Why Do So Many Embryos Fail in IVF?

The Context: Early human embryos created for IVF (in which an egg is fertilized and grown outside the body before being implanted to begin a pregnancy) are known to have low survival rates: most don’t make it past five days once fertilized. Understanding what causes an embryo to fail during development is critical for improving success rates of this procedure. Frequent loss of an embryo also occurs after natural fertilization, making it more difficult to get pregnant.

The Study: When a single-cell embryo begins to divide, spontaneous errors in how it replicates its DNA can lead to an abnormal number of chromosomes in newly created cells and cause an embryo to fail, finds a new study in Cell by NYSCF – Robertson Stem Cell Investigator Alumnus and former NYSCF Research Institute scientist Dieter Egli, PhD, of Columbia University. 

The Importance: This study provides fundamental new insights into the basic biology of human reproduction, shedding light on a cause of genetic abnormalities and pregnancy loss, which could inform strategies for improving the success of IVF. Understanding the origin of disease-causing genetic variation in early human development could also reveal clues about how to prevent genetic changes that cause disease.  

Chromosomes in the Wrong Homes

“Duplicating the genome is a challenging task for the early embryo,” Dr. Egli, the Maimonides Assistant Professor of Developmental Cell Biology (in pediatrics) at Columbia University Vagelos College of Physicians and Surgeons said in a press release.

To create a successful embryo, the fertilized egg needs to start by self-replicating to make a bunch of new cells, a process known as mitosis. Before a cell divides, it makes a copy of its DNA – 46 chromosomes made of more than 3 billion base pairs. Then, as it splits, it must shepherd the duplicate chromosomes into separate daughter cells.

In IVF, embryos tend to fail because these daughter cells often end up with the wrong number of chromosomes.  

What causes this to happen?

The working theory has traditionally been that in the final stage of cell division, when the chromosomes are being ushered to their new home in a daughter cell, the microtubule spindle, a structure that pulls the sets of chromosomes apart, falters. However, Dr. Egli’s team found that the central issue is likely happening much sooner in the process, before a cell divides.

Errors in Duplicating DNA Put a Cell in Danger

It turns out that mistakes the embryo makes when copying its DNA often lead to its eventual failure. 

Dr. Egli’s team examined embryos created in a dish – from individuals undergoing IVF and egg donors who were not seeking fertility treatment – to look for mistakes that could lead to incorrect numbers of chromosomes. The scientists found that often in these cells, abnormalities in DNA’s signature double helix shape can cause replication to stall, causing breakage of the DNA. When mitosis begins before replication finishes, the spindle isn’t able to place chromosomes into daughter cells correctly. The result: a failed or compromised embryo.

“This has largely been overlooked in previous studies—because why would the embryo allow the integrity of the genome to be compromised when this is such a critical requirement for normal development?” pointed out Dr. Egli.

Implications for IVF and Beyond

“Many women undergoing fertility treatment require multiple IVF cycles in order to get pregnant, and some never get pregnant at all. Not only is this enormously expensive, it’s emotionally taxing,” remarked Jenna Turocy, MD, a fertility specialist at Columbia University Fertility Center and a co-author of the study.

The researchers will further examine DNA damage during replication, hopefully informing new strategies for improving the success of IVF, and preventing genetic abnormalities.

Dr. Egli stresses that this work was only possible with support from NYSCF.

“This work was inspired by findings from when I was a scientist at The NYSCF Research Institute, and could only have been done thanks to funding from the NYSCF – Robertson Stem Cell Investigator Program,” he said. “I’m very grateful for NYSCF’s visionary support in pursuing this important research, which will hopefully improve the lives of many struggling with infertility and pregnancy loss.”

Journal Article:

Replication stress impairs chromosome segregation and preimplantation development in human embryos
Katherine L. Palmerola, Selma Amrane, Alejandro De Los Angeles, Shuangyi Xu, Ning Wang, Joao de Pinho, Michael V. Zuccaro, Angelo Taglialatela, Dashiell J. Massey, Jenna Turocy, Alex Robles, Anisa Subbiah, Bob Prosser, Rogerio Lobo, Alberto Ciccia, Amnon Koren, Timour Baslan, Dieter Egli. Cell. 2022. DOI: https://doi.org/10.1016/j.cell.2022.06.028