Although assisted reproductive technologies (ARTs) have helped numerous couples to achieve live birth, this is not feasible in a significant proportion of cases, despite several attempts. Recurrent implantation failure (RIF) remains a difficult problem both for clinicians, struggling to help patients, as well as for patients, anxiously seeking solutions.
The current absence of a consensus in the definition of recurrent implantation failure leads to significant methodological and interpretational problems of available research. Currently, management of recurrent implantation failure consists of either non-evidence-based interventions or interventions evaluated in a small number of patients and RCTs.
RIF and Preimplantation Genetic Testing for Aneuploidy
Preimplantation genetic testing for aneuploidy (PGT-A) has been used in patients with recurrent implantation failure to identify and transfer chromosomally normal embryos, with the aim increase the probability of pregnancy. In a retrospective study, significantly higher pregnancy rates were present following array comparative genomic hybridization (array CGH) (n = 43) as compared to embryo transfer without PGT-A (n = 33) (68.3% versus 21.2%, p = 0.609, respectively). However, the therapeutic value of this strategy needs to be confirmed in relevant randomized controlled trials (RCTs).
Embryo Manipulation and RIF
Although assisted hatching has been shown to increase the probability of live birth in women with recurrent implantation failure (relative risk [RR]: 2.51, 95% confidence interval [CI]: 1.06–5.96), this was based on a pooled analysis of only two small RCTs including 250 patients. Evidently, conclusions based on a small number of patients analyzed, although supporting the need for further research, cannot be used to shape routine clinical practice.
IMCI Versus ICSI in Patients With RIF
Intracytoplasmic morphologically selected sperm injection (IMSI) has been proposed as a treatment in couples with recurrent implantation failure. This, however, is currently based on a subgroup analysis of an RCT in patients younger than 35 years of age, with two or more failed attempts (n = 139), and oligoasthenoteratozoospermia (OAT), who were treated by IMSI or intracytoplasmic sperm injection (ICSI) (clinical pregnancy rate: 29.8% versus 12.9%, respectively; p = .017). Prior to introducing IMSI in routine clinical practice, however, this finding should be confirmed by appropriate RCTs.
RIF and Acquired Uterine Conditions
It is generally accepted that submucosal fibroids of any type negatively affect IVF outcome and implantation. On the contrary, subserosal fibroids have no impact on implantation and IVF outcome. Although intramural fibroids have been suggested to exert a negative impact on the probability of pregnancy, it is still not clear whether this effect is associated with their number and diameter.
The exact pathophysiological mechanism supporting a negative effect of intramural fibroids on endometrial receptivity is not clear. Gene expression profiling of leiomyomas has shown that only few alterations are present in genes related to the window of implantation. Apparently, the knowledge gap that exists in routine clinical practice regarding the effect and optimal management of uterine fibroids extends to patients with recurrent implantation failure.
A similar situation is present regarding adenomyosis. Although published meta-analyses suggest that its presence be associated with significantly lower clinical pregnancy rates ([RR 0.72; 95% CI 0.55-0.95], [OR 0.73; 95% CI 0.60-0.90]), significant heterogeneity in the included studies limits the value of the conclusions drawn. In addition, the basis for the impaired implantation associated with the adenomyosis is not clear. Not surprisingly, it is still not known which is the best treatment approach for women with adenomyosis seeking fertility. No comparative studies exist between conservative and surgical treatment in women with adenomyosis. Moreover, the consequences of surgical treatment for a future pregnancy have not been evaluated.
RIF and Endometrial Polyps
The role of endometrial polyps in recurrent implantation failure is indirectly shown by their higher incidence in these patients (up to 45%) as compared to patients undergoing their first ART attempt (11%-22%). Due to the lack of high-quality prospective studies in women with endometrial polyps undergoing IVF, their proposed unfavorable effect on implantation is based on indirect evidence from studies comparing IVF outcomes in patients with and without polyps. These studies, however, have also produced controversial results supporting or negating a beneficial effect of polypectomy, which complicates the overall assessment of the contribution of endometrial polyps in recurrent implantation failure.
Chronic Endometritis in Patients With RIF
The association between chronic endometritis and recurrent implantation failure is based on its higher incidence in patients with recurrent implantation failure (range: 15%-60%) as compared to asymptomatic infertile patients before their first IVF attempt (range: 3%-15%). However, scarce data exist regarding the value of antibiotics for treating women with chronic endometritis and recurrent implantation failure. In a retrospective study, similar ongoing pregnancy rates were observed between women with histologically confirmed chronic endometritis who were either treated (n = 68) or not (n = 20) by antibiotics (29.4% versus 25.0%, respectively, p = .701) (34). In addition, alternative treatments such as hysteroscopic removal of bacterial biofilms have been proposed, although they are still not supported by relevant RCTs.
Manipulating Endometrium in Patients With RIF
Endometrial injury has been proposed as a method to increase the probability of pregnancy both in the overall population as well as in patients with recurrent implantation failure. However, currently published relevant studies are of moderate quality and apply different methods of endometrial injury in different types of patients. More importantly, a biological mechanism supporting endometrial injury is still lacking.
Endocrine Causes in RIF
Endocrine disorders may play a role in recurrent implantation failure, affecting implantation through the interaction of various hormones with their corresponding receptors in endometrium. Vitamin D deficiency, polycystic ovary syndrome (PCOS), and thyroid disease have been implicated in recurrent implantation failure; however, their exact role is not yet fully understood.
Conflicting evidence exists regarding the value of LT4 supplementation for increasing the probability of delivery and lowering the probability of miscarriage rates in women with subclinical hypothyroidism or euthyroid women with TSH concentration above 2.5 mIU/mL, while such information is not currently available in women with recurrent implantation failure. The probability of live birth in women with thyroid autoimmunity (TAI) is significantly lower compared to women without TAI (odds ratio [OR] 0.73; 95% CI 0.54-0.99, p = .04; I2 = 41%), while the presence of TAI has been associated with an increased risk of spontaneous miscarriage. However, it appears that treatment of these women is not beneficial regarding the probability of pregnancy, while no data exist in women who in addition suffer from recurrent implantation failure.
Vitamin D Supplementation
Although probability of live birth is significantly higher in women replete in vitamin D as compared to women with deficient or insufficient vitamin D status (OR 1.33, 95%CI: 1.08-1.65), it is not yet clear whether vitamin D supplementation in the latter group is beneficial either in the general population or in women with recurrent implantation failure.
Although it has been shown that early pregnancy loss (EPL) is significantly decreased (0.19 95% CI: 0.12–0.28, p <.001) in women with PCOS treated with metformin, it is not yet known whether such treatment is beneficial for pregnancy achievement in women with recurrent implantation failure.
Intrauterine Administration of Immune Cells in Patients with RIF
The endometrium plays a key role in the process of implantation, which is thought to be affected by the immune system. Intrauterine administration of autologous peripheral blood mononuclear cells (PBMCs) has been investigated in this respect as an inflammation inducer. A non-randomized trial showed that intrauterine administration of autologous PBMC (35 women/35 cycles) increased live birth rates in women who had more than two failed embryo transfers (PBMC treated group, n = 17: 55.6%-nontreated group, n = 18:7.6%, p = .013). However, this intervention has not been evaluated in relevant RCTs.