Expensive IVF add-ons 'not evidence based'

Behind the Headlines

Monday November 28 2016

Don't assume that new treatments are guaranteed to work

IVF add-ons can cost up to £8,000

"Nearly all costly add-on treatments offered by UK fertility clinics to increase the chance of a birth through IVF are not supported by high-quality evidence," BBC News reports, covering the findings of a review by experts in evidence-based medicine.

IVF "add-ons" include a wide variety of treatments such as pre-implantation genetic screening, where the chromosomes of conceived embryos are checked for genetic conditions, and transfer of a "mock" embryo, as well as various drug treatments for blood clotting and immunity.  

The researchers reviewed 38 interventions offered by private clinics, and found most of them aren't supported by good evidence.

The NHS watchdog the National Institute for Health and Care Excellence (NICE) only provides clear recommendations for the use of 13 of these treatments, and most of these should only be used in specific circumstances. 

Systematic reviews have been carried out for 27 interventions, but there is only evidence that a handful actually improve live birth rates. Even then, the underlying studies behind the reviews have quality issues.

People seeking fertility treatment in the UK can be in a vulnerable situation and end up paying thousands to private clinics for treatments that may or may not work.

The authors of this review and other experts have rightly called for good-quality research into these treatments, and the publication of patient-friendly summaries so people can make an informed decision about their treatment.

Until then, while not particularly user-friendly, websites like NHS Evidence, the Trip Database and the Cochrane Library provide up-to-date information on the evidence base for various interventions.

Where did the story come from?

The study was carried out by researchers from the Centre for Evidence-Based Medicine at the University of Oxford.

The Centre was commissioned by the BBC Panorama team to carry out an independent review of the evidence for fertility treatments additional to IVF in the UK.

However, the BBC was said to have had no role in the review’s protocol, methodology or the interpretation of the findings.

Individual researchers also declared funding from several other sources, including the World Health Organization (WHO), the National Institute for Health Research, and the Wellcome Trust.

The study was published in the peer-reviewed British Medical Journal (BMJ) on an open access basis, so it is free to read online.

What kind of research was this?

This review aimed to look at the evidence on fertility treatment. As the researchers say, about one in seven couples are affected by fertility problems.

Many treatment options are extremely costly, with a reported 59% of them not funded by the NHS. This can put a large financial burden on couples.

But is there actually enough evidence to say these treatments are safe, effective and based on the latest research?

The authors aimed to try to provide evidence for a set of questions the Human Fertilisation and Embryology Authority (HFEA), the regulator of fertility treatment in the UK, suggests couples seeking fertility treatment might wish to ask when considering their treatment:

  • Is this treatment recommended by NICE? If not, why not?
  • Are there any adverse effects or risks (known or potential) of the treatment?
  • Has this treatment been subjected to randomised controlled clinical trials that show it is effective, and is there a Cochrane review available?

The Cochrane organisation produces internationally recognised systematic reviews on primary research in healthcare.

Cochrane reviews are considered to be of the highest standard of evidence-based healthcare resources.

What did the researchers look at?

The researchers first obtained a list of all clinics that provide fertility treatment in the UK from the HFEA.

They reviewed the websites of these clinics to gather a list of the treatments they offer to try to improve fertility outcomes, aside from standard IVF.

They excluded treatments for specific conditions like spinal injury or polycystic ovaries, treatments involving donor eggs or sperm, and complementary therapies. This gave 38 fertility treatments.

Six were described as alternatives to IVF, including intra-cytoplasmic sperm injection (ICSI) – where the sperm is injected directly into the egg – and intrauterine insemination. 

Five were described as preservation treatments, which included freezing of eggs, sperm and embryos.

The remaining 27 treatments were classed as "add-ons" to fertility treatment. This included a wide variety of treatments, such as genetic screening prior to implantation, sperm DNA test, mock embryo transfer, antioxidants, and aspirin treatment.

For all of the 38 treatments, the researchers looked for evidence in two literature databases to identify systematic reviews and randomised controlled trials, or next-best evidence if not available, published up to April 2016.

Are the treatments recommended by NICE?

NICE gives clear evidence recommendations for about a third of the treatments investigated (13 interventions, 34%). All of the recommended ones (11) are only advised when there are specific indications.

These evidence-based treatments include ICSI, sperm, egg and embryo freezing, frozen embryo transfer, ovulation induction, and intrauterine insemination.

NICE specifically advises against two interventions: assisted hatching and examination of the uterus (hysteroscopy).

For 19 interventions, NICE either did not mention their use or the evidence was unclear. This included various pre-implantation genetic testing methods, mock embryo transfer, time lapse embryo imaging, and ovarian tissue freezing. 

Six other interventions had research recommendations, including the use of aspirin, heparin and steroids. See the original study for the full list.

How good is the evidence?

A systematic review of the evidence had been carried out for just under three-quarters of the procedures (27 out of 38).

There was review-level evidence that only five of the 38 interventions improved live birth outcomes:

  • blastocyst culture – where embryos are transferred after a few days incubation
  • endometrial scratching – a procedure to help embryos implant in the uterus lining
  • adherence compounds – where compounds are used to increase the possibility that implanted embryos will adhere to the uterus
  • antioxidant treatment – where one, or both, of the parents are given antioxidants prior to IVF treatment
  • intrauterine insemination in a natural cycle – where sperm implantation is timed to combine with a woman's natural menstrual cycle in an attempt to maximise the chances of success

However, even for these interventions, there were quality limitations for the underlying studies. There was insufficient evidence for 13 interventions, and seven were found to have no effect on birth rates.

There was no systematic review evidence available for 11 interventions, and for eight of these only a single trial or observational study was identified that showed no benefit.

Three treatments had no evidence at all beyond expert opinion: segmented IVF (separating collection and transfer cycles), dummy embryo transfer, and quad therapy (a combination of four drugs affecting the clotting and immune system).

What are the possible side effects?

Evidence on the harms of fertility treatments seems limited. NICE only mentions that for IVF with or without ICSI there is a low risk of long-term adverse effects, and the possibility of a small increased risk of ovarian cancer can't be ruled out.

When using drugs to stimulate ovulation, NICE recommends that the lowest possible dose and duration should be used.

The reviews provided limited information on harms, mostly as the underlying studies were unclear or said little about harms.

Conclusion 

The researchers rightly say "people seeking fertility treatment need good-quality evidence to make informed choices".

As the system currently stands, people seek treatment from a variety of private UK fertility clinics.

In their desire for a baby, many couples are in a vulnerable situation and rely heavily on the guidance of health professionals.

But clinics may offer treatments that aren't sufficiently backed by the evidence.

The researchers highlight several problems. The standard first-step recommendation is for people to ask their GP for advice.

But GPs are unlikely to have the specialist knowledge around the evidence on the safety and effectiveness of various fertility treatments. Evidence-based and up-to-date online sources for further information are also lacking.

The researchers suggest that the two regulators, NICE and HFEA, could work together to provide clear guidance for patients and professionals on the services available and the evidence behind them.

They say advice should focus particularly on live birth rates rather than pregnancy rates, which don't give a good indication of success.

Various experts have also commented. Dr Yakoub Khalaf, from King's College London, succinctly points out that "what does not add value to treatment should not add to the bill".

And a fitting conclusion is provided by Professor Adam Balen, chair of the British Fertility Society, who said: "It is important that patients receive full information about everything that is being offered, the current evidence for benefit and whether there are any side effects or risks associated with it."

Analysis by Bazian. Edited by NHS Choices. Follow NHS Choices on TwitterJoin the Healthy Evidence forum.

Analysis by Bazian

Edited by NHS Choices

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