Research into the epigenetic impact of assisted conception

Readers will have noticed a couple of news reports and Rosalind John's excellent commentary on this topic in the last few weeks, but I make no apology for returning to the subject so soon. I believe this area of research will spark interest from the media for years to come. This is not because I fear research will necessarily uncover some unsuspected risk to the health of people born after IVF (we can't know until we do the research) but because we are bringing epigenetics, a scientific field in its infancy, to the complex, emotionally-charged field of infertility and assisted conception. Like explorers discovering a new land, the first glimpses are exciting and fire the imagination - and there is the rub. Whilst imaginative research questions and experimental designs are important drivers of scientific progress, the imaginative use of preliminary findings can also serve all kinds of other 'causes'. There is often an asymmetry in the early findings, or at least in those that are published, because it is often expensive and time consuming to fully assess early results that point to a link between an exposure and a particular outcome. Refuting early claims and making those refutations stick can take a long time, as we know to our cost with the MMR (measles, mumps and rubella) vaccine / autism debacle.

So what to make of last week's Sunday Times article entitled - IVF babies 'risk major diseases' (reported in last week's BioNews)? For a start, the quotation marks definitely embrace a huge amount of uncertainty! The epigenetic research reported does not establish any new adverse health associations with assisted conception. This was actually reporting work published in October 2009 (1) from the laboratory of Dr Sapienza, who happens to be contributing to the session 'Children of Assisted Reproductive Technologies: Their Health and New Genetic Issues' at the 2010 annual meeting of the American Association for the Advancement of Science in February. And there will be a lot of important issues to discuss.

Regular epidemiological follow up studies have indeed shown some adverse outcomes associated with assisted conception. Much of this is due to twins and higher order multiple births, but a recent review (2) concludes that singletons also have significantly higher rates of premature delivery, low birth weight, very low birth weight, infants who are small for gestational age and perinatal mortality compared to spontaneously conceived singletons (after adjustments for maternal age and parity). To these relatively common outcomes must be added the rare imprinting disorders Beckwith-Wiedemann syndrome (BWS) and Angelman Syndrome (AS) that occur more frequently than would be expected, based on the normal incidence of these disorders. Imprinting disorders are a particular type of epigenetic disturbance of gene activity and these latter findings have encouraged more general research into the epigenetic impact of assisted conception. Epigenetics refers to the biochemical processes, such as DNA methylation, that lead to an enduring change in the pattern of gene activity during development and beyond, but without changing the DNA sequence or code itself. Instead epigenetic molecules sit atop the DNA, switching genes on or off as the function of the different cell types demands or as we respond to key early life experiences. Such epigenetic 'marks', as they are called, can be faithfully copied during cell division as the organism grows thus explaining the enduring nature of epigenetic states across a life time.

Epigenetics is one of the molecular mechanisms that mediates the body's adaptation to the early environment, so epigenetic analysis was a natural choice for those exploring the underlying causes of the adverse outcomes associated with assisted conception. As Rosalind John's commentary illustrated there are two broad hypotheses; some aspect of the IVF procedure itself triggers epigenetic changes that lead to the increase in perinatal problems, or these different epigenetic states are 'a characteristic of the patient population served by assisted reproductive technologies', as Dr Sapienza puts it in the October 2009 paper. Clearly, infertility or sub-fertility is the principle characteristic but there may be others that influence the transmitted epigenetic states. All these scenarios carry an emotional toll for the couples seeking assisted conception. We have to be careful to avoid adding the further burden of later life health risks such as obesity, diabetes and high blood pressure ahead of the scientific evidence. Much more research is needed.

As mentioned in last week's BioNews, Sapienza's team examined samples taken from the placenta and umbilical cord blood of 10 IVF children and 13 children who were conceived naturally and were able to identify differences in the DNA methylation pattern between these two groups. They found that certain genes in babies conceived following IVF tended to have lower DNA methylation levels in placental tissue and higher DNA methylation levels in umbilical cord blood, compared to babies among the group that had been conceived naturally. This is one of the first studies to do a systematic study of the DNA methylation of the regulatory region (promoter) of a large number of genes, but at 736 this is still only about 3 per cent of our genes. They also studied the activity (transcription) of some genes in which DNA methylation differed between IVF and naturally conceived babies. There was no neat correlation between gene activity and methylation status - such is the nature of preliminary research on clinical samples compared to laboratory cell lines - so the interpretive jump from DNA methylation change to altered gene activity to adult health risk is farfetched. Importantly, Sapienza starts his discussion of altered gene activity following IVF with this sentence: 'At this juncture, the differences observed in transcript levels are of unclear phenotypic significance'.

We are at the very beginning of research into the possible role of epigenetics in mediating the link between assisted conception and adverse health outcomes. The only way to clarify these risks and hopefully reduce them is more systematic and thorough research. DNA methylation analysis techniques are becoming cheaper and more powerful, but these advances achieve nothing if there are not the patient participants and the systematic collection of relevant samples for analysis. It behoves everyone involved - patients, clinical staff, scientists, grant funding bodies and regulators - to promote this research.