Why Does a Euploid Embryo Fail to Implant?

Why Does a Euploid Embryo Fail to Implant?

The transfer of a chromosomally normal (euploid) embryo is often perceived as the ultimate guarantee of success in IVF. While it substantially increases the probability of pregnancy, it does not ensure implantation or live birth. Clinical studies consistently demonstrate that even after transferring a euploid blastocyst selected through preimplantation genetic testing (PGT-A), live birth rates plateau at approximately 60–70% (Forman et al., 2014; Rubio et al., 2020). This means that nearly one in three patients will not achieve pregnancy despite a genetically normal embryo.

Understanding why this occurs is one of the central challenges in reproductive medicine today. Implantation is not solely dependent on the embryo—it requires a finely tuned interaction between the embryo, the endometrium, the maternal immune system, and systemic health factors.

1. Endometrial Factors

• Window of implantation (WOI): The endometrium is receptive for only a short and individualized time frame. If transfer does not coincide with this window, even a euploid embryo may fail to implant. Tools such as the Endometrial Receptivity Analysis (ERA) have been proposed, though evidence remains mixed.
• Progesterone levels: Low serum progesterone in hormone replacement therapy (HRT) cycles has been consistently associated with poorer outcomes; individualized luteal phase support is critical.
• Chronic endometritis: Subclinical inflammation, identified via CD138 biopsy, can impair receptivity. Antibiotic treatment improves outcomes when confirmed.
• Uterine pathologies: Polyps, submucosal fibroids, adhesions, or septa may compromise implantation. Surgical correction improves success rates.
• Hydrosalpinx: Reflux of tubal fluid into the uterine cavity is toxic for implantation. Salpingectomy or proximal occlusion is the standard of care.
• Endometrial microbiome: Non–Lactobacillus-dominant flora may reduce implantation potential, though current data remain preliminary.

2. Immunological Factors

• uNK cells and Th1/Th2 balance: Excessive inflammatory activity can interfere with trophoblast invasion.
• Antiphospholipid syndrome (APS): Leads to microthrombosis; treatment with low-dose aspirin ± LMWH is effective when APS is confirmed.
• Experimental immunotherapies: Corticosteroids, IVIG, or intralipids are used in select cases but remain controversial with limited supporting evidence.

3. Embryo-Intrinsic “Invisible” Defects

PGT-A is powerful but not omniscient. Euploid embryos may still harbor defects:

• Mitochondrial dysfunction: Insufficient energy production may impair hatching and invasion.
• Epigenetic or imprinting errors: Altered gene regulation can disrupt early development.
• Mosaicism: Trophectoderm biopsy may not capture the true genetic constitution of the inner cell mass; some “euploid” embryos may in fact contain mosaic regions.

4. Systemic and Lifestyle Factors

• Endocrine dysfunction: Thyroid disease, hyperprolactinemia, and poorly controlled diabetes can all reduce implantation potential, but are readily treatable.
• Vitamin D deficiency: May impact immune modulation; supplementation is safe though evidence is moderate.
• Obesity, smoking, stress, sleep disturbances: Each contributes cumulatively to implantation failure.
• Sperm DNA fragmentation: May compromise embryo competence despite euploidy.

5. Modifiable vs. Non-Modifiable Causes

• Modifiable: Uterine pathology, hydrosalpinx, chronic endometritis, low progesterone, thyroid/prolactin/glucose abnormalities, lifestyle interventions.
• Partially manageable/experimental: Immunomodulation, microbiome-targeted therapy.
• Non-modifiable: Mitochondrial and epigenetic abnormalities.

Conclusion

A euploid embryo represents the optimal starting point in IVF, but it is not a guarantee of pregnancy. Implantation depends on a delicate synchrony between embryo quality, endometrial receptivity, immunological tolerance, and maternal systemic health. Identifying and addressing modifiable factors, while recognizing the current limitations of our diagnostic tools, remains essential.

As research advances, particularly in the fields of endometrial biology and embryo–maternal dialogue, we can expect clearer answers. For now, individualized, evidence-based care offers the best path toward improving outcomes in patients who experience implantation failure despite euploid embryo transfer.