By Georgia Scott

Progress Educational Trust (PET)’s annual conference was held at Amnesty International headquarters in December 2019. This one-day event titled “Reality Check: A Realistic Look at Assisted Reproduction” explored the limitations of the evidence base for interventions in assisted reproductive technology (ART).

We Need To Talk About Add-Ons

Assisted hatching, endometrial scratching and pre-implantation genetic testing for aneuploidy (PGT-A) are all examples of ‘add-ons’: interventions offered to people seeking fertility treatment, in addition to standard treatment, controversial for their lack of evidence.

Commencing the day’s talks, Søren Ziebe introduced the Human Fertilisation and Embryology Authority (HFEA)’s traffic light system for grading the evidence base for add-ons, as follows:

• Red – no evidence for intervention’s efficacy and safety
• Amber – a small, conflicting body of evidence for the intervention
• Green – at least one high quality randomised controlled trial (RCT) in favour of intervention’s efficacy and safety. Routinely recommended.

No add-on has a green rating, yet they are still offered at an additional cost to the patient.

The title of Professor Ziebe’s talk, ‘My patients can’t wait for evidence’, shed some light on why these non-evidenced add-ons are still performed. Age is the single most important predictor of success in ART. Patients may therefore feel time-pressured to try anything, opposed to waiting for enough evidence for an add-on’s status to change to ‘green’.

Later, one add-on with an amber rating, time-lapse imaging, was presented to us in detail by  Dr Cristina Hickman.

Embryos are usually cultured within an incubator, and their development  checked each day by an embryologist who assesses their suitability for transfer via direct visualisation. Time-lapse imaging incorporates artificial intelligence to this process. The time-lapse incubator has an inbuilt camera, which takes photos of the embryo as it divides, compiling them into a video. This is viewed by the embryologist, who then decides which embryo(s) to transfer, reducing the need to remove the embryos from the optimal conditions of the incubator.

The theory is that time-lapse imaging could improve embryo quality through limiting the disturbance of embryos, hence is enticing to patients and clinics. There is, however, no evidence as of yet that it increases live birth rates.

The Sister Test

Even add-ons labelled ‘red’ by the HFEA are legal in the UK; doctors are the only gate-keepers of said treatments. A debate on the duties of a fertility doctor introduced ‘the sister test’:

“What advice regarding add-ons would you give to your sister, desperate to have a child, who would try anything?”

Some participants suggested this test explained the difficulty of refusing an add-on which, despite lacking evidence of effectiveness, may possibly increase the likelihood of successful treatment.

However, professors Ziebe and Braude swiftly pointed out that non-evidence based practice is unjustified in other areas of public health, including food safety, medicine development, or surgery. In those fields, risk of unnecessary harms and costs are not accepted. Members of the audience suggested that privatisation of ART and financial incentives for clinics are the driving force behind this ‘double standard’.

Scrutinizing Current Techniques

Outside the world of technologically advanced add-ons, in subsequent talks we  heard about inconclusive evidence in more traditional ART practices.

In his talk, ‘Recipes of embryo culture media, who needs to know?’ Dr Roger Sturmey demonstrated that even culture (the materials in which an embryo is grown) vary substantially between clinics and we are yet to know which is ‘best’.

Mild ovarian stimulation (using lower doses of ovarian stimulatory hormones than the standard) was the next technique to be considered. Professor Geeta Nargund argued that due to the resulting reduced treatment burden for women, it should become mainstream. This was countered, however, by Dr Raj Mathur. He reminded us that severe ovarian hyperstimulation syndrome, a complication of hormonal ovarian stimulation treatment, is extremely rare. Higher levels of stimulation generate an increased number of eggs which can lead to more embryos. These two professionals therefore highlighted another area of debate: do the benefits of mild stimulation outweigh the reduced number of embryos?

Finally, the overuse of intracytoplasmic sperm injection (ICSI) was presented by Professor Christopher Barratt. ICSI is only recommended by NICE in those with male factor infertility, or when previous IVF cycles have failed. However it is often used in other situations, potentially unnecessarily, similar to an add-on. More evidence is required to assess whether this could perpetuate harmful downstream effects to future generations, including fostering increased rates of male factor infertility.

Improving the Evidence Base

Dr James Duffy, obstetrician and gynaecologist, and Professor Nick Macklon, medical director of the London Women’s Clinic, suggested there are too many single-centre, underpowered trials with non-generalisable populations in the field of ART. They called for:

• RCTs with larger sample sizes
• Diverse methodologies with variation in population
• Outcome measures that assess effectiveness (i.e. outcomes under pragmatic scenarios) versus efficacy (outcomes under ideal circumstances)
• Focusing research attention to address the established infertility research priorities

Restricting add-ons to RCTs was suggested. However, some employees of fertility clinics reported patient resistance to entering RCTs, not wanting to risk receiving placebo in place of a potentially effective intervention. Fear of losing business to competitors offering add-ons makes randomisation even harder for clinics.

28, 35, 42

A poignant talk from Dr Catherine Hill, head of communications at PET and previous ART patient, closed the conference. Diagnosed with subfertility aged 21, Hill ‘ignored’ her diagnosis for years, and at aged 41, was surprised she was not eligible for NHS ART treatment due to her age.

Dr Hill is passionate that women should be better educated of the reality of their own fertility statistics, and stressed the significance of ages 28, 35 and 42:

• 28 (when fertility starts declining)
• 35 (where a rapid decline in fertility ensues)
• 42 (when there is an extremely slim chance of conceiving).

Dr Hill self-funded her ART treatment, and eventually gave birth to a healthy daughter, her only child. Despite being ecstatic at this outcome, Dr Hill divulged that she had agreed to subject her embryos to PGT-A, an add-on with an additional cost, that resulted in disposal of a number of her embryos due to a perceived risk of aneuploidy.

Had she known then what she now knows of the questionable evidence surrounding add-ons, she may not have opted for PGT-A.  Whether she could have had more children is a question she continues to carry with her.

Reflections

Dr Hill’s enlightening talk emphasised to me the tangible consequences of  irresponsible add-on use. A medical professional’s duty is to protect the best interests of their patient; the distinction between fertility doctors and businessmen must be clearer. Striving towards a stronger evidence base, not just for add-ons but even the more ‘standard’ areas of treatment is vital for improving the journey and outcomes of patients.

 

Acknowledgements: I would like to thank the Institute of Medical Ethics, whose generous support enabled me to attend this conference.

Declaration of Interest: None.