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  • Release date: September 26 2022

Recurrent Failure of IVF (recurrent implantation failure)

It is the failure to achieve pregnancy after transfer of at least four good quality embryos, fresh or frozen, at least 3 separate times (cycles) to a woman under 40 years of age. Implantation is when the embryo (fertilized egg) adheres to the endometrium (the lining of the uterus) and then moves to the lower layers and attaches to the uterus. 

 

While implantation was initially thought to depend only on the embryo and endometrium, recent studies have shown that cumulus (cloud) cells may also play a role. Successful implantation is only confirmed when the gestational sac can be seen by ultrasound.

 

In IVF treatment, the gestational sac becomes visible on ultrasound 3 weeks after the day of egg collection. In a normal IVF treatment, while the implantation success rate is 25% per embryo in the transfer of day 2-3 embryos, it increases up to 40% in day 5-6 embryos.

 

Implantation failure can be evaluated in 2 ways. The first is a negative β-Hcg (pregnancy hormone) after the transfer and the second is the failure of the gestational sac to form (biochemical pregnancy).

 

Ovarian reserve, egg quality and number play an important role in recurrent implantation failures. The number and quality of eggs decreases with advancing maternal age. DNA damage to mitochondria (the energy organelle of cells) increases.

 

Fertilization success decreases and the rate of aneuploidy (numerical chromosome disorder such as Down syndrome) increases. As with egg quality, sperm quality also plays an important role in recurrent IVF failure. We know that routine sperm tests (spermiogram) are not able to show the actual quality of the sperm. We know that sperm DNA damage impairs embryo quality, reduces implantation success and increases miscarriage rates. Sperm DNA damage (fragmentation) can be detected by tests such as TUNEL. According to our classical knowledge, an index above 27% decreases the success of IVF. Antioxidant support therapies and smoking cessation can improve sperm quality.

 

Genetic problems of the father-to-be called balanced chromosomal translocation can also cause recurrent IVF failures. Congenital uterine anomalies are also among the causes. The most common uterine anomaly is uterine septum (membrane inside the uterus). This can be treated with hysteroscopy surgery. It is known that miscarriage rates decrease after treatment.

 

Endometrial polyps, fibroids and adhesions can also cause recurrent pregnancy losses. These pathologies can be corrected with hysteroscopic operations. Adenomyosis (the extension of the uterine lining into the uterine muscle tissue) is the most difficult of these pathologies to diagnose and is not easy to treat surgically. Hydrosalpinx means fluid inside the tubes. Patients with hydrosalpinx have a 50% lower rate of giving birth to a live baby with IVF treatment than those without hydrosalpinx. It is still unclear what role the immune system plays in recurrent IVF treatment failures.

 

It is known that blood clots (thromboembolism) can lead to recurrent IVF failure. In particular, patients with antiphospholipid syndrome can achieve pregnancy after aspirin and heparin treatment. However, thrombophilia, a disorder with a tendency to clot, has not been shown to cause recurrent implantation failure. It is controversial whether PGD (preimplantation genetic diagnosis) reduces recurrent IVF failure rates. 
 

There are reports that injecting granulocyte growth factor into the uterus may reduce this problem, but more studies are needed on this treatment. In patients who have problems with uterine wall thickening: thin endometrium; we know that vaginal use of sindenafil may be beneficial. There are publications showing that the use of luteal phase GnRH a and endometrial scraping may be useful especially in patients with recurrent IVF failure with thin endometrium. In patients with endometriosis and adenomyosis, we know that the use of ultra-long protocol increases pregnancy success. Removal of fibroids larger than 5 cm in the uterus may increase pregnancy rates.

 

Detailed examination is needed to determine whether there is an underlying cause for recurrent IVF failure. Ovarian function is assessed by assessing the antral follicle count, FSH and AMH levels. Increased sperm DNA fragmentation may be the cause. Uterine anomalies such as fibroids, endometrial polyps, congenital anomalies and intrauterine adhesions should be evaluated by ultrasonography and hysteroscopy. Hydrosalpinx (fluid in the tubes) can be the cause of implantation failure. It should be diagnosed and corrected by hysterosalpingography or laparoscopy if necessary. Treatment should be evidence-based and aimed at improving embryo quality and the perception of the uterine wall (endometrium). Sperm, egg or embryo donation can be used if the problem is related to reproductive cells. If the problem is an uncorrectable pathology of the uterine wall or the uterus itself, surrogacy treatment can be implemented. 

 

Even if we resort to all the details and these minor solutions, we may not be able to achieve pregnancy and live birth. Egg donation, sperm donation or embryo donation can be performed in Cyprus. If the issue is the uterus and pregnancy cannot be achieved in any way, the couple can have a child by using their own eggs and sperm through surrogacy.