RECURRENT IMPLANTATION FAILURE

Recurrent implantation failure refers to failure to achieve a clinical pregnancy after transfer of at least four good-quality embryos in a minimum of three fresh or frozen cycles in a woman under the age of 40 years.

What is Implantation?

Implantation is a complex process whereby the embryo attaches itself to the inner lining of the uterus (the endometrium) followed by its migration and invasion into the deeper layer of the endometrium to become embedded there and grow.

What is successful implantation?

Clinically implantation is successful if there is the ultra-sonographic evidence of an intrauterine gestational sac (In most cases, a pregnancy can be seen with ultrasound as early as 5-6 weeks’ gestational age or 1-2 weeks after a missed period).

If the process of implantation began but could not be completed due to various reasons it can only be detected in blood (BHCG) or urine as positive pregnancy hormone test before disappearing, this is called Biochemical pregnancy.

What is RIF?

It is the failure to achieve a clinical pregnancy following the transfer of at least four good-quality embryos in a minimum of three fresh or frozen cycles in a woman of age below 40 years.

Where does the problem lie?

Successful implantation involves two main components, a healthy embryo that should have the potential to implant and a receptive endometrium that should enable implantation. The cross-talk between them is essential. These processes involve many mediators and the maternal immunologic system. Any abnormality attributed to the embryo, the endometrium or the immune system will result in implantation failure.The cause can be with the embryo, uterine lining- endometrium and the environment

Embryonic causes are responsible for 1/3rd of RIF cases. The current methods used to assess embryo quality are subjective and not always accurate. Good and normal looking embryos can be genetically abnormal. Thick embryonic zona (covering shell) can be there which prevents the embryo from hatching. Abnormalities may be due to the egg or the sperm or may arise de novo during development of the embryo. Good quality egg and sperm are essential to generate a healthy embryo.

Eggs: Reduced quality of eggs can be due to advanced maternal age, genetic problems, Polycystic Ovarian Syndrome, endometriosis, ovarian surgery and other factors

Sperm- Reduced quality and quantity of sperm are due to advanced age, lifestyle (alcoholism, smoking, obesity, certain drugs etc.), Diabetes. These can lead to sperm DNA fragmentation and affect the fertilization potential of the sperm.
Genetics:Increased incidence of chromosomal translocations, mosaics, inversions and deletions of genetic material were reported in patients with RIF

Endometrial factors: Endometrial receptivity can be adversely affected due to the presence ofanatomic abnormalities of uterus like uterine septae, sub mucous or intramural fibroids, endometrial polyps, intrauterine adhesions. Function could be impaired due to thin endometrium, adenomyosis and endometritis.

There can be problems of maternal Immune system, PCOS, Thrombophilia (which disturbs the blood supply in the uterus).

Multifactorial: Environment which the gametes and embryo get in body of the woman and the lab may be affected due to advanced age, diabetes, obesity, hydrosalphynx, endometriosis, suboptimal ovarian stimulation, suboptimal culture conditions in lab.

The technique of embryo transfer is also important.

 

MANAGEMENT OF RIF:

Modifying life style factors like stop smoking, Limit alcohol consumption, reduce stress level;lose weight, eating healthy food, avoid sleep deprivation. 

All women hoping to conceive should be taking 400mcg folic acid and 2000 IU of vitamin D daily.

PCOD & endometriosis can be managed before starting the process.

Use of antioxidantsis advised to enhance quality of the gametes.

Thyroid, diabetes and blood pressure should be well controlled.

Thorough investigations should be carried out to ascertain whether there is any underlying cause of the condition.

Ovarian function should be assessed by measurement of antral follicle count, FSH and anti-Mullerian hormone.

Increased sperm DNA fragmentation may be a contributory cause.

Various uterine pathology including fibroids, endometrial polyps, congenital anomalies and intrauterine adhesions should be excluded by ultrasonography and hysteroscopy.

Hydrosalpinges are a recognized cause of implantation failure and should be excluded by hysterosalpingogram; if necessary, laparoscopy should be performed to confirm or refute the diagnosis.

Treatment offered should be evidence based, aimed at improving embryo quality or endometrial receptivity.

Laser assisted hatching helps in releasing the embryos from its thick coveringzona.

Endometrial scratching: Endometrial scratch in your next treatment cycle has shown to increase success rates. This is a simple procedure, similar to having an embryo transfer. It is ideally done 7-10 days prior to the periods date in a previous month of planned embryo transfer procedure.

Preimplantation genetic tests such as PGT/PGD can be done before implantation to select good quality normal embryos, This is the testing of the genetic composition of embryos. It helps to identify chromosomally normal embryos

Blastocyst culture and transfer to increase the chances of implantation

Endometrial Receptivity Assay (ERA) is the most recent test of endometrial receptivity to assess the optimal time to place an embryo into the uterus to promote a successful implantation and pregnancy. It is reproducible and very accurate at determining when the window of implantation is open so it tells us if the endometrium is receptive or not. Some women might have a receptive uterus at an earlier time than expected and some might be receptive at a later time.

A good controlled ovarian stimulation protocol helps.

Karyotyping of the couple is done to identify any genetic abnormality.

If maternal age is above 40 years then donor egg could be a preferred option.

High magnification IMSI or surgical sperm retrieval (TESA) can be done to select the best quality sperm for ICSI especially in high sperm DFI.

Donor sperm can be used in cases of azoospermia or in severe male factor issues.

Medications and Therapieshave been tried for certain conditions. While some of these have proven therapeutic value, others still lack definite clinical evidence.

For Thrombophilia problem Heparin, Aspirin, Steroids should be considered.

For Immunological causes IVIG, Intralipid and Immunotherapy can be considered.

Othersare considered rarely- GCSF, PRP (Platelet rich plasma), PBMC (peripheral blood mononuclear cells-stem cells)

Donor eggs and Surrogacy:A woman who is too old or has premature ageing of her ovaries might not have a successful in vitro fertilization (IVF) cycle. Such patients may opt to use donor eggs. If the uterine problem cannot be resolved then surrogacy is the option.

The trauma of repeated failures, combined with the lack of a clear explanation about the cause of the failures leads to continued stress in patients. Couple should not lose hope as RIF can be diagnosed and can be managed increasing the chances of conceiving by IVF.

 

RECENT EVIDENCE SHOWS THAT RECURRENT IMPLANTATION FAILURE IS A RARE CONDITION WITH JUST 5% OF IVF PATIENTS WITH EUPLOID EMBRYOS (GENETICALLY NORMAL EMBRYOS CHECKED BY DOING PGT-A TEST) WERE UNABLE TO ACHIEVE PREGNANCY AFTER TRANSFER OF 3 CONSECUTIVE SINGLE EMBRYO TRANSFERS.

IMPLANTATION RATES OVER THE 3 TRANSFER CYCLES WERE 70% IN THE 1^ST TRANSFER, 60% IN THE SECOND TRANSFER AND 60% IN THE 3^RD TRANSFER.