ESHRE adds its name to HFEA statement on add-ons

"IVF clinics are pushing women to buy needless extra treatments", Sophie Borland in The Daily Mail, 29 March 2017.

Published 18 January 2019

UK regulator, with the signed support of ESHRE, calls for clear patient information on adjuvant treatment safety and effectiveness.

ESHRE has added its name and endorsement to a statement from the HFEA on adjuvant treatments and tests in IVF. The UK regulator's statement urges a change in how optional treatment add-ons are offered to patients and is published in response to 'growing evidence' that many of these extra treatments are offered without conclusive evidence that they will increase the chance of pregnancy.

While the statement is aimed specifically at UK clinics, its endorsement by ESHRE (as one of ten professional and patient group signatories) now provides formal representation of ESHRE's position on this contentious subject.

The essential principles of the statement are that:

* Clinics should only offer an adjuvant treatment where more than one high quality study demonstrates it to be safe and effective

* Clinics should stop offering the treatments if there are concerns about safety or effectiveness

* Patients must be clearly informed of the experimental nature of any treatment add-on where there is no robust evidence of safety and/or effectiveness

* Patients should not be charged extra to take part in a clinical trial

Many of these principles will be familiar to ESHRE members. In 2017 Joyce Harper and several leading ESHRE members proposed in a Human Reproduction report that 'alarmingly, there are currently numerous examples where adjunct treatments are used in the absence of evidence-based medicine and often at an additional fee'.(1) ESHRE itself, especially through the statements of the PGD Consortium, has also repeatedly questioned the evidence favouring PGT-A in the improvement of live birth rates.(2)

Moreover, the HFEA statement cites only one reference, and that is the model framework proposed by ESHRE's SIG Ethics & Law in 2014 for distinguishing between experimental and established new developments in ART.(3) This model in essence proposed a new second stage of development - 'innovative' - and thus described 'a continuum' from experimental to innovative and eventually to established treatment. The tool sought in its objective to facilitate decision-making about the introduction of new technologies in the clinic.

The HFEA statement actually follows an acrimonious two-year public debate in the UK about add-ons, which was questionably initiated by the BBC and reported in 2017 in Focus on Reproduction.(4) A study commissioned by the BBC and published in the BMJ claimed there was little evidence of benefit in most of 27 add-ons identified and studied.(5) These included 'ovarian reserve testing', assisted hatching, hysteroscopy, PGS V1 and V2 and sperm DNA testing. A letter criticising the study was sent to the BMJ from Adam Balen, chair at the time of the British Fertility Society, and 60 other leading international specialists. The letter's main objection was that the study had obscured the real definition of add-ons and that many of them - such as ovarian reserve testing or testicular sperm extraction - had a 'clearly defined role in specific situations'. The study was thus 'inherently flawed', its scientific basis 'clinically and scientifically unsound'.

This domestic tiff took on a wider perspective when Joyce Harper, a former Chair of the PGD Consortium, and other internationally recognised experts, including the then Chairman of ESHRE, offered their 'opinion' in Human Reproduction that there are 'numerous examples where adjunct treatments are used in the absence of evidence-based medicine and often at an additional fee'.(1) The paper examined six add-ons - embryo glue and adherence compounds (evidence 'suggestive' of benefit), sperm DNA fragmentation testing (limited evidence), time-lapse imaging (limited evidence), PGS (limited evidence), mitochondrial DNA load measurement (no evidence), and assisted hatching (no evidence) - and repeated the advice that new introductions should always depend on preliminary work on animal models, human embryo research and well designed RCTs with a follow-up of all children born from the procedure.

And this is the position which the HFEA seems to have adopted in its statement - that treatments should be safe, ethical, effective and proven. The HFEA is presently using a traffic-light rating system to indicate if each of several add-ons is effective enough for routine use. So green for more than one 'good-quality' RCT, amber (further research required) or red (no evidence of safety or efficacy). Among the reds so far are assisted hatching, intrauterine culture, reproductive immunological testing, IMSI - with no adjuvant treatment so far given a green. PGT-A remains at the red (at day 3) and amber stage, and time-lapse at amber. The HFEA reports that in the past two years the most commonly used add-ons at UK clinics were endometrial scratch (27%), embryo glue (23%) and time-lapse (22%).

In commenting on ESHRE's involvement in the HFEA staement, Chairman Roy Farquharson said: 'Couples with infertlity suffer loss of confidence and remain vulnerable and susceptible in their wish to  create a family. This document provides us all with an objective approach that attempts to raise awareness and improve the critical analysis of interventions that cost a lot but have little, if any, potential benefit.'

1. Harper J, Jackson E, Sermone K, et al. Adjuncts in the IVF laboratory: where is the evidence for ‘add-on’ interventions? Hum Reprod 2017; 32: 485-491.

2. Harper J, Coonen E, De Rycke M, et al. What next for preimplantation genetic screening (PGS)? A position statement from the ESHRE PGD Consortium steering committee. Hum Reprod 2010; 25: 821-823.

3. Provoost V, Tilleman K, D'angelo A, et al. Beyond the dichotomy: a tool for distinguishing between experimental, innovative and established treatment. Hum Reprod 2014; 29: 413-417.

4. Brown S. Adding up the cost of IVF adjuvants. Focus on Reproduction May 2017.

5. Heneghan C, Spencer E, Bobrovitz N, et al. Lack of evidence for interventions offered in UK fertility centres. BMJ 2016; 355: i6295. doi:10.1136/bmj.i6295.