ICSI and Birth Defect Risks: What 30+ Years of Medical Evidence Shows
Key Takeaways
Some studies link ICSI with a small rise in birth defects, but they do not prove the injection causes it. Parental infertility may play a part. Absolute risk stays low. ASRM 2026 does not advise routine ICSI without a male factor or prior poor fertilization with standard 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) entered clinical use in 1992. It helps fertilization when sperm quality is very poor, or when standard IVF has already failed to fertilize eggs well. It overcomes a fertilization barrier. It does not treat the genetic or biological cause of male infertility.
ICSI places one sperm directly into the egg. That step skips natural selection at the egg surface. For that reason, child health after ICSI has been studied for more than 30 years.
Long-term cohort studies — groups of people followed over time — look reassuring for many outcomes. They do not prove that every health result matches natural conception. Some genetic risks still need careful counseling before treatment.
Major Birth Defect Rates: What Do the Numbers Show?
Some large studies report a modest link between ICSI and birth defects, and the absolute risk stays low. The studies are observational (they watch real-world care; they do not randomly assign ICSI), so they cannot prove that the injection itself caused the rise (Davies et al., 2012).
Study numbers are also hard to compare. Teams define “birth defect” differently, follow children for different lengths of time, and choose different comparison groups.
A 2013 systematic review by Hansen et al. — a structured survey of many studies, pooled in a meta-analysis — also found higher birth-defect rates after assisted conception than after natural conception. It combined 45 cohort studies. The gap was still seen when only major defects, or only single births, were counted. The review looked at assisted conception as a whole, not ICSI alone.
Two recent studies compared ICSI directly with standard IVF. A single-center cohort from Peking University Third Hospital in China looked back at 46,167 standard-IVF cycles and 33,247 ICSI cycles with fresh embryo transfer. Malformations were recorded in 5.44 per 1,000 live births after standard IVF and 5.78 per 1,000 after ICSI. After adjustment the difference was not statistically significant (adjusted odds ratio 1.10, 95% confidence interval 0.79–1.53) (Zhang et al., 2024).
A registry study from Denmark, Finland, Norway, and Sweden covered 7.7 million births and looked at congenital heart defects. Major heart defects were found in 1.84% of children born after assisted reproduction and 1.15% of children born after natural conception (adjusted odds ratio 1.36). The risk was similar after ICSI and standard IVF, and it was highest in multiple births (Sargisian et al., 2024). Studies still disagree on whether ICSI carries more risk than standard IVF, so the question stays open.
Evidence box: Davies 2012 numbers and what they do — and do not — show
In the South Australian study by Davies et al. (New England Journal of Medicine, 2012), 308,974 births were followed to age five. Any birth defect was recorded in 8.3% of assisted-conception pregnancies and 5.8% of pregnancies without assisted conception. After adjustment for other factors, the odds ratio (a relative-chance measure) was 1.28 for assisted conception overall, 1.07 for IVF, and 1.57 for ICSI (95% confidence interval 1.30–1.90) (Davies et al., 2012).
After adjustment, the ICSI link stayed statistically significant (unlikely to be chance alone under the study model). The IVF link did not. A history of infertility without assisted conception was also linked with birth defects. So parental factors may explain part of the signal. The study could not say how much came from the procedure itself.
These are study-specific associations. They are not a personal risk figure for every ICSI pregnancy.
Parental Subfertility: Procedure vs Reason for Treatment
The key clinical question is simple. Does the small rise come from the laboratory step, or from the biology of couples who need ICSI?
The Davies study leaves that question open. Parental subfertility and pregnancy factors may explain part of the association. Current evidence does not let us say they explain all of it, or that the injection step is biologically neutral.
Male Factor and Genetics: 4 Key Clinical Considerations
The technique and the reason for using it are separate questions. Severe male-factor infertility can carry genetic risks on its own. Observational studies have not fully separated any extra effect of the injection step.
1. Y-Chromosome Microdeletions
Some men with severe oligozoospermia or non-obstructive azoospermia are missing a tiny piece of the long arm of the Y chromosome (AZFa, AZFb, or AZFc). The EAU guideline reports these deletions in about 8–12% of men with azoospermia and 3–7% of men with oligozoospermia. They are extremely rare (about 0.7%) when sperm concentration is above 5 million/mL (EAU guideline).
- What it means clinically: If a sperm with an AZFc deletion fertilizes an egg, that same deletion passes to 100% of biological sons. In men with an AZFc deletion, sperm production ranges from none (azoospermia) to low (oligozoospermia). So a son’s fertility may be affected to different degrees.
- Testing guidance: The EAU guideline recommends Y-chromosome microdeletion testing at sperm counts of ≤1 million/mL, and says it should be considered below 5 million/mL. Results should be discussed with genetic counseling before ICSI.
2. Chromosome Changes in Prenatal Tests
A Brussels team ran 1,586 prenatal tests in ICSI pregnancies. New (de novo) chromosome changes were found in 1.6%, compared with about 0.5% in general-population prenatal tests at a similar maternal age. The excess came mainly from changes in the sex chromosomes and, to a lesser extent, from structural changes in other chromosomes. New changes were more common when the father’s sperm concentration or motility was low (Bonduelle et al., 2002). Rates vary by cohort, how cases were found, and the father’s diagnosis. One fixed percentage should not be applied to every ICSI pregnancy.
3. Imprinting and Epigenetic Disorders
Rare imprinting disorders — including Beckwith-Wiedemann, Angelman, Prader-Willi, and Silver-Russell syndromes — have been studied after assisted reproduction. Evidence is mixed. In a Nordic register study, Beckwith-Wiedemann syndrome was more common after ART (adjusted odds ratio 2.84) but still rare: about 10.7 per 100,000 newborns. Angelman, Prader-Willi, and Silver-Russell syndromes were not increased (Henningsen et al., 2020). The numbers are small and hard to interpret, so they justify neither false reassurance nor undue worry.
4. Long-Term Health into Adulthood
A 2018 systematic review pulled together studies that followed ICSI children beyond the newborn period (Catford et al., 2018):
- Brain development, growth, vision, and hearing: Results look broadly similar to children conceived naturally. That is not proof that every outcome matches natural conception.
- General physical, metabolic, and reproductive health: Some differences have been reported. Their clinical meaning is still unclear, and larger, longer studies are needed.
The Brussels team that has followed ICSI children since the 1990s has now studied them as young adults. In 54 men aged 18–22 who were conceived by ICSI for male infertility, median sperm concentration and total sperm count were lower than in peers conceived naturally (Belva et al., 2016). That supports counseling about possible paternal transmission of impaired sperm production. It does not mean every ICSI son will have the same result.
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
Match tests to the semen results and the clinical picture.
- Semen analysis: Count, motility, and strict morphology (WHO standards).
- Blood karyotype: EAU recommends this plus genetic counseling in azoospermia, or when sperm concentration is below 5 million/mL. The guideline’s explanatory text also mentions a wider range, below 10 million/mL. That wider figure is not the strong recommendation threshold (EAU guideline).
- Y-chromosome microdeletion testing (AZF): Recommended at ≤1 million/mL. Consider it below 5 million/mL. A positive result changes retrieval planning and counseling about sons.
- CFTR gene testing: Recommended for men with a structural abnormality of the vas deferens, such as congenital bilateral absence of the vas deferens (CBAVD). Test the partner too and offer genetic counseling.
Frequently Asked Questions for Dr. Aksoy
Does ICSI increase the risk of birth defects in the baby?
The large majority of babies born after ICSI are healthy. Some studies have reported that congenital anomalies appear a little more often in children conceived by microinjection. An important distinction remains: we do not know with certainty how much of that increase comes from the microinjection procedure itself and how much from the parents’ underlying infertility.
Some genetic problems that cause severe male infertility can also affect the health of a future child. For that reason, I do not tell patients that ICSI is completely risk-free, and I also do not present it as a method that frequently causes birth defects. What matters to me is using microinjection when it is truly needed.
Will a boy born after ICSI be infertile later in life?
No. We cannot say that every boy born after ICSI will be infertile later. If the father has a genetic problem that impairs sperm production, however, there is a chance it may be passed to a son. Certain Y-chromosome microdeletions, for example, can be transmitted to sons and affect their sperm production as well.
Small studies have found lower sperm counts in young men conceived by ICSI. We still do not fully know how much of that finding relates to traits inherited from the father.
I place particular importance on completing the indicated genetic workup beforehand in couples for whom we plan microinjection because of a very low sperm count or azoospermia. That way we can discuss possible hereditary risks before treatment begins.
Why do you not recommend routine ICSI for everyone when semen parameters are normal?
Because doing more in the laboratory does not always mean a higher chance of pregnancy. In standard IVF we bring eggs and sperm together in the dish; in microinjection, the embryologist places one selected sperm directly into the egg.
Large studies in couples without a male factor have not shown that ICSI raises live-birth rates compared with standard IVF. So when semen parameters are normal and there has been no previous fertilization problem, I do not see routine microinjection as necessary.
ICSI may still be preferred if fertilization failed in a previous cycle, if frozen eggs will be used, or if certain genetic tests on the embryos are planned. My approach is not to apply the most technology to every patient, but to choose the method that is likely to help.
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;126:49–56.
- 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.
- Zhang N, Tian T, Li J, et al. A comparison of pregnancy outcomes and congenital malformations in offspring between patients undergoing intracytoplasmic sperm injection and conventional in vitro fertilization: a retrospective cohort study. Fertil Steril 2024;121(6):982–990.
- Sargisian N, Petzold M, Furenäs E, et al. Congenital heart defects in children born after assisted reproductive technology: a CoNARTaS study. Eur Heart J 2024;45(45):4840–4858.
- Belva F, Bonduelle M, Roelants M, et al. Semen quality of young adult ICSI offspring: the first results. Hum Reprod 2016;31(12):2811–2820.
- Bonduelle M, Van Assche E, Joris H, et al. Prenatal testing in ICSI pregnancies: incidence of chromosomal anomalies in 1586 karyotypes and relation to sperm parameters. Hum Reprod 2002;17(10):2600–2614.
- European Association of Urology. EAU Guidelines on Sexual and Reproductive Health: Male Infertility. 2026 edition.
- 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.
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The content has been created by Dr. Senai Aksoy and medically approved.