Is enough being done to help women and men optimise their chance of a baby before fertility treatment? This was the theme underpinning a campus course organised by SIG reproductive endocrinology this month in London, and the consensus was that everyone – from clinicians to policymakers – must try harder to make this key time in a patient’s life course a priority.
Speakers outlined several challenges. Information on periconception is too generic, that evidence to support lifestyle changes is of poor quality especially on dietary supplements, and that there are significant data gaps including maternity statistics.
The impact of this is that clinicians cannot provide patients with informed advice because they do not have robust evidence for what does or does not improve outcomes.
On a more positive note, campus attendees heard there is hope on the horizon from innovative approaches that could be gamechangers in both male and female infertility.
The campus began with a head-to-head debate on the state of preconception care. Sesh Kamal Sunkara outlined that there are a wealth of interventions and guidance publicly available from governments, professional bodies and health agencies on topics ranging from alcohol use to genetic conditions to improve maternal and child health.
Healthcare professionals make every effort to follow this guidance in everyday practice, said Dr Sunkara from King’s College London.
But guidance stops short of specific guidelines for IVF patients. Dr Sunkara posed the question: do they need separate advice? The data suggest yes because women with infertility and those undergoing IVF are at higher risk of complications such as hypertension. However, the data are not robust enough for clinicians to attach medical value to preconception interventions. Results from a recent Cochrane review (1) show that evidence on the impact of lifestyle advice on live birth rates (LBR) is of very/low quality and insufficient to draw conclusions, hence the need for more RCTs.
Another issue is how does the fertility sector measure if enough is being done to improve periconception care? Some countries perform regular maternal mortality audits but Sarah Martins da Silva said more and better-quality data need to be collected. The UK for example does not capture detailed information on IVF conceptions, and the aim is to address this by linking maternity service databases with health data from the Human Fertilisation and Embryology Authority. Other initiatives in the pipeline include a World Health Organisation guideline which will serve as a ‘report card’ on the state of preconception care.
A recurring message from this campus meeting was not to forget about men. Dr Martins da Silva from the University of Dundee outlined how clinicians can do more to empower men such as advising on optimal abstinence and on scrotal temperature although she cautioned clinicians against focusing excessively on lifestyle (and for women too). In addition to providing information to improve lifestyle, Dr Martins da Silva said she takes detailed personal histories in the clinic to identify factors which might inform preconception care (eg prior bariatric surgery).
What (if any) interventions and dietary supplements prior to ART improve the chances of conception? In his presentation, Professor Christophe Blockeel from University Hospital Brussels talked about the impact of body weight, specifically the link between body ‘disbalance’ (being under/overweight) and reproductive failure, worse fecundability ratios related to poor self-image, and reduced response to ovulation induction therapies. When BMI is combined with age, the data (2) show that their impact on outcomes is significant: the older the woman, the more weight she must lose to increase her pregnancy chances.
However, George Lainas said BMI was problematic in preconception care. In his talk, he said the available evidence is not based on RCTs so could be more marginal than expected and no studies show that BMI affects oocyte yield.
Countries including the UK use high/low BMI as an exclusion criterion for government funded fertility treatment despite the fact the measurement does not distinguish between excess fat, muscle, or bone mass. On this basis, Dr Lainas from Eugonia IVF Unit made the case for BMI being unethical and discriminatory: diabetes is associated with stillbirth yet patients are not denied IVF unlike those with a high/low BMI. He proposed that prior to start of IVF treatment women with high BMI could sign a consent form as they do before undergoing a caesarean section.
Next, Dr Lainas examined the evidence on weight loss interventions. Their high dropout rate undermines success, and patients especially those of advanced age may feel they do not have months/years to spend shedding excess weight before IVF. Bariatric surgery is effective but not risk-free, he said.
Much hype surrounds lifestyle/periconception supplements, but the conclusion drawn from this workshop is that any positive effects on fertility outcomes remain unproven. Dinka Pavicic Baldini from the University of Zagreb gave an overview of data on myo-inositol (MI) to conclude that selected infertile women may benefit, especially those with typical PCOS phenotype who demonstrate abnormally high testosterone levels. However, Professor Baldini emphasised that MI cannot be recommended as a standardized therapy for all.
As for antioxidants, there are plenty of data available but of poor quality, therefore clinicians struggle to extrapolate results. Stratis Kolibianakis presented findings from Cochrane database reviews (3) based on low/very low-quality evidence that antioxidants improve LBRs in infertile women and sub fertile males; and the position of international societies, including ESHRE, reflects this lack of robust data.
Professor Kolibianakis from the Aristotle University of Thessaloniki said this poses a major dilemma for clinicians on what to advise patients. The approach he uses in his own clinic is to give patients antioxidants only within clinical trials, never on the basis of opinion.
The biological evidence that Vitamin D and omega-3 have a role in gamete and embryo quality was outlined by Alexandra Kermack from the University of Southampton who said that more mechanistic studies are required. Meta-analysis has shown possible benefit of vitamin D on LBR but none for omega-3. A shift may be needed away from individual supplements to examining whole diets, she suggested, based on evidence that mono-unsaturated fatty acids could affect LBR.
The final session on effective measures of preconception care emphasised how little is known about sperm function (in the context of oxidative stress) and about the mechanisms that determine oocyte quality.
Evelyn Telfer discussed the potential for new therapies based around the antioxidant effect of sirtuins: animal studies have demonstrated that sirtuin enhancers nicotinamide adenine dinucleotide (NAD) and melatonin benefits the development potential of oocytes. Professor Telfer from the University of Edinburgh also gave an update on her work on growing eggs from stem cells to maturity in the lab to reduce the need for donor eggs. Phase one is ongoing and her team hope to apply for a licence soon to progress to phase two.
Sarah Martins da Silva detailed the pros and cons of treatment options for male infertility. Studies show ICSI is currently the only proven effective approach, but she described AZD5904 (MPOi) as a potential’ gamechanger’ with in vitro studies suggesting this myeloperoxidase inhibitor improves sperm function.
This campus identified many gaps in knowledge around preconception care and this limits the evidence-based support that clinicians can provide to patients. SIG co-ordinator Professor Ying Cheong from the University of Southampton said the next step will be to engage with ESHRE. This is to reach consensus on the best way to inform members how they can help improve outcomes in preconception care.
1 Boedt T at al. Preconception lifestyle advice for people with infertility. Cochrane Database of Systematic Reviews 2021, Issue 4. Art. No.: CD008189. DOI: 10.1002/14651858.CD008189.pub3.
2 Filipa Rafael F et al. The combined effect of BMI and age on ART outcomes. Hum Reprod, Vol 38, (5); May 2023; 886–894, https://doi.org/10.1093/humrep/dead042
3 de Ligny W et al. Antioxidants for male subfertility. Cochrane Database of Systematic Reviews 2022 (5). Art. No.: CD007411. DOI: 10.1002/14651858.CD007411.pub5.