The legal climate surrounding reproductive health care and fertility preservation has changed drastically since the June 2022 Supreme Court decision to overturn Roe v Wade, which revoked the constitutional right to abortion. With this ruling, individual state legislatures are now able to pass laws restricting abortion at any stage of fetal or embryo development, beginning at fertilization. Although the link between abortion and intentional family building may not be immediately obvious, these restrictive laws have a significant and concerning impact on the fertility preservation options available to patients undergoing gonadotoxic cancer therapies.
Elizabeth Constance, MD
The issues this could raise for providers in oncology were described at the 2022 Pan Pacific Lymphoma Conference by reproductive endocrinologist Elizabeth Constance, MD, Director of the Fertility Preservation Program at Heartland Center for Reproductive Medicine, and Professor in the Department of Obstetrics and Gynecology at the University of Nebraska Medical Center, Omaha.1
As Dr. Constance explained, the process of in vitro fertilization (IVF) requires fertilizing eggs, then growing, freezing, thawing, and sometimes genetically testing embryos. Currently, nine states with abortion bans in the United States define an abortion as any medication or procedure that prevents a fertilized egg from becoming a living baby; although some of these states specifically exclude IVF, many do not. Legally protecting these embryos from the time of fertilization could infringe on individuals’ ability to genetically test their own embryos, freeze them for future use, or discard them. Hypothetically, a person could even be forced to use embryos with genetic abnormalities.
“States that do not specifically include an exemption for IVF in their bills run the risk of intentionally or otherwise eliminating our ability to provide IVF at the current standards of care—especially when states then attach criminalization of physicians with felony charges, ranging anywhere from 2 years to life in prison for a first offense,” Dr. Constance explained. This has created a very real risk that IVF clinics will shut down entirely or move out of those states, leaving patients without access to these crucial fertility preservation services, she added.
The Impact of Cancer on Fertility
“For many adolescents and young adults of reproductive age, the desire to preserve the ability to have biological children in the future is an important aspect of their quality of life after treatment,” stated Dr. Constance. “Unfortunately, cancer and cancer-related therapies can have a significant detrimental impact on future fertility in all individuals of reproductive age.”
The threat to reproductive function following cancer therapy is twofold: first, gonadotoxic therapies can lead to complete gonadal failure characterized by premature menopause or absence of sperm production; second, even for individuals who don’t experience complete gonadal failure, most will experience impaired fertility and shortening of the reproductive window.
Many studies have shown that an infertility diagnosis carries the same psychological impact on an individual as a cancer diagnosis.— Elizabeth Constance, MD
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“Interestingly, many studies have shown that an infertility diagnosis carries the same psychological impact on an individual as a cancer diagnosis,” Dr. Constance noted. “So, in this population, individuals are often met with both of these diagnoses simultaneously.”
Consequently, multiple organizations—including ASCO, the American Society for Reproductive Medicine (ASRM), and the American Academy of Pediatrics (AAP)—have all published guidelines recommending that all patients newly diagnosed with cancer of reproductive age be counseled regarding reproductive risks of treatment and referred to a fertility preservation specialist prior to treatment.
“I acknowledge this this is easier said than done,” commented Dr. Constance. “Walking the balance between the overwhelming experience to the patient and family of a new cancer diagnosis, the need to quickly and efficiently initiate life-saving treatment, and the desire to ensure quality of life after cancer as it pertains to fertility isn’t easy.”
Incorporation of reproductive endocrinology, urology, and fertility preservation specialists into the multidisciplinary cancer team has been shown to further improve patient outcomes by streamlining this essential counseling and, when appropriate, initiating a timely treatment, she added.
“Studies have shown that one of the biggest regrets survivors have has been not knowing about or pursuing fertility preservation options before treatment,” said Dr. Constance. “To lessen the risk of regret later on, consultation with a fertility preservation specialist can be beneficial for all individuals of reproductive age, even if they don’t choose to pursue fertility preservation therapy.”
Cancer Therapy and Loss of Fertility
Dr. Constance provided a disclaimer on language. She describes fertility preservation treatments for “people with ovaries” and “people with testicles” rather than “female” and “male,” to respect and acknowledge the spectrum of human experience with biological sex and gender.
In people with ovaries, natural fertility begins to decline around age 35, with significantly impaired reproductive function after age 40, from reduction in both oocyte quantity and quality. Thus, fertility preservation methods are unlikely to provide benefit beyond the age of 43, but this differs from person to person. Fertility consultation is always appropriate if the patient expresses a desire, she noted.
Chemotherapy, radiation therapy, and surgery accelerate this natural loss of oocytes, effectively shortening an individual’s reproductive window and leading to premature ovarian failure and early menopause. Testicular fertility is similarly damaged by these gonadotoxic therapies. Providers should familiarize themselves with which common chemotherapy and radiation protocols carry the most risk to fertility; of note, regimens listed as low risk still warrant further discussion and possibly referral, she advised.
All of us, as health-care providers, should be concerned any time laws criminalize our colleagues for the provision of standard-of-care medicine.— Elizabeth Constance, MD
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Established and Experimental Options for Fertility Preservation
To better understand the potential magnitude of this threat to reproductive health care and fertility preservation, providers should first understand the fertility preservation options available to their patients. For people with ovaries preparing to undergo fertility-compromising therapies, the most common fertility preservation options are oocyte or embryo cryopreservation (only in postpubertal patients). Dr. Constance noted that oocyte cryopreservation—as opposed to creating and freezing embryos—has become the preferred option for most patients regardless of relationship status, as the success rate with freezing and thawing mature oocytes is now, in terms of outcomes, on par with IVF using fresh eggs. Patients who choose to freeze eggs over embryos could also face fewer legal hurdles in states that have banned abortion.
“It’s important to note that once oocytes have been fertilized to create embryos, both partners have equal legal rights over the future use and disposition of those embryos,” she explained. “Therefore, because relationships can change with time, it is generally recommended that all individuals cryopreserve oocytes to be fertilized later, at the time when they’re ready to pursue pregnancy.”
When embryo cryopreservation and IVF are pursued, preimplantation genetic testing can identify known genetic mutations in either parent, therefore minimizing the risk of transmitting these genes to their children. “This can test for things like BRCA mutations, genetic mutations associated with Lynch syndrome, or any other hereditary cancer syndromes. That’s another important factor to consider when counseling patients,” Dr. Constance said.
Other well-established options include ovarian shielding, ovarian transposition, and ovarian tissue cryopreservation (in which strips of ovarian cortical tissue are frozen and then retransplanted after treatment has been completed and childbearing is desired).
One of the key limitations to ovarian tissue cryopreservation (currently the only fertility preservation option available for prepubertal children with ovaries) is the relatively short graft survival time. Current data suggest that transplanted ovarian tissue lasts anywhere from 2 to 5 years, typically resulting in the need for multiple grafts and surgeries over the reproductive lifespan of an individual. “The data are inconsistent among studies, in part because there are no standard protocols established yet for this method,” she stated.
One experimental option for ovarian fertility preservation is hormonal suppression with a gonadotropin-releasing hormone (GnRH) agonist such as leuprolide or goserelin. This method can be used alone in patients who cannot or do not want to pursue other fertility preservation options or in conjunction with other methods such as egg or embryo freezing.
“Although this is still considered experimental and off-label use, the theory behind this method is that by suppressing the ovarian function, the hormone-producing cells of the ovaries involved in constant oocyte recruitment, growth, maturation, and survival will be less metabolically active during treatment,” she explained. “Therefore, we may be able to lessen the gonadotoxic effects of these treatments and preserve ovarian function.”
For adult and postpubertal adolescents with testicles, sperm cryopreservation is the fertility preservation treatment of choice. Multiple collection attempts are typically preferred to bank as much sperm as possible before initiating gonadotoxic therapy, but there is no standard for how much sperm is considered adequate to achieve future pregnancy.
For prepubertal children with testicles, testicular tissue cryopreservation is currently the only option for fertility preservation. However, this method is still very early in the experimental phase, with no spermatogenic recovery or pregnancies yet reported.
Options After Cancer Treatment
For patients hoping to conceive following cancer therapy, options include ovarian stimulation and ovulation induction using oral and injectable medications (depending on an individual’s posttreatment ovarian reserve) as well as intrauterine insemination (IUI). IUI is the process by which either fresh or frozen sperm is placed in the partner’s uterus around the time of ovulation, allowing for fertilization to take place.
“IUI requires a sample containing at least 1 million motile sperm and is a good option for patients who are either able to bank a relatively large amount of sperm upfront or for those who have reduced, but still present, sperm production after treatment,” she noted.
Finally, IVF is the only option for using cryopreserved eggs or embryos. “This option may be the best available for patients who have a small amount of sperm frozen prior to treatment, to maximize the chances of success with what they have available,” she added.
For patients unable to bank eggs or sperm prior to cancer therapy who subsequently undergo premature gonadal failure, third-party reproduction methods such as utilization of donor eggs, sperm, or embryos may be necessary. For patients who require hysterectomy or have significant damage to the uterus from pelvic radiation, use of a gestational carrier is an option.
Dr. Constance emphasized that the threat to many of these fertility preservation options is real, and the potential ramifications for patients pursuing these methods remains to be fully seen. “All of us, as health-care providers, should be concerned any time laws criminalize our colleagues for the provision of standard-of-care medicine,” she commented.
DISCLOSURE: Dr. Constance is partner and co-owner of the Heartland Center for Reproductive Medicine.
REFERENCE
1. Constance ES: Fertility preservation. 2022 Pan Pacific Lymphoma Conference. Presented July 18, 2022.
