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Fertility preservation for cancer patients

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Largely due to today’s career and culture shift, women worldwide are giving birth later in life. For example, the average age of births was 25.4 years following the second World War, but it rose sharply to 30.6 years in 2017. Thanks to advancing fertility preservation technologies, many modern women have the option to “stop” their biological clock by freezing their eggs.

Apart from optional fertility preservation for social reasons, there are also patients who desperately need the technology. For example, cancer is a major health concern and usually involves harsh treatment that is commonly detrimental to reproductive function. Unfortunately, young cancer survivors are at a high risk of losing their fertility after chemotherapies. While they can recover from cancer, the loss of fertility is often permanent as women are born with all the eggs that they will ever have.

To prevent treatment induced fertility damage, women are now generally offered fertility preservation options before undergoing cancer therapies.

Mature egg cryopreservation (freezing)

The most widely used fertility preservation technique is egg freezing, which starts by stimulating the production of multiple eggs using hormones. Ovarian stimulation lasts for 10-12 days, enabling usually 6-15 eggs to mature. The eggs are then collected from the ovaries using an ultrasound guided probe and taken to the laboratory. From there, the eggs undergo a freezing procedure called vitrification, allowing the eggs to be stored for many years.

This method might remind you of the process of IVF, and they are indeed similar. IVF cycles usually start with the same ovarian stimulation, egg pickup and freezing. Frozen eggs can be thawed at a later date, fertilised, and transferred back to a woman’s uterus in what’s known as the “frozen embryo transfer”.

In one study of 176 cancer patients who underwent egg cryopreservation by either slow freezing or vitrification, 10 patients returned for fertility restoration. The live birth rate was 44% per embryo transfer cycle, similar to patients without cancer.

Although egg freezing is routinely performed in fertility clinics with great success, it may not be a viable choice for women requiring urgent cancer treatment as the ovarian stimulation protocol takes days. Also, certain types of cancer are hormone-sensitive, meaning that ovarian stimulation could potentially further complicate the patient’s cancer condition.

Ovarian tissue cryopreservation

Ovarian tissue cryopreservation is an alternative preservation technique that does not require ovarian stimulation. Instead of individual egg, some ovarian tissue is harvested during a surgical procedure and frozen before cancer treatment commences. When the patients wish to get pregnant, the ovarian tissue can be transplanted back in a second surgery.

The first live births from implanted frozen-thawed ovarian tissue were reported in Belgium and Israel. To date, more than 130 live births have been documented worldwide.

This technique is suitable for prepubertal girls and patients requiring urgent treatment; however, it does require two surgeries and carries the risk of reintroducing malignant cells at transplantation. For example, transplanting ovarian tissue back in blood cancer survivors can be riskier. The success rate of tissue grafting is variable as it also depends on the surgeon’s experience.

In vitro maturation

In vitro maturation (IVM) is a new fertility preservation method that was first applied in patients with polycystic ovaries syndrome (PCOS), who are at high risk of developing ovarian hyperstimulation syndrome (OHSS) after hormonal stimulation.

IVM involves the retrieval of immature eggs from ovaries after minimal or no hormonal stimulation and then either immediate cryopreservation or at matured stage after IVM. Since immature eggs are not competent yet in being fertilised, they need to be grown in specialised culture medium that attempts to mimic a woman’s ovary.

To date, the clinical outcome of IVM is still suboptimal as lab matured eggs are likely not as good as those matured in a woman’s ovary. As such, IVM procedure is considered as experimental and researchers worldwide are working on optimising the in vitro culture conditions.

Having said that, IVM does bring some notable advantages. It eliminates the risk of reseeding cancer and allows for fertility preservation without hormonal stimulation or delays in cancer treatment. By removing the need to administer hormones, IVM avoids costly drugs and frequent monitoring.

In Australia, immature oocytes were first collected from patients with PCOS, resulting in one live birth in 1994. The first live births using frozen-thawed embryos from in vitro-matured oocytes of cancer survivors were reported in Singapore, Belgium, and the United States.

Ovarian protection medications

Currently, the only medication for ovarian protection during chemotherapy is gonadotrophinreleasing hormone (GnRH) agonist. However, its efficiency remains controversial.

In 2013, The American Society for Reproductive Medicine recommended the use of GnRH agonist in combination with other fertility preservation methods, such as one discussed above.

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Fisch & Abir, 2018

For more information regarding fertility preservation, you can contact Melbourne-based fertility specialist and gynaecologist, Dr Alex Polyakov here.

Nutrition and supplementation facts for preconception planning

During the famous Dutch famine of 1944–1945, the daily nutritional intake of pregnant women was reduced to only approximately 400–1000 calories, which is well under the 1800-2400 calories recommendation. As a result, infants who were subjected to mid or late gestation calorie restriction were born lighter. Later in adulthood, these children also experienced reduced glucose tolerance. But interestingly, children whose mothers were exposed to the famine during early gestation had a normal weight at birth but higher body mass index in adulthood.

These puzzling results led early researchers to the “foetal origins” hypothesis, which proposes that the in utero environment can set the trajectory for the subsequent development of childhood or adult diseases. For example, a foetus starved in the mother’s womb may be more likely to develop obesity, diabetes and other conditions later in life.

Although the Dutch famine is a rather extreme example of unfavourable in utero environment, it is now well recognised that lifestyle factors such as nutrition are crucial even from the early stage of preconception planning.

With almost an infinite number of food choices nowadays, many people are actually more confused than ever as to what they should eat. The 2013 Australian Dietary Guidelines suggests that healthy women can meet their nutritional requirements by eating a balanced diet, with a focus on whole foods rather than supplements. However, pregnancy increases the daily requirement for some key nutrients to provide for the growing foetus, making it sometimes helpful to use supplements if a woman is at risk of deficiencies.

Folic acid

Folic acid is one of the most well-known pregnancy supplementations for preventing birth defects such as neural tube defects. In fact, folic acid is made mandatory in bread-making wheat flour in 2009, which drastically decreased the occurrence of neural tube defects by 300% each year.

In addition, a large-scale study involving 65,643 pregnancies shows that folic acid supplementation is also beneficial to reduce the risk of miscarriages, which occur in at least 15% pregnancies. The new findings revealed that folic acid supplementation is more beneficial when started well before conception. Women who started supplementing at least 3 months before conception had a 10% lower risk of miscarriage than those who started 1-2 months before conception or after conception.

Therefore, regular folate supplementation (0.5mg daily) is recommended to sexually active women. A tenfold higher dose may be needed for women who have obesity, pre-existing diabetes, a known MTHFR mutation, multiple pregnancy, epilepsy diagnosis, or a history of neural tube defects. Ideally, supplementation should begin 12 weeks before conception to ensure abundant stores.

Iodine

Thyroid activity increases during pregnancy, accompanied by an increase in the recommended daily intake of iodine (220mcg/day). When iodine intake is inadequate before conception, the foetus may not acquire enough iodine during pregnancy, leading to detrimental effect on its early brain development. This could mean infant death or affected mental capacity later in life.

Similar to folic acid, iodine fortification has also been made mandatory in bread. Iodised salt, eggs, meat, dairy, seafood and kelp are also sources of iodine. Despite that, surveys of pregnant Australian women have found that many still are at risk of iodine deficiency. In such cases, women may need to supplement with 150mcg iodine daily throughout preconception planning and pregnancy.

Iron

Iron deficiency is well known to cause anaemia. During pregnancy, iron demands increases, but supplementation is not routinely recommended for healthy women without a history of anaemia.

Red meat, green vegetables and whole grains are good sources of iron. Iron absorption can also be increased by pairing with vitamin C-rich foods such as citrus fruits. In contrast, tannins in tea and some minerals like calcium can reduce the absorption of iron when consumed together.

Vitamin D

Although Australia is known for its sunshine, vitamin D deficiency is unfortunately not uncommon. It is estimated that more than 30% of adult Australians have a mild, moderate or even severe deficiency, which leads to bone and joint problems.

The Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) recommends supplementation with 10mcg (400IU) of vitamin D3 daily as part of a pregnancy multivitamin if the woman is unlikely to achieve the adequate daily intake of 5mcg. For example, women receiving limited sun exposure due to having darker skin, spending daylight hours indoors, or applying heavy sunscreen may benefit from supplementation.

Apart from the aforementioned, there are many other nutrients that are important for pregnancy. However, this does not mean that supplements are always beneficial. In fact, daily vitamin A supplement has been associated with congenital malformations and daily vitamin C associated with preterm birth.

It is always important to aim for adequate nutrition through whole foods first and only turn to supplementation when there is a good reason to do so, as indicated by your healthcare provider.

For more information regarding preconception planning, you can contact Melbourne-based fertility specialist and gynaecologist, Dr Alex Polyakov here.