In vitro fertilization (IVF) is a complex medical process offering a path to parenthood for many people struggling with infertility. While modern technology has improved success rates, a significant number of IVF cycles do not result in a live birth. IVF failure is generally defined as multiple unsuccessful embryo transfers (often three or more) or repeated early pregnancy loss, even when high-quality embryos were transferred. Understanding the underlying biological and physiological causes of failure can help inform future treatment decisions.
Factors Related to Gamete Quality
The quality of the egg and sperm, known collectively as gametes, determines the genetic and energetic foundation of a future embryo. The greatest factor affecting egg quality is the age of the female partner, as oocytes are finite and age along with the body. As a woman ages, the eggs accumulate damage and experience a decline in mitochondrial function, which are the powerhouses of the cell. This decline significantly increases the likelihood of chromosomal errors in the egg.
The quantity of eggs, or ovarian reserve, is measured by tests like the Anti-Müllerian Hormone (AMH) blood test and Antral Follicle Count (AFC) ultrasound. Low ovarian reserve often correlates with a diminished response to ovarian stimulation medication, resulting in fewer eggs retrieved for fertilization.
Sperm health is also a factor, evaluated not only for its count, motility, and shape but also for the integrity of its genetic material. A high Sperm DNA Fragmentation Index (DFI) indicates extensive damage to the DNA within the sperm head. High DFI is associated with lower fertilization rates, poorer embryo development, and a reduced likelihood of achieving a live birth, even when using Intracytoplasmic Sperm Injection (ICSI). This DNA damage can introduce errors that the egg’s repair mechanisms cannot fully correct.
Failures in Embryo Development
Once fertilization occurs, the ensuing developmental process in the laboratory can halt for various reasons, with the embryo’s genetic composition being the dominant factor. The most frequent cause of IVF failure is a chromosomal abnormality, known as aneuploidy, where the embryo has an incorrect number of chromosomes. This often leads to either a complete failure to implant or an early miscarriage, serving as the body’s natural rejection of a non-viable pregnancy. The risk of aneuploidy rises dramatically with advanced maternal age.
Another common failure is developmental arrest, which occurs when the embryo stops dividing and growing, typically around day three of development. This critical stage is when the embryo switches from relying on the egg’s stored maternal factors to activating its own genome. Arrest at this point usually signals an intrinsic, non-repairable defect, either genetic or metabolic.
Preimplantation Genetic Testing for Aneuploidy (PGT-A) is a screening tool used to identify these chromosomal errors by sampling cells from the embryo’s outer layer, the trophectoderm. PGT-A can also identify mosaicism, a condition where an embryo contains a mix of both chromosomally normal (euploid) and abnormal (aneuploid) cells. While mosaic embryos have a lower implantation potential and a higher miscarriage rate compared to fully euploid embryos, they may still be considered for transfer when no euploid embryos are available.
Issues with Uterine Receptivity
Even a genetically normal, high-quality embryo requires a receptive environment within the uterus to implant successfully. The endometrial lining must thicken in response to hormones to provide a supportive cushion for the embryo. Most fertility specialists consider an endometrial thickness between 7 and 14 millimeters to be optimal for successful implantation. A persistently thin lining, often measuring less than 7 millimeters, is associated with significantly lower success rates, as the embryo cannot properly embed itself.
Structural issues within the uterine cavity can also mechanically interfere with implantation. Conditions such as submucosal fibroids or endometrial polyps can distort the uterine cavity and disrupt communication between the embryo and the uterine wall. Asherman’s Syndrome, characterized by intrauterine adhesions or scar tissue, often develops following prior uterine surgery or infection. This scarring reduces the functional area of the endometrium.
Successful implantation also depends on a precise, time-sensitive interaction known as the window of implantation. This window is hormonally controlled and varies slightly among individuals. If the embryo transfer occurs outside of this specific time frame, the endometrium may not be biologically ready to receive the embryo, leading to failure. Testing to assess the individual timing of this receptive window may be considered.
Specific Underlying Medical Conditions
Certain systemic medical conditions can create a hostile environment for the implanting embryo. Chronic endometritis (CE) involves persistent, low-grade inflammation of the endometrial lining, often caused by an altered balance of uterine microbiota. This chronic inflammation disrupts the delicate molecular communication required for the embryo to successfully attach to the uterine wall. CE is often asymptomatic and requires a specialized endometrial biopsy for diagnosis.
Immunological factors also play a role, as the body must temporarily suppress its typical immune response to accept the genetically foreign embryo. An imbalance in specific immune cells, such as an overabundance of Natural Killer (NK) cells or certain autoimmune markers, can cause the immune system to mistakenly attack the implanting embryo. This prevents the necessary immune tolerance required for pregnancy progression.
Another systemic issue is the presence of thrombophilias, conditions that increase the tendency to form blood clots. Inherited mutations, like Factor V Leiden, or acquired conditions, such as Antiphospholipid Syndrome, can lead to the formation of microthrombi in the small blood vessels supplying the uterus. This clotting impairs blood flow, reducing nutrient and oxygen supply to the implantation site and preventing the embryo from establishing placentation.