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  • Review Article
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Intracytoplasmic sperm injection for male infertility and consequences for offspring

Nature Reviews Urology volume 15, pages 535–562 (2018)Cite this article

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Abstract

Intracytoplasmic sperm injection (ICSI) has become the most commonly used method of fertilization in assisted reproductive technology. The primary reasons for its popularity stem from its effectiveness, the standardization of the procedure, which means that it can easily be incorporated into the routine practice of fertility centres worldwide, and the fact that it can be used to treat virtually all forms of infertility. ICSI is the clear method of choice for overcoming untreatable severe male factor infertility, but its (over)use in other male and non-male factor infertility scenarios is not evidence-based. Despite all efforts to increase ICSI efficacy and safety through the application of advanced sperm retrieval and cryopreservation techniques, as well as methods for selecting sperm with better chromatin integrity, the overall pregnancy rates from infertile men remain suboptimal. Treating the underlying male infertility factor before ICSI seems to be a promising way to improve ICSI outcomes, but data remain limited. Information regarding the health of ICSI offspring has accumulated over the past 25 years, and there are reasons for concern as risks of congenital malformations, epigenetic disorders, chromosomal abnormalities, subfertility, cancer, delayed psychological and neurological development, and impaired cardiometabolic profile have been observed to be greater in infants born as a result of ICSI than in naturally conceived children. However, as subfertility probably influences the risk estimates, it remains to be determined to what extent the observed adverse outcomes are related to parental factors or associated with ICSI.

Key points

  • Intracytoplasmic sperm injection (ICSI) was introduced to overcome the most severe forms of male factor infertility and has become the most frequently used method of fertilization in assisted reproductive technology (ART).

  • Existing evidence does not support ICSI in preference over in vitro fertilization (IVF) in the general non-male factor ART population; however, in couples with unexplained infertility, ICSI is associated with lower fertilization failure rates than IVF.

  • Percutaneous and open sperm retrieval methods are highly effective for harvesting sperm from men with obstructive azoospermia; open microsurgical testicular sperm retrieval has been associated with improved sperm retrieval in men with nonobstructive azoospermia.

  • Existing evidence indicates that children conceived through ICSI have an increased risk of chromosomal abnormalities, particularly those affecting sex chromosomes, compared with naturally conceived children.

  • Whether the risk of cancer is increased among children conceived using ICSI is unclear, but some evidence indicates that certain cancer types are more common in children conceived using ICSI than in naturally conceived children.

  • All efforts should be made to evaluate and treat subfertile men, both to improve the safety and efficiency of ICSI and to allow natural conception or the use of less-invasive assisted conception methods when appropriate.

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Fig. 1: Assisted fertilization methods.
Fig. 2: Seminal alterations associated with male infertility.
Fig. 3: Sperm selection methods.

Part a adapted from ref.273, Macmillan Publishers Limited, CC BY 4.0. Part d adapted from ref.274 with permission from Ass. Prof. Igor Crha, CS., Faculty of Medicine, Masaryk University, created in collaboration with Service Center for E-Learning, Faculty of Informatics, Masaryk University, Czech Republic.

Fig. 4: Sperm retrieval methods.

Parts a, c, and d reproduced with permission from ref.18, Clinics, CC BY-NC 3.0. Part b reproduced with permission from ref.80, Clinics, CC BY-NC 3.0.

Fig. 5: The epigenetic reprogramming cycle.

Figure reproduced with permission from ref.275, Ann Van Soom.

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Review criteria

An extensive search of studies examining the relationship between intracytoplasmic sperm injection and male infertility was performed using PubMed and MEDLINE. The start and end dates for the search were January 2006 and February 2017, respectively. The overall strategy for study identification and data extraction was based on the following key words: “assisted reproductive technology”, “intracytoplasmic sperm injection”, “male infertility”, “pregnancy outcomes”, and “children”, with the filters “humans” and “English language”. Using the aforementioned criteria, 209 relevant articles were identified. Data that were solely published in conference or meeting proceedings, websites, or books were not included. Citations dated outside the search dates were included only if they provided conceptual content.

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Authors and Affiliations

  1. ANDROFERT, Andrology and Human Reproduction Clinic, Campinas, Brazil

    Sandro C. Esteves

  2. Department of Surgery (Division of Urology), Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, Brazil

    Sandro C. Esteves

  3. Faculty of Health, Aarhus University, Aarhus, Denmark

    Sandro C. Esteves, Thor Haahr & Peter Humaidan

  4. ORIGEN, Center for Reproductive Medicine, Rio de Janeiro, Brazil

    Matheus Roque

  5. Division of Reproductive Medicine, Department of Gynecology and Obstetrics, University of São Paulo (USP), São Paulo, Brazil

    Giuliano Bedoschi

  6. Fertility Clinic, Skive Regional Hospital, Skive, Denmark

    Thor Haahr & Peter Humaidan

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  1. Sandro C. Esteves
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  2. Matheus Roque
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  3. Giuliano Bedoschi
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  4. Thor Haahr
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Contributions

S.C.E. designed the manuscript, helped in data interpretation and coordination, and drafted the manuscript. M.R., G.B., and T.H. participated in the acquisition of data and drafted the manuscript. P.H. helped in data interpretation and coordination and drafted and revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Sandro C. Esteves.

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Esteves, S.C., Roque, M., Bedoschi, G. et al. Intracytoplasmic sperm injection for male infertility and consequences for offspring. Nat Rev Urol 15, 535–562 (2018). https://doi.org/10.1038/s41585-018-0051-8

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