Research into IVF embyos

“Drugs used to stimulate the ovaries of older women undergoing IVF treatment may be causing genetic defects in the embryo,” The Independent reported today.

This finding comes from a preliminary presentation of a study looking at fertilised eggs with chromosomal abnormalities, such as those found in children with Down’s syndrome, obtained from 34 couples undergoing in vitro fertilisation (IVF). The research used new lab techniques to analyse abnormalities in the fertilised eggs and the point when they occurred. The results suggest that the pattern of abnormalities differs from what would be seen in natural conceptions. However, as this study had no comparison group, it is not possible to confirm whether the type or rate of abnormalities differs from what would occur naturally (without IVF), therefore further research is needed to clarify the situation. Furthermore, if such an increase in risk does exist, it may only apply to the specific fertility techniques tested during the research; not all IVF techniques.

Therefore, the results of this preliminary study should not alarm couples undergoing IVF. However, abnormal embryos can reduce the chances of successful fertility treatment, and could result in parental distress due to subsequent miscarriage or the choice of termination, or impact the future health of any offspring. Therefore, it is important that this research is extended to determine whether there is an increased risk of chromosomal abnormalities with fertility treatment, and whether this could be avoided in future.

Where did the story come from?

The study was carried out by researchers from the London Bridge Fertility, Gynaecology and Genetics Centre, and from other research and fertility centres in Europe and Canada. It is being presented at the conference of the European Society of Human Reproduction and Embryology in Stockholm this week, and has not yet been published in print. No sources of funding were mentioned in the conference abstract.

BBC News, The Daily Telegraph, The Independent and the Daily Mail all covered this study. They all reported the basics of the research and The Independent was appropriately cautious, reporting that the researchers want to reassure older women considering IVF treatment: “[The researchers] said further work needs to be done fully to explain the findings and there is no evidence to suggest that IVF babies of older women are at any higher risk of birth defects than babies conceived naturally by women of the same age.”

What kind of research was this?

This was a case series looking at the how common chromosomal “number” abnormalities (such as having too many or too few chromosomes) are in eggs and embryos from women undergoing fertility treatment.

The researchers say that, after both normal conception and in vitro fertilisation (IVF), it is the embryo having too many or too few chromosomes (called chromosome aneuploidy) that is a major cause of miscarriage, as well as of foetal abnormalities. The risk of these abnormalities is increased with the increasing age of the mother. Chromosomal abnormalities often mean that the embryo cannot survive, but some chromosome abnormalities are not fatal to the embryo, and instead cause conditions such as Down’s syndrome (also called trisomy 21, where an individual usually has three of chromosome number 21).

The researchers thought that the ovarian stimulation used to encourage egg production during IVF might disturb the normal formation of eggs, making the chromosomes divide earlier than they might do otherwise. This could potentially increase the likelihood of these chromosomal abnormalities.

This type of study can tell us how common a particular phenomenon is in a particular group, such as women undergoing IVF. However, as there was no comparison (control) group, it is not possible to say how more or less common the phenomenon is here than in other groups. At present, we cannot tell how the rates of these chromosomal abnormalities observed compare against those in women not undergoing IVF treatment.

What did the research involve?

Only limited information on the methods and results of this study are available from the conference abstract. The press release accompanying the conference presentation suggests that the study was initially designed to look at the reliability of a new technique for looking for chromosome abnormalities, called “microarray comparative genomic hybridisation”. Once they had tested the method, the researchers apparently realised they could also look at their results to see if they could learn more about the risk of chromosomal abnormalities in IVF embryos.

The researchers looked at 34 couples having fertility treatment. The average age of the women was 40. They looked at the DNA that came from the women’s eggs at different stages of maturation, and at the fertilised eggs, to identify any that were carrying genetic abnormalities. Those that were carrying abnormalities underwent further testing to see exactly what type of abnormalities were present.

Of the couples taking part in this study, 31 had agreed to do so because the female was older (aged 35 or more) while a further three couples had an increased risk of chromosome abnormalities because the female partner was known to carry a chromosome abnormality herself. The researchers fertilised the women’s eggs by injecting them with sperm (called intracytoplasmic sperm injection, or ICSI), and then collected two small cells that are by-products of the formation of the mature egg, called polar bodies. They tested these to see if they contained too many or too few chromosomes. If the polar bodies did contain an abnormal number of chromosomes, this would indicate that the mature egg would also be likely to do so, leading the researchers to test the fertilised egg for confirmation. The results from this testing of the abnormal fertilised eggs were reported in the abstract.

During the formation of a mature egg there are two divisions that occur in the parent egg cell (oocyte), called meiosis I and II. These stages allow the formation of an egg with half the genetic material of a normal cell, with the other half of an embryo’s genetic material provided by the father’s sperm. One polar body is formed in the first division of the parent egg cell and the second in the second division, so by looking at the polar body DNA the researchers could tell at which division the chromosomal abnormality developed.

What were the basic results?

The researchers identified 105 fertilised eggs with an abnormal number of chromosomes. It was not clear from the conference abstract how many fertilised eggs had been tested in total.

The researchers analysed 2,376 chromosomes in all, and of these, 227 chromosomes (9.5%) contained an abnormality which occurred during the formation of the egg. These abnormalities could affect any of the chromosomes.

The researchers found that just over half of the chromosomal abnormalities (55%, 125 errors) occurred at the time of the first oocyte division (meiosis I), and the remainder (45%, 102 errors) at the time of the second division (meiosis II). They also found that, in 48 cases, an error that had occurred in the first division had been corrected in the second division.

Of the 64 fertilised eggs with chromosomal abnormalities arising from the egg only (and not from the sperm), 58% had more than one extra or missing chromosome. The researchers also identified 48 fertilised eggs where the chromosomal abnormality did not come from the egg, and therefore could have either come from the sperm or occurred after fertilisation.

Down’s syndrome is caused by the embryo carrying an extra chromosome 21. The researchers say that of the 16 fertilised eggs where there was an extra chromosome 21, only a minority of the division errors occurred in the first division of the oocyte (four cases, 25%), with over half of the cases occurring in the second division (nine cases, 56%), and the remainder presumed to come from the sperm (three cases, 19%).

How did the researchers interpret the results?

The researchers concluded that the pattern of chromosomal errors seen in these women undergoing IVF, most of whom were of advanced maternal age, “is significantly different from natural conception”. As an example, they say that in most cases of Down’s syndrome (caused by an extra chromosome 21) that occur after a natural conception, the error occurs in the first division of the oocyte, which was not the case in the fertilised eggs analysed in their study.

The researchers say that these differences and the high rate of fertilised eggs with multiple chromosomal errors “may indicate a role for ovarian stimulation in perturbing meiosis in ageing oocytes”. In other words, this may indicate that artificial stimulation of the ovaries could potentially disrupt the division process in older parent egg cells.

Conclusion

This study suggests that eggs produced in fertility treatment may be more likely to have chromosomal abnormalities. There are several points to note:

• Only limited information on the methods and results of this study are available from the conference abstract, therefore it is difficult to judge fully the quality of the study.
• As yet, this research has only been presented at a conference, and as such should be treated as preliminary. Studies presented at conferences have not yet been through the full peer review quality control process that they undergo when being published in a medical journal. Sometimes the preliminary findings presented at conferences change when the full analysis is carried out and published.
• There was no control group (couples who had not had fertility treatment, and whose eggs and embryos had been similarly examined). Therefore it is not possible to be certain that these abnormalities are more or less common than what would be expected normally. In women not undergoing fertility treatment, these abnormal embryos may be formed, but may not survive to produce a pregnancy or live baby.
• The number of women included in this study was small, and received a particular form of IVF called ICSI, so they may not be representative of all women receiving fertility treatment.
• Some newspapers have suggested that the high doses of the chemicals used to induce ovulation may be responsible for these problems. However, without a control group who did not receive these chemicals, or received less of them, it is not possible to say that this or other procedures used during IVF are responsible. The authors note in the press release accompanying this abstract that they need to look further at the pattern of errors occurring after different types of stimulation regimes to determine if some are associated with fewer abnormalities than others.

Finally, it is important to note that this study looked at eggs fertilised in the laboratory and not at outcomes in live babies produced by the IVF technique. Even if fertilised eggs with chromosomal abnormalities were returned to the woman’s body, they may not have the ability to bring about a successful pregnancy, and therefore not all the affected egg cells would result in an affected baby.

Nevertheless, the presence of abnormal embryos can potentially reduce the chances of successful fertility treatment, and could result in miscarriage, the choice of termination, or a child being affected by a condition involving chromosomal aneuploidy. Therefore it is important that research continues to determine whether there is an increased risk of chromosomal abnormalities with fertility treatment, and whether by modifying procedures this could be avoided in future.