A major cause for repeated IVF failure, as well as a likely factor in unexplained infertility and recurrent pregnancy loss, is represented by the failure of the embryo to properly implant and thrive in the uterine lining, known as an implantation defect or implantation deficiency.
Recurrent implantation failure (RIF) is usually diagnosed when a clinical pregnancy is not achieved during 3 or more consecutive IVF cycles, using good quality embryos for transfer. Although implantation deficiency can only be diagnosed when undergoing IVF, it is reasonable to assume that it may also be an underlying cause of unexplained infertility in women who are trying to conceive naturally.
Conception cycle: overview of ovulation, fertilization and implantation
Symptoms
The symptoms of an implantation defect are usually recurrent IVF failure in spite of high quality embryos being transferred, unexplained infertility in couples trying to conceive naturally and recurrent early pregnancy losses (<8 weeks of pregnancy, including the very early so-called ‘chemical pregnancies’ that only register as positive pregnancy tests).
Causes of implantation deficiency
Anatomic causes
Congenital malformations, such as a septate, unicornuate or bicornuate uterus, can make it difficult for a pregnancy to implant and progress well. These conditions are also associated with complications such as ectopic pregnancy, miscarriage and preterm delivery. In a similar way, uterine growths like polyps, large or multiple fibroids and intrauterine adhesions can create an unfavorable environment for implantation and pregnancy. Hydrosalpinx (an accumulation of fluid in the fallopian tubes) often promotes chronic inflammation in the uterus that can interfere with implantation. It’s recommended that such anatomic conditions of the uterus be surgically corrected when trying to conceive and especially before undergoing any expensive fertility treatments.
Endometrial receptivity
A thick and receptive uterine lining is essential to the process of implantation. Ideally, the endometrial thickness should be between 10-15mm during the implantation window (the short timeframe when the uterus is biochemically prepared for the embryo to attach). When the endometrium is thin and responds poorly to estrogen and progesterone, it can cause infertility, since it isn’t properly prepared to receive and nurture the embryo. This is believed to happen in about two thirds of the implantation failure cases. Sometimes a poorly receptive endometrium develops after a medical intervention to the uterus (like a curettage or surgery) and in this case it can prove quite difficult to treat.
Thrombophilia
Thrombophilia is a condition in which coagulation abnormalities in the blood make someone more prone to develop blood clots. It is also called a hypercoagulable state and is often associated with repeated pregnancy loss as well as implantation failure. The mechanism of its effect on fertility is not entirely clear, but it is possibly due to disturbed blood flow to the endometrium, embryo and placenta.
Inflammation
A local inflammatory response in the uterine lining can make it difficult for a pregnancy to implant or thrive. Endometritis (acute or chronic) is generally caused when bacteria that typically resides in the vagina manages to reach the uterine cavity. In the case of chronic endometritis, this infection may show no or very little symptoms but may carry on for months and even years, causing infertility in the process.
Immunological
The immune system plays a crucial role in fertility, since it mediates the interaction between the mother’s body and the pregnancy, preventing the maternal immune system from attacking and rejecting the embryo. This is why certain dysfunctions of the immune system can cause implantation failure and miscarriage, by triggering an aggressive response at the site of implantation.
HLA (Human Leukocyte Antigen) incompatibility between partners is often the reason why the pregnancy is not correctly recognized by the body, which allows the mother’s Natural Killer (NK) cells to attack the embryo. HLA is a gene complex that encodes the proteins which regulate the immune system in humans. Sharing common HLA alleles with your partner can lead to repeated implantation failure. Even as few as one shared allele was shown to negatively impact fertility.
Autoimmune conditions are also known to trigger repeated miscarriages and infertility. Antiphospholipid syndrome (APS) comes with an increased risk of blood clotting and will affect fertility in the same way that thrombophilia does.
Antinuclear antibodies (ANA) are a type of autoantibody that cause the immune system to target the proteins inside the body’s own cells and a very high number of ANAs in the blood often alter fertility by impairing placental functioning and embryo development.
Additionally, an overly aggressive population of local uterine Natural Killer cells can hinder implantation by attacking the pregnancy in its very early stages.
Due to the high costs of testing and immunotherapy, it has routinely been recommended that immunological testing is carried out last, when all the other likely causes of an implantation deficiency have been ruled out and/or treated. However, due to more recent medical advancements, more affordable testing and treatment options that are similarly effective are becoming increasingly popular.
Biochemical and immunological aspects of implantation
Embryonic factor
A problem with the embryo can be the factor in about one third of all implantation failure cases, with genetic incompatibility between partners accounting for a large proportion of these cases. An abnormal genetic karyotype may stunt the implantation process and/or the correct development of the embryo. The abnormality can occur randomly in the embryo during the process of cellular division or it can be the result of balanced translocations (a type of chromosomal anomalies that don’t affect survival) in the mother, the father or both parents. When one of the partners is the carrier of balanced translocation, around two thirds of their offspring will be genetically unbalanced and unable to survive the uterine environment, resulting in repeated IVF failure or recurrent early miscarriages. This is why couples dealing with these outcomes are encouraged to undergo karyotype testing.
Male factor
Poor sperm quality may affect embryo quality through the occurrence of DNA fragmentation. Many of these embryos will be unable to grow and thrive. Poor sperm morphology can occasionally be missed by regular sperm analysis, but spotted on ultra high magnification sperm analysis, which is used for selection purposes in IMSI (intracytoplasmic morphologically selected sperm injection). Although this cutting edge analysis technology is not usually offered separately from the IMSI procedure, it may be available in certain fertility clinics.
A: Normal sperm; B: Abnormal sperm (large nuclear vacuoles can be observed)
Tests and Diagnosis
A transvaginal ultrasound is an easy and relatively inexpensive test to perform and is often the first to suggest or diagnose an anatomical or functional issue with the uterus, such as a malformation, polyps, fibroids or an inadequate endometrial thickness. 3D sonography is particularly accurate in detecting uterine malformations, as well as IUDs (intrauterine devices) and fibroids.
Hysterosalpingography (HSG) and Hysteroscopy are also highly accurate in detecting uterine anatomical abnormalities, including the more elusive adhesions (synechiae), however they are more invasive than an ultrasound and may involve anesthesia.
During a hysteroscopy, biopsy samples can be taken to assess endometrial inflammation, receptivity, local Natural Killer cells activity, as well as the nature of any suspicious polyps and fibroids. An endometrial culture can check whether any pathogens are causing an inflammatory response in the uterine lining.
The endometrial receptivity histological test (also known as ERA) is the best choice in assessing endometrial receptivity during the implantation window, as well as the best time for an embryo transfer for each particular woman. It was observed that 1 in 5 women have a slightly different implantation window than the majority and knowing this may help increase their odds of IVF success by transferring the embryos right at the time when their endometrium is most receptive. This test involves taking one or more small biopsy samples from the uterine lining and analysing them for the expression of over 200 endometrial receptivity genes to determine the optimal time for implantation. Particularly important is the expression of integrin, an adhesion molecule that’s essential to implantation.
Endometrial immune profile (EIP) or Endometrial Natural Killer Cell testing are investigations that study biopsy samples from the endometrium to check for local dysregulated immune activity in NK cells and other factors like proinflammatory cytokines.
For women trying to conceive naturally and dealing with difficulties obtaining a pregnancy, hormonal blood levels are usually assessed, such as Follicle-Stimulating Hormone (FSH), Luteinizing Hormone (LH), Estrogen (Estradiol), Progesterone, Prolactin and Thyroid Stimulating Hormone (TSH).
A complete Thrombophilia panel is generally recommended when dealing with implantation deficiency, unexplained infertility or recurrent early pregnancy loss. The panel should test for the most common thrombophilia factors, like antithrombin III, free protein S, protein C, factor V Leiden, Homocysteine, factor XIII, MTHFR (C677T), MTHFR (A1298C), PAI-1, etc. Testing for Antiphospholipid Syndrome is also advised, by measuring the levels of the following autoantibodies: anticardiolipin, beta-2 glycoprotein 1 and lupus anticoagulant.
Measuring ANA (antinuclear antibodies) titers in the blood can be useful if the cause of the implantation deficiency is suspected to be immunological.
To rule out or confirm a genetic cause, the HLA (Human Leukocyte Antigen) matching test is usually performed to ensure the partners are compatible to conceive a pregnancy that will be accepted by the mother’s body, as well as a Karyotype profiling for each partner to check for balanced chromosomal translocations that may increase the risk of genetically unstable embryos.
A regular Sperm Analysis, while undoubtedly a helpful and reliable test in most cases, can sometimes miss less obvious morphological abnormalities in the sperm, which would otherwise be detected under Ultra High Magnification. Certain fertility clinics may offer the latter, but it isn’t yet widely available.
Treatment options for implantation defect
Treating an implantation defect and improving implantation chances means effectively treating the condition that is causing it.
For anatomical causes, the best treatment is the surgical correction or removal of the culprit, whether it is hydrosalpinx, uterine malformations, polyps, fibroids or adhesions.
Most common uterine malformations (Mullerian malformations)
For endometrial receptivity issues, hormonal and vasodilator treatments are used to increase blood circulation in the area, making the lining more nourishing and receptive.
For women that don’t respond well to hormonal and vasodilator therapy, endometrial perfusions with G-CSF (granulocyte colony-stimulating factor) has proven effective in some studies, increasing the endometrial thickness and/or improving pregnancy rates in otherwise reluctant cases.
Somewhat unexpectedly, it has been observed that certain types of endometrial injury often lead to significantly better rates of implantation. For example, the following 2 cycles after an endometrial biopsy have been proven to be more favorable for implantation and yield better pregnancy rates. The reason may be related to the local inflammatory response, which probably stimulates and increases the endometrial receptivity. For this reason, a procedure named controlled uterine injury is sometimes performed before transferring the embryos, in order to increase the likelihood of IVF success.
When thrombophilia is the likely cause of the implantation deficiency (whether it is acquired, genetically inherited or immunological), the treatment of choice is low molecular weight heparin, administered by daily injections.
If endometritis is suspected or confirmed, antibiotic treatment is usually prescribed, the choice of antibiotic depending on the results of the endometrial culture. For stubborn infections, the treatment can be repeated up to 3 times.
Immunological causes of an implantation defect are often treated by IVIg (intravenous immunoglobulin), which is a more expensive but also very effective therapeutic option. It is helpful in cases of implantation failure and recurrent pregnancy loss of unknown cause, but particularly when there is HLA incompatibility between partners, positive ANA titers in the mother or other aggressive autoimmune conditions associated with the fertility issues.
Intralipid infusions have been shown to modulate cytokine and NK cell activity in women who have increased cytotoxic NK activity, significantly raising pregnancy rates as a result. It is a relatively inexpensive method (the infusion basically contains soybean oil, purified egg phospholipid and glycerol) and can be used to maximize the odds of pregnancy success in IVF cycles and not only.
Depending on each fertility specialist, immunosuppressant medications like Prednisolone are sometimes prescribed in women struggling with infertility, recurrent miscarriages and aggressive Natural Killer cell activity, to improve implantation and pregnancy success. The jury is still out on this approach, which comes with a host of possible side-effects. Some doctors view Prednisolone as a fertility wonder drug, while others would not consider using it at all.
When the embryo itself is suspected to be the cause of the implantation deficiency, various options are available to increase the odds of a successful IVF procedure. Preimplantation Genetic Diagnosis (PGD) is recommended for couples who have abnormal karyotypes. PGD means genetically profiling the embryos before transferring them, to make sure they are normal and able to implant and develop correctly. Sometimes the profiling is also done on the woman’s eggs (oocytes), before fertilizing them.
Daily progression of the fertilized egg
A few other IVF techniques have also been promising in increasing the odds of implantation.
Pre-implantation assisted hatching of the embryo works well for poor or average quality embryos, for women aged 38+ and for those dealing with recurrent implantation failure. Some clinics routinely use assisted hatching to improve implantation rates.
Zygote intrafallopian transfer (ZIFT) involves placing the embryos in the fallopian tube instead of the uterine cavity, to more closely recreate the natural process of implantation. It has shown good results, but it is also a more complicated procedure because it requires general anesthesia and laparoscopic surgery.
Blastocyst transfer (or Day 5 transfer) means transferring Day 5 embryos instead of Day 3 embryos. Day 5 embryos are called blastocysts and they have reached a more advanced developmental stage, where the father’s genetic contribution has already begun to show its effect. By using this approach you will usually get a higher pregnancy rate, but also a higher transfer cancellation rate, since fewer (but better) embryos actually make it to day 5. A sequential embryo transfer (or a double transfer) is another option, which involves transferring 2 embryos separately, one on day 3 and the other on day 5.
Finally, when inadequate sperm quality is likely the culprit for repeated implantation failure, the technique called IMSI (intracytoplasmic morphologically selected sperm injection), using ultra-high magnification for sperm selection, is showing promising results when undergoing IVF. This procedure is typically recommended when the partner has an abnormal sperm analysis, but it might be effective even in the case of a normal sperm analysis, since some subtle morphological defects may be missed with regular testing.
Certain supplements and vitamins can also be helpful in improving sperm quality, especially when taken over a few months.