A joint study by Spain’s IVI Foundation and Stanford University examined 69 human embryos and found differences in protein secretion according to chromosome status.
Differences in PAPP-A were observed on day 10 after fertilization, suggesting a way to study development through biological signals as well as appearance.
Choosing an embryo is an important part of in vitro fertilization (IVF). Embryos have traditionally been assessed using their appearance, developmental speed and chromosome test results. New research suggests that proteins released into their surroundings may also contain clues that distinguish embryos with a normal chromosome count from those with chromosome abnormalities.
Researchers from the IVI Foundation and IVIRMA in Spain, working with Stanford University in the United States, analyzed 69 human embryos and identified different secretion patterns according to chromosome status. Their findings were published in Human Reproduction.
The study is notable for exploring whether substances released by embryos could help assess their development beyond what is visible under a microscope.
Comparing 24 euploid embryos with 45 embryos with chromosome abnormalities
The researchers divided 69 human embryos into three groups: 24 euploid embryos with a normal chromosome count, 21 embryos with an extra copy of chromosome 21, and 24 embryos missing one copy of chromosome 21.
They used a three-dimensional culture technique incorporating endometrial cells. This created a laboratory environment resembling aspects of the uterine lining, allowing the team to observe embryo development and proteins released into the surrounding environment.
Embryos were cultured until day 14 after fertilization. The team analyzed secretion of pregnancy-associated plasma protein A (PAPP-A), placental growth factor (PlGF) and beta-human chorionic gonadotropin (β-hCG). Changes in embryo size and shape were also examined to assess developmental differences associated with chromosome status.
A clear difference in PAPP-A on day 10
The most notable finding involved PAPP-A. Its secretion on day 10 after fertilization distinguished euploid embryos from both types of chromosome 21 abnormality examined in the study.
PAPP-A and PlGF secretion increased as euploid embryos developed. Embryos with trisomy 21 did not show the same pattern of increase. Embryos with monosomy 21 showed differences earlier, including reduced secretion of some proteins from day 7.
Differences in shape were also observed. Euploid and trisomy 21 embryos expanded and changed shape during development, while monosomy 21 embryos remained rounded and did not expand sufficiently.
These findings suggest that chromosome abnormalities may affect not only embryo appearance but also the biochemical substances released during development.
Interaction with the uterine lining also matters
The culture environment made a difference. Embryos cultured without support from endometrial cells showed reduced viability and lower secretion of key proteins beyond day 10. In the three-dimensional environment containing endometrial cells, development could be observed until day 14, with relatively more active protein secretion.
This suggests that embryo development depends on interaction with the endometrium as well as the embryo’s own characteristics.
In pregnancy, implantation requires complex exchanges of biological signals between the embryo and uterine lining. The study demonstrated a way to observe and analyze aspects of that process in the laboratory.
Could secreted proteins complement embryo appearance?
Morphological assessment—observing cell arrangement and the pace of development—is widely used in IVF. Where indicated, preimplantation genetic testing for aneuploidy (PGT-A) is also used to assess abnormalities in chromosome number.
Appearance alone, however, cannot precisely establish chromosome status or subsequent developmental potential. Embryos that look similar may differ biologically.
The research suggests that analyzing secreted proteins could provide additional developmental information that existing assessments do not capture. Because the approach examines substances released into the culture environment rather than directly sampling embryo cells, it could potentially contribute to future non-invasive assessment methods.
An important qualification is that the main difference was observed on day 10 after fertilization—later than embryos are usually transferred or frozen in IVF. The findings therefore do not mean that an embryo-selection technique ready for clinical use has been developed.
Effects on pregnancy and live birth still need study
The limitations are clear. The sample comprised only 69 human embryos, and the chromosome abnormalities examined were limited to chromosome 21. It is not known whether other chromosome abnormalities produce the same secretion patterns.
Further research must also establish how laboratory differences in secretion relate to pregnancy or birth outcomes. This was basic research examining development and secreted proteins. It did not demonstrate that selecting embryos using a particular protein increases pregnancy or live-birth rates in IVF.
Nevertheless, it points toward a new direction in embryo assessment: studying not only how an embryo grows, but also what it releases and how it exchanges signals with its environment.
With sufficient validation, a future approach might combine morphology, developmental speed and genetic information with analysis of secreted proteins. The research begins to explore how to read an embryo’s biological signals alongside its appearance.
This article is based on “Mapping developmental and targeted secretory signatures of euploid and aneuploid human embryos using an advanced endometrial model,” published online in Human Reproduction in October 2026 by researchers from the IVI Foundation/IVIRMA Global Research Alliance in Spain and Stanford University in the United States. DOI: 10.1093/humrep/deag166. PMID: 42927452.
The image accompanying this article was created using generative AI (ChatGPT, OpenAI).
Related guide: Why can a euploid embryo fail to implant?
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