Why is implantation failure

There is some evidence that this procedure itself, or performing an endometrial scratch, can increase implantation rates. Genetic screening — We can use genetic screening to learn more about embryos before they are implanted, which helps us select the best embryos most likely to implant. Schedule an appointment to start your fertility journey with us. Treatments Implantation failure Book an appointment.

Investigations and treatments. Maternal blood tests. Because we do not have the ability to do PGS at our unit, we transfer in these cases as many embryos as possible. In cases with any hint of autoimmune disease, we treat with steroids 0.

During the past years, we have occasionally performed ZIFT to patients who failed five or more ET especially but not only if the embryo transfer was difficult. During the last year, we performed endometrial stimulation biopsies on days 12 and 21 of the cycle preceding the IVF treatment. There are many known and unknown reasons for RIF, and we do not have the tools to diagnose in each case the exact cause for the repeated failure.

There are no hard data from RCTs that any of the treatments has a significant value, but on the contrary, everyone agrees that taking a different approach achieves a pregnancy in many cases that failed repeatedly.

After three failures, repeated hysteroscopy and a try of blastocyst transfer are highly recommended. A change in the stimulation protocol has a place. AH, PGS and co-culture are probably beneficial in experienced hands. Long-term use of danazol or GnRH agonists probably has a place in repeated failures with endometriosis.

The use of IVIG is very controversial but may be justified after many failures in specific cases. Steroids might have a place in patients with any sign of autoimmunity, and ZIFT has a place in cases of difficult embryo transfers. Google Scholar. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search.

Search Menu. Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Definition of RIF. Assumed aetiologies for RIF. Decreased endometrial receptivity. Defective embryonic development. Multifactorial causes. Multifactorial treatment options. Margalioth , E. Margalioth 1. E-mail: ehudmd hotmail. Oxford Academic. Revision received:. Cite Cite E. Select Format Select format. Permissions Icon Permissions.

Table I. Assumed aetiologies for repeated implantation failure RIF. Open in new tab. Table II. Suggested methods for treatment of repeated implantation failure RIF. Google Scholar Crossref.

Search ADS. Endometrial fluid visualized through ultrasonography during ovarian stimulation in IVF cycles impairs the outcome in tubal factor, but not PCOS, patients. Recombinant versus urinary gonadotrophins for triggering ovulation in assisted conception.

Assisted reproductive technology in Europe, Uterine versus tubal embryo transfer in the human. Comparative analysis of implantation, pregnancy, and live-birth rates. Comparison of zygote intrafallopian tube transfer and transcervical uterine embryo transfer in patients with repeated implantation failure.

Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilization. Fibrin glue improves pregnancy rates in women of advanced reproductive age and in patients in whom in vitro fertilization attempts repeatedly fail. Preimplantation genetic diagnosis for aneuploidy screening in repeated implantation failure. Effect of paternal leukocyte immunization on implantation after biochemical pregnancies and repeated failure of embryo transfer.

Videocinematography of fresh and cryopreserved embryos: a retrospective analysis of embryonic morphology and implantation.

Google Scholar PubMed. Multiple thrombophilic gene mutations are risk factors for implantation failure. Zygote versus embryo transfer: a prospective randomized multicenter trial. De Geyter. Prospective evaluation of the ultrasound appearance of the endometrium in a cohort of 1, infertile women. De Vos. Zona hardening, zona drilling and assisted hatching: new achievements in assisted reproduction. Effect of treatment of intrauterine pathologies with office hysteroscopy in patients with recurrent IVF failure.

Antiphospholipid antibodies and pregnancy rates and outcome in in vitro fertilization patients. Effect of intramural, subserosal, and submucosal uterine fibroids on the outcome of assisted reproductive technology treatment. Moreover, in the setting of a distorted uterine cavity caused by leiomyomas, significantly lower IVF pregnancy rates were identified Pritts, ; Surrey et al.

There is limited molecular data to explain the mechanism behind these clinical observations. Recent studies demonstrated that leiomyomas may adversely affect the overlying endometrium and impair endometrial receptivity Matsuzaki et al. Moreover, HOXA10 expression was globally affected in the presence of a submucosal myoma rather than focally changed in the endometrium over the myoma Rackow and Taylor, Therefore, besides distorting the uterine cavity, submucosal myoma may result in global changes in endometrial receptivity.

Further studies are required to further delineate the molecular mechanisms of implantation failure in women with leiomyomas distorting the uterine cavity. Endometrial polyps are benign, localized overgrowths of endometrium. The mechanism by which polyps may adversely affect fertility is poorly understood, but may be related to mechanical interference with sperm transport, embryo implantation or aberrant expression of implantation markers.

Low IGFBP-1 and osteopontin levels were detected in uterine flushings in mid-luteal phase in patients with endometrial polyps Ben-Nagi et al. Moreover, significant increase in their concentrations in uterine flushings was observed following polypectomy Ben-Nagi et al. Endometrial polyps have decreased expression of PRs that may result in progesterone resistance. This may cause abnormalities in the secretion of progesterone-regulated implantation markers Peng et al.

Three nonrandomized studies also found an association between polypectomy and improved spontaneous pregnancy rates Varasteh et al. The effect of endometrial polyps on IVF remains unclear. However, further studies are required to examine the effect of larger polyps, polyp location and number of polyps on IVF outcome. Adenomyosis is a common gynecological disorder with unclear etiology that is characterized by the presence of heterotopic endometrial glands and stroma in the myometrium with adjacent smooth muscle hyperplasia.

An association between adenomyosis and subfertility has not been fully established. The presenting symptoms include a soft and diffusely enlarged uterus with menorrhagia, dysmenorrhea and metrorrhagia. Infertility is a less frequent complaint, since uterine adenomyosis is usually diagnosed in the fourth and fifth decade of life. However, since more women delay their first pregnancy until later in their 30 or 40, adenomyosis is encountered more frequently.

When adenomyosis is encountered in younger reproductive age women, it is likely to reduce endometrial receptivity in a manner similar to endometriosis. Further studies are required to delineate the molecular mechanisms of implantation failure in women with adenomyosis. Infertility associated with PCOS derives from chronic anovulation, and there are increasing data suggesting that implantation failure can further complicate achieving pregnancy in women with this disorder Giudice, Although ovulation is readily obtained with medical induction, implantation rates remain lower than fertile controls and early pregnancy loss rates are increased.

In women with PCOS, who are anovulatory or oligo-ovulatory, the regulatory roles of progesterone are suboptimal or absent, and this results in relatively constant unopposed action of estrogen in the endometrium Giudice, There is increasing evidence of dysregulated expression of markers of uterine receptivity in endometrium of women with PCOS.

In vitro HOXA10 expression was directly decreased by testosterone, suggesting a role for androgen reduction in improving endometrial receptivity.

Women with PCOS also exhibit significant differences in their complement of steroid receptors and coactivators when compared with fertile controls. Moreover, overexpression of the steroid receptor coactivators AIB1 nuclear receptor coactivator 3 and TIF2 transcriptional intermediary factor 2 may accentuate the activity of estrogen in endometrial cells from women with PCOS Gregory et al.

Overall, decreased expression of uterine receptivity markers and dysregulation of steroid receptor expression and activity may contribute to the lower pregnancy rates observed in women with PCOS.

Endometritis has been associated with infertility and implantation failure because of the possible action of microbial products on the endometrial receptivity Devi Wold et al. Moreover, a significant increase in pregnancy rates in subsequent IVF cycle was reported on completion of antibiotic treatment Feghali et al. Acute endometritis is most commonly caused by bacteria. It usually responds well to treatment and is only rarely associated with long-standing infertility.

In contrast, chronic endometritis can be caused by a variety of agents such as bacteria, viruses and parasites. There is a strong relationship between genital tuberculosis and infertility. Genital tuberculosis is a rare disease in developed countries, but it represents a frequent cause of chronic pelvic inflammatory disease and infertility in developing countries. It is almost always secondary to a tubercular lesion elsewhere in the body and usually affects women between the ages of 20 and 40 years Varma, In most cases of chronic endometritis, no causal pathogen can be isolated, and the inflammation is considered nonspecific.

The antibiotic regimen prescribed is, therefore, empirical. No data exist on pregnancy rates after histologically confirmed and subsequently treated nonspecific chronic endometrial inflammation. Ideally, a technique to assess endometrium and thereby predict endometrial receptivity must be easily performable within the daily clinical routine and would preferably be noninvasive.

These requirements are met by ultrasonographic evaluation of endometrial thickness and its echogenic pattern. Endometrial thickness is defined as the minimal distance between the echogenic interfaces of myometrium and endometrium, measured in the plane through the central longitudinal axis of the uterine body. Increased endometrial thickness is associated with improved pregnancy rates in IVF—embryo transfer cycles Zhang et al.

The data extracted from the donor oocyte programs suggest that a pregnancy cannot be achieved if the endometrium thickness is below a certain critical cutoff limit. Although there are studies revealing that the thickness of endometrium for a successful implantation can be as thin as 4 mm Noyes et al. However, no correlation was demonstrated between endometrial histology and endometrial thickness either in spontaneous ovulatory cycles or in IVF patients Sterzik et al.

The endometrium grows rapidly from menses until approximately cycle day 9 or 10, where endometrial growth slows despite rising estrogen levels and the absence of progesterone. The molecular determinants of this endometrial thickness set point are unknown at this time; however, several diseases associated with reduced implantation demonstrated reduced endometrial proliferative response.

These include endometriosis and PCOS. The ultrasonographic texture of the endometrium may have a prognostic value for implantation. In the proliferative phase, the endometrium has a hypoechogenic texture with a well-defined central line. This texture changes in the secretory phase, becoming hyperechogenic with no visualization of the central echogenic line.

Significantly, higher pregnancy rates in the group with a mid-luteal phase homogenous hyperechogenic pattern were detected compared with a nonhomogenous pattern Check et al. Assessment of endometrial blood flow adds a physiological dimension to the anatomical ultrasound parameters and draws a lot of attention in recent years.

Endometrial and subendometrial blood flows can now be objectively and reliably measured with 3D power Doppler ultrasound. Raine-Fenning et al. In women with unexplained infertility, endometrial and subendometrial vascularity was significantly reduced during the mid-late follicular phase, irrespective of estradiol or progesterone concentrations and endometrial morphometry Raine-Fenning et al.

However, the use of endometrial and subendometrial blood flow in the prediction of implantation and pregnancy remains unclear Ng et al.

Transvaginal ultrasonography, especially when performed during the late follicular phase, provides excellent imaging of the uterus and of endometrial abnormalities. Saline infusion sonohysterography SIS is a procedure in which saline is instilled into the uterine cavity to provide enhanced endometrial visualization during transvaginal ultrasound.

This technique improves detection of potential anatomic causes of reduced fertility, such as submucosal myomas, endometrial polyps and intrauterine adhesions.

In addition, it helps avoid invasive diagnostic procedures as well as optimize the preoperative triage process for women requiring therapeutic intervention. It is typically scheduled early in the follicular phase of the menstrual cycle, after cessation of menstrual flow and before Day 10, as the endometrium is thin at this point in the cycle.

Later in the cycle, focal contour irregularities of the endometrium may be mistaken for small polyps or focal areas of endometrial hyperplasia. Sonohysterography usually depicts leiomyomas and accurately assesses their location, size and degree of intramural extension. It has added advantage of better estimation of the percentage circumference projecting into the endometrial cavity.

Overall, even though ultrasound of the endometrium is easy to perform, and therefore, the imaging modality of choice in the detection of various endometrial pathologies, its prognostic value in determining pregnancy rate, is low. Hysteroscopy is generally considered to be the gold standard in the diagnosis of intrauterine pathology, including endometrial polyp and submucous myoma. There is no doubt that hysteroscopy should be performed when there is suspicion of intrauterine pathology on transvaginal ultrasonography or SIS.

However, the clinical significance of these findings is not sufficient to require hysteroscopic evaluation of all patients prior to IVF. Noyes et al. However, a number of weaknesses in Noyes' approach have been identified. Dating is most accurate in the early and late luteal phase, but not in the implantation window, as very few histological parameters allow differentiation within the time span of the receptive endometrium Myers et al. This lack of objective measures likely led to the high intra- and interobserver variability noted.

Intraobserver variability has been shown to be highest among infertile women during the implantation window Murray et al. Furthermore, ovarian stimulation in artificial cycles may lead to differences in the timing of endometrial maturation compared with natural cycles Papanikolaou et al. Finally, in clinical trials, histological dating does not discriminate between women of fertile and infertile couples and is therefore not a valid tool in routine evaluation of infertility or implantation failure Coutifaris et al.

Although targeted disruption of several genes leads to an implantation defect, often the endometrial histology is normal, demonstrating the ability of a purely molecular defect to cause implantation failure. There is however the high likelihood that molecular measures of endometrial receptivity will be more predictive than histology.

Overall, there is still no perfect clinical assay to detect implantation defects. Endometrial receptivity appears to be a major limiting factor in the establishment of pregnancy in number of gynecological diseases, and treatments to optimize implantation should be directed toward the underlying condition Table 2. The treatment of endometriosis is highly individualized and dependent on the desire for fertility or requirements for contraception.

Medical treatment options for endometriosis include hormonal drugs such as combined oral contraceptives, progestogens, GnRH analogs or aromatase inhibitors.

The aim of medical therapy is to prevent estrogen production or oppose its action. The role of medical therapies in infertility treatment has been reviewed, and there is little evidence to support their use in women with endometriosis who wish to conceive Hughes et al.

One study suggests that long-term GnRH agonist treatment prior to IVF may improve implantation in women with endometriosis Surrey et al. A recent Cochrane review demonstrated a small improvement in clinical pregnancy rates with laparoscopic surgery when compared with diagnostic laparoscopy only OR: 1.

Leiomyomas that distort the uterine cavity, irrespective whether they are submucous or intramural, adversely affect fertility both spontaneous and during IVF treatment. The current management of myomas for fertility preservation or enhancement is surgical removal either by laparotomy, laparoscopy or hysteroscopy.

The goals of myomectomy include: restoration of uterine morphology, return of normal menstrual function and enhancement of fertility. It is essential to use a precise surgical technique when performing a myomectomy so as not to adversely affect future fertility. Post-operative intrauterine balloon devices may be helpful in preventing adhesion formation.

Given the global nature of the effect on endometrium, restoration of a normal uterine cavity without complete removal of the fibroid, may not fully alleviate the endometrial defect Rackow and Taylor, The preferred treatment method of endometrial polyps is polypectomy.

Polypectomy can be performed blindly using a transcervical sharp curette; however, hysteroscopy-directed polypectomy using scissors, a loop electrode, electric probe or a morcellator is preferred to minimize damage to the surrounding endometrium and to ensure the polyp has been removed in its entirety.

But it is well-known fact that embryo and endometrium talk to each other using molecular signals, and such cross-talk is necessary for successful implantation. However, no reliable molecular markers for endometrial receptivity have been identified. This makes it difficult to find out whether the endometrium is receptive or not during an IVF cycle. During IVF, endometrial receptivity is assessed crudely with the help of ultrasound images.

Endometrial thickness is measured using ultrasound images, and an endometrium of greater than 8mm, which is trilaminar, is believed to be optimum for embryo transfer. It is a well-known fact that the endometrium becomes receptive only after progesterone exposure. Progesterone brings about necessary changes in endometrium converts the endometrium from proliferative to secretory phase so that it becomes ready to accept the embryo.

Recently, frozen embryo transfers are becoming much more successful than fresh embryo transfers in the field of IVF. It is hypothesized that high estrogen concentration in the body during the fresh IVF cycle compromises endometrial receptivity. There are also many unproved reasons cited for lack of uterine receptivity, which include immunological theories like the presence of high number of uterine NK cells, excessive HLA matching between partners, and blood clotting issues.

The ease with which the uterus can be negotiated for the embryo transfer also plays a pivotal role in achieving successful implantation. If the uterus is hard to access via the cervix for example, in patients with cervical stenosis , then other embryo transfer methods like ZIFT should be used in order to enhance implantation.

Yes, it can be treated, but only if the reason is known. The one and only well-known, scientifically proven reason for implantation failure is genetically incompetent embryos.

If you are a woman of advanced maternal age or if you have premature ovarian aging, even if you get some embryos to transfer during an IVF cycle, many a time they can be genetically abnormal and will not implant successfully. As a result, they believe that surrogacy can help them conceive, which is not true! I have seen so many women of advanced maternal age subjecting themselves to many useless therapies and ultimately finding success when they finally use donor eggs.

So if advanced maternal age or poor ovarian reserve is the cause of failed implantation, the only reasonable solution is to use donor eggs.

If your uterine cavity contains adhesions, fibroids or polyps which interfere with implantation, removing them will help in achieving embryo implantation. The role of endometrial thickness in successful implantation is still a question. Many women with thin endometrium do have successful implantation, but the scientific literature shows that an endometrium thickness of more than 8mm is optimum for achieving implantation.

Doctors should resist offering such treatments. They must make sure that the patient understands that the above-mentioned therapies are not evidence-based and may not be a panacea for their problem. When an embryo enters the uterus in the blastocyst stage, it initiates molecular cross-talk with the endometrium.

Are you ready to accept me? All this cross-talk happens by releasing appropriate protein molecules. It is believed that if there is some problem with this cross-talk, embryo implantation fails. It is hypothesized that the endometrium acts as a biosensor of embryo quality. This means if a genetically abnormal blastocyst enters the uterine cavity, the endometrium senses this by the signals sent by the embryo and prevents the implantation of the embryo.

That is, such women fall pregnant very easily because even genetically abnormal embryos are allowed to attach to the endometrium and establish a pregnancy. There are also studies which show that even if the endometrium is not optimally receptive, a genetically competent embryo can modify the endometrial environment to make it favorable, so that successful implantation is achieved.

When you talk to a well-experienced IVF specialist, he will say from his practical experience that when women suffer from recurrent implantation failure, most of the time changing the egg can bring about successful implantation and pregnancy!

The endometrium seems to act as a passive recipient.