Study of placenta genes reveals impact of artificial insemination on child development

About one in six couples trying to have a child faces infertility. Each year, more and more children are born through assisted reproductive technologies (ART), and to date, more than ten million children have been conceived through these methods worldwide.

Although children conceived through ART are generally healthy, there is a slightly increased risk of growth disorders as well as cardiovascular, metabolic and neuropsychiatric disorders. The reasons underlying these risks and whether they are due to ART procedures or parental infertility are unknown.

To understand the molecular mechanisms of the risk associated with ART, researchers from the University of Helsinki and Helsinki University Hospital studied newborns and placentas from 80 ART and 77 spontaneous pregnancies. When comparing the placentas, for the first time the different methods of ART as well as the sex of the babies were taken into account.

The placenta turned out to be an extremely interesting organ that connects mother and foetus, mediates environmental exposure to the baby and influences foetal development.

‘The placenta offers a unique window into the earliest stages of development that are otherwise difficult to study in humans,’ says Associate Professor Nina Kaminen-Ahola, leader of the study at the University of Helsinki.

The study is published in the journal Communications Medicine.

The genomic functions of placental genes and DNA methylation, the best known epigenetic mark involved in gene regulation, were studied. In addition, potential links between the observed changes and placental weight and neonatal weight and growth were investigated.

One of the most interesting findings concerned two commonly used ART techniques, fresh and frozen embryo transfer. In fresh embryo transfer, the IVF fertilised embryo is transferred directly from the culture cup into the uterus, whereas in frozen embryo transfer, the embryo is frozen for a certain period of time before transfer.

Several studies have found that placentas and babies born from fresh embryo transfers are on average smaller in size than babies born from frozen embryo transfers. This was also the case in this study. In particular, it was observed that the observed changes related to metabolism and growth were unique to placentas obtained from fresh embryo transfer.

‘Almost all placentas obtained by frozen embryo transfer were transferred to the uterus during the mother’s natural cycle, not during an artificial hormonal surge as in the case of fresh embryos. Consequently, the onset of pregnancy in these cases is more like a natural pregnancy,’ explains Pauliina Auvinen, a doctoral student involved in the project.

In addition, the researchers identified altered function of the DLK1 gene. The expression of this gene was reduced both in placentas obtained as a result of ART and in placentas from pregnancies of subfertile couples who sought fertilisation but became pregnant spontaneously.

The DLK1 gene regulates metabolism and has previously been linked to obesity and type 2 diabetes. It may also play a role in the mother’s physiological adaptation to pregnancy.

According to a previous study in mice, Dlk1 is required for the mother’s proper response to starvation during pregnancy, allowing a switch to utilise fat as an energy resource and thereby allowing fetal growth. Switching off Dlk1 has also been linked to lower offspring birth weight.

Kaminen-Ahola says that silencing the DLK1 gene has also been linked to low birth weight in humans.

The role of this gene in subfertility and growing metabolic disorders such as obesity and type 2 diabetes needs further investigation.

Despite the significant new findings, more samples need to be collected to better understand the effects of different fertility treatments, subfertility and gender on child development and health. In addition, long-term follow-up of children is needed to understand the long-term effects of ART.

‘Based on the findings, it will be possible to improve ART treatments and understand the causes of subfertility and infertility. We are continuously collecting new samples and warmly thank all families for participating in the epiART study,’ the researchers said.