The Lancet Obstetrics, Gynaecology, & Women’s Health: Lack of good evidence that majority of IVF ‘add-ons’ improve fertility, finds most comprehensive study to date

• Meta-analysis of 85 randomised controlled trials finds the majority of IVF add-ons either show no effect on fertility or remain inconclusive due to limited or low-quality data.
• Approximately half of potentially eligible studies were excluded from the meta-analysis due to trustworthiness concerns; authors call for future research to prioritise large, rigorous clinical trials. 
• In a second paper, authors undertake a randomised control trial which shows a new evidence-based IVF website improved patients’ understanding of the benefits, risks, and evidence quality of IVF add-ons, compared to typical online information.
• Authors say it is important that IVF patients and clinicians are informed by the best available evidence when considering the use of add-ons.

There is a lack of evidence to suggest the majority of in vitro fertilisation (IVF) add-ons improve fertility in patients undergoing IVF, according to a systematic review and meta-analysis published in The Lancet Obstetrics, Gynaecology, & Women’s Health journal. There is weak evidence for some possible benefit from three IVF add-ons: EmbryoGlue, endometrial scratching, and physiological intracytoplasmic sperm injection.

Many people with infertility use IVF; however, the probability of having a baby following IVF is only approximately 30-40% per cycle [1] and decreases significantly with age.

Over the past decade, many ‘add-on’ therapies - extra procedures, medicines or techniques used in addition to standard IVF with the aim of increasing the chance of success - have become available. The use of IVF add-ons is widespread; more than 70% of IVF patients in Australia, New Zealand and the UK report using one or more add-ons during IVF treatment [2,3].

Author Dr Sarah Lensen, University of Melbourne (Australia), says, “In many countries, infertility care is largely provided by private clinics where IVF is highly commercialised, and some add-ons are extremely expensive. Our review finds a lack of evidence that most of the IVF add-ons we assessed provide any benefit to patients. Unproven add-ons can lead to false hope, greater financial strain and unnecessary medical procedures at what already can be a very difficult time for patients. IVF clinics and clinicians should carefully consider whether it is appropriate to offer unproven add-ons, as their availability is often perceived by patients as implicit endorsement of benefit.”

There has been growing concern about the prevalence of problematic or untrustworthy randomised controlled trials within reproductive medicine, including those looking at IVF add-ons. The aim of this meta-analysis was to provide a comprehensive overview of the effectiveness and safety of ten common IVF add-ons, limited to high quality studies with no trustworthiness concerns [4].

Of 157 potentially eligible trials, 72 were excluded on trustworthiness grounds. Authors pooled data from the remaining 85 trials assessed to be trustworthy and looked at the effectiveness of ten widely used IVF add-ons for which patients have expressed a strong demand for evidence-based information.

The study found either no effect on fertility or inconclusive results due to limited or low-quality data for the following seven IVF add-ons: 

• Acupuncture – inserting thin needles into points on the body
• Corticosteroids – medication to reduce inflammation and suppress immune system activity
• Endometrial receptivity testing - a biopsy of the uterine lining to assess gene expression patterns
• Intralipid infusion - a liquid containing fats (soybean oil and egg yolk) that is administered into the blood
• Intraovarian injection of platelet-rich plasma - injecting platelet-rich plasma, made from a patient’s own blood and containing a higher concentration of blood platelets than normal blood, into the ovaries.
• Intrauterine infusion of platelet-rich plasma – insertion of platelet-rich plasma into the uterus.
• Pre-implantation genetic testing for aneuploidy - a screening test to check whether embryos have the expected number of chromosomes.

The review found weak evidence of some possible benefit from three IVF add-ons: 

• EmbryoGlue- an embryo transfer medium containing hyaluronic acid, a natural substance found in the reproductive tract which is considered important for embryo implantation. The evidence review found it may increase the probability of pregnancy and live birth, however the effect on live birth rates was not robust.
• Endometrial scratching- a minor procedure undertaken to scratch or disturb the lining of the uterus.The review finds this procedure may increase the probability of pregnancy and live birth.
• Physiological intracytoplasmic sperm injection (PICSI) - a technique used to select sperm based on their ability to bind to hyaluronic acid, which may be a sign that the sperm is mature and capable of fertilising an egg.There is weak evidence this may lower the risk of miscarriage.

To address the widespread availability and poor-quality information about IVF add-ons, Dr Lensen and her team developed the Evidence-based IVF website (www.unimelb.edu.au/ivf), providing patients with impartial, evidence-based information to help them make decisions about using IVF add-ons [5].

In a second study, also published in The Lancet Obstetrics, Gynaecology, & Women’s Health journal, a randomised controlled trial found the impartial website improved patients’ understanding of the benefits, risks, and evidence quality of IVF add-ons, compared to typical online information about these add-ons. 

The study also found 92% of the IVF patients surveyed in Australia relied heavily on IVF clinic websites for information and more than 60% of patients reported using social media platforms such as Facebook and Reddit for information to guide their IVF decision-making. 

Dr Lensen says, “There is widespread misinformation about IVF add-ons with private clinic websites and patient forums on social media - major information sources for patients - often overstating the benefits and omitting the costs and risks of add-ons. Our trial shows an evidence-based website, free from commercial interests, increased understanding and information satisfaction among IVF patients, addressing a clear unmet need. Although developed in Australia, the evidence is applicable to IVF patients globally and we hope to see this new resource endorsed and used by fertility specialists, clinics and patients around the world." 

 
Previous IVF patient and author on the website trial, Deanna De Cicco says, "When you are going through IVF you can be so overloaded with conflicting information, add in some intense emotions and it can be almost impossible to make a properly informed decision. This website really helps by giving patients an easy way to access the facts in a digestible way, helping to guide them to make a well-informed personal choice.”

The researchers note some limitations of their studies, including recognising that the TRACT checklist used to measure trustworthiness in the meta-analysis has not been validated and it is possible that some of the excluded trials provide reliable data [4]. For the trial looking at the website, authors note that all participants were living in Australia, meaning there may be differences to other regions in characteristics such as education and health literacy, which may limit generalisability to other settings.

Writing in a linked Comment, Dr David Barad from Center for Human Reproduction, New York who was not involved in the study, says, “These [...] papers are a case study in what evidence-based fertility care ought to look like. Claims should be judged against trustworthy trials; uncertainty should be communicated clearly, not concealed beneath optimistic language; and patient information should be treated as part of the clinical intervention, not as a marketing accessory.”


 

References:

1. https://www.unsw.edu.au/research/npesu/annual-reports.
2. https://www.hfea.gov.uk/about-us/publications/research-and-data/national-patient-survey-2024/#section-3
3. https://pubmed.ncbi.nlm.nih.gov/33942073/
4. Trustworthiness was assessed using the Trustworthiness in Randomised Controlled Trials (TRACT) checklist. Any studies with major trustworthiness concerns, such as being published only as conference abstracts without a detailed, peer-reviewed study or lacking prospective trial registration, were excluded from the analysis, unless these concerns could be resolved during author correspondence. The authors recognise that the TRACT checklist has not been validated and it is possible that some of the excluded trials provide reliable data.
5. Funding details and information on how the website works is available here:https://www.unimelb.edu.au/ivf/about-evidence-based-ivf

The studies were funded by the University of Melbourne and the Australian National Health and Medical Research Council. The studies were conducted by researchers from the University of Melbourne and other universities and with people with lived experience of IVF (for a full list, see the paper).

The labels have been added to this press release as part of a project run by the Academy of Medical Sciences seeking to improve the communication of evidence. For more information, please see: http://www.sciencemediacentre.org/wp-content/uploads/2018/01/AMS-press-release-labelling-system-GUIDANCE.pdf. If you have any questions or feedback, please contact The Lancet press office at pressoffice@lancet.com.

Quotes from Authors cannot be found in the text of the Article but have been supplied for the press release. The Comment quote is taken directly from the linked Comment.

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Evidence Article: https://www.thelancet.com/journals/lanogw/article/PIIS3050-5038(26)00054-3/fulltext 
Website Article: https://www.thelancet.com/journals/lanogw/article/PIIS3050-5038(26)00114-7/fulltext