A Culture of Transparency: are we failing our patients and their future progeny?

Phoebe Pottinger

Introduction

Informed consent is a guiding principle in the practice of ethical medicine (1). To obtain valid consent from patients wishing to undergo Assisted Reproductive Therapy (ART), this consent must be voluntary and informed whereby the patient understands the risks of the entire process, including the in-vitro culture of their embryos (1). Presently, there is growing uncertainty concerning the long term risks of human embryo culture media on future offspring (3), and the exact qualitative and quantitative composition of the media remains known only to the manufacturers. This raises ethical concerns as to whether patients can fully appreciate and consent to the risks of embryo culturing procedures, when these risks are largely unknown to their clinician.

Since the birth of Louise Brown in 1978 (4), the past decade has seen rapid advances in the success of ART. In 2018, £320 million in revenue was made by the UK fertility sector (5). This ever-advancing commercialisation of the field has meant women in the unfortunate position of seeking ART are forced to navigate evermore choices at each stage of the process. To minimise the cumulative biological, psychological, and financial pressures exerted by each cycle of ART, patients are desperate to select the most effective clinics and techniques. Due to regulatory failures these are often unclear and may lead to over-diagnosis, over-treatment, or the prescription of non-evidence based and overly exorbitant treatments for shareholder interests (6). In fact, inadequate provision of information to patients leading to consent for overtreatment has been listed in a suggested ‘taxonomy of abuse’ in ART (7).

IVF culture media is no exception to these issues. During IVF, before being implanted into the mother, human embryos are grown first in a nutrient rich liquid (culture media), ideally designed to replicate the would-be surroundings of the embryo in a natural conception. To protect commercial interests, manufacturing companies withhold information pertaining to the composition of their media.

Although this information is made available to regulatory bodies, the inability of clinical trials to associate composition rather than brand of culture media to clinical outcomes is argued to impede scientific advancement. This is especially important as there is insufficient evidence to conclude which brand of media is optimal and indeed, safest (8).

Through this essay I add to the small but ever-growing clamour of voices demanding transparency for the composition of our embryo culture media (9-12), with the hope that this will lead to real improvement in ART outcomes and through that, women’s reproductive lives.

Current regulatory processes regarding culture media

In 2008 (30 years after the birth of Louise Brown), IVF culture media was classified as a class III Medical Device under the Directive 93/42/EEC in the EU (13). The way medical devices are regulated and placed on the market in Great Britain (England, Scotland and Wales) has changed since the exit from the EU, mainly via passing of secondary legislation. A brief understanding of how culture media is regulated is important – through this we may be able to identify areas in legislation where we can improve manufacture transparency.

All medical devices must be registered with the MHRA and be approved by UK Approved Bodies. Manufacturers must submit their application to the Approved Body, which contains data pertaining to product design, quality assessment and compliance with international standards. After a successful evaluation by the Approved Body, manufactures will be provided with certification allowing them to issue their device with UKCA marking (14). The device can then be placed onto the market in Great Britain. Once on the market the manufacturer is required to carry out post-market surveillance and submit vigilance reports to the MHRA regarding adverse medical incidents (14).

UKCA marking requirements for medical devices are subject to the requirements of the relevant Annexes to the Directive 93/42/EEC on medical devices (to note, these have been modified by Schedule 2A to the UK MDR 2002) (14). Under this directive, Section 1.13 ‘Information supplied by the manufacturer’ details information that should accompany each device (13). Although the new regulation states that ‘transparency and adequate access to information’ (13) is essential to allow patients and health professionals to make informed decisions, it only specifies medium composition should be revealed in technical documentation by the manufacturer and not to the end users. Not only are manufacturers not legally bound to provide this information, all parties are obligated to protect the confidentiality of these
intellectual property rights.

In contrast to medical devices, medicinal products are required under The Human Medicines Regulations 2012 to provide ‘a statement of the active substances expressed qualitatively and quantitatively per dosage unit’ (15). To classify as a medicinal product, the action is usually through direct administration to human beings. IVF culture media is used indirectly for human beings in the sense of promulgating pregnancy meaning it is classified as a medical device rather than product. Culture medium does not achieve actions directly in or on the human body as embryos are not recognised as human persons in the eyes of UK law. Consequently, through a borderline technicality IVF culture media composition isn’t subject to the same scrutinous protocols as medicines.

However, there may be an argument that the above does not hold true: embryo culture media may have unintended effects on the endometrium when implanted and additionally, some culture mediums contain substances that would be classified as medicinal products, such as antibiotics.

For commercial reasons therefore, manufacturers rarely include full composition details of their product in the Instructions For Use. This undermines cross-talking between culture medium companies and IVF facilities regarding performance of the culture medium and adverse events.

The current regulatory processes keep our culture medium protected from scientific scrutiny and the true workings of our embryo culture media shrouded in secrecy. The current directives are not enough to keep our future generations safe.

Current transparency within culture media composition

Chronopoulou et al 2015 (9) investigate the ‘composition of current commercial culture media as defined in companies’ brochures and websites.’ I re-evaluated this information through another search of the same sources on their websites and constructed Table 1. I cross-referenced this with the culture media investigated by Tarahoumi et al (16), who chemically analysed the composition of 15 commercially available culture media, before and after sham culture and storage. I did not include discontinued products.

The information on composition was difficult to access and detail was extremely variable between companies. Exact concentrations weren’t provided by any of the companies on their product sheets. Some products listed simply ‘amino acids’ as components of the media without listing which specific ones included. The rest of the components were listed with either vague ranges of concentrations or no mention of concentration at all.

Additionally, disparities were found between product descriptions and the results from Tarahoumi et al 2019 (16). For example, glutamine was said to be present in in Sage-Quinn’s Advantage Blastocyst Medium on their data summary sheet but was not detected by Tarahoumi et al. 2019. Indeed, Tarahoumi el at. found 15 of the analysed media to contain iron despite the fact none of the manufacturers listed this in their product composition, and that there is ‘no specific report for iron in human preimplantation embryos’ (16). Therefore, it is difficult to know whether the provided list of components is complete or even accurate for each product, and thus the definitive composition of commercial culture media is likely to be far more complicated than the key constituents we know about. It is clear to see from Table 1 that formulations are variable between different branded media, demonstrating the lack of consensus on how best to optimise culture media. The scientific rationale behind each constituent is usually unclear.

Tarahoumi et al. 2019 were surprised to find the presence of two liver enzymes, Aspartate Amino Transferase (ASAT) and Alanine Amino Transferase (ALAT) which they concluded was likely contamination from the addition of human albumin, and may be responsible for changing amino acid concentrations of the media post culture (16). Amino acids are essential in embryonic development for gene expression and protein synthesis. Therefore, the presence of unlisted compounds that may affect their concentrations in culture media is concerning and necessitates further study.

In summary, there is extremely limited data released by companies on their product composition, and this data cannot always be relied on to be accurate. The degree of variation in the composition of embryonic culture media should surprise not only the scientific field, but the general public who assume the highest quality of evidence underpins their fertility treatment. It could even go so far as to undermine patient confidence in IVF processes. Tarahoumi et al. conclude by urging manufactures to release both the components and evidence underpinning them to facilitate advancement of the field (16).

Why is IVF culture media composition important?

8 million children worldwide have been conceived through ART (17). This is not just statistics. For each birth there is a woman who underwent the difficult and, in some cases dangerous process of IVF – injections of hormones, egg retrievals, embryo insertion then the pregnancy itself. Behind each live birth is another unseen figure – the even higher number of IVF cycles that didn’t result in pregnancy and the suffering behind each of these.

The growing body of evidence therefore, that singleton babies born through ART are at a higher risk of neonatal complications such as pre-term birth (PTB) and low birth weight (LBW) is concerning (18, 19). LBW and postnatal catch up have shown strong associations with diabetes and cardiovascular diseases as far as into adulthood (20-22). This supports the Barker hypothesis, which states that the nutritional status of the mother directly affects the foetus’ risk of future chronic disease (23). Put simply, undernourishment of early embryos causes them to adapt or ‘reprogram’ their metabolism; when implanted into the nutritious maternal environment the embryo experiences overgrowth, leading to permanent metabolic consequences in later life (19).

This is not altogether surprising: at the time embryos are most vulnerable, completely dependent on their environment for nutrients, they are also at a critical period of developmental plasticity. It follows then, that even small changes at this time could have far reaching effects. Culture media replicates the maternal environment and nutrition in the first days of development and so is postulated to be a key mediator of this association between ART and poorer neonatal outcomes.

There is an accumulating body of evidence that types of culture media can affect the BW of babies born through ART (24). This is not replicated in all studies (25,26), but this may be due to differences in the composition of culture medias compared. Youssef et al 2015 in a systematic review of the effect of culture on neonatal outcomes failed to draw any conclusion on the basis that studies were poor quality and no two studies compared the same culture media (8). Compelling evidence however has been demonstrated by Kleijkers et al 2016 who performed a large multi-centre prospective RCT (27). Children born after embryo culture in Vitrolife G5 culture medium compared human tubal fluid (HTF, Quinn) had a statistically reduced BW difference of 158g (27).

Even less investigated is the potential effect of culture media on long-term health of children born through ART. Given the demonstrated effect on BW and our understanding of the Barker’s hypothesis this area demands further study. A prospective RCT in The Netherlands demonstrated that differences in BW from embryos born in either Cook or Vitrolife culture medium not only were evident from 2nd semester, but that these differences persisted up to 2 years of life (28). Furthermore, a follow-up study by the same group demonstrated this difference of culture medium was ‘associated with differences in body weight, BMI, truncal adiposity, waist circumference and waist/hip ratio at the age of 9’ (29). Chillingly, the liquid an embryo floats in for a few days can affect the health of the child 9 years later.

As well as neonatal and long-term health outcomes, there is evidence that type of culture media may influence clinical pregnancy and live birth rates (LBR) (30). The importance of this is clear – optimising our culture media could increase success rates, reducing the number of ART cycles women must go through and with that the risks of physical and psychological harm associated with this. Notwithstanding these grave concerns, there are also ethical arguments dictating the need for more transparency around IVF culture media.

The practice of medicine is built on core principle of autonomy. Autonomy is ‘the right of competent adults to make informed decisions about their own medical care’ (31). In order to make an informed decision, patients must be informed of the evidence of benefits and risks of the treatment they are consenting to.

To consent to a treatment, we must first know what is in it. How many of us would consent a mystery pill prescribed from our doctor without any explanation? Further, how many of us would consent to the mystery pill on behalf of our children?

Not many, because as a population we’ve come to reasonably expect evidence-based care. If the embryologists are unable to access information on the risks and benefits of the culture mediums they are using, then our patients certainly cannot be expected to know.

This is eloquently summarised by Barnhart (32), who argues that there was greater scientific rigour in the choice treatment of scurvy (in 1747) than embryo culture medium in the 21st century. It is further reiterated by Evers (33) who goes one step further to point out the insanity of the situation – we know the exact composition of peanut butter because manufacturers are legally bound to print it on the tub. How ridiculous we have higher standards for our peanut butter than our embryo culture media.

Commercialisation of IVF culture media: a barrier to transparency

The commercialisation of ART incentivises companies to keep their culture media composition a secret. Commercial companies such as Cook Media who design these products legally have the right to decide what information they do or do not share with their end users. The secrecy of these companies is essential in recovering the money invested into its research and design. Without this regulation, commercial companies may be discouraged from investing in and improving these products or might decide to remove them from the UK/EU market altogether. However, IVF clinics could be encouraged to only use culture media from companies that are transparent about their composition, reducing the likelihood of this harm. It is also argued that the competitive nature of the market improves the quality of culture media. I would object that this is only true in so far as it improves quality in relation to one another, which is distinct from improving culture media overall.

For example, it is debated whether the addition of hyaluronate or EmbryoGlue© to culture media improves LBR. A systematic review by Heymann et al demonstrated a significant improvement in pregnancy and LBRs with its addition (34). Hyaluronic acid is not however, included in all culture medias and furthermore, is sometimes only available at an extra cost of £200 per cycle in some clinics (35). This is dubiously ethical at best.

After 30 years of IVF, why don’t we know what is the best culture media to grow embryos in? By not knowing the answer to these questions and many more, we are failing not only our patients, but the future generations to come. Not knowing is no longer an option.

Recommendations

Through this essay I have identified the barriers to improving IVF culture media. The key factors and their barriers are seen in Figure 1:

1. Failing to disclose culture medium composition and scientific justification for each constituent means the scientific community cannot repeat the findings. To judge the efficiency and safety of media, we are completely limited to comparing them to one another. The media is therefore not subject to independent critical analysis, reducing published studies on commercial culture media to the level of ‘uncritical advertisements’ (10). Without regulatory pressure, there is no incentive for pharmaceutical manufacturers to reveal media composition. This pressure could come from a change in legislation, although as current regulations are based on EU directives this could be recognisably difficult to achieve. This could be via amendment of the current directive, or a reclassification of IVF culture media as a medicinal product rather than device. It is stated by the Human Fertilisation and Embryology Society (HFEA) that it is outside of their remit to regulate culture media (36). The HFEA regularly collates data and analyses the effectiveness of IVF culture media. It must exert its leading authority in the field to put pressure on the government to bring companies to account. Additionally, the government should clearly publish their list of Approved Bodies and the information required for manufactures to submit in order to obtain the UKCA mark.

2. IVF clinics to put pressure on companies to be transparent about their media composition via commercial incentives.

3. Results from clinical trials are often confounded by differing of practices in embryo culture, selection and transfer between different clinics (37). Currently data on fertility rate, embryo quality, implantation, pregnancy and LBR have to be closely reported and analysed by individual clinics. This should be expanded to develop a protocol for enabling structured follow-ups for offspring health and well-being, detailing the exact culture media and conditions of each embryo created. The creation of a national confidential registry would permit the conduction of large-scale prospective trials into this issue.

Concluding remarks

Women and their partners place their precious embryos and with that, their future hopes of children within our metaphorical hands and chosen culture media. Sadly, we can’t promise each woman their embryo will undergo implantation and result in a health live pregnancy – what we can do is enforce transparency between manufacturers and end users. This will enable the conduction of large-scale epidemiological trials needed to determine the most effective and safest culture media for our embryos. Financial interests of biomedical companies must not override our duty of the highest quality of fertility care to our patients.

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