Abstract
In this chapter, the evidence and use of in vitro fertilisation (IVF) add-ons in the UK is explored. In addition, the stance of professional and regulatory bodies is described. The term ‘add-on’ has been coined to describe the additional ‘extras’ to a routine or intracytoplasmic sperm injection cycle that are commonly offered to those undergoing treatment with the aim of improving livebirth rates. A summary of the highest quality available evidence for the following add-ons is presented: endometrial scratching; time-lapse imaging; assisted hatching; preimplantation genetic testing (PGT-A); endometrial receptivity array; GM-CSF containing culture media; Embryo Glue (hyaluronic acid); artificial egg activation with calcium ionophore; intracytoplasmic morphologically selected sperm injection (IMSI); physiological intracytoplasmic sperm injection (PICSI); sperm DNA test; and reproductive immunology procedures. There remains a paucity of evidence to support the routine use of add-ons based on the available randomised controlled trial and systematic review evidence. This is particularly important given that most patients pay additional fees to utilise add-ons. In order for patients to receive high- quality care in IVF clinics, clinicians must be prepared to discuss the relevant evidence regarding efficacy and safety of the specific add-on being considered.
8.1 Improving Outcomes in Assisted Reproduction
8.1.1 Introduction
Couples undergoing infertility treatment are a vulnerable population, who are often desperate to optimise any chance of having a baby regardless of the personal and financial cost. For couples undergoing in vitro fertilization (IVF), a plethora of medical and non-medical adjuncts is available; these are known as ‘add-ons’. The Human Fertilisation and Embryology Authority (HFEA) defines them as ‘optional extras you may be offered on top of your normal fertility treatment, often at an additional cost. They are sometimes emerging techniques that may have shown some promising results in initial studies, or they may have been around for a number of years, but haven’t necessarily been proven to improve pregnancy or birth rates.’
ART is a fast-paced area of medicine, with growing demand for treatment, accompanied by rapid innovation which is often driven by industry and pharmaceutical companies. Novel add-on therapies arrive on the market purporting to improve the chance of pregnancy and live birth and they have become established as part of normal working practice in many private clinics, 70% of which offer at least one add-on. Unfortunately, most add-ons are unsupported by good quality randomized evidence. The cost of add-ons is usually borne by patients and provides revenue to the clinics.
Clinics vary with regard to how much information they give patients about whether add-ons have been shown to improve their chance of achieving a much wanted baby, and whether they are cost-effective.
8.1.2 IVF
IVF has been the most advanced and successful treatment option for many infertile couples for almost 40 years. But the success rate from one cycle remains relatively static at approximately 25%–30% (Figure 8.1). This low rate may be an unpleasant surprise for patients.
8.1.2.1 Common Reasons for IVF Failure
A poor response to ovarian stimulation means that women have too few oocytes to collect and use in an IVF cycle. Recurrent implantation failure (RIF) is another common reason for IVF failure: embryos are transferred but pregnancy does not progress. Implantation is one of the most critical steps in determining IVF outcome. It is poorly understood but appears to involve complex signalling and synchronisation between the endometrium and embryo.
Treatment Costs
NHS funding for IVF varies by region across the United Kingdom, ranging from three funded cycles to none at all.
IVF is expensive, costing between £3,000 and £5,000 per cycle.
Approximately 59% of couples self-fund their IVF cycle.
Most add-ons come at additional cost. This varies enormously between clinics but can be many hundreds of pounds.
8.1.3 The Stance of Professional and Regulatory Bodies on Add-Ons
A British Fertility Society review of the evidence for routine use of IVF adjuncts found that in most cases there was no adequate evidence-based rationale for their use. The sole exception among the interventions that they considered was use of metformin for women with polycystic ovary syndrome undergoing IVF.
The HFEA has created a webpage with consumer-friendly information about the most commonly offered add-ons, with a traffic-light rating system indicating the latest evidence on the efficacy of the most commonly offered add-ons. Red indicates there is no evidence to show that it is effective and safe, amber that there is a small or conflicting body of evidence, meaning further research is still required and the technique cannot be recommended for routine use, and finally, green which indicates that there is more than one good quality randomised controlled trial (RCT) which shows that the procedure is effective and safe.
Currently none of the add-ons assessed by the HFEA are rated green. This means that the HFEA do not think that any of these techniques should be used routinely.
In January 2019 the HFEA and 10 leading professional and patient fertility groups published a consensus statement on add-ons. The key points were as follows: Clinics should offer add-ons only where more than one high-quality study demonstrates a treatment to be safe and effective; clinics should stop offering the treatment add-on if concerns are raised about safety or effectiveness; where evidence is limited or conflicting, clinics offering add-ons should be open with their data to add to the evidence base; where there is no robust evidence, treatment add-ons should be offered only to patients in a research setting; patients must be clearly informed of the experimental nature of any treatment add-on which is offered where there is no robust evidence of its safety or effectiveness; patients should not be charged to take part in a clinical trial; transparent declaration of financial or other interests is essential in discussion with patients.
8.2 Specific Adjuvants
All information on adjuvants discussed in this chapter is based on the latest systematic review and RCT evidence available following database searching (Table 8.1).
Table 8.1 HFEA traffic light coding for add-ons, 2019. Information obtained from https://www.hfea.gov.uk/treatments/treatment-add-ons/
Commonly Used Add-Ons
Surgical
○ Endometrial scratching
Laboratory
○ Time-lapse imaging of embryos
Gamete, endometrial and embryological
○ Granulocyte-macrophage colony-stimulating factor (GM-CSF)–containing culture media
○ Assisted hatching
○ Preimplantation genetic testing (PGT-A)
○ Endometrial receptivity array
○ Embryo glue
○ Egg activation with calcium ionophore
○ Intracytoplasmic morphologically selected sperm injection (IMSI)
○ Physiological intracytoplasmic sperm injection (PICSI)
○ Sperm DNA testing
Medical
○ Reproductive immunology procedures such as
Intravenous (IV) immunoglobulin
IV lymphocyte immunotherapy
IV intralipids
Intrauterine granulocyte colony-stimulating factor (GCSF)
Intrauterine peripheral blood mononuclear cells (PBMCs)
Subcutaneous tumour necrosis factor (TNF)-alpha blocking agents (e.g. adalimumab, infliximab)
Subcutaneous leukaemia inhibitory factor (LIF)
Oral steroids (e.g. prednisolone)
8.2.1 Endometrial Scratching
8.2.1.1 Background
Endometrial scratching (or injury), is intentional damage to the endometrium. It is a simple, low-cost outpatient procedure (Figure 8.2) which is sometimes performed prior to IVF or ICSI, particularly in cases of recurrent implantation failure (RIF). It usually involves passing an endometrial pipelle (small sterile flexible plastic tube) through the external os (opening) of the cervix into the uterus.
It is hypothesised that endometrial scratching may improve endometrial receptivity, thus making it more likely to lead to embryo implantation. The main proposed mechanisms are:
Stimulation of decidualisation, a process whereby the endometrium prepares to receive an embryo by modifying stromal cells, uterine glands, uterine vessels and immune cells in order to enhance implantation.
Stimulation of an inflammatory response with the release of various cytokines and growth factors, which can improve vascularisation and may facilitate embryo implantation.
Retardation of endometrial maturation, leading to better synchronicity between the embryo and the endometrium. The process of ovarian stimulation for IVF and ICSI leads to abnormal maturation of the endometrium, such that it may be overly mature at the time of embryo transfer and thus less receptive to the embryo.
Potential Disadvantages
Discomfort, with possible uterine cramping and some bleeding
Risk of uterine perforation with the pipelle device, and the possibility of infection of the endometrium (endometritis)
Chance of disturbing a very early spontaneous pregnancy, if endometrial scratching is undertaken in the latter half of a natural menstrual cycle
Cost (approximately £150)
8.2.1.2 Best Evidence on Clinical Outcomes
In 2019, the largest RCT to date on endometrial scratching for women undergoing IVF was published [1]. More than 1,300 women were randomised to receive an endometrial scratch or no intervention. The primary outcome was live birth. There was no significant difference between the groups in rates of live birth, ongoing pregnancy, clinical pregnancy, multiple pregnancy, ectopic pregnancy or miscarriage. The strengths of this trial include its large sample size, robust allocation concealment and its pragmatic approach across 13 fertility clinics internationally, which improves generalizability of results.
In 2020, the results of the multicentre, RCT ‘Endometrial Scratch Trial’ were published. 1048 women undergoing their first IVF/ICSI treatment were recruited and randomised to an endometrial scratch in the mid-luteal phase prior to treatment, or to no scratch prior to treatment. Women were aged <37 and expected to be good responders. The findings revealed no difference in livebirth or clinical pregnancy rates between the two arms of the study (livebirth 195/525 in the control arm and 201/523 in the intervention arm, relative risk (RR) 1.03 95% confidence interval (CI) 0.89 to 1.21). The study concluded that endometrial scratch should be ceased in women undergoing their first cycle of IVF/ICSI who are expected to be good responders (2).
The preliminary results of the SCRaTCH study, a multicentre RCT conducted in the Netherlands were published in 2020. In this study, 936 women with one failed IVF/ICSI cycle were randomised to a scratch in the mid-luteal phase prior to ovarian stimulation, or no intervention. The livebirth rate was 22.6% in the scratch group and 18.6% in the control group (RR 1.21, 95% CI 0.94-1.56) (3).
In 2015 a Cochrane review of endometrial scratching was published. It included 14 RCTs (2128 women). The review concluded that endometrial injury performed between day 7 of the previous cycle and day 7 of the embryo transfer (ET) cycle was associated with an improvement in live birth and clinical pregnancy rates in women with more than two previous embryo transfers. There was no evidence of an effect on miscarriage, multiple pregnancy or bleeding and endometrial injury on the day of oocyte retrieval was associated with a reduction of clinical and ongoing pregnancy rates (4).
This review is due to be updated soon, and will include data from the three new large RCTs mentioned above, which may alter its conclusions.
8.2.2 Time-Lapse Imaging
8.2.2.1 Background
Embryos develop in incubation, moving through the fertilisation stage to cleavage stage and on to blastocyst stage in some cases. Embryologists check the developing embryos to select those most likely to implant and develop into a baby. Traditionally, every day the embryo is removed briefly from the controlled environment of the incubator and placed under a light microscope to undergo a morphological check by the embryologist. Time-lapse imaging allows the embryologist to monitor the developing embryo without removing it from the incubator and to select the best embryo for transfer based on the timing and synchronicity of early mitotic divisions and abnormal cleavage patterns that generate morphokinetic parameters. There has been widespread uptake of TLS in IVF clinics worldwide.
The availability of detailed digital images of developing embryos, which can be compiled to create a time-lapse sequence of their development
Achievement of an undisturbed culture environment for embryos, which avoids exposing embryos to mechanical disturbance or changes in temperature, pH, humidity and gas composition
The availability of embryo selection software, with complex algorithms based on a combination of morphokinetic parameters and selection and de-selection criteria which help the embryologist to select the optimal embryo for transfer
Potential Disadvantages
Exposure of embryos to light during the acquisition of digital images of embryos, often as frequently as every 5–10 minutes. Although the total dose of ultraviolet radiation is likely to be very low, there is potential for harm, which could influence clinical outcomes such as miscarriage and stillbirth. However, overall light exposure is thought to be lower than with traditional embryo assessment under a light microscope.
Costs approximately £850
8.2.2.2 Best Evidence on Clinical Outcomes
A 2019 Cochrane systematic review included nine RCTs (2,955 women) and concluded that there was insufficient good quality evidence of differences in live birth or ongoing pregnancy, miscarriage, stillbirth or clinical pregnancy to choose between TLS, with or without embryo selection software, and conventional incubation [4]. The evidence was low or very low quality overall because of a high risk of bias in two studies secondary to lack of adequate randomisation and allocation concealment, indirectness because of the largest study using donor oocytes from young women and imprecision of the results, with broad confidence intervals stretching from significant benefit to significant harm.
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