It is more than 45 years since the first baby conceived using IVF – Louise Joy Brown – was born, yet the procedure is still a roll of the dice for many couples. Can new research change that?
With steady hands, an embryologist picks up a culture dish containing four human egg cells. Each one has just been fertilised by a sperm – these eggs will start to develop into embryos. Hopefully, at least one of them will go on to become a healthy baby. Hundreds, maybe even thousands of couples will leave clinics around the world on the day you read this story, counting on success. It means the world to them.
For people who undergo in vitro fertilisation (IVF), the days that follow are a tense, agonising waiting game. They have already put themselves through a lot, physically and emotionally, to reach this point.
Some might opt for additional peace of mind. For a fee, the embryologist can slide the dish containing those precious embryos into a high-tech looking machine called a time-lapse imaging device. A button press activates it. The microscope and camera inside then takes a picture of the developing embryos every ten minutes over the next few days, watching over them. Staff often explain to couples that such analysis could increase the chance of a successful birth.
Sadly, it isn’t true. A study published in the leading medical journal The Lancet in July 2024 compared outcomes across more than 1,500 IVF procedures. Some used time-lapse imaging, some didn’t. “There was no significant difference in the live birth rate,” says Priya Bhide, a clinical senior lecturer at the Women’s Health Research Unit at Queen Mary University of London and a co-author of the study.
More than 10 million children have been born worldwide thanks to IVF since the birth of Louise Brown on 25 July 1978. Brown was the first person to be conceived using the technique following more than a decade of research, an achievement that features in the film Joy – named after Brown’s middle name.
And yet the live birth rate, per embryo transfer cycle, for women aged 35 or so is still just 30% in the UK and 39% in the US. In women of all ages, only 45% of embryo transfer cycles led to a live birth in the US, although that has grown from 36% in 2011.
It is clear that an IVF cycle is still a long, agonising roll of the dice.
Serenity Strull/ BBCWhile there have been some improvements in IVF success rates, efforts to stack those dice more in the favour of patients hoping to have children have had mixed results. Doubts over time-lapse imaging, for one, have been around for years. Bhide contributed to a previous high-quality review of evidence on the subject known as a Cochrane Review. It had already suggested there was little evidence that the technique had an impact on live birth rates. The data available at the time, Bhide says, was not as robust as that gathered in her and her colleagues’ latest work.
“People got very excited with this new technology and just started to use it without actually having good evidence,” says Bhide.
Meanwhile, IVF remains gruelling for those who find themselves going through it. Multiple cycles, each one often costing thousands, can end in failure. Women inject themselves with drugs for weeks at a time, endure painful surgical procedures, while the emotional toll on couples can be severe enough to end relationships.
Scientists around the world are trying to help by working on techniques that might improve the odds of success. While there are many interwoven reasons for why IVF treatment can fail, it is possible that other interventions could make a difference. And they might transform the lives of millions.
One major set of challenges is extracting enough eggs in the first place, and handling these fragile cells without damaging them. Earlier this year, a vet in the UK tested out a new solution – carefully inserted a probe into a dairy cow’s uterus. They were hunting for eggs – and they had a special tool to help them. The vet, from the University of Nottingham, was using a new kind of needle to reach into one of the oval-shaped follicles where eggs develop inside the cow. With the gentlest touch, they took up a tiny amount of follicular fluid and eggs into the needle. But there were more eggs still inside the follicle. Luckily, the needle was designed to make it possible to flush some fluid back into the follicle while not losing the already retrieved eggs.
The fluid exits the needle through two microscopic holes along its shaft. This creates a slight, circular current within the follicle, moving the fluid around the remaining eggs, or oocytes, allowing the vet to then suck more of them up into the needle. This intricate design was dreamt up by a pair of mathematicians and their colleagues. It’s an alternative to existing needles that also flush fluid into follicles to help release eggs – but apparently in a less effective way. Those needles don’t seem to create the same broad turbulence within the interior of the follicle.
“Ultimately, the richer the fluid motion you induce, the more likely you are to extract an oocyte,” says Radu Cimpeanu, an expert in fluid dynamics at the University of Oxford. He and colleagues published a paper about their needle design in November last year, where they modelled how it might affect the flow of fluid in a follicle during egg collection. The results of the research testing the prototype of the needle in the cow in Nottingham are yet to be published, but are promising, says Cimpeanu.
He hopes that experiments using human eggs will be possible within the next few years. “We can produce higher numbers of really high quality oocytes,” he says, explaining that the new design means practitioners don’t have to be quite as accurate when placing a needle inside a follicle during an egg extraction procedure. If this does boost the number of eggs retrieved, and their quality, that might conceivably have a measurable impact on live birth rates. But this would have to be proven in large human clinical trials.
Eggs and embryos are delicate. They didn’t evolve to be sucked up by pipettes and flushed into culture dishes. And so, in Spain, another idea is in the works that could make it easier to move these tender foundations of a potential human being around. It involves sticking magnetic nanoparticles to eggs and embryos so they can be manipulated without ever having to physically grasp them.
“We developed a pipette where you have a magnet on the top,” explains Maria Jiménez-Movilla, who studies reproductive cell biology at the University of Murcia, in Spain. The magnetic nanoparticles are first joined with a protein known to bind to the surface of eggs and embryos. In March 2024, Jiménez-Movilla and colleagues published the results of tests using the technique on pig and rabbit eggs. They found that the magnetic nanoparticle mixture stuck specifically to mature eggs. This means that once a group of eggs was drawn into a pipette, only these mature eggs remained when the fluid surrounding them, along with any immature eggs, were subsequently washed out. Like holding onto ripe apples while you discard the unripe ones.
This approach should help the embryologist to pick out only the mature eggs that are most likely to be successfully fertilised. These can then be deposited elsewhere. “You move the magnet and then the cells release,” says Jiménez-Movilla.
The study looked at whether eggs manipulated in this way would go on to form healthy rabbit embryos, and result in live births. The results were encouraging – though there was no statistically significant difference in the live birth rate for rabbit embryo implantations that used this technique versus those that did not.
The researchers say their technique could make it easier for embryologists to manipulate a healthy batch of eggs without damaging them, for instance, though the extent to which this results in IVF failure is unknown. Whether the magnet-based technique would affect live birth rates in humans remains to be seen.
Serenity Strull/ BBCElsewhere, researchers are working on new ways of analysing embryos as they develop, in order to try and tell which are most likely to yield a live birth.
One technique under development in Australia uses light to measure the quantity of lipids, fatty compounds, found inside those embryos. Although only tested on mouse embryos so far, it gives an indication of how metabolically active the embryo in question is, explains Kylie Dunning, associate professor of reproductive biology at the University of Adelaide. “There are decades of research on how important embryo metabolism is for that embryo to develop into a live birth,” she says. An excess of lipids could indicate a less metabolically active egg, for example.
It’s early days for this approach, though Dunning hopes that the technology will prove more impactful than time-lapse imaging did. “We don’t want to end up in the same position,” she says. The hope is that their lipid measurements will prove predictive of human embryo success. Again, this would have to be tested in a clinical trial.
“Everything sounds potentially good,” says Joyce Harper, professor of reproductive science at University College London, who also works with the UK’s Human Fertilisation and Embryology Authority. “Then the research studies happen and we realise it doesn’t work,” she adds, referring to previous efforts to improve IVF success rates.
And yet most IVF cycles are still more likely to end in failure rather than success. “IVF is big, big money,” says Harper. “Now we have all these super high-tech shiny labs. I’m not convinced they are producing better success rates,” she says.
Harper is sceptical that tweaks to embryology procedures will boost live birth figures. And she knows what it is like to stare IVF’s woeful odds in the face. Harper has experienced multiple rounds of treatment herself. “It was heart-breaking,” she says. She isn’t able to say how many rounds she had – she stopped counting because the experience was so traumatic. Happily, Harper now has three children, all of them born thanks to IVF. “It took me seven years,” she says.
Embryos are, she laments, “just not very good” – they are delicate, they fail easily, they often contain genetic abnormalities. Making IVF significantly more successful may not actually be feasible, Harper suggests. But a different, emerging method of obtaining eggs and sperm could help couples out.
Serenity Strull/ BBCIn vitro gametogenesis, or IVG, is a technique that may allow for the generation of sperm or egg cells from a simple tissue sample, such as a person’s skin cells. It has been pioneered in Japan though there are now biotech start-ups in the US also working on the technology. To date, the research has focused on creating mouse egg cells from other cells in a mouse’s body. Experiments to try something similar with human cells are generally considered to be years away by fertility researchers.
The possibilities are mind-boggling, though. IVG could make having children a possibility for people who cannot naturally produce sperm or eggs. “Because they were treated for cancer, because they were born that way,” says Eli Adashi, a professor of medicine at Brown University who chaired a National Academy of Medicine workshop on IVG. “They could potentially be helped whereas before they could not.”
Same-sex parents could also, in theory, have children without the need for donor eggs or sperm. And it might even be possible to take tissue from a single woman, make sperm and eggs from it, and allow that woman to have a baby – entirely on her own. This particular concept, sometimes called “Solo IVG”, is especially controversial, however. The likely genetic similarity between the parent and child in such a case has even led one researcher to question whether the woman’s baby could be considered a “delayed twin”, as opposed to a “clone” – due to the mix of different varients, or alleles, of genes the technique would lead to in the child.
In principle, a non-invasive means of acquiring eggs or sperm could be transformative, argues Paula Amato, professor of obstetrics and gynecologyat Oregon Health & Science University. “If it comes to fruition, it would be revolutionary – almost as revolutionary as IVF itself,” she says. Embryos made with the help of IVG might not themselves be any more or less likely to result in a live birth but it might be much easier to select a high quality embryo and have cycle after cycle, if necessary. “You would just have so many more eggs to work with, so many more embryos to work with,” says Amato.
There are many ethical questions that need to be weighed up before such a technique becomes available, says Amato. Among the hypothetical scenarios already under discussion include the risk that someone could somehow acquire skin cells from a celebrity without their consent and use that to make a baby genetically related to, say, a famous pop star or a successful footballer. “You can think of this as theft of biological material,” says Adashi, who adds that IVG clinics would have to be heavily regulated.
And there are still lots of fundamental questions over how reliable IVG would be, if it proves to be possible in humans at all. “Making eggs from a skin cell – how genetically similar are those eggs to natural eggs? That’s the question mark at the moment,” says Tim Child, associate professor of reproductive medicine at the University of Oxford.
Child is well aware that new technologies could create feverish interest from couples desperate to overcome fertility issues – but only evidence-based studies will prove that any of them work. Child is on the way to becoming an Instagram influencer. He was inspired to do so having seen what he calls “absolute rubbish” content from non-experts discussing IVF on the platform.
“I’m not really the Instagram generation, I’m 56 – my kids in their 20s are quite amused,” he says, noting that he does not make any money from his myth-busting social media presence. To battle misinformation, Child shares results from scientific studies that he judges to be robust, and engages in live question-and-answer sessions with his followers. While he cannot give personal medical advice to participants, he says he is able to tackle questions around “generic” topics of interest – how one’s diet or “add-on” procedures such as acupuncture could affect IVF success, for instance. (Studies suggest the latter doesn’t improve live birth rates, as Child has explained.)
IVF is significantly better today than it was when it first emerged more than 45 years ago. The science gradually improves – just not drastically, says Child: “There are small gains being made [but] it’s very unusual that there’s a complete eureka moment,” he says.
While infertility still presents a major and sometimes emotionally devastating challenge for couples worldwide, it is worth remembering that IVF has brought hope – and happiness – to many. Recently, a patient sent Child a message that sums it up.
“After three years of trying, they had their positive test,” he says, “and a heartbeat on scan this morning.”
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