4 of 12

Fertility Preservation for Cancer Patients

Lesson 4 of 12

The Risks of Infertility & Other Possible Risks

Video Lesson

Written Lesson

The Risk of Fertility Challenges Regardless of a Cancer Diagnosis

If someone plans to try to conceive in their late 30s (or beyond), the odds they’ll need fertility treatment tend to rise. In this scenario, freezing one’s eggs seems more worthwhile because the odds those eggs will be used are greater. Let’s take a look at a few charts.

First, regardless of whether a person has been given a cancer diagnosis, the degree to which they’ll have trouble conceiving depends on a number of factors. As we covered in the previous lesson, one driving factor is related to the age of the person contributing eggs, as you can see in the data below. For instance, many hopeful parents with ovaries in their late 30s and early 40s struggle to conceive within a 12 month frame.

In addition, there are other characteristics that make it far more likely someone will need to build their family with the help of fertility treatment. If you’re someone with one of the below characteristics, the odds are significantly higher you’ll need treatment to conceive and again, the value in freezing eggs (or embryos) grows as a person’s age increases because the odds of needing them are higher.

Other characteristics that may require fertility treatments:

  • Blocked fallopian tubes (from a history of STD’s or any other reason)
  • A partner with male factor infertility
  • Reason to believe they have endometriosis
  • A family history of early menopause
  • Have a genetic disorder that they want to screen for
  • Reason to believe they’ll use a sperm donor later on
  • A lesbian relationship and may want to do “reciprocal IVF” at some point
  • A male partner who has been treated for cancer, so they expect to use frozen sperm

If someone requires fertility treatment the extent to which it will lead to a live birth is also a function of the age they undergo treatment. Below is data that reflects how treatments like IUI and the much more effective IVF become less likely to succeed with time.

As you can see below, rates of success tend to dip dramatically towards the late 30s. If you undergo fertility treatment, you’d far prefer working with your 35-year-old eggs than your 42-year-old eggs.

The Risk of Infertility in the Context of a Cancer Diagnosis

As to the question of how often cancer patients face challenges of infertility, that is often a function of the nature of their cancer diagnosis, the type of treatment they’ve undergone, the age at which they were treated, and other variables (in addition to at what age they ultimately try to conceive.)

In these next few charts, we will elucidate how all of these factors can impact the risk of infertility. These charts, and this discussion, is meant only to showcase how varying factors can be relevant. It’s not meant to identify the odds of risk for specific people. As always, you must reserve that discussion for your clinical team.

Finally, many of these charts and graphs will distinguish between absolute risk and relative risk. These are differing concepts. Absolute risk refers to the percentage of people within a population who are likely to encounter a challenge (e.g. 1 in 100 people develop a disease.) Relative risk refers to the increased (or decreased) level of risk compared to a population. For instance, if person A has a 1% absolute chance of developing an issue, and person B has a 40% higher relative risk of developing the same challenge, person B’s absolute risk is still only 1.4% on absolute basis.

Let’s look at data from over 3,000 cancer survivors who were diagnosed under the age of 21 and their relative risk of infertility compared with their siblings. As you can see in the data below, cancer survivors had a 48% higher relative risk of infertility. However, not all groups encountered the same level of risk. As you can see below, the risks adjusted depending upon a number of factors, for instance, how much “uterine radiation” or “alkylating agent” chemotherapy they received (both tended to correlate with a significantly higher relative risk.)

One possible explanation would be that uterine radiation and higher doses of alkylating chemotherapy destroys a part or all of the finite pool of eggs in a person’s body. In another study, investigators tracked 700+ cancer survivors between the ages of 18–39 who’d developed a variety of cancers (e.g. breast, lymphoma, thyroid.) Tracking patient AMH levels (a surrogate for egg quantity), investigators noticed those receiving higher treatment toxicity (dark blueline) recorded an immediate and sustained AMH drop-off compared to those in the low (light green) or medium (dark green) groups.

However, radiation doesn’t need to be focused solely on the ovaries to possibly have an effect. For instance, once a person conceives, the relative odds of miscarriage grow if they’ve received cranial or abdominopelvic radiation.

The Childhood Cancer Survivor Study (tracking 10,000+ cancer survivors) aimed to ascertain levels of infertility risk amongst patients (compared with siblings) diagnosed after the age of 15 and treated with a suite of newer chemotherapy agents. In this study, investigators noted a differing risk of infertility based upon gender.

The authors noted the degree to which infertility became a factor may well relate to the age at which survivors ultimately tried to have children. For instance, the risk of infertility was more pronounced (compared with siblings of a similar age) in women who tried to conceive in their 30s than in their 20s.

When investigators looked at the drugs and doses female cancer survivors received, some drugs seemed to coincide with greater risk (e.g. Busulfan), while other drugs (e.g. Lomustine) showed no correlation (e.g. Ifosfamide) with greater risk and in some cases it really depended upon the dose.

What is probably safe to say is that as a group, cancer patients have a higher risk of encountering fertility challenges (than their siblings) but the degree to which cancer patients are impacted is highly variable. Likely in only very specific circumstances (e.g. surgical removal of ovaries or uterus) does a cancer diagnosis or cancer treatment entirely foreclose a person’s chance to become pregnant and deliver a genetically-related child.

That said, there are tools that may lend insight. One smaller study of 40+ early- stage breast cancer patients showed that pre-treatment AMH levels “were a significant predictor” of whether a woman was able to menstruate 5 years after treatment.

The Risk of Carrying or a Delivery After a Cancer Diagnosis

By-and-large, the risk to the person delivering varies by cancer diagnosis. Some cancer treatments increase cardiovascular risks, and since pregnancy can be demanding on the cardiovascular system, the risks of becoming pregnant needs to be discussed with a doctor. While the rates of issues like preeclampsia or gestational diabetes tend to track the broader population, the risk of cesarean delivery (which carries its own risks and complications) are roughly 1x–2x higher.

Cancer survivors are roughly 1.5x–2.0x more likely to deliver a child pre-term (before week 37) and this likely is what drives the 2.0x–3.0x higher (7%–15% on an absolute basis) odds of delivering a lower weight baby. The amount of abdominopelvic radiation a patient receives seems to be a driving factor.

The Risk to Offspring After a Parent’s Cancer Diagnosis

A common fear is that cancer treatments have the potential to cause "germline mutations" and as a result, some hopeful parents wonder whether their decision to undergo treatment impacts the odds their offspring will develop cancer.

In one large registry from Finland, investigators noticed an increased risk that offspring of cancer survivors would develop an issue when compared with offspring from a sibling, and we showcase the data below.

However, percentages were in the low single digits, and once investigators removed cancers "with a probable hereditary cancer component", the correlation was no longer statistically significant. The investigators concluded the study "showed that offspring of cancer patients are not at an increased risk of cancer except when the patient has a cancer-predisposing syndrome."

Risks Associated with Fertility Treatment, Egg Freezing, or IVF

We believe there are three main risks to be considered here, namely the risks associated with:

  1. Delaying cancer treatment to undergo a retrieval
  2. Fertility drugs and their impact on patients with a cancer diagnosis
  3. In vitro fertilization risks to patient and offspring

Risk 1: Delaying cancer treatment to undergo a retrieval

In one study of roughly 300 breast cancer patients, investigators noted that the patients who opted to undergo an egg retrieval started therapy about 45 days post-diagnosis or nearly 12 days later than those who went right into cancer treatment. At the two year follow-up, investigators found the rate of cancer-free survival was similar between both groups. Multiple studies have arrived at similar conclusions. Said differently, when the delay is limited to a few weeks, across populations, it does not appear to have longer-term consequences.

That said, fertility doctors should eliminate any delay in providing a patient their diagnostic work-up and initiating hormone stimulation therapy. As we’ll discuss, initiating a “random start” protocol (rather than waiting to begin treatment in coordination with a patient’s cycle) is likely a useful decision.

Risk 2: Fertility drugs and their impact on patients with a cancer diagnosis

On one hand, giving patients more injectable hormones increases the number of eggs retrieved and raises the odds that retrieval culminates in a live birth down the road. On the other hand, increased use of these hormones increases a patient’s estrogen exposure, which in the context of a cancer that feeds off of estrogen, is a risky proposition.

In the study we last cited (showing cancer patients who underwent fertility treatment had no higher rates of recurrence), and in other studies, doctors modified the fertility drugs prescribed, adding letrozole (at the beginning and the end of the cycle) or tamoxifen which serves to both lower the amount of drug needed and attenuates the patient’s estrogen rise.

In one study of 47 breast cancer patients, those who received letrozole recorded rates of success similar to those who used a more standard protocol, but required far less gonadotropin (see “Total FSH dose” below) and thus recorded a lower level of estrogen. This may be one reason the rate of two year cancer recurrence was no higher in the last study we looked at when investigators compared those who underwent fertility preservation and those who skipped it.

Risk 3: IVF’s impact on offspring

While the data on how undergoing IVF impacts a child’s health are difficult to disentangle, the majority of evidence is reassuring. A major question is whether a patient’s (or couple’s) infertility in-and-of-itself contributes to an increased risk rather than the treatment itself.

Here we’ll look at a number of studies that are focused on babies born to IVF patients writ-large and not necessarily those who underwent IVF and had any cancer diagnosis. At times, you may find this analysis gets slightly “too in the weeds.”

Issues Associated With Twin or Triplet Pregnancies

During an IVF cycle, once embryos are created there is a decision of how many to transfer to the uterus at one time. When multiple embryos are transferred, the risks that an IVF pregnancy results in a multiple gestation birth rise from 1% to as high as 30%. This results in greater risk to the person carrying and to the offspring, as you can see in three excellent studies below.

Twins and triplets are more likely to be born prematurely, possibly missing out on a period of in-utero development critical for grey matter development in the brain. As a result, prematurity has been associated with lower cognitive function, as you can see in an analysis that appeared in the Journal of the American Medical Association.

Much of this risk can be mitigated by transferring one embryo per transfer. While this may increase the odds the first transfer doesn’t work (requiring an additional transfer), it doesn’t lower the odds the IVF cycle itself will lead to a live birth (a cycle starts when a person does stimulation ahead of a retrieval).

Risk of Birth Defects to Offspring

Before we launch into this question, we should say this is a difficult subject to study for two reasons. First, the definition of “birth defects” vary by type and the age of the offspring. Second, IVF patients often have fertility issues, and by definition are different from the general population. As a result, any difference in the rates of birth defects in offspring could be on account of the factors that produced infertility in the first place, the IVF process itself, or even another factor. It can be difficult to disentangle these possible factors.

Generally speaking, 1%-3% of babies born in the general population incur from some birth defect. When a couple has had trouble conceiving, that rate climbs to 3%–5%. This is best evidenced by one large Finnish registry that includes nearly 30,000 offspring. Amongst the groups needing fertility assistance (using ovulation induction, IUI, or IVF), those requiring IVF were more likely to produce a child with a birth defect, but, as you can see below, the absolute difference is 1%– 2%.

When we look more closely at the Finnish data, amongst singleton births, in many categories, children born from any type of fertility treatment (not just IVF) are more likely to have a birth defect than those conceived without assistance. But that does not get IVF off the hook necessarily. As you can see below, babies born from IVF do have more issues than those born from IUI or ovulation induction, especially babies assigned male at birth.

That said, and again, one should keep straight the difference between “relative” and “absolute” risk here. In the example below, babies assigned male at birth born from IVF are 1.6x more likely on a relative italics basis to have a birth defect compared to boys in the general population. But since the odds of that happening in the general population are low (~3%), the absolute risk of babies assigned male at birth born from IVF developing a birth defect is only about 5%.

If a patient is focused on any birth defect risks associated with IVF, there are a number strategies for mitigating risk but two include:

  • Deploying more single embryo transfers, as babies born from multiple gestation pregnancies are more likely to encounter physical and cognitive challenges.
  • Only using ICSI as a fertilization technique when absolutely necessary. As one large New England Journal of Medicine study showed, the incidence of birth defects is lower when conventional insemination is deployed. However, a confounder in the data is that those IVF patients who required ICSI may be different than those who used conventional insemination (namely, having a severe male factor infertility issue.)