As a fertility specialist, recurrent implantation failure is one of the most difficult and heartbreaking problems we face. Over the last forty years, we’ve made tremendous improvements in both IVF protocols and lab techniques. A high-quality embryo may have up to a 70 percent chance of yielding a live birth. However, how do we approach the patient when high quality embryos are not taking? And what does the evidence really say? Everything in IVF is based on the blueprint of the natural menstrual cycle. The correct timing of the embryo transfer seems to be worked out for most women. Some data that suggest that after three euploid embryo transfers, 95 percent of women have had a successful implantation. The data have been extrapolated to most women with recurrent implantation failure, however, can we truly extrapolate the data? As it turns out, recurrent implantation failure may actually be more common than the data would suggest. The commonly quoted studies excluded a lot of women, even those with biochemical pregnancies, donor egg cycles, and adenomyosis. I would argue that we cannot generalize these studies to most women who enter our fertility clinics.
How then, do we take an evidence-based approach to recurrent implantation failure? When high quality embryos are not taking, we must then look to the uterine environment to see where the disconnect could be. Studies in the last few years have looked at inflammation within the endometrium (chronic endometritis) and whether treating this condition leads to better outcomes. Although the data are mixed, there are reasonably high-quality data that pregnancy rates and ongoing pregnancy rates are higher when endometritis is treated with antibiotics.
Another area that has been studied is endometrial receptivity. This relates to the idea of the “window of implantation,” i.e., whether the endometrium is receptive to an embryo at the time the embryo transfer is typically performed. The endometrial receptivity analysis previously gained much momentum, although the original studies may have been biased. More recent studies have shown that endometrial receptivity testing does not help to improve live birth rates, and in some women, the outcomes were actually worse. This has caused most of us in the field to stop using the test altogether.
Other environmental factors could be endometriosis, either overt or “silent,” and adenomyosis. We know that the presence of endometriosis lowers success rates by about 10 percent per transfer; however, some women seem to benefit from medical and/or surgical treatment before a transfer. The thought is that the endometriosis creates inflammation, which makes the environment less hospitable to a developing embryo. If a patient with recurrent implantation failure does not already have a diagnosis of endometriosis, it may make sense to evaluate for it. It’s estimated that up to 40 percent of people with infertility have endometriosis. Adenomyosis has also recently gained attention in terms of worse outcomes in IVF. There are also data that treating adenomyosis (which is often comorbid with endometriosis) medically prior to an embryo transfer increases the chance for success.
In an attempt to gain some clarity, in 2023, the European Society of Human Reproduction and Embryology came out with recommendations for recurrent implantation failure. Based on an extensive literature search, the interventions which were recommended were reassessment of lifestyle factors, reassessment of endometrial thickness, and assessment of antiphospholipid antibody syndrome. The strategies which can be considered included karyotyping for both partners (if relevant), 3D ultrasound and hysteroscopy, endometrial function testing, chronic endometritis testing, assessment of thyroid function, and progesterone levels. Interventions and testing which were not recommended are as follows: vitamin D testing, microbiome profiling, peripheral and uterine natural killer cell testing, uterine T lymphocytes, blood cytokine levels, HLA-C compatibility, mitochondrial DNA content and sperm DNA fragmentation testing.
One variable which has not been studied in this context is the role of stress. Forty percent of women in general meet criteria for anxiety and depression at the first infertility appointment, and this number goes up with each unsuccessful cycle. There are data to show that hair cortisol levels in IVF patients correlated with lack of success. Salivary alpha amylase levels have also been studied, which correlated with infertility and increased time to pregnancy. Dr. Ali Domar showed a decrease in depression and anxiety and an increase in pregnancy rates when mind-body programs were employed. When we look at female physicians with infertility, we see that they have higher infertility rates and higher pregnancy complications compared with their non-physician counterparts. We know that in female physicians, this difference is not explained by deferred childbearing (age) alone. On a more social level, we know that stress can affect quality of life in relationships. It can also create analysis paralysis, less meaningful follow through with treatment plans, more mistakes, and eventually stopping treatment altogether.
I do believe we should follow the ESHRE recommendations on recurrent implantation failure. I also believe we need to stop viewing this as an uncommon phenomenon and see that it affects a high percentage of women. The existing studies are not generalizable to most women with recurrent implantation failure. We also need to honor the role of stress, which has not previously been acknowledged, and encourage fertility patients to seek additional support, whether through a therapist, a support group, an experienced fertility coach, or a combination. We can change the landscape of recurrent implantation failure, both in terms of the ultimate outcome, and also how it feels to go through it along the way.
Erica Bove is a double board-certified obstetrician-gynecologist and reproductive endocrinology and infertility (REI) specialist at the University of Vermont Medical Center, where she also directs the REI fellowship program. She is the founder and CEO of Love and Science: Thriving Through Infertility, a platform dedicated to guiding individuals and couples through the challenges of fertility with evidence-based medicine, coaching, and community.
Dr. Bove is passionate about supporting women physicians in building their families with confidence and compassion, blending science with intuitive, whole-person care. She extends her work beyond the clinic through her podcast and outreach on LinkedIn, Instagram, and Facebook.
Her academic contributions include studies on physician wellness and burnout, fertility preservation in oncology patients, and reproductive outcomes in complex medical contexts, with publications in Obstetrics and Gynecology, Journal of Graduate Medical Education, Endocrinology, and American Journal of Clinical Oncology.
Through clinical care, teaching, and advocacy, Dr. Bove is committed to advancing reproductive medicine, supporting healers, and creating a legacy of connection, empowerment, and compassion.
