Why two-thirds of IVF embryos suddenly stop developing

A new insight into why some IVF embryos go into “developmental arrest” could help researchers create treatments that coax them into growing normally

By Clare Wilson

The development of a human embryo

Tong Guoqing (CC-BY 4.0)

About two-thirds of embryos created during in vitro fertilisation (IVF) inexplicably stop growing – and scientists may be starting to understand why.

The discovery gives some hints as to how such embryos may one day be coaxed into developing normally. This could lead to higher IVF success rates, with only around 1 in 4 treatment rounds leading to pregnancy in Europe.

In IVF, several eggs are placed in a dish with sperm and checked regularly through a microscope to see which ones have been fertilised, leading to an embryo.

Some then develop into a blastocyst, a ball of about 100 cells, and can be transferred into someone’s uterus. But about 6 in 10 embryos never reach the blastocyst stage. Instead, they stop developing about three days after fertilisation, when they consist of only a few cells.

Why some stop developing was a mystery, says Andrew Hutchins at the Southern University of Science and Technology in Shenzhen, China.

To learn more, Hutchins’s team investigated 17 arrested embryos by sequencing their RNA, strands of genetic material that show which genes are active. For active genes, an RNA molecule is produced using the gene’s DNA as a template. The RNA is then used as instructions for making a protein. The team also looked at the arrested embryos’ chromosomes, packages of DNA within cells.

The researchers combined this with similar data on six other arrested embryos from a previous study, before comparing the whole set with existing RNA sequencing work on embryos that seemed to be developing normally.

They were surprised to find that the arrested embryos didn’t have higher rates of chromosome abnormalities than healthy embryos.

Instead, they discovered that arrested embryos could be divided into three groups. In type 1, the embryo makes proteins from maternal RNA that had been in the egg, but fails to start making proteins from its own DNA, a crucial step in its development.

Type 2 and 3 arrested embryos fail to make a crucial transition in how they obtain energy. Healthy embryos shift from a metabolism that is dependent on oxygen to one that requires little oxygen. This is because in very early pregnancies, once the embryo has implanted into the uterus and before the placenta has developed, its oxygen levels are low.

In type 2 arrested embryos, their oxygen-dependent metabolism continues, while in type 3, it falls to low levels, with neither correctly moving to a non-oxygen-dependent metabolism.

In a second part of the experiment, Hutchins’s team tried treating a group of arrested embryos with compounds that have antioxidant effects, including resveratrol, found in red wine. “We will basically be forcing the cells… to alter the balance of their metabolism,” he says.

Resveratrol seemed to restart development in about half the 42 arrested embryos. But most still stopped growing later on, with only three reaching the blastocyst stage. And even these didn’t seem to have normal gene activity, says Hutchins. “We’re sort of forcing them to develop, even though they really don’t want to,” he says.

However, the abnormal gene activity may have occurred because the embryos were allowed to remain at the arrest stage for too long, he says.

The findings are early-stage work, but could one day help doctors reduce the number of embryos that arrest in the first place, says Virginia Bolton at King’s College London. “That could increase the number of embryos a couple would have available to them for pregnancy,” she says. “What they found is absolutely fascinating.”

Journal reference: PLoS Biology , DOI: 10.1371/journal.pbio.3001682