Breakthrough study reveals how assisted reproduction affects placenta and child's growth

Although ART-conceived children are generally healthy, a slightly increased risk of growth disturbances as well as cardiovascular, metabolic, and neurodevelopmental disorders has been observed. The underlying causes of the risks, and whether they result from the ART procedures or parental subfertility, are unknown.

To understand the molecular mechanisms behind ART-associated risks, researchers from the University of Helsinki and Helsinki University Hospital have examined newborns and placentas from 80 ART and 77 spontaneous pregnancies. When the placentas were compared, they considered different ART methods as well as the children´s sex for the first time.

The placenta has proven to be an extremely fascinating organ which connects the mother and the fetus, mediates environmental effects on the fetus and influences fetal development.

"The placenta offers a unique window into the very early developmental stages, which are otherwise difficult to study in human," says Associate Professor Nina Kaminen-Ahola, the leader of the study in the University of Helsinki.

Frozen embryo transfer resembles natural pregnancy

Genome-wide placental gene function and DNA methylation, the most well-known epigenetic mark involved in gene regulation, were examined. Also, potential connections between the observed changes and the placental weight as well as newborns' weight and height were studied.

One of the most interesting findings concerned the two commonly used ART methods, fresh and frozen embryo transfer. In the fresh embryo transfer, the IVF-fertilized embryo is transferred directly from the culture dish into the uterus, while in the frozen embryo transfer the embryo is frozen for a varying period before the transfer.

Several studies have discovered that placentas and children from fresh embryo transfer are smaller on average compared to those from frozen embryo transfer. This was also the case in the current study. Particularly, it was seen that the observed changes related to metabolism and growth were specific only to placentas from fresh embryo transfers.

"Almost all placentas from frozen embryo transfers had been transferred into the uterus during the mother's natural cycle, rather than during an artificial hormone surge as in the case with fresh embryo transfers. Consequently, the onset of pregnancy in these cases resemble more spontaneous pregnancies," explains Pauliina Auvinen, the doctoral researcher on the project.

Altered gene is linked to obesity and diabetes

In addition, the researchers identified altered function of a gene called DLK1. The expression of this gene was reduced in both ART placentas and in placentas from pregnancies of subfertile couples who had applied for fertilization treatment but who got pregnant spontaneously.

The DLK1 gene regulates metabolism and has been associated previously with obesity and type 2 diabetes. Additionally, it can have a role in maternal physiological adaptations to pregnancy.

According to a previous mouse study, Dlk1 is essential for proper maternal fasting response during pregnancy, enabling the switch to using fat for energy resource and thereby securing fetal growth. Silencing of Dlk1 was also associated with the offspring's lower birth weight.

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

"The role of this gene in subfertility and the increasing metabolic disorders such as obesity and type 2 diabetes," needs to be further clarified.

More research needed

Despite the significant new results, more samples need to be collected to better understand the effects of the different fertility treatment methods, subfertility, and sex on the children´s development and health. In addition, understanding the long-term impact of ART requires long-term monitoring of the children.

"Based on the results, it will be possible to improve ART treatments and understand the causes of sub- and infertility. We are continuously collecting more samples, and we warmly thank all the families for participating in the epiART study," says Kaminen-Ahola.