Fertility

Fertility and the future of reproductive medicine

Four decades after the world’s first IVF baby was born, Cath Bennett explores the future of reproductive medicine.

When Louise Brown, the world's first IVF baby, was born in 1978, it was feared the human race was standing on an ethical precipice from which there could be no safe return, as panic about 'assembly-line fetuses' and 'Frankenbabies' reigned.

Forty years later, an estimated 6.5 million people are alive thanks to assisted reproductive technology (ART), with around 1500 born annually in New Zealand. But what's next for the one in four couples who struggle to conceive naturally? Can in vitro fertilisation – a process which brings egg and sperm together in a lab setting before the resulting embryo is implanted in the womb – be further improved to enjoy higher success rates?

With an increasing social preference for starting a family later, can we push human biology to the point where most first-time mums are in their 40s? And how far away are we from turning evolution on its head by creating artificial wombs and building babies from stem cells?

Beating the biological clock

As most women are aware, one of the biggest barriers to getting pregnant is age. The ticking biological clock is impossible to ignore, which explains why the average woman using ART is 35.8 years old – with one in four aged over 40.

The challenge is that with advancing years both the production and quality of eggs declines, which has led to a huge focus on establishing whether this natural decline could be stopped, or even reversed.

In recent years possible options have ranged from using synthetic hormone supplements to a more experimental procedure being trialled overseas, whereby the ovaries of menopausal women are injected with their own blood in the form of platelet-rich plasma (PRP) – better known for its use in 'vampire facials' – thereby hoping to restart their menstrual cycles.

Although New Zealand experts are skeptical of such research, they are more optimistic about studies into slowing down the ovarian ageing process.

While fertility specialist Dr Andrew Murray, a medical director at Fertility Associates, warns "there's no magic bullet yet", he suggests anti-ageing developments in other areas of medicine could have knock-on benefits for eggs.

"We've looked at research for melatonin and coenzyme Q10 – both supplements that potentially might be of value," he says. "But I'd emphasise that for as many studies that show benefits, there are several that show none."

There is no doubt the concept of a pill or diet that could improve the quality of our ageing eggs, helping us retain fertility, is an appealing one.

University of Otago anatomy research fellow Dr Karen Reader, who established AgResearch's IVF Invermay Campus laboratory for sheep, points to the fact farmers feed up ewes prior to putting them out to ram to increase ovulation rates – and potentially improve their egg quality. And although it's yet to be established, the same could be true for women.

"However, it's really difficult with human studies to control everything to know if something is working or not," she adds. "But we're understanding more and more that nutrition, even prior to pregnancy, affects the quality of the egg right from the start."

Healthy harvest: freezing your eggs

When it comes to stopping the clock on our reproductive ageing, one method that has seen results, and is expected to gain further traction, is egg freezing.

Medically known as oocyte cryo-preservation, it involves the stimulation, harvesting and storing of eggs when a woman is younger, that will then be thawed at a later date, fertilised, and transferred to the uterus as embryos.

Formerly viewed as an experimental procedure, it has become so mainstream that tech companies including Google, Facebook and Apple offer it as a perk for their US employees.

It has had considerably slower uptake in New Zealand, but as success rates have improved so has interest.

"When we first started egg freezing in the early 2000s, we would get around 50% of the eggs to survive the freeze-thaw process," says Dr Murray, one of the fertility experts on the popular TVNZ documentary series Inconceivable. "It's now over 90%."

This doesn't automatically mean nine in 10 eggs will result in pregnancy – it's more like one in two – but as Professor Cindy Farquhar of the University of Auckland's Department of Obstetrics and Gynaecology explains, "what you've gained is the possibility".

"It's a type of insurance policy but it's not," she adds. "When you take out insurance against damage to your car you pay a bit more to get 100% cover – you can't pay more to get 100% cover with this."

The use of the freeze-thaw method doesn't stop with eggs. Since 2005 the cryopreservation of ovarian tissue for cancer patients has been an option in New Zealand.

Dr Reader explains that although it's an invasive procedure, this has the advantage that when transplanted back into the body, natural hormones can stimulate the thousands of eggs contained within the tissue, which can then start to grow and ovulate naturally.

Cryopreservation of ovarian tissue not only helps fertility, she says, but improves women's health "because it returns their natural hormones to the body and they can menstruate again and actually restore fertility. There are babies which have been born naturally using this method."

While quick to clarify that natural conception is not a guarantee from ovarian tissue freezing, Dr Reader doesn't rule out the possibility it could become a more widely accepted option, especially if it evolved to the point where it became a simpler process.

Dr Dean Morbeck, scientific director at Fertility Associates, agrees it has broader potential in the future.

"It might turn out that it's way more effective than freezing eggs – which requires an entire stimulation to get the eggs versus just taking a little strip which contains thousands of them," he says.

"But freezing ovaries as a routine way to preserve fertility is probably 10 years away – it's more invasive and there is still a big cost."

Using tests to ensure success

Of course, egg freezing is no guarantee of egg quality, and while abnormalities are less likely in younger women, concerns about chromosomal issues and genetic defects are a reality for most mums-to-be.

This has led to developments in genetic screening, with IVF patients now able to opt for preimplantation genetic screening (PGS). The process involves biopsying then freezing embryos while establishing chromosomal makeup, helping embryologists pick those with the most potential to successfully implant, reducing the likelihood of miscarriage or resulting in a child with disability.

It's particularly useful for women who have had multiple miscarriages or those aged 37 and over, who are more likely to experience chromosomal issues. While currently only conducted on around 10-20% of IVF patients in New Zealand, in some American clinics they test every embryo, which begs the questions, in the future could – and should – that happen here?

Dr Morbeck, who prior to moving to New Zealand spent a decade working at the famed Mayo Clinic in America, doesn't believe so, suggesting the technology is something of a double-edged sword.

"Last year a big study indicated the screening doesn't help women under 35 get pregnant any quicker," he explains, adding this is due to there being less prevalence of chromosomal issues for younger women.

"Where it becomes a benefit is for older women, but it's a double whammy – because most women of age 40 are only going to make one or two embryos. If you're trying to get pregnant, do you really want to put an embryo through those steps of testing when you could just transfer it?"

Another groundbreaking strand of genetic testing is preimplantation genetic diagnosis (PGD), a process which when first mooted several years ago created fears of 'designer babies', which parents might select for eye colour, potential intelligence or perhaps likelihood of going bald at a young age.

In reality, while it has become a tool for sex selection, a practice most famously used by Kim Kardashian – but which is illegal in New Zealand – it has been valuable in avoiding inherited diseases.

If carriers of conditions such as cystic fibrosis, Tay-Sachs and Huntington's disease go through PGD, doctors can avoid implanting any embryos which carry the gene disorder, a process which has far-reaching implications for the future.

"There is the potential for a debilitating neurological disease like Huntington's to be completely eradicated by doing PGD – you would stop it from ever being passed on in those family trees," explains Dr Murray.

Dr Morbeck agrees that if all those at risk were willing to have PGD, which has to be performed in conjunction with IVF, "something like cystic fibrosis could be slowly removed from the population".

Beyond this, the next step would be germline engineering, through which technology is used to manipulate an embryo's DNA. While this raises serious ethical questions, it could also be a game-changer in disease prevention.

"I think in the future gene editing might come, whereby we tinker with the genes, improving health for particular conditions," says Professor Farquhar, who is coordinating editor of the Cochrane Gynaecology and Fertility Group.

"We're not there yet but I think it does have possibilities."

Science fiction becoming reality

Yet the more manipulation and intervention that goes on, it seems the closer we get to possibilities as alien to us now as IVF was to objectors who showered Louise Brown's family with hate mail four decades ago.

If you look up the word 'ectogenesis' in The Oxford English Dictionary, the definition – 'the development of embryos in artificial conditions outside the uterus' – includes the qualification: 'chiefly in science fiction'. Yet the use of an artificial womb is now less fiction and more laboratory reality.

Last year researchers at the Children's Hospital of Philadelphia announced the development of a 'biobag' which success-fully 'grew' premature lambs, while in 2016 Cambridge University scientists managed to keep a human embryo alive in a lab for nearly two weeks using a mix of nutrients which mimicked conditions in the womb.

While such innovation could make a huge difference for premature babies, it certainly gives pause for thought.

"You wonder, what is the actual impact of being in a womb for the development of a child – and how do we test that?" says Dr Morbeck, who lectures at the University of Auckland. "And that's the step after we figure out how to do it biologically. It's something I think is a long way away."

Even more questions – and appre-hension – surround making embryos without sperm or egg. Scientists have already created baby mice from adult mouse skin cells, with some believing it's only a matter of time before a baby can be fully 'built' using lab-generated reproductive cells, or gametes.

"It's an amazing possibility but one fraught with a lot of risk," says Dr Morbeck. "It's something we'll not see in our lifetimes – and maybe not ever."

Dr Reader agrees. "There's an awful lot of manipulation that has to be done with artificial gametes, and it comes with various epigenetic imprinting problems that can affect the embryo," she says.

"We don't know how it would impact on the health of the offspring – and the problems may actually carry over to multiple generations."

And those challenges don't take into account the ethics of such practices.

"I think it's appropriate that we have somewhat of an ethical handbrake on reproductive medicine," says Dr Murray, pointing out that even commercial surrogacy can have horrific implications. This was highlighted by the 'Baby Gammy' case, in which a newborn with Down syndrome was left with the surrogate after the people who paid her only took the baby's healthy twin.

"Scientists will keep developing the boundaries, but that doesn't necessarily mean we should use that technology," says Dr Reader, who is on the Ministry of Health's Advisory Committee on Assisted Reproductive Technology (ACART). "It's really up to the general public to decide."

And here in New Zealand, where fertility clinics operate within regulations imposed by the Human Assisted Reproductive Technology Act (HART) of 2004, we may be more hesitant than other countries to adopt some of the more forward-thinking technologies.

The hurdles for New Zealand: Standing in our own way

HART's relatively strict guidelines have recently been called into question by New Zealand academics, who in June petitioned for a review into the fact they are currently prohibited from using viable embryos for research purposes.

"It means New Zealand is not able to compete in global scientific endeavours about embryo research," says Professor Farquhar, whose own investigations have been limited by the legislation. "If I had been able to do the 'day of transfer' study into whether day three versus day five embryo transfer in IVF is superior, patients would have that answer now."

And for infertile couples, every morsel of research that might make ART that little bit more successful is cause for hope.

According to Fertility Associates data, 40% of those who start a single IVF cycle before they are 38 will have a baby, a percentage that drastically drops with age – making it in no way a guarantee.

While it's generally agreed IVF has been pushed almost to its limit – Dr Murray refers to a future "ceiling of effectiveness limited by human biology" – the current focus is on refinements that might incrementally improve its efficacy.

Time Lapse Morphometry Imaging (TLMI); developing embryos in incubators which each contain a tiny camera, allows scientists to monitor the progress of an embryo without disturbing it, something Dr Morbeck expects will become "the standard of care at some point".

Another focus is on the cultures embryos are nurtured in, as researchers not only establish which of those available is the best, but also explore how far science can better imitate what goes on naturally in the human body.

"Embryos don't just sit in the same solution the entire time, so we could be recreating what is happening in the reproductive tract, delivering small amounts of nutrients and removing waste," says Dr Morbeck.

He is also excited by the imminent launch of technology that will determine the health of the embryo simply by analysing the solution it has been developing in – a less invasive form of genetic screening.

And IVF isn't the only ART being refined. Professor Farquhar recently carried out research into the effectiveness of intrauterine insemination (IUI), a process where the best quality sperm is identified and given 'a head start' by being placed directly in the uterus. Usually combined with medication to stimulate egg ovulation, Professor Farquhar found it makes pregnancy three times more likely for couples trying to conceive naturally.

"There are quite a lot of studies around how many cycles you do, how much sperm and so on," she says. "I think there are a few refinements – and I now want to compare it with IVF."

What is clear is there is no shortage of research in this area of medicine. And while the options for women struggling to get pregnant are rapidly advancing, there is no magic solution to 'fix' infertility arriving any time soon.

The key message experts want women to keep in mind over the next 10 years? For all the artificial intelligence, research and knowledge we have at our fingertips, it's the same as it's been for the past decade.

"Don't leave starting a family too late, and if you are going to defer having kids, look into the options," says Dr Murray. "I think that sort of message will help improve options for future generations."

The advantages of egg freezing

Egg freezing has the potential to be a game-changer for many Kiwi women – and Fertility Associates is at the fore-front of making it a viable option in New Zealand.

Over the past 18 months thetreatment specialists have been running a trial to establish the effectiveness of the procedure. Eggs from eight donors were frozen and thawed, which resulted in pregnancies in seven women, and so far two healthy babies have been born.

"It shows us that our egg freezing process on donor eggs works really well, and allows us to feel more confident when advising people who want to preserve their fertility," explains scientific director Dr Dean Morbeck.

The process involves all the steps of an IVF cycle, and regulations allow the storage of eggs for up to a decade, making it a good option for younger people who want help preserving their fertility until they are ready to start a family.

Fertility Associates medical director Dr Andrew Murray (pictured) points out the process has a further advantage when it comes to New Zealand's drastic shortage of egg donors.

"Instead of having all her eggs used immediately, a single donor can actually freeze those eggs and potentially allocate them to more than one couple," Dr Murray says. "So that has the impact of increasing the availability of donor eggs as well."

Around 95% of eggs survive the freeze-thaw process, with approximately 40% reaching the stage when they can be implanted, although Dr Morbeck expects technology to improve these rates.

"In Sydney they have developed an automated freezing machine which has the potential to improve the way we freeze eggs so that hopefully there will be a higher success rate."

Starting the fertility journey

Infertility can be a rollercoaster ride, from exploring your options to the cost of treatment to finding a support group.

Some couples may be eligible for two rounds of publicly-funded treatment, but wait lists can be long and, given time is of the essence when it comes to fertility, couples may choose to go the private route.

Currently it costs around $10,000 for a cycle of IVF, and egg freezing – without storage and later embryo creation – is the same price. Fertility Associates undertakes both private and publicly funded treatment. They also provide free nurse consultations to help anyone seeking advice to get the help they need.

If you're going through treatment, or struggling with the emotional aspects of infertility, Fertility NZ can help. They offer support gatherings, workshops and contact groups throughout the country.

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