Enter “Repeated Planting Failures”

Introduction: IVF embryos have been transferred several times without any sign of pregnancy, which is medically known as: repeated implantation failure. This is one of the most confusing problems in the field of assisted reproductive technology. Is it due to the embryo? Or is it the endometrium? Doctors often have trouble explaining themselves, and patients are even more baffled as to what is going on. What are the reasons for this? What aspects should we consider and deal with this difficult problem? There should always be an explanation. Patients ask in the clinic, “Doctor, why have I had several unsuccessful transplants?” Although the success rate of IVF is increasing year by year, in our center, for example, the clinical pregnancy rate of each transfer cycle has reached more than 50% and the bed placement rate of each transferred embryo is more than 40%. However, there are still some normal looking embryos that do not germinate in the endometrium, which is medically known as “implantation failure”. There is no standard definition of repeat implantation failure, but in the past, it was defined as repeat IVF treatment for more than 3 transfer cycles; or cumulative transfer of ≥10 high-scoring embryos without pregnancy; or a custom number of embryos transferred at each center. Since single embryo transfer and blastocyst culture techniques have become popular in recent years, it is clear that the past criteria are no longer applicable, so it has been proposed to count embryos as a criterion if cumulative transfer of 4 high scoring embryos, or 2 blastocysts still fails to result in pregnancy. Repeated implantation failure, like recurrent miscarriage, remains a worldwide problem, and both can be considered sequential adverse pregnancy outcomes with a wide range of complex causes that are difficult to identify. There are still two main aspects to consider: the embryonic cause and the endometrial cause. Who is the main cause requires an individualized analysis and a targeted treatment plan. Embryos with good developmental potential can implant in the fallopian tube, in the uterine scar, and even in the abdominal environment; therefore, embryo quality is the most critical factor for embryo implantation. Embryo morphology score: The embryo morphology score, which is widely used, is convenient and practical, and there is some correlation between the score and embryo implantation rate, but it does not really reflect the quality of embryos and their ability to develop at implantation. Blastocyst culture may be considered for further screening of embryos in patients with multiple transfers of high scoring embryos without pregnancy. Embryo chromosomal abnormalities: Embryo chromosomal aneuploidy is one of the causes of embryo implantation failure. For patients of advanced age, recurrent implantation failure, and recurrent spontaneous miscarriage, including especially those with at least one post-embryonic arrest chorionic villus chromosomal abnormality, preimplantation genetic screening (PGS) may be considered to screen for chromosomally normal embryos for transfer. Embryo growth rate and timing: The modern microscopic system for dynamic observation of embryos, the embryo microfilm technique (Time Lapse), allows assessment of the growth rate and rhythm of the embryo as it develops and selection of the embryos with the most normal developmental timing for transfer. Of course, this is not a foolproof insurance and the technique is still in the process of clinical research. 1. Uterine cavity abnormalities: Suitable endometrium is needed for embryo implantation to occur. Various uterine cavity pathologies such as endometrial polyps, submucosal fibroids, uterine cavity adhesions, endometritis, and uterine diaphragm may affect embryo implantation. Ultrasound is widely used clinically to measure endometrial thickness, morphology, uterine cavity morphology and blood flow to assess the ability of the endometrium to tolerate embryos. Hysteroscopic surgery may resolve or improve the endometrial environment in some patients and improve the embryo implantation rate. 2. Endometrial vascular thrombosis: Many causes, such as genetic mutations in the coagulation system, elevated autoimmune antibodies, and endothelial damage, may cause thrombosis in the small vessels at the placental implantation site, making the endometrial blood supply inadequate and making it difficult for the embryo to survive. These are often referred to as “antiphospholipid syndrome” and “thrombophilia”. However, a series of complicated tests are needed to confirm the diagnosis. Anti-clotting and thrombosis inhibiting drugs such as aspirin, corticosteroids and low molecular heparin can be used for prevention, which has certain clinical effect. 3. Tubal effusion: Tubal effusion contains various inflammatory mixtures that can interfere with the normal embryonic implantation process if it refluxes into the uterine cavity. For those with moderate to severe hydrocele and normal ovarian function, we suggest to deal with the fallopian tubes first and block or remove them to prevent the effect of fluid accumulation on implantation. 4. Endometriosis: There are many causes of infertility caused by endometriosis, which may reduce the quality of the eggs and change the environment of the endometrium, affecting the embryo’s ability to be bedded. Drugs or laparoscopic surgery will usually be considered to improve the pelvic environment and increase the embryo implantation rate. 5. Immune cell activity of the endometrium: It has been found that abnormally elevated activity of natural killer cells in the whole body or endometrium locally may have cytotoxic effects on the embryo and hinder the implantation. Immunotherapy can be performed by intravenous infusion of immunoglobulins, but these results are uncertain, the efficacy is still in the clinical observation phase, and the safety of blood products is under concern. 6. Active immune deficiency: These patients are unable to produce active immune antibodies to protect the embryo, and have an immune attack on the embryo, which is often referred to as “closed antibody” deficiency, and can induce their own active immune function through lymphocyte injection by the husband. However, the current flow cytometry test does not really reflect the active immune status of the body, so there is a certain blindness in the treatment. Other 1.Improve lifestyle: Both parties’ poor lifestyle (such as obesity, smoking, alcoholism, etc.) and environment may affect the implantation rate of embryos. Exercise, weight reduction, antioxidant treatment, lifestyle improvement and acupuncture may have some improvement effects. 2. Reduction of ovulation-promoting drug stimulation: For patients with unexplained recurrent implantation failure, we can adopt microstimulation or natural cycle egg preparation protocols to improve egg and embryo quality. 3. Endometrial stimulation or uterine perfusion: It is possible to regulate the local endometrial environment to promote embryo implantation through micro “injury”. However, the efficacy of these methods is uncertain and needs to be further observed. The causes of repeated embryo implantation failure are complex, and it is a path of exploration for clinicians to analyze the causes and find countermeasures to increase the implantation rate and improve pregnancy outcomes. The causes and countermeasures vary from person to person, and we need to analyze them comprehensively and use countermeasures individually, expecting better pregnancy outcomes for patients with recurrent implantation failure!