Assisted Reproduction Safety and Risks

In vitro fertilization (IVF) in mammals: epigenetic and developmental alterations. Scientific and bioethical implications for IVF in humans

Ventura-Juncá P, Irarrázaval I, Rolle AJ, Gutiérrez JI, Moreno RD, Santos MJ

Published December 18, 2015 Biological research
DOI 10.1186/s40659-015-0059-y PMID 26683055 PMC PMC4684609

RRM Academy Synopsis

IVF laboratory steps alter gene activity in animal embryos

In animals, IVF laboratory steps produce epigenetic changes that alter gene activity in embryos. The 2015 narrative review summarizes mostly animal research on four steps: egg stimulation, sperm injection, embryo culture and transfer. Its clearest result is large offspring syndrome in ruminants. The syndrome resembles Beckwith–Wiedemann syndrome in humans.

Study at a glance, narrative review: IVF laboratory steps alter gene activity in animal embryos
Study at a glance, narrative review: IVF laboratory steps alter gene activity in animal embryos. Source: Ventura-Juncá P et al., 2015, PMID 26683055.

Key Findings

  • In one human study of 20 metaphase II oocytes, 15 showed a normal unmethylated maternal pattern of the H19 gene. Five, from two patients, showed a methylated pattern.
  • In a mouse study of ten imprinted genes, embryos moved by transfer alone showed aberrant expression. Embryos cultured before transfer showed more genes with aberrant allelic expression.
  • Embryo culture is probably the most relevant factor in the altered epigenetic reprogramming and development seen in animal embryos produced by IVF.
  • In ruminants produced by IVF, large offspring syndrome means large birth size and enlarged organs. One study found no methylation at KvDMR1 on the maternal allele, the main marker of Beckwith–Wiedemann syndrome.
  • A recent mouse study associated suboptimal embryo culture with transgenerational changes in glucose metabolism and liver enlargement in male offspring.

Interpretation

The paper is a narrative review that reports no search method and pools no data, and its evidence comes mostly from animal experiments. The authors state that applying animal results to humans has limits and that the effect of each IVF step is hard to separate. Ethics restrict epigenetic studies in human embryos, so the authors say the long-term consequences in humans are mostly unknown. They agree that clinical follow-up should cover the whole life of every child born by IVF.

RRM Context

The review places fertilization and early embryo development in the maternal oviduct. The authors describe the oviduct as a setting with unique conditions. Restorative reproductive medicine works to restore the couple's reproductive function, so conception happens in that setting. IVF moves these steps into a laboratory. IVF bypasses the reproductive system and does not establish why conception failed.

Abstract

The advent of in vitro fertilization (IVF) in animals and humans implies an extraordinary change in the environment where the beginning of a new organism takes place. In mammals fertilization occurs in the maternal oviduct, where there are unique conditions for guaranteeing the encounter of the gametes and the first stages of development of the embryo and thus its future. During this period a major epigenetic reprogramming takes place that is crucial for the normal fate of the embryo. This epigenetic reprogramming is very vulnerable to changes in environmental conditions such as the ones implied in IVF, including in vitro culture, nutrition, light, temperature, oxygen tension, embryo-maternal signaling, and the general absence of protection against foreign elements that could affect the stability of this process. The objective of this review is to update the impact of the various conditions inherent in the use of IVF on the epigenetic profile and outcomes of mammalian embryos, including superovulation, IVF technique, embryo culture and manipulation and absence of embryo-maternal signaling. It also covers the possible transgenerational inheritance of the epigenetic alterations associated with assisted reproductive technologies (ART), including its phenotypic consequences as is in the case of the large offspring syndrome (LOS). Finally, the important scientific and bioethical implications of the results found in animals are discussed in terms of the ART in humans.

Topics

Related research

Assisted Reproduction › Safety and Risks › Long Term Child Outcomes
Patricio Ventura-Juncá, Isabel Irarrázaval, Augusto J Rolle, Juan I Gutiérrez, Ricardo D Moreno, Manuel J Santos
P Ventura-Juncá, I Irarrázaval, A Rolle, J Gutiérrez, R Moreno, M Santos
PMID 26683055 26683055 DOI 10.1186/s40659-015-0059-y 10.1186/s40659-015-0059-y Ventura-Juncá et al. 2015, Ventura-Juncá 2015