Conventional in-vitro fertilisation versus intracytoplasmic sperm injection for the treatment of non-male-factor infertility: a randomised controlled trial

doi:10.1016/S0140-6736(00)05179-5

The Lancet

Volume 357, Issue 9274, 30 June 2001, Pages 2075-2079

https://doi.org/10.1016/S0140-6736(00)05179-5 Get rights and content

Summary

Background

Intracytoplasmic sperm injection (ICSI) is a more invasive option than conventional in-vitro fertilisation (IVF), which can be successful even when semen characteristics are poor. Reports of higher fertilisation rates after ICSI suggest that this technique may be better than the conventional method for all couples seeking IVF. We undertook a multicentre randomised controlled trial comparing clinical outcome after ICSI or traditional IVF in couples with non-male-factor infertility.

Methods

415 eligible and consenting couples at four UK centres were randomly assigned IVF or ICSI (total 435 treatment cycles: IVF 224; ICSI 211). Usual clinical and laboratory protocols for the two treatment procedures were followed in each of four participating centres. The primary outcome was the implantation rate (number of gestation sacs per embryo replaced expressed as a percentage). Secondary outcomes were pregnancy and fertilisation rates associated with each treatment. Analyses were by intention to treat.

Findings

The implantation rate was higher in the IVF group than in the ICSI group (95/318 [30%] vs 72/325 [22%]; relative risk 1·35 [95% CI 1·04–1·76]). The pregnancy rate per cycle was also higher after IVF (72 [33%] vs 53 [26%]; 1·17 [0·97–1·35]). Mean associated laboratory time was significantly shorter with IVF than with ICSI (22·9 [SD 12·1] vs 74·0 [38·1] min; 95% CI for difference 45·6–56·6).

Interpretation

ICSI offers no advantage over IVF in terms of clinical outcome in cases of non-male-factor infertility. Our results support the current practice of reserving ICSI only for severe male-factor problems.

Introduction

Originally used in women with tubal damage, in-vitro fertilisation (IVF) is now acknowledged to be an effective treatment for long-term subfertility of other causes. However, the limited success in couples with very poor semen quality encouraged the development of intracytoplasmic sperm injection (ICSI),¹ a technique that involves microinjection of spermatozoa into mature oocytes. ICSI has the potential to overcome possible fertilisation problems when semen characteristics are poor or when fertilisation rates in previous IVF cycles have been low. Uncontrolled data suggest that the rate of embryo implantation associated with ICSI (16–26%)2, 3, 4 is higher than that associated with IVF (9–12%).5, 6, 7 Although this difference could be ascribed to higher fertility in otherwise healthy partners of infertile men,⁸ the possibility that ICSI-derived embryos are of better quality and have superior implantation potential cannot be ruled out. Reports of high implantation and livebirth rates after the more invasive technique have lowered the threshold for ICSI. In fact, Fishel and colleagues suggested that ICSI rather than conventional IVF should be considered the treatment of choice in all cases requiring assisted reproduction.⁸ Given the complex and more invasive nature of ICSI, adoption of such a policy would have wide implications for the future of IVF, with a major effect on use of resources and safety.⁹ Previous studies comparing IVF and ICSI have had inconsistent results. Most of the published trials8, 10, 11, 12, 13, 14, 15 compared the effect of IVF and ICSI on sibling oocytes, and therefore comment on clinically meaningful outcomes such as implantation or pregnancy rates was not possible. Other randomised studies targeted couples in specific diagnostic categories and had the drawback of small sample sizes.16, 17, 18 A systematic review in 2000¹⁹ concluded that the use of ICSI improved rates of fertilisation but not conception and highlighted the need for future clinical trials of IVF versus ICSI. We report a comparison of IVF and ICSI in cases of non-male-factor infertility in a multicentre pragmatic randomised controlled trial.

Section snippets

Participants

Four UK centres offering both IVF and ICSI took part in the trial. Ethical approval for the study was obtained from the ethics committees of the participating hospitals.

Eligible couples were awaiting IVF for an indication other than severe male-factor infertility. The inclusion criteria were age of the female partner below 37 years²⁰ and minimum acceptable semen characteristics, including sperm density of 20 million/mL, progressive motility 40%, and acceptable morphology (as defined by local

Results

415 couples were randomly assigned a total of 435 treatment cycles (figure). 20 couples were recruited to the trial for a second time after failure to achieve pregnancy with the first cycle of treatment and were rerandomised. Baseline characteristics were similar in the two randomised groups (table 1).

In the IVF group, four women became pregnant spontaneously and 14 withdrew from treatment. Of the 206 cycles started, 186 proceeded to oocyte recovery and 159 to embryo transfer. In the ICSI

Discussion

Our results show that the use of ICSI in couples suitable for conventional IVF treatment does not offer any clinical benefits. Indeed, there may be a marginal disadvantage associated with such an approach. We found a significant difference in implantation rates in favour of IVF, but the clinical relevance of this statistical finding can be questioned. In particular, this analysis was not adjusted for the correlated outcomes resulting from the clustering of embryos transferred to each woman.

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Cited by (259)

Multivariate analyses on male factors and construction of a nomogram for predicting low in vitro fertilization rate
2024, Heliyon
Low fertilization rate (LFR) and total fertilization failure (TFF) are often encountered in routine in vitro fertilization (IVF) procedure. To solve this problem, multivariate analyses on the relationship between male factors and in vitro fertilization rate were performed, and a nomogram for prediction of LFR was constructed. This retrospective study contained 2011 couples who received IVF treatment from January 2017 to December 2021. Man factors and in vitro fertilization rate were collected. Among these couples, 1347 cases had in vitro fertilization rates ≥30 % (control group), and 664 cases had in vitro fertilization rates <30 % (LFR group). Univariate analyses of male factors found that between the two groups there were significant differences (p < 0.05) in sperm progressive motility (SPR), sperm concentration (SC), total sperm number, normal sperm morphology rate (NSMR), DNA fragmentation index (DFI), sperm acrosin activity (SAA) and the clinical diagnosis of primary or secondary infertility. Multivariate logistic regression analyses showed that SPR, SAA, and SC were independent risk factors for LFR. An algorithm and a correspondent nomogram for predicting high LFR risk were constructed using data from the training cohort. The LFR nomogram exhibited an excellent discrimination power and a high fitting degree in both the training cohort (AUC = 0.90, 95 % CI: 0.88–0.92), (H-L: x² = 5.43, p = 0.71) and validation cohort (AUC = 0.89, 95 % CI:0.87–0.92), (H-L: x² = 7.85, p = 0.45), respectively. The decision curve analysis (DCA) demonstrated a high efficiency of the LFR nomogram for clinical utility. SPR, SAA, and SC are independent risk factors for LFR. The LFR nomogram established based on these factors could be a useful tool to predict high risk of LFR, and patients with high risk of LFR can be guided to direct ICSI procedure. Clinical application of the LFR nomogram may increase the in vitro fertilization rate by facilitating the decision making in IVF service.
Intracytoplasmic sperm injection versus conventional in-vitro fertilisation for couples with infertility with non-severe male factor: a multicentre, open-label, randomised controlled trial
2024, The Lancet
Introduced in 1992, intracytoplasmic sperm injection (ICSI) was initially indicated for severe male infertility; however, its use has since been expanded to non-severe male infertility. We aimed to compare the efficacy and safety of ICSI versus conventional in-vitro fertilisation (IVF) in couples with infertility with non-severe male factor.
We conducted an investigator-initiated, multicentre, open-label, randomised controlled trial in ten reproductive medicine centres across China. Couples with infertility with non-severe male factor without a history of poor fertilisation were randomly assigned (1:1) to undergo either ICSI or conventional IVF. The primary outcome was live birth after first embryo transfer. We performed the primary analysis in the intention-to-treat population using log-binomial regression models for categorical outcomes or linear regression models for continuous outcomes, adjusting for centre. This trial is registered with Clinicaltrials.gov, NCT03298633, and is completed.
Between April 4, 2018, and Nov 15, 2021, 3879 couples were screened, of whom 2387 (61·5%) couples were randomly assigned (1184 [49·6%] to the ICSI group and 1203 [50·4%] to the conventional IVF group). After excluding couples who were ineligible, randomised twice, or withdrew consent, 1154 (97·5%) in the ICSI group and 1175 (97·7%) in the conventional IVF group were included in the primary analysis. Live birth after first embryo transfer occurred in 390 (33·8%) couples in the ICSI group and in 430 (36·6%) couples in the conventional IVF group (adjusted risk ratio [RR] 0·92 [95% CI 0·83–1·03]; p=0·16). Two (0·2%) neonatal deaths were reported in the ICSI group and one (0·1%) in the conventional IVF group.
In couples with infertility with non-severe male factor, ICSI did not improve live birth rate compared with conventional IVF. Given that ICSI is an invasive procedure associated with additional costs and potential increased risks to offspring health, routine use is not recommended in this population.
National Natural Science Foundation of China, National Key Research and Development Program, Beijing Municipal Science & Technology Commission, and Peking University Third Hospital.
Comparing reproductive outcomes between conventional in vitro fertilization and nonindicated intracytoplasmic sperm injection in autologous embryo transfer cycles: a Society for Assisted Reproductive Technology Clinic Outcome Reporting System Study
2024, F and S Reports
To compare clinical outcomes between nonindicated intracytoplasmic sperm injection (ICSI) and conventional insemination.
Autologous cycles performed from 2014–2017 were identified, excluding frozen oocyte cycles. Outcomes were compared between conventional insemination (in vitro fertilization [IVF]) and nonindiated ICSI and analyzed separately for fresh, frozen-thawed preimplantation genetic testing (PGT) and frozen-thawed non-PGT cycles.
US-based fertility clinics reporting to the Society for Assisted Reproductive Technology.
A total of 187,520 patients underwent 318,930 cycles, 57,516 (18.0%) using conventional IVF and 261,414 ICSI (82.0%).
Intracytoplasmic sperm injection, with or without indications (male factor, prior fertilization failure or any PGT [2012 recommendations]/single-gene PGT [2020 recommendations]).
Odds ratios (ORs) for live birth rates and clinical pregnancy rates were calculated after multivariable adjustment for maternal age, body mass index, infertility etiologies, prior IVF births, and number oocytes retrieved.
Intracytoplasmic sperm injection was indicated in 151,627 (58.0%) of cycles according to 2012 American Society for Reproductive Medicine Practice Committee recommendations, and 108,895 (41.7%) according to 2020 recommendations. In multivariable models, nonindicated ICSI among fresh cycles was associated with reduced odds of completing a blastocyst-stage transfer (OR, 0.72; 95% confidence interval [CI] [0.7, 0.75]; P<.001), resulting in reduced odds of live birth (OR, 0.80; 95% CI [0.78, 0.83]; P<.001). Among completed fresh transfers, clinical pregnancy and live birth rates were comparable between nonindicated ICSI and IVF. Nonindicated ICSI in frozen-thawed cycles with PGT and without PGT was associated with comparable live birth and clinical pregnancy rates with IVF in multivariable models.
Nonindicated ICSI was associated with reduced blastocyst availability in fresh cycles compared with IVF, leading to lower live birth rates. Outcomes from completed transfers were clinically comparable.
Risk of congenital malformations in live-born singletons conceived after intracytoplasmic sperm injection: a Nordic study from the CoNARTaS group
2023, Fertility and Sterility
To investigate whether the risk of major congenital malformations is higher in live-born singletons conceived with intracytoplasmic sperm injection (ICSI) compared with in vitro fertilization (IVF)?
Nordic register-based cohort study.
Cross-linked data from Medical Birth Registers and National ART and Patient Registers in Denmark, Norway and Sweden. Data were included from the year the first child conceived using ICSI was born: Sweden, 1992; Denmark, 1994; and Norway, 1996. Data were included until 2014 for Denmark and 2015 for Norway and Sweden.
All live-born singletons conceived using fresh ICSI (n = 32,484); fresh IVF (n = 47,178); without medical assistance (n = 4,804,844); and cryo-ICSI (n = 7,200) during the study period.
Different in vitro conception methods, and cryopreservation of embryos.
Risk of major congenital malformations on the basis of International Classification of Diseases codes. The European Concerted Action on Congenital Anomalies and Twins was used to differentiate between major and minor malformations.
Among singletons conceived using fresh ICSI, 6.0% had a major malformation, compared with 5.3% of children conceived using fresh IVF; 4.2% of children conceived without medical assistance; and 4.9% of children conceived using cryo-ICSI; adjusted odds ratio (AOR) 1.07 (95% confidence interval [CI] 1.01–1.14) in ICSI vs. IVF; and AOR 1.28 (95% CI, 1.23–1.35) in ICSI vs. no medical assistance; and AOR 1.11 (95% CI, 0.99–1.26) in ICSI fresh vs. cryo-ICSI. When malformations were grouped by different organ systems, children conceived using ICSI had a higher risk of respiratory and chromosomal malformations compared with children conceived using IVF, but there were very few cases in each group. When categorizing children conceived using ICSI according to treatment indication (male factor infertility only vs. other indications), we found a higher risk of hypospadias when ICSI was performed because of male factor infertility only (AOR 1.85 [95% CI 1.03–332]). The indications for ICSI changed over time, as male factor infertility did not remain the primary indication for ICSI throughout the study period.
In this large cohort study, we found the risk of major malformations in live-born singletons to be slightly higher after fresh ICSI compared with fresh IVF. These findings should be considered when choosing the assisted reproductive technology method for couples without male factor infertility.
Riesgo de malformaciones congénitas en hijos únicos nacidos vivos concebidos después de una inyección intracitoplasmática de espermatozoides: un estudio nórdico del grupo CoNARTaS
Investigar si el riesgo de malformaciones congénitas mayores es mayor en bebés únicos nacidos vivos concebidos con inyección intracitoplasmática de espermatozoides (ICSI) en comparación con fertilización in vitro (FIV).
Estudio de cohorte nórdico basado en datos de registros de Dinamarca, Noruega y Suecia. Se incluyeron datos del año en que nació el primer niño concebido mediante ICSI: Suecia, 1992; Dinamarca, 1994; y Noruega, 1996. Se incluyeron datos hasta 2014 para Dinamarca y 2015 para Noruega y Suecia.
Todos los hijos únicos nacidos vivos concebidos mediante ICSI en fresco (n = 32.484); FIV en fresco (n = 47.178); sin asistencia médica (n = 4.804.844); y crio-ICSI (n = 7200) durante el período de estudio.
Diferentes métodos de Concepción in vitro, y criopreservacion de embriones.
Riesgo de malformaciones congénitas importantes según los códigos de la Clasificación Internacional de Enfermedades. Para diferenciar entre malformaciones mayores y menores se utilizó la Acción Concertada Europea sobre Anomalías Congénitas y Gemelos.
Entre los fetos únicos concebidos mediante ICSI fresco, el 6,0 % tuvo una malformación mayor, en comparación con el 5,3 % de los niños concebidos mediante FIV fresco; el 4,2% de los niños concebidos sin asistencia médica; y el 4,9% de los niños concebidos mediante crio-ICSI; odds ratio ajustado (AOR) 1,07 (intervalo de confianza [IC] del 95 %: 1,01–1,14) en ICSI frente a FIV; y AOR 1,28 (IC 95 %, 1,23–1,35) en ICSI versus ninguna asistencia médica; y AOR 1,11 (IC 95 %, 0,99–1,26) en ICSI fresco versus crio-ICSI. Cuando las malformaciones se agruparon por diferentes sistemas de órganos, los niños concebidos mediante ICSI tenían un mayor riesgo de malformaciones respiratorias y cromosómicas en comparación con los niños concebidos mediante FIV, pero hubo muy pocos casos en cada grupo. Al clasificar a los niños concebidos mediante ICSI según la indicación del tratamiento (infertilidad por factor masculino únicamente frente a otras indicaciones), encontramos un mayor riesgo de hipospadias cuando se realizó ICSI debido a infertilidad por factor masculino únicamente (AOR 1,85 [IC 95% 1,03–332]) Las indicaciones de ICSI cambiaron con el tiempo, ya que la infertilidad por factor masculino no siguió siendo la indicación principal de ICSI durante todo el período del estudio.
En este gran estudio de cohorte, encontramos que el riesgo de malformaciones mayores en bebés únicos nacidos vivos es ligeramente mayor después de un ICSI en fresco en comparación con una FIV en fresco. Estos hallazgos deben considerarse al elegir el método de tecnología de reproducción asistida para parejas con infertilidad sin factor masculino.
Intracytoplasmic sperm injection does not improve the outcome of IVF treatments in patients with advanced maternal age or low oocyte number: A randomized controlled trial
2023, Journal of Gynecology Obstetrics and Human Reproduction
Intracytoplasmic sperm injection (ICSI) was introduced to achieve fertilization in cases of severe male factor infertility. However, ICSI is often used in cases of non-male factor infertility, such as advanced maternal age or low oocyte number, but the clinical benefit of the method in these indications has not been proven.
A prospective randomized study was conducted in a university clinic between 2018 and 2020. Patients with ≥40 years of age and/or ≤4 oocytes with non-sever male factor infertility were randomized into conventional IVF or ICSI groups. Fertilization rate, embryo quality, implantation, clinical pregnancy and live birth rates were compared.
A total of 336 IVF cycles (169 conventional IVF and 167 ICSI) were involved in the study. The fertilization rate was higher in the conventional IVF group compared to the ICSI group (IVF: 61.7%, ICSI: 53.4%, P=0.001). Embryo development and morphology did not show considerable difference between groups. Implantation, clinical pregnancy and live birth rate were 13.1%, 24.3% and 11.4% in the conventional IVF and 10.4%, 19.0%, 12.0% in the ICSI group. The differences were not significant. Subgroup analysis showed a significantly better clinical outcome following conventional IVF when advanced maternal age was accompanied by low oocyte number (Implantation: 11.7% vs 2.6%, P=0.027; Clinical pregnancy: 18.5% vs 4%, P=0.020).
A significantly higher fertilization rate, a tendency for higher clinical pregnancy rate was found in conventional IVF treatments compared to ICSI. When advanced maternal age was associated with low oocyte number, ICSI resulted in a substantially lower chance of fertilization and clinical pregnancy. These data suggest that ICSI offers no advantage over conventional IVF in terms of fertilization, embryo quality, implantation and pregnancy rates for couples with advanced maternal age or with low oocyte number.
Alternatives to in vitro fertilization
2023, Fertility and Sterility
There have been concerns on the potential overuse of in vitro fertilization (IVF) in view of the lack of evidence on effectiveness in certain populations, potential short and long-term safety risks, and economic considerations. On the other hand, the use of alternatives to IVF seems to be underappreciated in clinical practice as well as research. In this review, we summarized the up-to-date evidence on the effectiveness, safety as well as cost-effectiveness of different alternatives to IVF, including expectant management, intrauterine insemination, tubal flushing, in vitro maturation as well as intravaginal culture. We also discussed the trend of IVF use over the last decade and the available tiers of service because of intravaginal culture, and revisited the roles of different alternatives to IVF in modern reproductive medicine from both clinical and research perspectives.

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ArticlesConventional in-vitro fertilisation versus intracytoplasmic sperm injection for the treatment of non-male-factor infertility: a randomised controlled trial

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Participants

Results

Discussion

Fertil Steril

Fertil Steril

Fertil Steril

Lancet

Lancet

Pregnancies after intracytoplasmic injection of a single spermatozoon into an oocyte

Lancet

High fertilization and implantation rates after intracytoplasmic sperm injection

Hum Reprod

A model for the incorporation of intracytoplasmic sperm injection into a private practice in vitro fertilization

Fertil Steril

The selection criteria on an IVF programme can remove the association between maternal age and implantation

Acta Obstet Gynecol Scand

High implantation rate and consequently high pregnancy rate by in vitro fertilization–embryo transfer treatment in infertile women with antisperm antibody

Fertil Steril

Intracytoplasmic sperm injection: achievement of high pregnancy rates in couples with severe male factor infertility is dependent primarily upon female and not male factors

Fertil Steril

Should ICSI be the treatment of choice for all cases of in–vitro conception?

Hum Reprod

Comparative follow up study of 130 children born after ICSI and 130 children born after IVF

Hum Reprod

Articles
Conventional in-vitro fertilisation versus intracytoplasmic sperm injection for the treatment of non-male-factor infertility: a randomised controlled trial