RECURRENT IMPLANTATION FAILURE (RIF): Does it really exist, - can it be treated?

By David H Barad, MD, MS, who is a Senior Scientist and head of Clinical IVF and Research at the CHR. He can be reached at Hello@ReproductiveTimes.com.

BRIEFING: Recurrent Implantation Failure (RIF) is a widely used diagnosis in reproductive medicine, yet it has remained controversial, with an increasing number of investigators questioning whether such a diagnosis even exists. The hypothesis of RIF basically suggests that failure to achieve pregnancy with a certain number of good-quality embryos (usually n=3-4), automatically suggests that – because of the good quality of transferred embryos – the failure to conceived must be caused by an implantation problem, an assumption based on the observation that at peak-fertility (in one’s 20s) a single embryo offers a ca. 30-35% pregnancy chance per month. Since the chance of conception per embryo, however, quickly declines with advancing female age, the hypothesis of RIF is not really sustainable for a large majority of infertility patients. The author further mathematically explains its shortcomings, however, also noting that this does not mean that efforts to improve implantation chances should not be pursued and then details what such efforts may include.


Few things are more frustrating for physicians and patients than the repeated transfer of high-quality embryos without achieving a pregnancy. Repeated implantation failure (RIF) is typically defined as the inability to achieve pregnancy after the transfer of three or four high-quality embryos. Yet there exists no universally accepted definition of RIF. 

If the expected implantation rate for a high-quality embryo is ca. 30%, then there is a 70% probability of failed implantation. After transferring two such embryos, the chance that both will fail to implant is 70% squared, or 49%. With three embryos, the probability that all will fail is 70% cubed, or approximately 34%, and this pattern continues with each additional embryo. Thus, even after transferring seven embryos, there remains a significant 8% chance that none will implant (70% raised to the seventh power equals about 8%). In scientific terms, an event is not typically considered rare unless its probability is less than 5%. In other words, even after seven embryos have failed to implant, that failure may simply be due to chance. To consider somebody to have a diagnosable medical problem (i.e., implantation failure) as cause of their infertility after the failed transfer of only three to four embryos makes little sense.

Even so, it is important to identify and address factors beyond chance over which we have some control. Unfortunately, these factors can be numerous. Factors that can contribute to the failure of a healthy embryo to implant include structural issues like fibroids, polyps, uterine scarring, hydrosalpinxes (fluid-filled fallopian tubes), and, likely, adenomyosis of the uterus; lifestyle factors such as stress, smoking, obesity, or excessive alcohol use; immunological factors; poor timing of embryo transfers; and problems with the uterine lining leading to poor endometrial receptivity.

While many of these issues can be identified and treated through a thorough diagnostic work-up, endometrial receptivity problems often remain among the most challenging to address. Endometrial receptivity refers to the ability of the endometrium to support embryo implantation, making it in IVF treatments a critical factor for achieving a successful pregnancy.

Many treatments have been proposed to address poor endometrial receptivity.  Hormonal support with sequential estrogen and progesterone is commonly used to prepare the endometrium for an embryo transfer.  If there is evidence of fibroids, polyps, or endometriosis, they can be surgically removed or treated to improve the environment of the uterus. 

Sildenafil citrate, commonly known as Viagra ®, has been explored as a treatment option to improve endometrial blood flow and thickness in women undergoing fertility treatments. The underlying idea is that enhancing blood flow to the uterine lining may improve its receptivity to embryo implantation.  Research on sildenafil's effectiveness for improving endometrial receptivity has shown mixed results. Some small-scale studies report positive outcomes, while others find no significant benefit. Sildenafil is, therefore, not universally accepted for this purpose. Its use is considered off-label, and more extensive clinical trials are needed to establish efficacy and safety conclusively.

Endometrial scratching is a medical procedure involving a minor injury or "scratch" to the endometrium, which is the lining of the uterus. This procedure is often considered for women who have experienced repeated implantation failures during in vitro fertilization (IVF) treatments or other assisted reproductive technologies.  The procedure can be painful and can cause some vaginal bleeding. It also creates a small risk of infection. The exact mechanism by which endometrial scratching might enhance implantation is not fully understood, but several theories exist: The scratch may induce a mild inflammatory reaction, releasing growth factors and cytokines that may improve the receptivity of the endometrium; the procedure may alter the expression of genes involved in implantation, making the endometrium more hospitable to an embryo; the injury might promote the shedding of older endometrial cells and the growth of new cells that are more receptive. 

Initially proposed by Israeli investigators early studies, indeed, seemed to confirm that endometrial scratching may improve implantation rates. Then, however, several larger randomized clinical trials did not find significant effects. Most recently, a quite well executed meta-analysis demonstrated clear benefits, leaving the question about efficacy of this treatment again wide open.  

Granulocyte Colony-Stimulating Factor (G-CSF) has been proposed as a treatment option for women experiencing thin endometrium, which can be a significant barrier to successful embryo implantation during in vitro fertilization (IVF) cycles. G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes, stem cells, and release them into the bloodstream. It is commonly used in medicine to boost white blood cell counts in patients undergoing chemotherapy. G-CSF may stimulate the proliferation of endometrial cells, leading to a thicker uterine lining. It might improve blood circulation within the endometrium, providing a more supportive environment for embryo implantation. G-CSF could also influence the immune environment of the uterus, making it more receptive to an embryo.  At CHR we found that G-CSF was effective to promote endometrial growth in women with thin endometrium, but we were not able to show any benefit when G-CSF was given to women with normal endometrium to try to improve embryo implantation. G-CSF is typically administered directly into the uterus via a catheter. This targeted approach aims to maximize its effect on the endometrial lining.  Though G-CSF is well tolerated and has few reported side effects there is insufficient high-quality evidence to conclusively support the routine use of G-CSF for thin endometrium. More extensive, randomized controlled trials are necessary to determine its efficacy and safety definitively.

Platelet-Rich Plasma (PRP) therapy has emerged as a potential treatment for thin endometrium in women undergoing fertility treatments like in vitro fertilization (IVF). Thin endometrial lining can be a significant obstacle to successful embryo implantation, and PRP therapy aims to enhance the receptivity of the uterine lining. It is a fraction of the patient's own blood with 4-5 times enhanced platelet concentration which is rich in growth factors including platelet-derived growth factor (PDGF), endothelial growth factor (EGF), transforming growth factor (TGF), vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF), connective tissue growth factor (CTGF), hepatocyte growth factor (HGF), and cytokines (both anti-inflammatory and proinflammatory), such as several interleukins, TNF-α, IFN-α, and stromal cell-derived factor 1-α, which promote tissue regeneration through cell activities like migration, growth, differentiation, and angiogenesis. Originally introduced in sports medicine, because of alleged anti-inflammatory and regenerative effects, PRP is presently also widely used in orthopedics, dentistry, urology, surgery, wound healing, cosmetic procedures, and in female infertility.

PRP is prepared by centrifuging a sample of the patient's own blood to concentrate the platelets, which release growth factors and cytokines. Since PRP is derived from the patient's blood, the risk of allergic reactions or immune rejection is minimal. PRP is believed to enhance the endometrial environment by promoting angiogenesis (the formation of new blood vessels), reducing inflammation, and improving tissue repair. This treatment is thought to improve endometrial thickness and quality, which are crucial for successful implantation. The procedure is generally well-tolerated, although some women may experience mild cramping or spotting after the injection.

PRP is typically administered into the uterine cavity 48 hours before a planned frozen embryo transfer or in a fresh IVF cycle. Sometimes more than one administration of PRP is used. The procedure is generally considered safe although some patients may experience significant cramping with intrauterine administration.

Studies of PRP for RIF are hard to compare as there is little standardization in PRP preparation or administration. Some preliminary studies and case reports have shown that PRP therapy can increase endometrial thickness in women who have not responded to conventional treatments like estrogen supplementation. Improved pregnancy rates have also been reported in some cases. While early results are promising, the number of high-quality studies is limited. Some research has methodological weaknesses, such as small sample sizes and lack of control groups. Larger, randomized controlled trials are necessary to conclusively determine the effectiveness and safety of PRP therapy for thin endometrium.  PRP therapy for thin endometrium is still considered experimental and is not a standard treatment in fertility clinics. 

PRP therapy offers a promising avenue for treating thin endometrium by potentially enhancing the uterine lining's thickness and receptivity. While early studies show encouraging results, more extensive research is needed to establish its efficacy and safety conclusively.

In summary: RIF is challenging to define, and even when a definition is established, diagnosing a specific cause or prescribing an effective treatment remains difficult. Initial steps should involve diagnosing and treating underlying conditions such as polyps, fibroids, or uterine scarring. Additionally, lifestyle modifications like reducing stress, quitting smoking, maintaining a healthy weight, and limiting alcohol consumption can be beneficial. While a well-timed embryo transfer during a natural menstrual cycle can be successful, providing hormonal support to the endometrium with sequential estrogen and progesterone is often a primary approach to treating a thin endometrium. Further medical treatments such as the use of sildenafil (Viagra), endometrial scratching, intrauterine administration of Granulocyte Colony-Stimulating Factor (G-CSF), and intrauterine Platelet-Rich Plasma (PRP) remain promising, but the mechanisms of action and effectiveness of each of these measures need to be validated in future well-structured randomized trials.


READING LIST

Cutting ER, Abdallah KS, Mol BW. Is there a treatable cause of repeated implantation failure, or isit simply treatment failure by chance? Reprod Biomed Online 2024;48(6):103845

Tao Y, Wang N. Adjuvant vaginal use of Sidenafil Citrate in hormone replacement cycle improved live birth rates among 10,069 women during first frozen embryo transfers. Drud Des Devel Ther 2020;14:5289-5279

Van Hoogenhijze NE, Lahoz Casarramona G, Lensen S, Farquhar C, Kamath MS, et al., Endometrial scratching in women undergoing IVF/ICSI: an individual participant data meta-analysis. Hum Reprod Update. 2023; 29(6):721-740

Gleicher N, Kim A, Michaeli T, Lee H-J, Shohat-Tal A, Lazzaroni E, Barad DH. A pilot cohort study of granulocyte colony-stimulating factor in the treatment of unresponsive thin endometrium resistant to standard therapies. Hum Reprod 2013;28(1):172-177

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A MILESTONE STUDY: Comparing cumulative live births between cleavage- and blastocyst-stage embryo transfers