In vitro fertilization (IVF), the process of fertilizing an egg with sperm outside of the body, is a technique that has enabled couples with fertility problems to conceive. However, like most medical procedures, it is not without its risks and even though the first IVF procedure was performed in 1978, we are still far from fully understanding the implications and dangers. IVF risks are not only restricted to those undergoing fertility treatments, but are also a concern for the future children. Perhaps the most contentious and alarming topic in the field is whether IVF procedures are linked to imprinting disorders in children.
What is imprinting?
Since we inherit genetic information from our mothers and our fathers, we contain two copies of most genes. For the majority of genes, both parental copies are active but for some (less than 1%), only one parental copy is used and these genes are referred to as imprinted genes. Collectively these modifications are referred to as our epigenome and this too is heritable but is also influenced by our environment. This uniparental activation is achieved by epigenetic DNA modifications that are able to silence one copy of the gene (Figure 1).
Our genes are contained in our DNA which is collectively referred to as our genome, which we inherit from our parents. Chemical changes that affect our DNA, as well as proteins associated with our DNA, affect which genes are active and at which time.
What are imprinting disorders?
Imprinting disorders result when the uniparental activation of certain genes is disrupted, which occurs in Beckwith-Wiedmann syndrome, Angelman syndrome, Silver-Russell syndrome, Prader-Willi syndrome and retinoblastoma. Overall these disorders are quite rare but are associated with severe developmental abnormalities and cancer in the case of retinoblastoma. It is important to note that even though our environment can affect our epigenome, imprinted disorders are real diseases and are not simply physiological adaptations to environmental changes. Whether or not IVF treatments can disrupt the epigenome in a manner to cause imprinted disorders is still unclear.
The connection between IVF and imprinting disorders
The first, and perhaps strongest, evidence for a link between IVF treatments and imprinting disorders was the prevalence of large offspring syndrome in calves that were produced through IVF techniques. There was an increased incidence of large calves, with some having organ defects, when bovine oocytes matured and were fertilized in vitro. This was shown to be due to the loss of imprinting control over the insulin-like growth factor 2 receptor (IGF2R) gene. Based on this observation, several studies examined whether IVF treatments caused imprinting disorders in humans and several alarming papers were published that argued that this was the case.
In humans, imprinting disorders of the IGF2R gene cause Beckwith-Wiedmann syndrome, which also leads to fetal overgrowth and is diagnosed based on physical characteristics. An initial study examining the prevalence of Beckwith-Wiedmann syndrome in children born after IVF in comparison to the general population found that the disease was 6 times more common in the IVF group. From there, another study estimated that Beckwith-Wiedmann syndrome was 12 times more common in children born through IVF, while other studies argued that there was no association at all. Similar discrepancies were also reported for other imprinting disorders and the rarity of these disorders was suggested as a possible explanation for why it was hard to study a correlation.
A recent study by Vermeiden et al. sought to do a systematic review of published literature to determine if there was a causal relationship between IVF and imprinted diseases and overall there was no proof of this being the case. However, they did find that Beckwith-Wiedmann syndrome was significantly associated with IVF treatments and that Angelman syndrome and Prader-Willi syndrome were positively associated with families with fertility problems, but not with IVF.
Possible explanations for the increased prevalence of imprinted disorders in children born after IVF
If IVF treatments are not causing imprinting disorders, then why have some studies found an increased prevalence of these disorders in children born after IVF? A conclusive answer for this remains elusive, but Vermeiden et al. provide some explanations. They suggest that much of the misinterpretation may be due to the rarity of imprinted disorders. Collectively, these disorders have a prevalence of 1:30,000-10,000 and a consequence of the rarity of these diseases is the difficulty to perform studies with sufficient statistical power. Another issue is selecting a proper control group in comparison studies. In the normal population, only a small fraction of children are born to couples with fertility problems but 100% of children conceived after IVF are born to parents with fertility problems. In fact the authors suggest that the increased incidence of some imprinted diseases like Angelman syndrome and Prader-Willi syndrome after IVF can be explained by the fertility problems of the parents, instead of the IVF treatments themselves. Alternatively, the rate of multiple pregnancies is often increased after IVF treatments and some studies suggest that multiples have higher rates of developmental abnormalities, which may be related some way. Large scale studies have yet to be performed but will be crucial in definitively determining what if any association exists between IVF and imprinting disorders.
Screening for imprinting disorders
Currently, routine screening for imprinting disorders in children conceived with IVF has not been performed nor has it been recommended because of rarity of these disorders. However, some providers do offer laboratory tests that can be used for prenatal diagnosis of Prader-Willi syndrome and Angelman syndrome. In addition to testing for imprinting disorders, many other genetic disorders can be identified through preimplantation genetic screening practices that greatly reduce the risk of passing on a genetic disorder to future children.
Vermeiden, J.P. et al. Fertil. Steril. 2013; 99: 642–51. Are imprinting disorders more prevalent after human in vitro fertilization or intracytoplasmic sperm injection?
Figure 1. Epigenetic modifications on imprinted genes usually persist for the life of the organism. But they are reset during egg and sperm formation. Regardless of whether they came from the mother or the father, certain genes are always silenced in the egg, and others are always silenced in the sperm. Image courtesy of the Genetic Science Learning Center, The University of Utah.
— Geneyouin (@geneyouin) November 13, 2013