A euploid embryo possesses the correct number of chromosomes: 46 chromosomes organized into 23 pairs. Preimplantation Genetic Testing for Aneuploidy (PGT-A) confirms this normal chromosomal complement before embryo transfer. Despite the selection of these chromosomally normal embryos, implantation failure still occurs in a significant percentage of transfers, presenting a paradox in reproductive medicine. This suggests that factors other than chromosome count determine an embryo’s ability to successfully attach to the uterine wall and initiate a pregnancy. The failure to implant highlights the complexity of early human development, which involves a precise biological interaction between the embryo and the maternal environment.
Understanding the Limits of Euploid Testing
The PGT-A test provides information regarding the embryo’s chromosomal health, but it does not evaluate every aspect of viability. The test is performed on a small sample of cells, typically five to ten, taken from the trophectoderm, the layer that will eventually form the placenta. This small sample size introduces the possibility of mosaicism. Mosaicism occurs when the biopsied cells are euploid, but other cells in the embryo, particularly those that become the fetus, are chromosomally abnormal.
The sampling limitation means the test is only a representation of the whole, not a guarantee of genetic perfection across all cell lines. The presence of mosaicism can lead to the transfer of an embryo that is genetically less stable, potentially impairing its ability to sustain development and implant. The embryo’s developmental potential is also influenced by its internal energy production, which PGT-A does not assess.
The embryo’s capacity for energy production is managed by its mitochondria. The level of mitochondrial DNA (mtDNA) content serves as an indirect indicator of this health. Studies show that high mtDNA content in a euploid blastocyst is associated with lower implantation potential and reduced viability. This excess mtDNA may signal metabolic stress or cellular dysfunction not visible through standard chromosomal screening.
Beyond chromosome count and energy capacity, the embryo’s success depends on the precise timing and coordination of gene expression, governed by epigenetic factors. These epigenetic marks regulate how the embryo’s genes turn on and off at critical developmental junctures, orchestrating cellular differentiation and implantation. PGT-A does not examine these complex gene expression patterns. Therefore, a chromosomally normal embryo may still have subtle, non-chromosomal developmental defects that prevent it from progressing.
The Critical Role of Endometrial Receptivity
Once the embryo is confirmed as euploid, attention shifts to the uterine lining, which must be prepared to receive it. The uterus is only receptive for a brief period known as the Window of Implantation (WOI), typically six to ten days after ovulation. If the embryo transfer is mistimed, even by a single day, the lining may not be physiologically prepared to engage with the blastocyst, resulting in implantation failure.
Successful implantation requires the endometrium to meet specific physical criteria, including adequate thickness and morphology. A lining measuring less than seven millimeters is associated with reduced implantation rates, often indicating insufficient development or blood supply. The lining’s appearance on ultrasound, known as its morphology, must also be trilaminar, or triple-lined, to signal peak receptivity.
The uterine microbiome plays a significant role in establishing endometrial receptivity. A healthy uterine environment is typically dominated by Lactobacillus species, which promote an anti-inflammatory state conducive to implantation. An imbalance, or dysbiosis, where non-Lactobacillus bacteria are dominant, can negatively affect the uterine lining.
This dysbiosis is frequently linked to chronic endometritis (CE), a persistent, low-grade inflammation of the endometrial lining. CE is often asymptomatic and can be caused by bacterial overgrowth that disrupts the cellular processes required for the embryo to attach. Even with a euploid embryo, the inflammatory environment created by CE can act as a localized barrier, preventing successful decidualization and attachment.
Immunological and Systemic Causes of Failure
The maternal immune system must tolerate the embryo—which is genetically half-foreign—while maintaining its ability to fight off infections. An imbalance in this process can lead to the body mistakenly recognizing the embryo as a threat and initiating an autoimmune response. Specific immune cells, such as uterine natural killer cells and T-helper cells, must be appropriately regulated to facilitate, rather than reject, implantation.
Systemic factors, particularly those affecting blood flow, play a part in implantation success. Thrombophilias, or clotting disorders, can impair the necessary blood flow to the uterine lining. These conditions may cause local micro-clots at the implantation site, preventing the placenta from establishing a connection and acquiring nutrients.
Systemic hormonal imbalances can disrupt the physiological environment required for pregnancy. Uncontrolled thyroid conditions, such as hypothyroidism or Hashimoto’s thyroiditis, are known to have detrimental effects on female fertility and implantation. These systemic issues interfere with the signaling pathways that coordinate endometrial development and receptivity, creating an unfavorable environment.
Technical Factors in Embryo Transfer
Even when the embryo and the uterine environment are optimal, the procedural step of transferring the embryo can introduce variables that affect the outcome. The operator’s skill and experience in performing the transfer procedure are significant factors in determining success rates. Precise placement of the catheter tip within the uterine cavity is necessary to deposit the embryo in the ideal location, typically close to the fundus.
Difficulties encountered during the procedure, such as cervical resistance or the need to manipulate the catheter, can lead to mechanical trauma or uterine contractions. These events may displace the embryo or create an inflammatory response detrimental to implantation. The use of a soft, flexible transfer catheter under ultrasound guidance is preferred to minimize trauma to the delicate uterine lining.
The presence of retained fluid or blood in the uterine cavity at the time of transfer can interfere with the process. Fluid can flush the embryo away from the ideal implantation site or act as a physical barrier between the embryo and the endometrium. If the embryo is retained in the catheter after withdrawal, it requires a secondary, immediate re-transfer, which may reduce the chances of a successful outcome.