Use of ICSI on rise, but are outcomes better?

Results of a retrospective cohort study¹ by investigators from the Centers for Disease Control and Prevention (CDC) and Emory University show that use of intracytoplasmic sperm injection (ICSI) is on the rise but cast doubt on whether the technology is improving reproductive outcomes.

The findings, which were most striking in cases without male-factor infertility, reflect national trends with fresh cycles of in vitro fertilization (IVF) and have sparked significant discussion in the ob/gyn community.

Nearly 1.4 million fresh IVF cycles from 1996 through 2012 were represented in the study, based on data on fresh IVF and ICSI cycles reported to the US National Assisted Reproductive Technology Surveillance System (NASS) from 1996 to 2012. Using linear regression, the authors looked at trends in ICSI use during that period for ICSI in all fresh cycles and those with male factor infertility, unexplained infertility, maternal age 38 years of older, low oocyte yield, and two or more prior assisted reproductive technology (ART) cycles.

Reproductive outcomes for conventional IVF and ICSI from 2008 to 2012 were assessed and the data were stratified by the presence or absence of male-factor infertility.

From 1996 through 2012, ICSI was used in 65.1% of the 1,395,634 fresh IVF cycles and male-factor infertility was reported in 35.8% (499,135) cycles. Among cycles with male-factor infertility, ICSI use increased from 76.3% to 93.3% (P<.001), compared with an increase from 15.4% to 66.9% (P<.001) during that time period. Among the 35.7% of fresh cycles from 2008 to 2012 for which male-factor infertility was reported, the rate of multiple birth was lower than with conventional IVF (30.9% vs 34.2%; adjusted relative risk [RR], 0.87; 95% CI, 0.83-0.91). Among cycles without male-factor infertility, ICSI use was associated with lower rates of implantation (23.0% vs 25.2%; adjusted RR, 0.93; 95% CI, 0.91-0.95), live birth (36.5% vs 39.2%; adjusted RR, 0.95; 95% CI, 0.93-0.97), and multiple live birth (30.1% vs 31.0%; adjusted RR, 0.93; 95% CI, 0.95-0.95) versus conventional IVF.

The authors concluded that compared with conventional IVF, ICSI use was not associated with improved post- fertilization reproductive outcomes, irrespective of male-factor infertility diagnosis. They acknowledged that the study was limited, in that NASS does not collect information on fertilization rates, nor on outcomes for ICSI versus IVF for cryopreserved oocytes.

Reference

1. Boulet SL, Mehta A, Kissin DM, Warner L, Kawwass JF, Jamieson DJ. Trends in use of and reproductive outcomes associated with intracytoplasmic sperm injection. JAMA. 2015;313(3):255–263.

NEXT: Tech Editors Brian Levine, MD, MS, and Dan Goldschlag, MD, FACOG comment on the study.

Commentary by Contemporary OB/GYN Tech Editors Brian Levine, MD, MS, and Dan Goldschlag, MD, FACOG:

An initial review of this article suggests that intracytoplasmic sperm injection (ICSI), a type of assisted reproductive technology (ART) that requires a tremendous amount of skill and resources, is being over-utilized. A crucial argument not addressed in this paper but that may explain the “rise” in ICSI use is simple economic pressure, that is, supply and demand for in vitro fertilization (IVF).

With the dramatic increase in use of ART in the past 20 years, access to IVF has become more common, resulting in better technology and a drop in the costs of the requisite tools (and training). With that said, it is evident in both Figures 1 and 2 that the greatest increase in ICSI use was upon its introduction. In the last chronological quartile of the study, there appears to be little change in the relative frequency of ICSI.

As part of the ICSI procedure, the operator must select the best-appearing sperm, immobilize it, and then gently inject it into the egg. This selection process allows the operator to inject what may appear to be the best sperm into the eggs. Some may feel that this is “unnatural,” but embryologists and ICSI operators strive to identify the best gametes, which may ultimately make the best embryos, furthering what everyone would agree is the goal of IVF: creation of the healthiest pregnancy possible for both mother and baby. Discussing “natural selection” in the context of ART, thus, is awkward.

Boulet and colleagues do not ad- dress the relative importance of egg freezing in the armamentarium of tools that reproductive endocrinologists can offer their patients. With the advent and adoption of oocyte cryopreservation, many women are choosing to freeze their eggs for a multitude of reasons. That being said, cryopreserved eggs that are subsequently thawed must undergo ICSI for efficient fertilization because of the steps involved for proper freezing/ thawing. Therefore, as more women thaw and fertilize their eggs, use of ICSI is likely to increase.

Read: Should all women freeze their eggs?

Similarly, trophectoderm (Day 5) biopsies for preimplantation genetic diagnosis (PGD) can only be done on an embryo that has been fertilized by ICSI because excess sperm surrounding the embryo would skew the genetic results, potentially generating a false diagnosis. Increased use of ICSI in patients undergoing PGD-a population that is growing-is an indicator that practitioners are offering better genetic testing modalities (Day 5 instead of Day 3) to these women.

The authors of this article incorrectly focus on post-fertilization outcomes: specifically, rates of implantation, live birth, and multiple live births. It is possible that ICSI was associated with lower post-fertilization metrics in couples for whom male-factor infertility was not considered a primary diagnosis and instead, the male may have been subfertile but did not meet the threshold for being called infertile.

Tech Tool articles by Brian Levine, MD, MS, and Dan Goldschlag, MD, FACOG

Bioprinting: Creative disruptive technology

Cell free DNA and oncology

Top apps for ob/gyns and their patients in 2015

As such, some of the non-male-factor cases in which ICSI was used may, in fact, be some of the most complicated cases in the series and not cases “without any indication,” as the authors describe them. For example, the etiology of infertility may not have been labeled as male factor for a patient with a history of recurrent miscarriage and low ovarian reserve whose partner had low sperm motility.

Taking all of this information together, it is important to understand that, while this article has academic merit, it does not address the emergence of new technologies and the effects of market pressures and technological development on increased access to care. It is “good” that the cycles using ICSI had more Day 5 transfers and more embryos cryopreserved because we should try to avoid multiple gestations whenever possible.

This paper indirectly shows that IVF is becoming potentially safer and more available. However, given that this is a large retrospective study, all of the findings are worth discussing, but it is also important to understand that it suffers from the limitations of analyzing large registry-derived data. The hardest task would be designing and implementing a prospective study to address the authors’ concerns about the current state of IVF in America.

Dr. Levine is Clinical Fellow, Reproductive Endocrinology & Infertility, Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College, New York. Dr. Goldschlag is Assistant Professor of Clinical Obstetrics and Gynecology and Assistant Professor of Clinical Reproductive Medicine, Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine, Weill Cornell Medical College, New York.