For anyone navigating an IVF journey, there are likely to be many hurdles along your way. One of the first is making the decision to start fertility treatment and then deciding which treatment to do. There is no right answer to these questions. Clinicians are sometimes criticised for pushing people for IVF too soon, and others criticised for taking too long. How a couple progress through their fertility journey is very individual to them.
When you start IVF, chances are you are going to be paying for your treatment. IVF is a multi-billion-dollar industry, with the majority of treatments being privately funded by patients. I went through 7 years of fertility treatment and I lost count of the number of intrauterine insemination, IVF and frozen embryo transfer cycles I did. I was lucky enough to collaborate with IVF clinics which did my treatment for free, as I could not have afforded to pay, there was no NHS funding in my area, and I would not have been able to have my family. I am very aware that IVF is hugely expensive, often causing debt, mortgaging of homes, borrowing money and more. I have always wanted to be sure that we offer patients cost effective, evidence-based treatments, which will give them the best chance of getting pregnant. But in today’s IVF clinics, chances are you will be offered an IVF add-on, which can add thousands to your treatment cycle.
What are IVF add-ons?
An IVF add-on is any additional treatment which is not essential for an IVF/ICSI cycle and which are often claimed to improve LBR (live birth rate). There is a very long list of potential add-ons that you may be offered and I want to explain to you what you need to consider.
If any IVF treatment is going to claim to improve live birth rate (LBR), we should provide patients with evidence that this really is the case. There are many ways that scientists can test IVF add-ons, but the gold standard study is a randomised controlled trial (RCT). With an RCT we have a control group that doesn’t have the treatment and a treatment group that does have the treatment. Patients should be randomly allocated into one of the two groups and at the end of the study, we compare the LBR from both groups to determine if the treatment has improved the chance of a live birth. This sounds simple, but doing such studies is very time consuming and expensive, but I do not think it is an excuse not to do them, especially as add-ons are now common place and being offered routinely without the evidence that they improve live births.
Unfortunately, some randomised controlled trials are not good quality studies as they are poorly designed. For example, sometimes the LBR in the control group is much lower than it should be which will bias the results, as the treatment group will be compared to the control group so it could make the treatment group look better. Sometimes the studies are on very small numbers of participants which will cause bias. But one of the main issues is how the LBR data is presented. This data should be presented as LBR per egg collection procedure so that it is very clear what the chances are of getting pregnant per egg collection. And added to this should be births from frozen embryo transfer cycles which gives us the cumulative live birth rate. However, all sorts of ways of presenting the data from RCTs have been done. For example, sometimes the data is presented per embryo transfer procedure. There are some treatments where the clinic does multiple egg collections and pools the embryos before deciding which to transfer. This will give a high LBR per transfer, but if we looked back per egg collection it would give a very low rate as there would be several egg collections with no transfers. This is financially and emotionally very draining for a couple to go through. As you can see – it can get very complicated and difficult for non-scientists to understand the data.
HFEA Traffic Light System
The Human Fertilisation and Embryology Authority (HFEA) want to help patients navigate IVF add-ons. It was a pleasure to be part of the HFEA committee that developed a traffic light system which rates add-ons as red, amber or green. The committee looked at several key add-ons and examined all the studies that have been done, especially the RCTs and they rated the add-ons. A red rating means there is no evidence to show that the add-on will improve LBR, amber means there is conflicting evidence and green means there is robust evidence showing it will improve LBR. The rating may change as new studies are reported. Currently, the HFEA lists 12 add-ons on their web site (https://www.hfea.gov.uk/treatments/treatment-add-ons/): rated red are: asssited hatching, endometrial receptivity array, immunological tests and treatments for fertility, intracytoplasmic morphologic sperm injection (IMSI), physiological intracytoplasmic sperm injection (PICSI), intrauterine culture and preimplantation genetic testing for aneuploidy (PGT-A). Rated amber are artificial egg activation, elective freeze all cycles, endometrial scratching, hyaluronate enriched media (Embryo-Glue), and time lapse imaging. There are currently no green add-ons.
The traffic light ratings only apply when the procedures are being used as an add-on to try to improve LBR. Sometimes they may be used for other reasons. For example, time lapse imaging is a terrific incubator which produces a video of the embryo developing and embryologists can look at these images to determine which embryo to transfer. But time lapse is classed as an add-on if the clinic claims that using it will improve LBR. The data from the RCTs using time lapse have not shown conclusive evidence for an improvement in LBR. So even though it is a great incubator, patients should not be told that paying extra for time lapse will improve their LBR. Freezing all the embryos in a cycle rather than putting back any fresh embryos is also a procedure that has a value in certain circumstances, besides being an IVF add-on. There is a serious condition that can happen called ovarian hyperstimulation syndrome (OHSS) which can make the woman really ill if embryos are transferred in the fresh cycle. In cases of OHSS, it is highly advisable to freeze all the embryos to prevent OHSS. This certainly is an important use of freeze all and is not using freeze all as an add-on as it is not being used to improve LBR.
ESHRE – Good practice recommendations for add-ons
I have been part of the team from the European Society for Human Reproduction and Embryology (ESHRE) who have written a document titled ‘Good practice recommendations for add-ons in reproductive medicine’ which will be open for consultation very soon on the ESHRE web site (www.eshre.eu). We have included recommendations for many more add-ons than the HFEA, almost 30. We separated the add-ons into three categories: add-ons in diagnostic/diagnosis tests, laboratory tests and interventions, and add-ons in clinical management. One important add-on that we have included is the use of intracytoplasmic sperm injection (ICSI) for non-male factor infertility. ICSI is a treatment for male infertility where a single sperm is injected into the egg but it is often used when there is no male infertility as some think that it will improve LBR. All the studies to date have shown that ICSI for non-male factor infertility does not improve LBR.
Research into add-ons
I have been studying add-ons for many years. Since 1992 I have been working on preimplantation genetic testing (PGT) for inherited disease at University College London. But alarm bells started ringing for me in the mid 1990s when two groups in the USA suggested that we could use the PGT techniques to identify embryos that were chromosomally normal with the view of increasing LBR. This was originally called preimplantation genetic screening – PGS, but now called PGT -A for aneuploidy. The initial studies were of poor quality and were a long way from showing that the technique worked. Roll on almost 30 years and it makes me hugely sad to see that with the large number of studies that have now been done, no data has shown that PGT-A improves IVF LBR. The HFEA have rated PGT-A red.
I have published two studies looking at the number of PGT cycles done in the UK and USA. We have shown that in the UK, PGT only accounted for about 2% of IVF cycles, but in the USA, the data for 2017 showed that PGT accounted for 32% of USA cycles and three clinics used PGT for every single IVF cycle.
How do fertility clinics market IVF add-ons?
I have also looked at how IVF clinics market IVF add-ons and what medical directors think about add-ons. My studies have shown that patients often request IVF add-ons as the way they have been marketed online is very positive. As a result, this can lead patients to feel they are actively doing something to try to improve their chances by paying the cost of an IVF add-on, even when there is no evidence that it will improve their chance of live birth. I think this is so unfair and putting a huge extra burden on IVF patients. I know what it is like, and I tried many unproven techniques when I was trying. But now studies have been done and we all need to take note when the data shows it does not help. Recently the Competition and Markets Authority has looked at how clinics advertise IVF treatments and produced recommendations on the use and advertising of add-ons in the UK (https://www.gov.uk/government/news/cma-issues-ivf-guidance-on-consumer-rights). Their recent report has shown that IVF units are not complying with their recommendations and that ‘self-funding patients are not always getting the information they need to make informed decisions.’ (https://www.gov.uk/government/news/fertility-clinics-compliance-with-consumer-law-findings-published). If clinics fail to comply, the CMA could take enforcement action.
How much of a problem are add-ons?
The HFEA have done a number of patient surveys and their latest survey found that the overall use of add-ons has declined, but acupuncture and time-lapse imaging use have increased. They found that 65% of patients had used an IVF add-on and the most commonly used add-ons in the UK are: acupuncture, time-lapse imaging, hyaluronate enriched medium (commonly known as ‘embryo glue’), endometrial scratch and immunological tests (https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2021/).
How do you decide what is best for you?
I would certainly recommend the information on the HFEA web site (https://www.hfea.gov.uk/treatments/treatment-add-ons/). Clinics often promote their in-house figures for success rates, but if these are robust and unbiased, they should publish their data. Get as much advice as you can from different clinicians, but you will find they have different opinions. Think very carefully about the cost, as add-ons can cost up to £3000 extra. Make your own decision about what you feel is right for you.
Joyce’s publications on add-ons:
Olivia Iacoponi, Lucy van de Wiel, Jack Wilkinson, Joyce C Harper (2022), Passion, Pressure and Pragmatism: How Fertility Clinic Medical Directors View IVF add-ons, RBM Online https://www.sciencedirect.com/science/article/pii/S1472648322001316
Stein, J, Harper, JC (2021) Analysis of fertility clinic marketing of complementary therapy add-ons, RBM Society https://www.sciencedirect.com/science/article/pii/S2405661821000095
Roche, K, Racowsky, C, Harper, JC (2021) Utilization of Preimplantation Genetic Testing in the USA JARG https://pubmed.ncbi.nlm.nih.gov/33904009/
van de Wiel, L, Wilkinson, J, Athanasiou, P, Harper JC (2021) The prevalence, promotion and pricing of three IVF add-ons on fertility clinic websites. RBM Online, Volume 41, issue 5, 801-806 https://www.rbmojournal.com/article/S1472-6483(20)30392-8/fulltext
Theobald R, SenGupta S, Harper JC (2020) The current status of preimplantation genetic testing in the UK and USA, Human Reproduction, 35, 986–998, https://doi.org/10.1093/humrep/deaa034
Harper, J, Jackson, E, Sermon, K, Aitken RJ, Harbottle, S, Mocanu, E, Hardarson, T, Mathur, R, Viville, S, Vail, A, Lundin, K (2017) Adjuncts in the IVF laboratory: where is the evidence for ‘add-on’ interventions? Human Reproduction, 2(3):485-491. doi: 10.1093/humrep/dex004. https://academic.oup.com/humrep/article/32/3/485/2959525