Trends in the Use and Indications for Intracytoplasmic Sperm Injection Between 2005 and 2017: A State‐Wide Descriptive Cohort Analysis
Aleah Kink, Parinaz Mehdipour, Richard J. Hiscock, Beverley J. Vollenhoven, Catharyn J. Stern, Susan P. Walker, Mark P. Green, Tiki Osianlis, Franca Agresta, David Wilkinson, Stephen Tong, Roxanne Hastie, Amber L. Kennedy, Anthea C. Lindquist
TL;DR
This study examines how intracytoplasmic sperm injection (ICSI) was used in Victoria, Australia, from 2005 to 2017, finding a significant increase in its use beyond cases where it was medically necessary.
Contribution
The study provides new insights into the growing use of ICSI for non-essential indications in an Australian context.
Findings
ICSI use increased from 60.6% in 2005 to 79.5% in 2017.
Most ICSI cycles after 2008 were classified as 'unspecified' and not medically indicated.
Indications like donor sperm and pre-implantation genetic testing increased over time.
Abstract
Intracytoplasmic sperm injection (ICSI) was first developed to overcome male factor infertility. ICSI has increased in uptake globally, including in cases where its use is non‐essential for fertilisation. To identify temporal trends in the use of, and indications for ICSI in an Australian context. A statewide descriptive cohort study examining the trends in ICSI uptake and reported indication/s for ICSI use. The cohort included women undergoing IVF between 2005 and 2017 at IVF clinics across Victoria, Australia that resulted in a birth after 20 weeks' gestation. The dataset comprised 32 102 assisted reproduction cycles: 22 873 (71.3%) ICSI and 9229 (28.7%) conventional IVF. In 2005, ICSI accounted for 60.6% (1182/1952) of cycles, increasing to 79.5% (2344/2947) by 2017 (p trend < 0.001). Testicular sperm retrieval as an indication for ICSI remained consistent over time (p trend =…
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FIGURE 1
FIGURE 2
FIGURE 3| Demographics | IVF, | ICSI, | Total, |
|---|---|---|---|
|
|
|
| |
|
| |||
| Median (IQR) | 34.6 (31.7–37.3) | 34.8 (31.7–37.9) | 34.7 (31.7–37.8) |
| < 25 years | 53 (0.6) | 269 (1.2) | 322 (1.0) |
| 25–29 years | 934 (10.1) | 2621 (11.5) | 3555 (11.1) |
| 30–34 years | 2987 (32.4) | 7547 (33.0) | 10 534 (32.8) |
| 35–39 years | 2676 (29.0) | 7307 (31.9) | 9983 (31.1) |
| ≥ 40 years | 664 (7.2) | 2475 (10.8) | 3139 (9.8) |
| Missing | 1915 (20.7) | 2654 (11.6) | 4569 (14.2) |
|
| |||
| Male | 7339 (79.5) | 18 875 (82.5) | 26 214 (81.7) |
| Female | 8 (0.1) | 694 (3.0) | 702 (2.2) |
| Missing or no partner | 1882 (20.4) | 3304 (14.4) | 5186 (16.2) |
|
| |||
| Oceania and Antarctica | 1017 (11.0) | 4584 (20.0) | 5601 (17.4) |
| North‐West Europe | 80 (0.9) | 283 (1.2) | 363 (1.1) |
| Southern and Eastern Europe | 39 (0.4) | 147 (0.6) | 186 (0.6) |
| North Africa and the Middle East | 13 (0.1) | 77 (0.3) | 90 (0.3) |
| South‐East Asia | 79 (0.9) | 292 (1.3) | 371 (1.2) |
| North‐East Asia | 86 (0.9) | 263 (1.1) | 349 (1.1) |
| Southern and Central Asia | 124 (1.3) | 366 (1.6) | 490 (1.5) |
| Americas | 26 (0.3) | 83 (0.4) | 109 (0.3) |
| Sub‐Saharan Africa | 26 (0.3) | 90 (0.4) | 116 (0.4) |
| Missing | 7739 (83.9) | 16 688 (73.0) | 24 427 (76.1) |
|
| |||
| 0 | 2005 (21.7) | 5886 (25.7) | 7891 (24.6) |
| 1 | 1419 (15.4) | 4068 (17.8) | 5487 (17.1) |
| 2 | 596 (6.5) | 1600 (7.0) | 2196 (6.8) |
| ≥ 3 | 515 (5.6) | 1169 (5.1) | 1684 (5.2) |
| Missing | 4694 (50.9) | 10 150 (44.4) | 14 844 (46.2) |
|
| |||
| 0 | 5251 (56.9) | 14 448 (63.2) | 19 699 (61.4) |
| 1 | 1861 (20.2) | 5287 (23.1) | 7148 (22.3) |
| 2 | 167 (1.8) | 465 (2.0) | 632 (2.0) |
| ≥ 3 | 54 (0.6) | 154 (0.7) | 208 (0.6) |
| Missing | 1896 (20.5) | 2519 (11.0) | 4415 (13.8) |
|
| |||
| 0 | 4180 (45.3) | 11 101 (48.5) | 15 281 (47.6) |
| 1 | 436 (4.7) | 1566 (6.8) | 2002 (6.2) |
| 2 | 69 (0.7) | 251 (1.1) | 320 (1.0) |
| ≥ 3 | 14 (0.2) | 80 (0.3) | 94 (0.3) |
| Missing | 4530 (49.1) | 9875 (43.2) | 14 405 (44.9) |
|
| |||
| 0 | 1791 (19.4) | 3293 (14.4) | 5084 (15.8) |
| 1 | 3621 (39.2) | 8094 (35.4) | 11 715 (36.5) |
| 2 | 1006 (11.0) | 3997 (17.5) | 5003 (15.6) |
| ≥ 3 | 759 (8.2) | 4720 (20.6) | 5479 (17.1) |
| Missing | 2052 (22.2) | 2769 (12.1) | 4821 (15.0) |
- —Ferring10.13039/501100003122
- —National Health and Medical Research Council10.13039/501100000925
- —Mercy Foundation10.13039/501100016055
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Taxonomy
TopicsSperm and Testicular Function · Ovarian function and disorders · Reproductive Health and Technologies
Introduction
1
Intracytoplasmic sperm injection (ICSI) is an assisted reproductive technology, first introduced clinically in 1992 [1]. ICSI involves retrieval of sperm from an ejaculated or surgically obtained sample; a single spermatozoon is then injected directly into the cytoplasm of a mature oocyte during an in vitro fertilisation (IVF) cycle [2].
ICSI was developed to overcome male factor infertility, or fertilisation failure during conventional IVF [3]. It is now used in the context of thawed oocytes, where the vitrification and thawing process results in hardening of the zona pellucida, impeding the natural sperm penetration required in conventional IVF [4]. However, ICSI is increasingly used for indications where the evidence is less clear—low oocyte count (≤ 6) [5], pre‐implantation genetic testing for aneuploidy (PGT‐A) [6], oocytes that have undergone in vitro maturation (IVM) [7], unexplained infertility [8], poor quality oocytes [9], advanced maternal age (≥ 40 years old) [10], use of donor sperm and in human immunodeficiency virus (HIV) or hepatitis discordant couples [11].
In the absence of male factor infertility, evidence is limited to support the use of ICSI in improving fertilisation rate, embryo quality and number, implantation success or live birth rate [12, 13, 14, 15, 16, 17] and may increase the risk of birth defects when compared with conventional IVF [18]. Nevertheless, there continues to be an increase in the global number of assisted reproduction cycles [19], with a surge in the uptake of ICSI for non‐male factor infertility [20]. Some fertility centres now use ICSI in all IVF cycles [12].
There are limited studies examining trends in use and indications for ICSI. Should ICSI be associated with adverse childhood outcomes, then understanding both the magnitude and indications for use of ICSI is critical. Evidence of increased use of ICSI for non‐essential indications would support the need for further research into pregnancy, birth and childhood outcomes following ICSI conception compared with conventional IVF. Utilising a large Victorian cohort, our study aimed to examine the temporal trends in use and indications for ICSI between 2005 and 2017.
Materials and Methods
2
We performed a descriptive cohort study of all assisted reproduction cycles initiated between 2005 and 2017 from the three major IVF providers in Victoria during the study era: Melbourne IVF, Monash IVF and City Fertility Centre. Reported indications for the use of ICSI over conventional IVF were examined.
The study population included all ICSI or conventional IVF cycles occurring between 2005 and 2017 that resulted in a birth after 20 weeks' gestation (inclusive of multiple births, congenital anomalies, terminations and stillbirths). We excluded cycles if the cycle year or fertilisation method could not be determined, and cycles where half the oocytes were inseminated via ICSI, and the other half via conventional IVF. The dataset included patient demographics, cycle characteristics, embryo quality, pregnancy and birth outcomes.
Demographic data were extracted for patient age, region of birth, gravidity, parity, partner gender, number of miscarriages and number of prior IVF stimulation cycles. As the IVF databases did not define specific indications for ICSI or conventional IVF cycles, indication data were indirectly assessed by collating information from free text fields and other relevant variables (sperm collection method, sperm source, semen parameters and oocyte yield), with final indications determined by expert consensus. Where more than one indication for ICSI was reported, a single ‘most applicable’ indication was applied as per the following hierarchical order: testicular sperm retrieval, male factor infertility, vitrified oocyte thaw cycle, donor sperm, female factors associated with poor IVF outcomes, advanced maternal age (≥ 40 years old), pre‐implantation genetic testing, ‘unexplained subfertility’ and ‘unspecified’ [9]. Clear indications for ICSI were considered those in which ICSI is essential for fertilisation such as in male factor fertility and testicular sperm retrieval. There is also evidence supporting ICSI use for vitrified oocyte thaw cycles and previous fertilisation failure with conventional IVF [3, 4]. Less clear indications were considered those where ICSI is not definitively required for successful fertilisation such as cases of donor sperm, female factors associated with poor IVF outcomes, advanced maternal age (≥ 40 years old), pre‐implantation genetic testing, ‘unexplained subfertility’ and ‘unspecified’.
Male factor infertility included pre‐diagnosis of oligoasthenoteratozoospermia, total motile sperm count < 2 × 10^6^ post sperm preparation on the day of a planned IVF cycle, and other causes of male infertility such as sperm antibodies, chromosomal defects, and not otherwise specified. Testicular sperm retrieval assumed open or needle biopsy sperm retrieval. Female factors associated with poor IVF outcomes included previous failed conventional IVF cycle/s, poor ovarian response [21], low oocyte count (≤ 6), premature or occult ovarian failure, oncological fertility preservation, or post‐menopause. Pre‐implantation genetic testing included cycles where either genetic testing was planned or did occur. ‘Unspecified’ indication included cycles where an appropriate indication was not evident from the available data, including general indications for assisted reproduction, but not for ICSI such as tubal defects, polycystic ovaries, ovulation defects, endometriosis, genetic disorders, uterine polyps and/or fibroids.
Due to data collection and recording differences between the IVF labs, there was inconsistency in the availability of extracted data. Data were missing for some demographic variables, as well as those used to determine ICSI indication. The proportion of missing demographic data were examined.
Descriptive statistics were calculated, with frequency and proportion reported for all categorical variables. Analysis of variance was used to assess trends over time for categorical variables. The median and interquartile range were reported for continuous variables with a normal distribution. Baseline patient characteristics were provided for different cycle types. Pearson chi‐square tests were used to compare characteristics between ICSI and conventional IVF cohorts and between cohort years 2005 and 2017. Results are presented as % difference, with associated 95% confidence limits and p‐values.
Statistical analyses were conducted in Stata/BE (Version 18.0, College Station, TX, USA). All figures were constructed with GraphPad Prism (Version 10.0.1 (170)) and Microsoft PowerPoint (Version 16.75).
Informed consent was not required due to the retrospective nature of the study; all patient data were de‐identified, and a waiver of consent was provided by the Human Research Ethics Committee. Ethical approval for the creation of the dataset was obtained from the Mercy Health, Monash Health and Melbourne IVF Health Human Research Ethics Committees [22]. Amended ethical approval, specific to this study, was granted by the Mercy Health Human Research Ethics Committee (2018‐017).
Results
3
Our cohort included 36 931 assisted reproduction cycles. 4829 cycles were excluded as they were an ovulation induction or intrauterine insemination cycle (n = 1595), fertilisation method or cycle year could not be determined due to missing data (n = 782), or the cycle year was not between 2005 and 2017 (n = 2452) (Figure 1). The remaining 32 102 cycles included 22 873 (71.3%) ICSI and 9229 (28.7%) conventional IVF cycles.
Study inclusion flow‐chart. ART, assisted reproductive technology; ICSI, intracytoplasmic sperm injection; IUI, intrauterine insemination; IVF, in vitro fertilisation; OI, ovulation induction.
The median age among the overall study cohort was 34.7 years (interquartile range: 31.7–37.8; range: 20–53 years) (Table 1). Patient age data were missing for 14.2% (n = 4569).
Among the study cohort, 81.7% of patients (n = 26 214) had a male partner at the time of the cycle. Among same‐sex couples, 98.9% (694/702) underwent ICSI, with 1.1% (8/702) undergoing conventional IVF.
There was a high proportion of data missing for gravidity (46.2%, n = 14 844), parity (13.8%, n = 4415) and miscarriage (44.9%, n = 14 405). Based on available data, most patients were nulliparous (61.4%, n = 19 699) and 7.5% (n = 2416) of the total cohort had a documented previous miscarriage.
Patients undergoing an ICSI cycle had a significantly higher number of prior conventional IVF stimulation cycles, with 20.6% (4720/22 873) of ICSI patients having had three or more prior cycles compared with 8.2% (759/9229) of conventional IVF cycle patients.
There was a significant change in the proportion of ICSI cycles compared to conventional IVF cycles between 2005 and 2017 (Figure 2, Table S1). In 2005, ICSI accounted for 60.6% (1182/1952) of total cycles which increased to 79.5% (2344/2947) by 2017 (difference 18.9% (95% CI: 16.4–21.6), p trend < 0.001) (Figure S1). The proportion of conventional IVF cycles peaked in 2008, at 40.1% (963/2404). In 2009, there was a notable reduction in the total number of cycles. However, after this period, the proportion of ICSI cycles increased with each year, and the number of conventional IVF cycles decreased.
Line chart displaying annual number of conventional IVF, ICSI and total cycles, 2005–2017. IVF, in vitro fertilisation; ICSI, intracytoplasmic sperm injection.
Testicular sperm retrieval, a universal indication for ICSI, remained consistent over time, accounting for 7.9% (93/1182) of cycles in 2005, and 6.7% (156/2344) by 2017 (p trend = 0.15, difference −1.2% (95% CI: −3.0 to 0.6)) (Figure 3, Table S2, Figure S2). Male factor infertility was the primary reported indication for ICSI prior to 2008 but decreased over time (p trend = 0.007). The number of cycles with an ‘unspecified’ indication increased over time (p trend = 0.015), accounting for up to 45.9% (710/1548) of cycles by 2010.
Stacked area chart displaying the proportion of ICSI cycles, stratified by indication for ICSI, 2005–2017. ICSI, intracytoplasmic sperm injection; IVF, in vitro fertilisation. Testicular sperm retrieval: p trend = 0.15; male factor infertility: p trend = 0.007; vitrified oocyte thaw cycle: p trend = 0.016; donor sperm: p trend = 0.001; female factors associated with poor IVF outcomes: p trend = 0.005; advanced maternal age: p trend = 0.005; pre‐implantation genetic testing: p trend = 0.004; unexplained subfertility: p trend = 0.30, unspecified: p trend = 0.015.
The number of vitrified oocyte thaw cycles, as an indication for ICSI, did not surpass 1.7% (39/2293) of total cycles in any calendar year (p trend = 0.016). Cycles where the diagnosis was recorded as ‘unexplained subfertility’, accounted for no more than 0.4% (9/2048) of cycles in any given year (p trend = 0.30). The use of donor sperm as an indication for ICSI increased significantly during the study period, accounting for 3.6% (42/1182) of cycles in 2005, and 10.9% (255/2344) of cycles by 2017 (p trend = 0.001, difference 7.3% (95% CI: 5.7–9.0)).
Female factors associated with poor IVF outcomes increased significantly as an indication for ICSI during the study period (p trend = 0.005), as did advanced maternal age (p trend = 0.005). Pre‐implantation genetic testing as an indication for ICSI rose from 0.9% (14/1548) of cycles in 2010 to 14.7% (344/2344) of cycles by 2017 (p trend = 0.004, difference 13.8% (95% CI: 12.2–15.3)).
Discussion
4
Our large Australian study examines the temporal changes in utilisation and indications for ICSI in Victoria between 2005 and 2017. Our findings suggest an increase in uptake of ICSI over conventional IVF with each year, such that the uptake of ICSI now outweighs conventional IVF. In 2005, ICSI accounted for 60.6% of cycles, increasing to 79.5% by 2017. Testicular sperm retrieval as an indication for ICSI remained consistent over time. However, the use of ICSI in the absence of clear, reported indications has increased since 2009, now accounting for the majority of ICSI cycles. This reflects international trends which show a continued increase in utilisation of ICSI, with the largest relative increase in non‐male factor infertility as an indication [12, 20].
We observed a marked reduction in the overall number of assisted reproduction cycles (ICSI and conventional IVF) in 2009, with the number of cycles only returning to pre‐2009 rates by 2012. It is likely that this occurred due to a variety of socio‐economic factors, including the 2008 Global Financial Crisis, which caused a four‐year plateau in the use of fertility treatment in the United States [23], local Medicare funding concerns, legislative changes and an international shortage of cycle reagent.
Our findings suggest a growing preference for empiric use of ICSI over conventional IVF. In each calendar year of our study, there was no clear indication reported for the use of ICSI for at least 34.0% of ICSI cycles. Alongside the increased proportion of non‐male factor indications for ICSI, the increase in non‐indicated ICSI is in keeping with the findings of a 2015 study that assessed indications for, and uptake of, ICSI in the American setting [12]. It is possible in some settings that this preference is driven by financial incentives [24] although this is not currently the case in Australia.
Although testicular sperm retrieval as an indication for ICSI remained stable over time, male factor infertility as an indication declined, which may reflect changes in the determination of semen parameters and data reporting, in which fewer males met the criteria for male factor infertility [25]. Donor sperm as an indication for ICSI increased over time, as access to fertility treatment improved for same‐sex couples and single women. IVF only became available to these patients in Victoria from the early 2000s onward. Parameters relating to donor sperm quality which may necessitate the need for ICSI as opposed to IVF in this setting were not available from existing datasets.
With more women seeking fertility preservation through oocyte vitrification, it was important that our study was able to examine vitrified oocyte thaw cycles as an indication for ICSI [26]. Vitrified oocyte cycles were first available in Victoria from 2008 and have since increased dramatically in their uptake [27]. Given that a vitrified oocyte thaw cycle is an absolute indication for ICSI, it is likely that the use of ICSI over conventional IVF has continued to rise in response to the increase in oocyte vitrification. The impact of these changes requires ongoing examination.
ICSI utilisation has increased in Australia, despite some evidence that ICSI entails an increased risk of birth defects [18] and autism [28], when compared with conventional IVF.
Recent studies have indicated that IVF and spontaneously conceived children have equivalent school‐age development and education outcomes [22]. Comparable studies examining the childhood impact of ICSI are very limited. While recent data suggest that ICSI and IVF conceived children have equivalent early developmental outcomes [29], the long‐term childhood impacts need to be stringently evaluated, given the increasing use of ICSI in non‐essential cases.
Our study is strengthened by the use of state‐wide data, derived from the three major fertility providers in Victoria, which allowed for a detailed examination of statewide trends. Unlike other comparable publications, our ability to examine several indications for the use of ICSI among the study cohort, including vitrified oocyte thaw cycles and donor sperm, is novel [12].
Consistent with other observational studies, we found that a lack of data completeness hampered our analysis. There are no standardised templates for assessing indications for ICSI, and uptake relies heavily on individual clinician discretion. Coupled with a lack of standardised reporting among different IVF facilities and inconsistent recording of subfertility diagnoses, the indication for ICSI had to be indirectly assessed in some cases using multiple variables and free‐text fields. Absolute indications such as surgically acquired sperm, severe male factor infertility, and vitrified oocyte thaw cycles were expected to be accurately recorded. However, the absence of individual semen analysis results, and a lack of consistency across IVF laboratories globally in the diagnosis of ‘abnormal semen parameters’ limited our ability to stratify male factor infertility indications into categories such as oligoasthenoteratozoospermia and total motile sperm count < 2 × 10^6^. Unexplained subfertility accounted for up to 0.4% of ICSI cases per year, far less than the estimated 15%–30% [30] and likely reflects incomplete data entry. Improved data collection and reporting standards may have reduced the proportion of cycles with an ‘unspecified’ indication.
Our study population included only assisted reproduction cycles which resulted in a birth after 20 weeks' gestation since there are no Victorian statewide data documenting early pregnancy loss, including ectopic pregnancy and miscarriage—factors that may influence overall rates of ICSI uptake. All IVF research would benefit from the examination of every assisted reproduction cycle, and all pregnancy outcomes—information that is not currently universally recorded.
In summary, between 2005 and 2017, there was an 18.9% increase in the proportion of assisted reproduction conceptions using ICSI over conventional IVF in Victoria. Despite the possible risk of adverse reproductive outcomes and congenital abnormalities, there was an increase in the non‐essential use of ICSI for non‐male factor infertility during the study period. Further research is warranted to examine pregnancy, birth and long‐term childhood outcomes for children conceived via ICSI in both an Australian and global setting.
Conflicts of Interest
The authors of this manuscript have the following competing interests: B.J.V. has a paid role as a member of the Therapeutic Goods Administration. B.J.V., F.A. and C.J.S. own shares in respective IVF companies (Monash IVF, Virtus Health and Melbourne IVF).
Supporting information
Appendix S1: ajo70070‐sup‐0001‐AppendixS1.docx.
The reference list from the paper itself. Each links out to its DOI / PubMed record.
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