IVF remains largely a numbers game

Most healthy young couples seeking to get pregnant will try for a few months before they are successful. Those who are not will try for months more, or years, before concluding they need help and stepping into the waiting room of an IVF clinic. They often arrive in a state of acute emotional vulnerability, clutching at the hope that doctors will help.

For the woman, what follows is uncomfortable at best. There are internal ultrasounds, dozens of self-administered hormone injections into her increasingly bruised abdomen, the swelling of her ovaries until two clutches of hard grapes appear to be knocking about on either side of her pelvis. And unless she is in the lucky minority who get pregnant the first time, she will have to do it again. To take home a new life, most women and couples go through more than one cycle; sometimes, many more. Each brings with it physical discomfort and pain and intense loneliness, the emotional impact of being jacked-up on hormones and the fear of doing something that might impact her chances of having one more egg cell, one more viable embryo, one healthy pregnancy.

IVF helps overcome some of the challenges of making a baby in two ways: first, by increasing the number of mature eggs that a woman makes in one menstrual cycle by means of hormone injections; second, by ensuring that those eggs have the opportunity to be fertilised by sperm. This overcomes problems caused by ovaries that do not of themselves give up their eggs, by blocked Fallopian tubes which form a barrier between the egg and the sperm swimming to meet it and by sperm that aren’t good swimmers. When sperm are truly lacklustre, fertilisation can be more or less guaranteed by squirting one straight into the egg: “intracytoplasmic sperm injection”, or ICSI (see diagram).

In the case of, say, blocked tubes, the fertilised eggs produced by IVF may be the first of the woman’s eggs ever to have met any sperm. But that is not enough to guarantee a pregnancy. Every time a sperm and an egg fuse, the sum of their parts is a unique genetic package. Much of whether or not the resulting embryo is viable and able to develop into a healthy neonate is down to dumb genetic luck. Not every fertilised egg naturally leads to a pregnancy. This makes IVF a numbers game.

Globally, between six and seven out of every ten ivf cycles will not result in pregnancies which go to term. As a result, many women will try more than once. In each cycle, a woman may have one or more embryo transfers. Each of these can take months, and recovery adds more time. With medical tests, life, jobs and mental downtime in between, ivf treatments can easily take a year—for many it will be longer, with no guarantee of success.

The older a woman gets, the steeper the odds. She has all the “oocytes” which will ever develop into eggs in her ovaries when she is born. After puberty every menstrual cycle will see a number of them activated, but normally only one of them matures in a way that leads to ovulation. So month by month her “ovarian reserve” gets smaller. At the same time the dna in the oocytes which remain gradually fragments. By the time she is 45, her odds of a child will be less than 5% with every embryo.

Try, try again

Doctors are used to thinking in terms of probabilities across the population. Patients are not. Patients know people who got pregnant on their first IVF attempt; patients have friends whose walking, talking toddler was once a “low-grade” embryo given tiny odds of leading to a full-term pregnancy. Above all, patients believe they can and will make a life through IVF, because not believing is inconceivable and hope is what gets them to the next appointment, the next throw of the dice. It is possible to sink years and tens of thousands of dollars into multiple rounds of unsuccessful IVF and still feel the next one will succeed.

When an IVF cycle fails, especially if it is not the first time, people naturally seek out ways to change their treatment. “Rather than thinking ‘I have to keep rolling the dice’ people think ‘Something is wrong’,” says Sarah Lensen, a research fellow at the University of Melbourne in Australia. Right on cue, clinics—particularly private ones—step forward with a menu of “add-ons”. Through the grief of yet another failure to conceive, these optional, and generally paid-for, treatments offer hope that the next attempt might just be different.

Price tags range from zero to thousands of dollars, depending on the treatment, clinic and country. Several can be combined into each round. It is basic human psychology to think that if you pay more you might get more. The business model of many clinics trades on such hope.

Unfortunately, the evidence base for these additions is underwhelming. The draft conclusions of a study of 35 of them by the European Society of Human Reproduction and Embryology found that there was sufficient evidence to recommend that just one of the add-ons—the use of hyaluronic acid to help embryos stick to the uterine wall—be added to IVF treatment as a matter of routine. Another—choosing the best sperm by running them through microscopic channels, a procedure held to mimic some aspect of the environment they would encounter in vivo—did show some promising signs of increasing the overall chance of a birth, but those signs fell below the standards required for reliable evidence.

In some other cases there was a possibility that the add-on might, with further testing, be shown to help a specific subgroup; patients with an autoimmune disease, for example, might benefit from steroids. For the rest, though, there was not just an absence of evidence that they worked; there was sufficient evidence to be reasonably sure they did not. A meta-analysis that Dr Lensen led was similarly damning. None of the 12 add-ons it looked at was “supported by high-quality evidence that [it] is effective and safe”. Three treatments, including hyaluronic acid, seemed to provide a benefit, but the evidence was judged to be of poor quality.

One problem is that, given scant public funding for research in this area, randomised and blinded studies with large numbers of patients are infrequent. This may come as a surprise; patients tend to assume that medical interventions are required to go through such tests before they are approved. Often, though, add-ons are IVF-specific applications of procedures already approved for other purposes. “Endometrial scratching”, which involves lightly scarring the lining of the uterus with the aim of stimulating growth factors is exactly the same as an endometrial biopsy, normally carried out to test for cancer. “It got renamed,” says Dr Lensen.

Evening odds

Private clinics have little incentive to spend investors’ money on trials with thousands of patients, especially when there is a risk they will show add-ons that are already being sold to be ineffective. Both authors of this report were offered a trademarked test, costing roughly $1,000, that supposedly determines when a woman’s uterus is most likely to welcome an embryo, by a clinic that later admitted it had not yet been correctly evaluated, and that subsequent trials showed it did not improve chances of success and “may even be harmful”.

In September 2022, after a ten-month investigation into mis-selling, Britain’s Competition and Markets Authority and Advertising Standards Authority together admonished the sector for the way it uses claims about success rates and add-ons.

Some add-ons have become almost standard, even when they are only beneficial to, at best, a subset of patients. In Australia and New Zealand ICSI, which can cost up to a few thousand dollars a pop, is performed in 56% of IVF cycles. In America the share is 60%. Yet it has been proved to help only couples whose infertility is due to low sperm quality—around 30%.

More controversially, pre-implantation genetic testing (PGT) is now being used in roughly half America’s IVF cycles. The most commonly used version of the test, PGT for aneuploidy (PGT-A), involves counting the chromosomes in a few embryonic cells that are taken from the part of the embryo destined to form the placenta. Cells are meant to have an even number of chromosomes and finding that to be the case is taken as a good sign.

Its defenders see PGT-A, which typically carries a price tag of about $5,000, as a better way of telling which embryos will do best than peering down microscopes in order to assess shape and development, as is the historical norm. They argue that selection with PGT-A helps women who are over 35 to get pregnant faster and that it reduces miscarriage rates.

Detractors point out that randomised controlled trials have failed to demonstrate either of those benefits. And recent studies have shown that “mosaic” embryos, in which some cells have odd numbers of chromosomes, can lead to successful pregnancies even though PGT-A may rule them out. And if they are discarded there is a chance that the woman’s overall chance of getting pregnant may drop. ■