Reproductive Endocrinologist, CCRM New York
When we examine the risks of freezing one’s eggs, we believe it makes sense to look at the health implications to both the potential offspring and to the woman whose eggs were frozen. In this lesson we will examine both in the context of near-term and longer-term risks. Below is our high level synopsis of what we consider the best information currently available. You should be sure to have a conversation with your doctor to understand if you’re at heightened risk for any of these issues.
We have two studies that analyze the birth defect rate of babies born from frozen eggs. Birth defect rates land at 1.5 - 2.0% and the authors concluded the differences were not statistically different than children born from IVF using fresh eggs. Note, this comparison was not to children conceived naturally.
We’ve yet to see studies that thoughtfully track these offspring in the longer term.
Most of the theoretical medical risks of egg freezing stem from the use of injectable hormones which are used to help grow a large number of eggs at one time.
Unfortunately, there are few well-run studies looking at the impact of these drugs on egg freezers. Instead, the only data we have is how these drugs impact women who did IVF.
That is a problem because often, women who undergo IVF are different from women who undergo egg freezing - they normally turn to IVF after an infertility diagnosis, and infertility itself can be a risk factor for issues like future cancers. On the other hand, most egg freezers have not been diagnosed as infertile. Thus, it can be hard to extrapolate from data on IVF patients to egg freezers because they are likely different populations.
All the same, we believe this information can be of some use (egg freezing is the first step in IVF) provided we understand the data’s limitations.
Before we dig into the most relevant studies, let’s quickly cover a process that egg freezing and IVF have in common: administering the drugs.
During a woman’s natural, monthly cycle, she will produce a hormone called follicle-stimulating hormone (FSH), which signals a follicle or two in her ovaries to begin to grow an egg. Weeks later, the body emits another hormone, luteinizing hormone (LH), that instructs these follicles to release that egg, which is the process of ovulation. In a typical, natural cycle, the ovary releases a single egg that ultimately travels down the fallopian tubes to either be fertilized, or released.
During the egg freezing process, and during IVF, the ovaries are stimulated to release more mature eggs than the single egg the woman would naturally produce. A woman injects herself with hormones called gonadotropins (e.g. the FSH hormone we mentioned, in drug form), with the goal of encouraging follicle growth and producing as many eggs as possible.
During this period, the woman regularly returns to the clinic where the staff will check her follicle growth, monitor her hormone levels, and adjust the level and type of hormones she should inject. Ultimately, the doctor will decide when to have the woman inject a “trigger shot" (for example using the hCG hormone to mimic the functions of LH) to mature her eggs. Thirty-six hours later the doctor will surgically retrieve those eggs.
Ovarian hyperstimulation syndrome (OHSS) is a painful and potentially dangerous byproduct if a woman is improperly stimulated during egg freezing or IVF. OHSS symptoms include pain, nausea, dizziness, vomiting, hospitalization, organ failure or worse. OHSS occurs in 1 - 10% of IVF patients, but amongst egg donors (a population more akin to egg freezers) the incidence is closer to 10 - 15%.
That said, some patients are far more susceptible to OHSS--namely younger women, women with PCOS, a history of OHSS, an exceptionally high follicle count, women of African-American heritage, amongst other factors.
For OHSS to occur, two things must happen. The patient must be overstimulated and then improperly “triggered.”
When the woman is prescribed and subjected to more FSH than her ovaries can tolerate, she will become overstimulated. There are often clues this is happening, namely if she is growing a high number of large follicles or if she has an elevated estradiol level.
Next, for OHSS to transpire, the patient would need to have challenges when “triggered.” The trigger shot occurs when the woman has developed enough large follicles, and the doctor wants to mature those eggs for retrieval.
OHSS can be completely avoided if the trigger is not administered, but then the cycle must be cancelled.
While hCG is the most effective and reliable trigger, it remains in the woman’s system for up to 10 days and is more likely to incite OHSS. An alternative to using hCG would be to use a “GNRH agonist” trigger, namely Lupron. As you can see in the three studies on egg donors where patients were given either a hCG or a GnRH agonist (Lupron) for trigger, rates of OHSS virtually disappeared when the GnRH agonist (Lupron) was used.
Whether hCG, or an alternative like Lupron, will be used needs to be discussed early in the treatment process. This is because the decision will dictate the other drugs (and their timing) that can be used to stimulate a woman’s ovaries.
For patients likely to be at risk of OHSS, using a GnRH agonist trigger (like Lupron) may be a wonderful idea. However, some women don’t respond well to the GnRH agonists and they may still need to consider using hCG as their trigger shot (maybe at lower levels). Women who have been on prolonged birth control, have irregular menses and other characteristics can often be poor responders to hCG alternatives like Lupron.
This is because GnRH agonists, like Lupron, don’t work on the ovary directly but rather send signals to the body to make LH. For some patients, Lupron’s signaling is just too faint to incite the LH needed to help the eggs mature.
As a result, some doctors are uncomfortable using a GnRH agonist like Lupron to replace hCG as the trigger. Again, you must have this conversation at the outset of your cycle because your choice of trigger can influence your whole treatment protocol.
If you’re at high risk for OHSS, but doctor insists upon using hCG, they can often order a lower dose for the trigger shot (e.g. down from 10,000 units to 3,300 units) or an even lower dose in conjunction with a GnRH agonist.
First, as we’ve mentioned, nearly all of our studies on whether the use of fertility drugs coincides with (or causes) cancer have been done in patients who took these drugs for infertility reasons. That is a problem because infertility itself is a risk factor for cancer. By and large, egg freezing patients are not infertile. So it can be hard to make conclusions on the risk to egg freezers using only data from infertile patients.To make matters harder, the infertile patients studied were mostly treated in earlier eras (1980s and 1990s) and in geographies (northern Europe) where treatment is practiced differently than in the US today.
All the same, this data is clearly the best available to us and if there are especially troubling, or reassuring signals, we’d be wise to monitor them and take note.
Investigators study two types of risk and both are important to bear in mind here.
In this context, “relative risk” reflects how much more often IVF patients develop cancer than non-IVF patients. In some populations, these increased rates of risk can appear quite high, sometimes in the range of 30 - 70%.
Yet, a high “relative risk” does not reflect how likely a patient is to actually develop cancer. Instead, that is referred to as the “absolute risk.” Most cancers are rare, occurring in the low-to-mid single digits of the population. Thus, some women who do IVF may have a higher relative risk compared to the general population, and still a very low absolute risk of developing an issue.
You should ask your doctor about their perspective on the risks associated with developing cancer and hormone therapy. New data comes out continually, and there may be factors about your case that warrant a more specific discussion than what’s offered here.
Most fertility treatments involve stimulating the ovaries, which induces a spike in estrogen, and elevated estrogen has been associated with breast cancer risk. It’s unclear how taking fertility drugs, specifically gonadotropins, impacts a woman’s risk of developing breast cancer.
Below is our rundown of a handful of the studies we believe to be the most relevant to the subject and what we believe were the most useful observations by the investigators.
Reigstad’s 2014 investigation compared breast cancer rates amongst women who did IVF (infertile women) and women never did IVF (general population, presumably fertile). The data shows that amongst women followed for over 10 years, those who did IVF had higher rates of breast cancer. As you’ll see, that is likely a reflection of the differing patient populations and not the IVF treatment itself.
Here’s why. When treating just infertile women, Belt-Dusebout, Lindberg, Stewart and Zreik showed that IVF drugs and treatment did not raise their risk of developing breast cancer compared with non-IVF treatments. What’s more, Belt-Dusebout’s and Brinton’s studies in particular showed that even when the amount of drugs were increased, there was no correlation to cancer.
The above studies might be comforting to egg freezers. The intuition is that:
However, what may be unsettling for younger women considering egg freezing is that Stewart noted amongst infertile women under the age of 24, those who had IVF had a 56% higher relative risk of breast cancer than those infertile women who had no IVF. The Stewart study is a quality one with a long-duration (16+ years) of follow-up. When Sergentanis did a summary of studies (known as a meta-analysis) his data showed (narrowly missing statistical significance) a similar phenomenon for women under the age of 30. However, in both cases, the absolute risks were exceptionally low and what’s more, women with fertility issues at such young ages likely have little in common with otherwise healthy women of similar ages.
In the absence of data specifically on egg freezers, we’re keen to see data on either egg donors or women undergoing going IVF for issues that aren’t related to female infertility (like a partner with male factor infertility). As you’ll see in the next section on ovarian cancer, we’re armed with slightly better data.
The clues for how fertility drugs may impact egg freezers is easier to find in the context of ovarian cancer. In 2014, Sutcliffe analyzed an enormous sample set of the general population in the UK. He noted that women who underwent IVF for non female fertility related issues (and thus are more similar to egg freezers) had no higher relative risk of developing ovarian cancer than similar women who did not do IVF.
Over the last 30 years investigators have tried to isolate the risk of fertility drugs by looking solely at women with fertility issues and comparing the ovarian cancer rates between those who were treated with fertility drugs and those who were not.
Small studies in the early 1990s led investigators to believe the fertility drugs themselves drove a higher risk, but in the last decade a series of larger studies from Asante, Bjornholt, and Jensen have recorded that the fertility drugs themselves caused no higher risk.
Just as with breast cancer, it seems there are subpopulations of women receiving IVF (like those who don’t end up having a child after treatment) who are at higher risk for developing ovarian cancer. Most investigators conclude that the issue needs more study, even amongst those whose studies concluded that IVF didn’t pose a greater risk.
Below is a catalogue of the studies we believe are most relevant to the subject, and again, the observations we found most salient from the investigators.