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Deep Dive

What Is ICSI

As fertility patients, we remembered ICSI to mean “I Could Stomach It”, in that we could look past its $1,500 cost if it guaranteed our eggs would fertilize. While most in the field of fertility hail the advent of ICSI (which really stands for Intracytoplasmic Sperm Injection) as a milestone, there is spirited debate as to whether its overused.

Natural Fertilization


During the course of natural fertilization, sperm compete vigorously to fertilize a single egg. In the human body, this means each sperm swim through difficult conditions in the vagina and fallopian tubes, at a relative distance equivalent to a human swimming from Los Angeles to Australia. Less than 1% of the sperm ultimately arrive at the egg’s perimeter, and few are able to pierce its outer core. For this reason, a man’s sperm needs to meet certain criteria for speed (motility), shape (morphology) and volume (concentration) to make it likely that a few will be exceptional.

During an IVF cycle, “natural” fertilization means that an embryologist takes a single egg and surrounds it in a petri dish with droplets of sperm which compete to fertilize the egg.

Male Factor Infertility


In many cases of male factor infertility, a man’s sperm cannot naturally fertilize a woman’s eggs. This is most commonly due to a low sperm concentration, poor motility, or, and there’s debate on this one, incorrect morphology. Generally, doctors will use a semen analysis to determine where the issue lies. Male factor is the sole culprit in 30% of infertility cases, and it plays a contributing role in another 20% of cases.

ICSI


The artful solution to when sperm cannot fertilize an egg is to pluck a single sperm that looks promising and inject it directly into the egg. ICSI is microsurgery, and it’s the smallest procedure we do in medicine — by injecting one cell into another, we run the risk of doing real damage to the machinery of the egg, especially if the procedure is not done carefully. Roughly 5% of good quality eggs are damaged in the ICSI process.

ICSI takes place in the fertility clinic laboratory, at the hands of an embryologist. Typically, a high quality lab has a 70% or higher ICSI “fertilization rate”, which means that on average, for every 10 mature eggs that are retrieved, seven are successfully fertilized when ICSI is used.

Perfecting the skill requires months, or even years, of practice. Larger clinics may have more experience doing ICSI overall, but they can seldom tell you which embryologist will be performing your procedure, and how much experience they themselves have.

Higher Fertilization Rate for Male Factor Patients


Nearly every respected clinician in the field of fertility acknowledges ICSI is a difference-maker. ICSI, when deployed in the presence of male factor infertility, delivers per-cycle live birth rates 3 – 4% higher than similar circumstances where ICSI was not used. In the field of fertility, where success rates often hover in the 20 – 30% range, even a mid-single digit improvement is considered meaningful. Also worth noting is that these numbers include the entire spectrum of male factor patients. For some suffering from severe male factor like azoospermia, ICSI increases live birth rates more substantially.

ICSI’s benefit for male factor patients can also be seen in the reduced number of cancelled cycles. The chart below uses "cycles cancelled after retrieval and before transfer" as a proxy for failed fertilization. ICSI reduced cancellations from 14% to 6% in male factor patients.

Rise in Use


Today ICSI is standard-of-care treatment for the 30 – 50% of cases where male infertility plays a role. What’s more surprising is the extent to which ICSI has become standard where male factor is not present. ICSI is now used in roughly 70 - 80% of procedures in the US and, in many clinics, it’s used in every single IVF case. Below are specific cases where ICSI is popularly used, even when no male factor issues are present.

Outcomes in Non-Male Factor


When ICSI is deployed in cases of non-male factor infertility, the benefits of fewer canceled cycles effectively disappears. And, when it comes to live birth rates, things may in fact get worse.

Proponents of using ICSI in this population say this analysis is overly simplistic. They argue that in certain non-male factor groups (like patients with diminished ovarian reserve or advanced maternal age) ICSI still has benefits, and that when ICSI is used, it’s employed in more challenging cases that would otherwise have worse outcomes. But there is no evidence in the data, as of yet, to show these claims are true. Below, you’ll see that in cases where ICSI is frequently deployed in the absence of male factor, overall success rates do not improve when clinicians use it for fertilization.

One counterexample are circumstances where the patient previously underwent IVF, and few, if any of her eggs successfully fertilized. In those circumstances, ICSI is necessary, regardless of whether the male partner has a diagnosed fertility issue.

Reason for ICSI Use in Non Male Factor Patients: General Nervousness


Most clinicians will tell you the worst phone call they have to make is the one telling a patient that their eggs didn’t fertilize. If ICSI helps the patient feel they’ve taken every measure to ensure fertilization, in light of the costs and risks, many doctors want to do it. Doctors are often especially motivated if the patient has few eggs to work with. However, as we saw above, there is little evidence that this improves overall chances of success.

Reason for ICSI Use in Non Male Factor Patients: PGS


PGS theoretically reveals whether embryos have the right number of chromosomes, thereby helping doctors select the best embryo to transfer. The intended downstream impacts are reductions in the number of miscarriages and unnecessary multiple-embryo transfers. By our FertilityIQ estimates, PGS is now used in 35% of all IVF cases, and within 18 months will be used in nearly half of all cases.

There’s a fair amount of disagreement as to whether ICSI should be a requirement for PGS, but the proponents argue that it makes the results of PGS testing more accurate because biopsied cells aren’t inadvertently contaminated with DNA from all the sperm that didn’t fertilize the egg.

Here are a few thoughts. First, use of ICSI in the context of PGS, even where there is no male-factor issue, has exploded.

Next, while many doctors claim they only use ICSI because they want to do PGS, that is simply not true. Between 2008 – 2012, PGS was hardly ever used, but even for non-male factor cases, ICSI was used the majority of the time.

Finally, best we can tell, whether ICSI is used with PGS or not does not seem to impact outcomes.

Cost


ICSI costs typically range from $800 - $2,500, often depending on the location of your clinic. ICSI is likely one of the more profitable procedures a clinic will do, as the cost to pay an embryologist to perform ICSI is around $50 - $200.

In states where IVF treatment is covered, ICSI is often used more frequently. In countries where there is state-sponsored subsidization for IVF, and where payments caps are often placed, namely in the Nordic countries, or the U.K., ICSI utilization rates lag behind the US.

Risks


ICSI is an intervention on the egg itself, and in the process approximately 5% of good quality eggs are damaged. It’s harder to quantify the effects it has on resulting babies. A 300,000 patient study in Australia investigated rates of birth defects comparing children born naturally (5.8%) versus through IVF (8.3%). When the authors looked further into the IVF bucket, 7.7% of children born from IVF without ICSI had birth defects, while 9.9% of children who were born as the result of IVF with ICSI had birth defects.

After trying to correct for numerous factors like twins and maternal age, IVF without ICSI had no statistically higher rate of birth defects compared with a non-IVF patient population. But IVF with ICSI did. It’s hard to know if this is due to the underlying condition ICSI was treating — male factor infertility — or ICSI itself.

However, when a group later conducted a meta-analysis (which is typically rife with challenges) of several studies comparing risks to offspring from IVF with and without ICSI, they detected no significant difference.

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