ART Risks – European studies

Children born after assisted reproduction at greater risk of congenital malformations; doctors should be prepared to inform parents of these risks, scientists say

Gothenburg, Sweden:  Couples considering undergoing assisted reproductive technology (ART) treatment should be informed about the increased risk of congenital malformation posed by the use of ART, the annual conference of the European Society of Human Genetics will hear today (Monday).  Dr. Géraldine Viot, a clinical geneticist at the Maternité Port Royal hospital, Paris, France, will say that she believed that most doctors working in ART clinics in France only told couples about such risks if they were asked specific questions.

Dr. Viot and colleagues conducted a survey in 33 French centres registered for ART, around one third of the total number of clinics registered to perform ART procedures in France. All ART births from these clinics from 2003 to 2007 were included; 15 162 children in total.   The study was the largest to date on this subject.  Questionnaires were completed both by the parents and the paediatrician and the prevalence of malformations found compared with the data obtained from national registers and in published papers.

“We found a major congenital malformation in 4.24% of the children”, said Dr. Viot, “compared with the 2-3% that we had expected from previous published studies. This higher rate was due in part to an excess of heart diseases and malformations of the uro-genital system.   This was much more common in boys. Among the minor malformations, we found a five times higher rate of angioma, benign tumours made up of small blood vessels on or near the surface of the skin.   These occurred more than twice as frequently in girls than boys.”

However, the scientists say, their results are a long way from the 11% of major malformations that have been reported by some studies.  “Given that our study is the largest to date, we think that our data are more likely to be statistically representative of the true picture”, said Dr. Viot.

The average age of the parents of children born with malformations was not statistically different from the other parents in the ART group.  The origins of the malformations are probably multiple, says Dr. Viot.  “We need more research in order to understand the relationship between embryo culture media, timing of embryo transfer, the effects of ovarian stimulation, the use of ICSI, where sperm is injected directly into the egg, freezing of gametes and embryos and these disorders.

“We estimate that in France some 200 000 children have been born after ART and therefore a malformation rate of this magnitude is a public health issue.   It is important that all doctors and also politicians are informed about this.   We also need to follow up all children born after ART and to put much more effort into trying to understand which of the procedures involved is implicated in this problem.”

Dr. Viot and colleagues intend to follow up their work analysing a further 4000 questionnaires, from children born in 2008, and to look at the motor development of children born in 2003, who are now aged 7.   “By following all these children we hope to understand more about not only what can go wrong after ART, but why it goes wrong”, she said.  “At a time when infertility is increasing and more and more couples need to use ART to conceive, it is vitally important that we find out as much as we can about what is causing malformations in these children, not only so that we can try to counteract the problem but also in order for health services to be able to plan for their future needs.”

The scientists are now trying to find out the origin of parental infertility for each child born after ART who has been affected by major malformation or epigenetic disorders.  “With this knowledge, we can better establish the origin of the malformation and whether it is more likely to be related to parental infertility or the ART procedure itself”, said Dr. Viot.  “We already know that imprinting disorders – where the mechanism in which gene expression depends on parental origin – are clearly more frequent in our cohort than in the general population.”

Imprinting disorders are all acquired because of either a maternal or paternal deletion on a chromosome, through inheritance of both chromosomes of a pair from only one parent, through mutations in some imprinted genes, or because of loss or gain of methylation (a process which is normally removed during zygote formation and re-established through successive cell divisions during development.  “The prevalence of the imprinting disorder Beckwith Wiedemann syndrome in our cohort is six times higher than we would expect in the general population, and for retinoblastoma the prevalence among ART children is 4.5 higher than in the general population”, said Dr. Viot.

“These results could be due to the effect of a number of different mechanisms. They could be due to the infertility itself, the ovarian stimulation for supernumerary oocyte production, the in vitro maturation of oocytes, the use of ICSI (direct injection of sperm), the culture media, the cryopreservation of gametes and embryos – we just don’t know at present.  Finding this out will be a major step towards improving the health of children born after ART.”
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Should the results of individual genetic studies be disclosed to participants?  Study queries the right to information in every case

Gothenburg, Sweden: Individual results of genetic research studies should not be disclosed to participants without careful consideration, a scientist will tell the annual conference of the European Society of Human Genetics today (Monday).  Dr. Robin Hayeems, from the Department of Health Policy, Management and Evaluation at the University of Toronto, Canada, will say that she believes that the view held by many ethicists that individual genetic research findings should always be reported to participants involved in genetic research studies was perhaps misguided, and that to do so without careful consideration of evidentiary assumptions and clinical capacity could distort the responsibilities of researchers and lead to misunderstanding.

Dr. Hayeems leads the GE3LS (Genomics and its Ethical, Economic, Environmental, Legal and Social Aspects) component of a Genome Canada funded basic science project that is looking at identifying the genes that can modify the severity or clinical effects of cystic fibrosis (CF).   Together with the study co-lead Professor Fiona Miller, in charge of the GE3LS component of the Genome Canada funded autism genome project, her team surveyed researchers from around the world who were involved in genetics research related to CF and autism.   “We were interested in their perspectives about sharing genetic research results with individual study participants in order to be able to add their voices to the ongoing debate about whether and under what circumstances researchers are under an obligation to report these results to research participants”, she said.

The survey found that 80% of the researchers agreed that individuals in whom a genetic variation had been identified should be informed of this finding if it were judged to be clinically significant.   Yet it also revealed considerable variation among researchers in deciding when a result was clinically significant. Researchers felt less confident about the clinical significance of a result when the finding was related to autism research, was less scientifically robust, and was incidental to the condition being studied.  Further, researchers were 40% less likely to report it when they were unable to provide participants with the requisite medical advice related to the finding.  There were also differences between scientific disciplines, with clinical researchers being 1.8 times more likely to class a particular finding as clinically significant and 1.5 times more likely to report it to study participants than were molecular and statistical researchers.

“Our understanding of how genetic factors contribute to the heterogeneous collection of conditions that comprise the autism spectrum disorders is in its infancy.   By contrast, though much remains to be learned about the genetics of CF, the clinical consequences of classical CF and the basic genetic defect that causes it has been known for some time”, said Dr. Hayeems.

“I think our discovery that an autism-relevant finding engenders less confidence with respect to clinical significance compared to a CF-relevant finding reflects researchers’ implicit sense of the fundamental uncertainty that still prevails with respect to the genetics of autism.   What is interesting about the survey design is that we can say overall that confidence in an autism-related genetic finding was lacking compared to a CF-related finding, even when the autism-related finding they were asked to judge was, by design, quite robust.

“Most, but not all, ethicists endorse an obligation to report genetic research results about individuals because they consider it to be clinically relevant information that individuals have a right to receive.  This argument presumes that these research results constitute such information, and that the judgment of clinical significance is relatively straightforward.  Our work suggests that this presumption may be misplaced. The results of the survey identify a set of factors that appear to influence researchers as they consider whether a result is clinically significant and whether it should indeed be reported. These factors go beyond scientific standards of robustness to include underlying uncertainties about the role of genetics in certain conditions, as well as researcher training and research team capacity”, she said.

The GE3LS team now intends to encourage institutional research bodies and the wider research ethics community to revisit their thinking about the obligation to report research results to include a broader set of factors so that the complexity of the issue is fully reflected.  “Our work highlights an important intersection between health research and health care”, said Professor Miller.  “This intersection raises important questions.  Are results being interpreted and reported in the context of a research relationship in which the norms of clinical care cannot be expected or, in the context of clinical care, in which case these norms are assumed?  What context is assumed, and who is responsible – researchers, or health care systems – for ensuring appropriate disclosure and follow up?” she concluded.
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Mary Rice:
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