Fluid biopsies for in vitro fertilization: Non-invasive innovations (Review)

Non-invasive fluid biopsies are emerging as a promising, low-risk complementary method to traditional diagnostic approaches in reproductive biology, allowing for repeated sampling throughout different stages of assisted reproductive technology. These approaches hold significant potential, not only for clinical diagnosis, but also for personalized medicine. The present review summarizes recent findings on key biomolecular components found in accessible body fluids, such as follicular fluid, embryo culture medium, uterine secretions and saliva, namely cell-free nucleic acids, extracellular vesicles and microRNAs. These biomarkers indicate critical cellular events, such as apoptosis, oxidative stress, mitochondrial dysfunction and intercellular signaling pathways. Special emphasis is placed on the molecular profile of granulosa and cumulus cells, which are essential for oocyte maturation and have strong predictive value for fertilization potential and subsequent pregnancy outcomes. Their molecular signatures provide critical information about the developmental competence of the oocyte and early embryo. However, limitations such as maternal contamination, mosaicism and variable compliance, along with a lack of guideline-level approval, currently restrict their routine clinical use. These non-invasive samples are valuable complements to current invasive methods, providing information about chromosomal competence and embryo viability without compromising embryo integrity. Overall, the current evidence highlights the potential of fluid-based biomarker discovery to improve the outcomes of in vitro fertilization (IVF) and support the development of personalized, sustainable fertility treatments. The present review aimed to summarize and critically evaluate developments in non-invasive liquid biopsy techniques in IVF, highlight their clinical applications for improving IVF outcomes, and examine the molecular profile of granulosa and cumulus cells as determinants of oocyte and embryo quality. The fundamental hypothesis is that non-invasive liquid biopsies can serve as effective, low-risk alternatives to traditional invasive diagnostic approaches, minimizing harm to patients and embryos, while improving embryo selection, preimplantation genetic testing and overall IVF success.