicine. Intracytoplasmic sperm injection for nonmale factor indications: a committee opinion. Fertil Steril 2026; Practice Guidance Document.
• Davies MJ, Moore VM, Willson KJ, et al. Reproductive technologies and the risk of birth defects. N Engl J Med 2012;366(19):1803–1813.
• Hansen M, Kurinczuk JJ, Milne E, et al. Assisted reproductive technology and birth defects: a systematic review and meta-analysis. Hum Reprod Update 2013;19(4):330–353.
• Belva F, Bonduelle M, Roelants M, et al. Semen quality of young adult ICSI offspring: the first results. Hum Reprod 2016;31(12):2813–2820.
• Bonduelle M, Liebaers I, Deketelaere V, et al. Neonatal data on a cohort of 2889 infants born after ICSI (1991–1999) and of 2995 infants born after IVF (1983–1999). Hum Reprod 2002;17(3):671–694.
• ESHRE Capri Workshop Group. Birth defects in children conceived by in vitro fertilization: an update. Hum Reprod Update 2014;20(4):561–573.
• Jungwirth A, et al. EAU Guidelines on Sexual and Reproductive Health: Male Infertility. Current guideline chapter, accessed 2026.
• Catford SR, McLachlan RI, O’Bryan MK, Halliday JL. Long-term follow-up of ICSI-conceived offspring compared with spontaneously conceived offspring: a systematic review of health outcomes beyond the neonatal period. Andrology 2018;6(5):635–653.
• Henningsen AA, et al. Imprinting disorders in children born after ART: a Nordic study from the CoNARTaS group. Human Reproduction 2020;35(5):1178–1184. doi:10.1093/humrep/deaa039.

Dr. Senai Aksoy

Dr. Senai Aksoy studied and trained in France before returning to Turkey, where he was a founding member of the ICSI team at Sevgi Hospital, Ankara — the country's first ICSI centre (1994-95) — and a co-author on the first Turkish ICSI publications produced in collaboration with the Brussels Van Steirteghem group (Human Reproduction, 1996; PMID 8671323). He helped build the IVF programme at the American Hospital Istanbul and has been running his own fertility practice since 1998.

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The content has been created by Dr. Senai Aksoy and medically approved.