Repeated Implantation Failure
What is Repeated Implantation Failure?
Over the past three decades, in vitro fertilization (IVF) has helped millions of women worldwide to conceive healthy babies. Despite the continuous improvement in IVF success rates, however, many IVF cycles end in frustration for women and couples as seemingly normal embryos fail to implant in the uterus and develop into a fetus. When failed implantation takes place in multiple IVF cycles, the patient or couple is considered to have recurrent implantation failure (RIF). There is no widely-accepted consensus on the definition of RIF among fertility specialists. One commonly used definition is the failure to conceive after three embryo transfers with seeming high-quality embryos. RIF includes negative pregnancy tests as well as biochemical pregnancies, those in which fertilization was achieved but implantation failed before a pregnancy sac could be visualized by ultrasonography. With the advent of pre-implantation genetic testing of embryos for chromosome abnormalities (PGT-A), the definition of RPL might be updated to include the failure to conceive after three single embryo transfers of chromosomally-normal (euploid) embryos.
Many known factors contribute to RIF. It is likely that many others have not yet been identified. Known factors include advanced maternal and paternal age, genetic competency of embryo(s), uterine abnormalities including congenital defects, fibroid tumors and polyps, chronic infections and inflammation of the fallopian tubes as well as the tissue lining the inside of the uterus (endometrium), autoimmune factors, hormone abnormalities, obesity, and environmental toxins including maternal tobacco, alcohol and drug use. As women age, the number of oocytes (eggs) diminishes and a higher proportion of oocytes are genetically abnormal. Failed implantation and the incidence of biochemical pregnancy increase with maternal age, particularly in women aged 38 and older. As RIF can occur, however, even with embryos that are deemed chromosomally-normal, age is just one factor contributing to RIF.
For any woman or couple who experience RIF, a logical, evidence-based evaluation must be performed that is both time-efficient and cost-efficient. Some information available to patients on the internet, in books and even from physicians and blogs can be valuable and supportive, while other information can be misleading and not evidence-based. A comprehensive evaluation should include an extensive medical and reproductive history from both partners, an appropriate evaluation of genetic, hormonal and immunologic factors, and a detailed assessment of the uterus, fallopian tubes and ovaries. Advanced testing of sperm may be warranted in some cases of RIF.
Many treatments are used commonly to help reduce the incidence of implantation failure. Hormonal supplementation, blood-thinning medications, uterine or other pelvic corrective procedures, antibiotic therapy, limited immunotherapy, and IVF with PGT-A might be appropriate treatments for some patients but not others. While many treatments are based on well-designed scientific studies, others are based on poorly-designed studies that do provide adequate data. As many patients feel desperate for answers, they may even partake in expensive, non-evidence based treatments.
All patients deserve state-of-the-art care that is based on sound medical and ethical parameters. RIF can be devastating and it is imperative for patients and couples to empower themselves with research and targeted questions and seek expert care and emotional support as they build their family.
IVF and ICSI can be very successful treatment methods. However, some cycles don’t finish with successful implantation, even after a number of transfers with apparently good embryos. Also, sometimes a cycle achieves a conception, but the pregnancy doesn’t develop to term.
There are various biological reasons why these two circumstances could be related, which lead us to look at potential therapies which could help.
Investigations and treatments
There is support for several treatment options for women with “recurrent implantation failure” (defined as 2 or more failed embryo transfers in IVF/ICSI treatment cycles). However, the available evidence is limited for many of the possibilities, due to a lack of suitably large clinical studies. Listed below are options we can talk about in a follow-up appointment in the upsetting event of a failed implantation or miscarriage. In devising treatment programmes, there are investigations we can carry out before treatment commences, which help us to tailor your treatment closely to your needs. There are also options carried out in the process of treatment that could help implantation.
If you’d like to talk about your options after an implantation failure or miscarriage, we’re here to help.
Maternal blood tests
- Clotting (thrombophilia) screen – Small clots in the blood have been identified as a possible cause for a pregnancies failing to progress. In some cases this can be treated with aspirin, or heparin injections to thin the blood.
- Immune screen – Increased levels of uterine natural killer cells (white cells) and autoantibodies (antibodies attacking specific organs) have also been suggested as a cause for repeated failure of cycles. The use of steroids, intralipids and other drugs to suppress the immune system and to help a pregnancy develop are controversial. More clinical trials are needed to understand the ways in which the immune system affects pregnancy and which treatments might benefit which women). Some of the drugs used in these treatments have side effects for both a mother and her developing baby, and it’s important to understand these risks before deciding with your doctor whether testing or treatment is recommended.
Endometrial tests
- Hysteroscopy or endometrial scratch – We may suggest a hysteroscopy (passing a flexible telescope into the womb under general anaesthetic) if we suspect scar tissue formation or the presence of a fibroid or polyp inside the womb which needs to be removed. There is some evidence that this procedure itself, or performing an endometrial scratch, can increase implantation rates.
- Endometrial Receptivity Array – A small amount of tissue from the womb lining (endometrium) can be sampled and analysed for the presence of over 200 genes known to be associated with implantation. Studies have shown that for some women this “window of implantation” is shifted either earlier or later in the menstrual cycle, or it is very narrow. Furthermore, by moving the planned embryo transfer to the appropriate time, chances of successful implantation can be improved.
Paternal factors
- Sperm DNA fragmentation – Assessing the degree of damage to sperm DNA help identify those couples that would benefit from ICSI treatment.
Embryo factors
- 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.
- Embryoscope™ (Time-lapse imaging) – Recording information by time-lapse photography allows us to assess more subtle changes seen during embryo development and identify the best embryos for transfer.
- Laser-assisted hatching – Assisted hatching is a physical or chemical treatment carried out immediately before embryo transfer. It weakens an area of the zona pellucida (the embryo’s ‘shell’) with the aim of improving the chances of implantation. We use a laser, as it is considered to be the safest and most accurate method.
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