IVF Failures

IVF has become a cornerstone of assisted reproductive technologies (ART), offering hope to couples facing infertility. However, failure to achieve a clinical pregnancy after multiple IVF cycles can cause significant emotional, physical, and financial stress. Repeated IVF failure, commonly defined as three or more unsuccessful cycles, necessitates thorough evaluation to identify underlying causes (Zegers-Hochschild et al., 2017).

While the aim of any fertility treatment is to obtain a positive result, it is also important to accept that some treatments may fail. When faced with a failure, it is easy to get lost in emotions and have overwhelming negative thoughts. However, one important thing to keep in mind is that sometimes, after a failed IVF cycle, it might be possible to find clues that will lead to a more effective treatment later on. Even though infertility testing provides a very good picture of your fertility status, it may not always successfully predict how your ovaries will respond to certain medication or how the quality of the eggs will turn out. A failed IVF cycle, while depressing, can provide extremely useful information to your IVF specialist such as your ovarian response, egg quality, fertilization rates and embryo quality. Based on these observed characteristics, a future cycle can be more thoroughly planned in an attempt to correct problem(s) that could explain why your treatment may have failed.

After a failed IVF cycle, it will be important for your IVF specialist to go over your file and correlate previous test results with the details of the failed cycle. It will be essential to see if measured cycle outcomes were in line with pre-cycle infertility assessment. If pre-cycle expectations were not met with the measured cycle outcomes (such as number of eggs, quality of eggs, quality of sperm, fertilization rates, cleavage embryo formation rates, blastocyst embryo formation rates), your IVF specialist may ask for additional tests in order to be able to explain the discrepancy.

Repeated in vitro fertilization (IVF) failures remain a significant challenge in reproductive medicine. Despite advances in techniques, understanding why a patient may experience repeated IVF failures is not an easy quesion to answer even with some advanced testing. We will review some primary causes of IVF failures, encompassing embryological, uterine, and systemic factors, alongside male contributions and external influences.

1. Embryological and Laboratory Factors

1.1. Poor Embryo Quality

Embryo quality is pivotal to IVF success. Genetic anomalies in embryos, such as aneuploidy, are common and increase with maternal age (Fragouli & Wells, 2012). Morphological assessments and preimplantation genetic testing for aneuploidy (PGT-A) can provide insight, but even morphologically normal embryos may harbor genetic defects (Alfarawati et al., 2011). Embryo quality is determined by its developmental potential, genetic integrity, and ability to implant into the uterine lining.

Embryos that develop too slowly or too quickly are often considered poor-quality. For instance, an embryo that does not reach the blastocyst stage by Day 5 may have reduced viability. This asynchrony can result in a mismatch between the embryo’s developmental stage and the receptivity of the uterine lining, leading to implantation failure.

Poor-quality embryos are more likely to have chromosomal abnormalities (e.g., aneuploidy, where there is an incorrect number of chromosomes). Embryos with aneuploidy often fail to divide correctly, leading to arrest in development or implantation failure. Even if implantation occurs, chromosomal abnormalities are a major cause of early pregnancy loss. Embryos with structural or genetic abnormalities often fail to adhere to the uterine lining. This is a critical step in establishing pregnancy. Blastocyst-stage embryos with poor morphology (abnormal cell size, fragmentation, or poorly defined inner cell mass) are less likely to implant successfully. Screening embryos for chromosomal abnormalities can improve the selection of viable embryos for embryo transfer, reducing the likelihood of transferring embryos that can have chromosomal problems. More information can be found on our “Pre-Implantation Genetic Testing” page.

Fragmentation can also be a concern when it comes to embryo quality. Fragmentation refers to small pieces of cellular debris that form within the embryo during cell division. High fragmentation rates reduce the overall quality of the embryo, impeding normal cellular communication and function.

Poor-quality embryos, in general, may lack the necessary cellular machinery and energy to divide and develop into a viable fetus. This includes suboptimal mitochondrial function or inadequate epigenetic programming during development. Sometimes, structural problems may be observed in a developing embryo. For instance, the zona pellucida (outer shell of the embryo) may be too thick, preventing hatching and implantation. Abnormalities in the inner cell mass or trophectoderm (the part of the embryo that forms the placenta) can also impair the embryo’s ability to implant and sustain pregnancy.

1.2. Laboratory Conditions

Suboptimal culture conditions, media composition, or temperature fluctuations in the embryology laboratory can affect embryo development (Swain, 2019). Even minor procedural inconsistencies can compromise implantation potential. Nevertheless, with today’s technology, laboratory conditions are well-monitored and controlled in most IVF laboratories.

2. Uterine Factors

2.1. Structural Abnormalities

Uterine anomalies such as fibroids, polyps, adhesions, and congenital malformations can impede embryo implantation (Pundir & El-Toukhy, 2010). Hysteroscopy or other means of imaging are often used to diagnose and possibly treat these conditions.

2.2. Endometrial Receptivity

The window of implantation (WOI) represents a limited period when the endometrium is optimally receptive. Variations in WOI timing or chronic endometritis can impair implantation, necessitating personalized approaches (Díaz-Gimeno et al., 2013). Latest approaches include Granulocyte‐colony stimulating factor (G‐CSF) or platelet rich plasma (PRP) injection into the endometrium approximately 2-3 days prior to an embryo transfer when endometrial thickness or appearance becomes a concern.

2.3. Immunological Dysregulation

Abnormal uterine immune responses, including an imbalance of uterine natural killer (uNK) cells, have been implicated in recurrent IVF failures (Kwak-Kim et al., 2012). However, NK populations found in blood testing may not necessarily correlate with the NK populations found inside the reproductive tract. Therefore, sometimes these tests may not be useful for diagnostic or therapeutic purposes. Advanced immune testing can be quite cost-prohibitive. In some cases, prophylactic measures can be taken without such invasive and cost-prohibitive tests.

3. Systemic and Hormonal Factors

3.1. Maternal Age and Ovarian Reserve

Advanced maternal age correlates with reduced ovarian reserve, poorer oocyte quality, and increased embryo aneuploidy rates (Broekmans et al., 2009). Tests like anti-Müllerian hormone (AMH) and antral follicle count (AFC) help assess ovarian reserve.

Factors such as poor egg quality, advanced maternal age, and unhealthy lifestyle choices can affect embryo quality. Addressing these through nutrition, supplements (e.g., CoQ10, fisetin, Omega-3, NMN, etc.), and lifestyle changes can help. Please refer to our “oocyte anti-aging protocol” for more information.

Patients in more advanced age brackets may need to consider certain alternative options such as ovarian PRP, Mitochondrial replacement therapy and possibly IVF treatment using donor eggs.

3.2. Endocrine Disorders

Conditions such as thyroid dysfunction, polycystic ovary syndrome (PCOS), and hyperprolactinemia can disrupt the hormonal environment required for successful implantation (Palomba et al., 2015). Optimizing these conditions is essential before initiating IVF. This is why an endocrine assessment involving FSH, LH, AMH, Prolactin, TSH and fT4 should be included prior to any IVF treatment.

3.3. Thrombophilia and Coagulation Issues

Inherited or acquired thrombophilic conditions, such as antiphospholipid syndrome, may lead to impaired placental development and recurrent implantation failure (Rai & Regan, 2006). Anticoagulant therapy may be beneficial in selected cases after thorough assessment by an IVF specialist.

4. Male Factor Contributions

4.1. Sperm Quality

Poor sperm quality, particularly high levels of DNA fragmentation, can contribute to poor fertilization and embryo development outcomes (Simon et al., 2017). More information on sperm health and sperm-related problems can be found on our “Sperm Anti-Aging Protocols” page. In cases where sperm DNA fragmentation is a problem, advanced sperm selection methods such as “magnetic activated cell sorting” can be employed in order to reduce the likelihood of selecting genetically abnormal sperm cells.

4.2. Epigenetic and Chromosomal Abnormalities

Emerging evidence suggests that sperm epigenetic changes and chromosomal anomalies also play a role in recurrent IVF failures (Zini et al., 2011). Screening embryos for chromosomal abnormalities can improve the selection of viable embryos for embryo transfer, reducing the likelihood of transferring embryos that can have chromosomal problems. More information can be found on our “Pre-Implantation Genetic Testing” page.

5. External and Lifestyle Factors

5.1. Environmental Exposures

Exposure to toxins, such as endocrine-disrupting chemicals (EDCs), can negatively affect gamete quality and implantation rates (Hannon & Flaws, 2015).

5.2. Lifestyle Factors

Obesity, smoking, and excessive alcohol consumption are linked to reduced fertility and IVF success rates. Lifestyle interventions can significantly improve outcomes (Bellver et al., 2013).

5.3. Psychological Stress

The psychological burden of infertility and IVF itself may impair outcomes through neuroendocrine pathways, though findings remain inconclusive (Matthiesen et al., 2011).

Repeated IVF failures often result from a combination of factors, requiring a multidisciplinary approach for diagnosis and treatment. Innovations in diagnostic testing, personalized medicine, and ART techniques hold promise for improving outcomes. Clinicians must also consider the emotional well-being of patients, offering comprehensive care to optimize both medical and psychosocial outcomes.

Tailoring protocols to the individual patient can result in better-quality eggs and embryos. For this, our IVF team will take a careful look at your previous IVF protocols and custom-design a protocol that is likely to provide us with more optimal results. In some cases, when a woman’s ovarian activity has substantially declined, multiple egg retrievals can be planned in order to maximize the number of embryos obtained, thus, increasing the chance of obtaining viable embryos for embryo transfer.

References:

Alfarawati, S., Fragouli, E., Colls, P., et al. (2011). The relationship between blastocyst morphology, chromosomal abnormality, and embryo gender. Fertility and Sterility, 95(2), 520–524.

Bellver, J., Rossal, L. P., Bosch, E., et al. (2013). Obesity and the risk of miscarriage after IVF or ICSI. Human Reproduction Update, 19(3), 252–265.

Broekmans, F. J., Knauff, E. A., Valkenburg, O., et al. (2009). Female reproductive ageing: Current knowledge and future trends. Trends in Endocrinology & Metabolism, 18(2), 58–65.

Díaz-Gimeno, P., Ruiz-Alonso, M., Blesa, D., et al. (2013). The accuracy and reproducibility of the endometrial receptivity array is superior to histology as a diagnostic method for endometrial receptivity. Fertility and Sterility, 99(2), 508–517.

Fragouli, E., & Wells, D. (2012). Aneuploidy screening for embryo selection. Seminars in Reproductive Medicine, 30(4), 289–302.

Hannon, P. R., & Flaws, J. A. (2015). The effects of phthalates on the ovary. Frontiers in Endocrinology, 6, 8.

Kwak-Kim, J., Yang, K. M., & Gilman-Sachs, A. (2012). Recurrent pregnancy loss and recurrent implantation failure: Immune mechanisms. Clinical Obstetrics and Gynecology, 55(3), 914–927.

Matthiesen, S. M., Frederiksen, Y., Ingerslev, H. J., et al. (2011). Stress, distress and outcome of assisted reproductive technology (ART): A meta-analysis. Human Reproduction, 26(10), 2763–2776.

Palomba, S., Santagni, S., Falbo, A., et al. (2015). Complications and challenges associated with polycystic ovary syndrome: Current perspectives. International Journal of Women’s Health, 7, 745–763.

Pundir, J., & El-Toukhy, T. (2010). Uterine factors in recurrent implantation failure. Current Opinion in Obstetrics and Gynecology, 22(3), 229–234.

Rai, R., & Regan, L. (2006). Recurrent miscarriage. The Lancet, 368(9535), 601–611.

Simon, L., Brunborg, G., Stevenson, M., et al. (2017). Clinical implications of sperm DNA damage in assisted reproduction. Human Reproduction, 32(7), 1309–1317.

Swain, J. E. (2019). Optimizing the culture environment in the IVF laboratory: Impact of pH and temperature on gamete and embryo quality. Reproductive Biomedicine Online, 38(3), 283–291.

Zegers-Hochschild, F., Adamson, G. D., de Mouzon, J., et al. (2017). The international glossary on infertility and fertility care. Fertility and Sterility, 108(3), 393–406.

Zini, A., Bielecki, R., Phang, D., et al. (2011). Sperm DNA integrity testing: Clinical aspects and implications. Journal of Andrology, 32(2), 151–165.