ICSI

If you are going to a fertility clinic this year, be prepared to have your clinic strongly encourage you to do ICSI. As you can see below, nearly all patients with a male factor diagnosis will have it performed, as will two thirds without such a diagnosis. In the next section, will look into which patients are proven to benefit by ICSI, versus who can probably avoid it.

Generally speaking, the trials to measure ICSI’s value are unsatisfying. If you are interested in reading how we select and calibrate these trials, we have more detail below. Otherwise, feel free to skip below to the chapter on “Male Factor” to learn about who benefits, and who is hindered by ICSI.

Detail On Trials For ICSI

First, we are often dealing with small, single center studies. As you saw above, embryologist skill varies and to generalize about ICSI’s effectiveness based upon a few embryologists working at one clinic requires caution.

Second, many of these studies are poorly-designed and do not measure the important variable: live birth rates. Rather, many compare (and poorly at that) what percentage of eggs fertilize with CI or ICSI or what percentage of the time a patient had none of their eggs fertilize (again, known as Total Fertilization Failure, or TFF). Again, improving fertilization rates often does not translate into improving live birth rates.

Speaking of TFF, this endpoint is highlighted in studies because doctors worry that if a cycle ends in “no fertilization” the patient will be angry with them. However, oftentimes when we use ICSI to mitigate TFF, live birth rates are not improved. If our goal is to improve live birth rates, we think patients (and thus doctors) should focus less on the TFF endpoint.

Finally, we consider “fertilization rate” to be the least important endpoint because most investigators do not calculate it consistently. For CI, fertilization rate is calculated using the “total number of oocytes retrieved” as the denominator. For ICSI, they use “mature oocytes” as the denominator, which is an inherently smaller number and thus makes ICSI look more potent.

Below is our hierarchy and definitions for the endpoints you should care about:

Next, we rely on CDC data (and population studies) which has the benefit of capturing data from nearly all U.S. centers, but suffers from the risk the populations receiving ICSI or conventional insemination (CI) may not be the same and so comparing effectiveness is hard.

Finally, we rely upon “meta-analysis” where a researcher looks at all of the studies addressing a specific question (e.g. does ICSI cause birth defects). While these studies may incorporate data from many centers, they suffer from “investigator discretion”: the researcher gets to choose which studies to exclude and how much to weight the studies they include.

ICSI was developed to treat severe forms of male factor infertility and in these cases it is necessary and effective. The data is poor in characterizing if ICSI helps improve live birth rates in cases of “mild” or “moderate” male factor infertility, which encompasses most male factor patients. Below are the three main measures to characterize a man’s male factor issues:

• Concentration: The volume of sperm produced per milliliter is below 15 million
• Motility: Less than 40% of sperm are able to swim forward
• Morphology: Less than 4 - 5% are of the proper shape

At a high-level, when the CDC reviewed how male factor patients fared with ICSI versus CI, ICSI had lower rates of cycle cancellation (6% vs 14%) likely on account of TFF and higher live birth rates (37% sv 34%), but the difference was surprisingly narrow to us.

Severe Male Factor

For patients with no ejaculated sperm (azoospermia) or sperm that does not swim forward, ICSI clearly increases rates of live birth and in our opinion, ICSI is a requirement

For example, at Cornell, when patients with non-obstructive azoospermia (considered the hardest to treat) have a testicular biopsy and sperm is discovered, over 36% of transfers lead to a pregnancy. Most fertility doctors will tell you these patients would have otherwise terrible odds of success without ICSI.

Poor Morphology

In cases where semen parameters are otherwise good but fewer than 5% of the sperm have normal shape, the better-run studies indicate ICSI does not improve live birth rates. A team from the University of Utah concluded in their recent meta-analysis that in this population ICSI is ineffective.

“Moderate Male Factor”

What do we do in cases where men have low, but not severely low, scores on the semen analysis? In this context, the quality of our data is poor, especially since the majority of these men will be told they must do ICSI. The studies available are conducted on small volumes of patients (often less than 50 cycles) and do not measure the important statistic: live birth rates.

The best study (in an otherwise unimpressive batch) demonstrates using ICSI reduces the risk of TFF in a meaningful way. However the study is small for our liking (76 cycles) and overly-broad in whom it includes (patients with count, motility and morphology issues) and does not elucidate if any one group especially benefits, or doesn’t, from ICSI’s use. The authors concluded that for every three patients that underwent ICSI, one was saved the heartbreak of having none of their eggs fertilize.

The CDC looked at all patients treated without a male factor issue. They noted cancelled cycles (likely on account of TFF) were similar between ICSI and CI and so were live birth rates. In effect, using ICSI did not help this broad group of patients.

Similarly, the best studying comparing ICSI vs CI outcomes showed no statistical difference in pregnancy rates. However, the analysis may not extend to women over 37 or couples that previously had low rates of fertilization (<20% of eggs fertilized), as these groups were excluded.

In this case, 33 couples had to undergo ICSI to save one couple from TFF. Compare that with the MFI patients, where only three couples needed to undergo ICSI to save one from TFF.

As you will see, “non-male factor” is a broad group and when we sub-segment it, we note the differences in rates of success between ICSI and CI vary by patient population. We’ll tackle what those sub-segments might look like below.

When there is no discernible cause for infertility, and the man’s semen parameters are within normal range, it’s common for doctors to use ICSI. That likely is unwarranted.

We have three small, single center studies that consistently show using ICSI virtually eliminates TFF. A larger meta-analysis from 2013 confirms the observation. However, only one study went so far as to compare live birth rates (in women under 40) and the study showed no significant difference between the two groups (though the study’s power was low).

The CDC data showed the rates for cancellation (likely on account of TFF) were similar between the groups and also showed the ICSI population had a slightly lower live birth rate.

We have one small, single center study from Spain that looked at ICSI in patients that retrieved six-or-fewer oocytes. Surprisingly, TFF rates were identical between ICSI and CI and, while pregnancy rates were higher in the ICSI group, this didn’t meet significance (likely because the power was so low).

The sub-segment analysis is interesting here. The findings were consistent across age groups. However, when the group looked at outcomes for women with three-or-fewer embryos, ICSI patients recorded fewer TFF issues. However, given the study’s small size, the group couldn’t declare it statistically significant.

The CDC data looks at women with four-or-fewer oocytes. The data clearly shows the ICSI group had a lower rate of cancellation (likely on account of TFF). But, the ICSI group recorded fewer live births (15% vs 13%). The implication here is that in this setting ICSI may do more harm than good. Indeed, when few oocytes are retrieved, dismissing 20%–30% that are not mature, and then taking the risk of damaging a remaining oocyte seems ill-advised. That said, many experts quible with this assertion and continue to perform ICSI for those who produce few eggs.

We have no prospective, randomized trials on whether ICSI improves outcomes for women of advanced maternal age (defined here as 38 and older).

The CDC data shows no difference in the percentage of cancellations (likely on account of TFF). From a live birth rate perspective, patients who used ICSI performed mildly worse.