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."