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What you need to know about fertility at advanced maternal age

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Prior to embarking on any fertility treatment, it is invaluable to be able to predict an outcome. This heavily depends on the woman’s ovarian reserve, which is most reliably determined by the female age.

At age 20, only approximately 2.4% of sexually active women cannot achieve a live birth. However, by age 40, 35% of women have troubles falling pregnant. This increases sharply to 50% at the age of 41 and 90% at the age of 45.

The impact of age is two-fold: there is a progressive depletion of the number of fertilisable eggs, which is also accompanied by an age-related decrease in quality.

Since advancing age is not reversible, it is a good idea for couples to plan ahead how many children they would like to have and when. If you are willing to go through assisted reproductive technologies, it may be acceptable to delay childbearing for a few years. However, there is always the possibilities that things may not go as planned. The following table can be used as a general guideline for the latest female age to start building a family of certain size, with or without IVF.

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Ovarian reserve testing

A more personalised and accurate strategy for family planning is to test the ovarian reserve. The most common ovarian reserve test in the clinic nowadays involves checking the levels of Anti-Müllerian hormone (AMH).

AMH is described as the “follicular gatekeeper” that limits the size of the follicle cohort available to respond to hormonal signals each month. Since AMH is only produced by follicles at the later stages of development, they represent a “functional” pool of the ovarian reserve.

Women with a very low AMH level can be predicted to produce a low number of fertilisable eggs upon controlled ovarian stimulation, which dramatically reduces the efficiency of IVF treatment. In these women, the conventional stimulation protocol may not be helpful for the purpose of producing multiple eggs per cycle.

In addition, AMH has recently been proposed as a biomarker for optimising the dosage of ovarian stimulating drugs. It has proved to be a great predictor for ovarian hyperstimulation, a life-threatening condition associated with gonadotrophin stimulation.

What can women do to “stop” the ticking clock?

One way to plan for the future is to freeze eggs or embryos at a younger age. Ideally, eggs should be retrieved before 30 and definitely before 35. This is because both the quantity and quality of eggs that can be retrieved per cycle plummet after mid-30s.

While frozen transfers are frequently successful nowadays, the use of egg freezing is by no means a safeguard option against age-related fertility decline. Women of advanced maternal age are also more likely to have other conditions that increase the risk of adverse pregnancy outcomes, independent of egg quality itself.

Importantly, women should avoid multiple pregnancies and only undergo single embryo transfer to ensure safety. Since age is also correlated with increased genetic mistakes known as aneuploidy. preimplantation genetic screening for aneuploidy is highly recommended to select chromosomally normal embryos.

Takeaways:

  • Couples may consider fertility evaluation testing, especially AMH test for ovarian reserve, as part of family planning or before fertility treatment.

  • Woman at advanced reproductive age should be aware of the risks of poor ovarian response, reduced egg retrieval and fertilisation rates.

  • Woman at advanced reproductive age are encouraged to be evaluated for other comorbidities that may complicate the pregnancy.

  • In women above the age of 40 with a low AMH level, egg donation may be discussed as an alternative.

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

References

The role of mitochondria in egg quality and ageing

The female egg is the largest cell in the human body and the richest in mitochondria – the energy powerhouse for all of our cellular activities. The egg is tasked with many energy-demanding activities, including ensuring the correct amount of genetic materials passed down to our offspring.

Interestingly, the inheritance of mitochondria is tightly maternal. Although the male sperm carries mitochondria into the egg during fertilisation, they have to be eliminated inside the egg through degradation. When this process is defective, the embryo contains more than one set of mitochondrial DNA, which harms the ensuing embryo development in a condition known as “heteroplasmy”.

Mitochondria as an indication of egg quality

The amount of mitochondria in the egg can be used to predict the ATP generating capability, which is a key determinant for its fertilisation potential. Good quality eggs that can lead to blastocysts are found to produce a certain level of ATP. This is because the total amount of mitochondria does not increase further during the first few days after fertilisation, making it critical to have an abundant reserve to start with.

When an egg is selected for final maturation before fertilisation but have inadequate mitochondrial activity, the last steps of maturation may be delayed or terminated. This can increase the rate of chromosome segregation defects (aneuploidy), which is directly related to a decline in pregnancy rate.

Apart from its best-known function in energy production, mitochondria are also involved in regulating oxidative stress, cell death and key signalling pathways. As mitochondria produce the cellular fuel, ATP, they also release a detrimental by-product called reactive oxygen species (ROS). This must be detoxified by antioxidants as they can lead to damages to our DNA and proteins.

Ageing and mitochondrial dysfunction

The female age is the single biggest factor in determining woman’s fertility, due to a decline in the quantity and quality of her eggs.

As women age, the number of mitochondria sharply declines in the egg, reducing the availability of cellular fuel. At the same time, the deleterious oxidative stress increases, contributing to lower egg quality. These dysfunctions are largely due to mutations or damages in the mitochondrial DNA.

When cellular fuel is reduced, the assembly of the spindle machinery which separates chromosomes can be disrupted. This usually leads to increased rates of aneuploidy and spontaneous abortions. It is estimated that the incidence of aneuploidy in young eggs from women in their 20’s is 2%, but dramatically increases to 35% around 40 years old.

Ways to improve mitochondrial function

There are currently a few methods that aim to improve mitochondrial health in eggs, but few have yet proven safe and effective.

For women with known mitochondrial mutations that could not sustain life, donor mitochondria or egg content (cytoplasm) can be transferred to replace defective mitochondria. However, this leads to the issue of “3 parent genome”, where the offspring may suffer from potentially harmful effects of mitochondrial heteroplasmy. Since the effect of having more than one mitochondrial genome on the offspring health is not entirely clear, the US FDA suggested that this technique be suspended in 2002.

There are other less radical approaches for improving mitochondrial health such as dietary supplementation. CoQ10 is a coenzyme that works in the mitochondrial respiratory chain. Since CoQ10 declines with age, supplementation may be able to compensate for the loss. Indeed, some evidence suggests that supplementation with CoQ10 may improve egg and embryo quality, especially in women with advanced reproductive age.

Having said that, supplementation is not necessarily suitable for your unique condition. For more personalised information regarding your fertility, you can contact Melbourne-based specialist, Dr Alex Polyakov here.