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How do special NK cells get to the uterus?

How do special NK cells get to the uterus?


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When an embryo is creating a placenta in the uterus, some special kinds of Natural killers cell of the mother will move and gather towards this placenta (for exmaple for growth components increasing blood of the placenta). But how do these NK cells know where to go… do they kind of 'smell' the uterus?


They are attracted via chemokines, which are molecules that NK cells sense and move towards the increased chemical gradient.


Uterine natural killer cells

Uterine natural killer (uNK) cells make up approximately 70% of maternal lymphocytes during pregnancy, occupying both the decidua basalis of the endometrium at the implantation site and the mesometrial lymphoid aggregate of pregnancy (MLAp) that surrounds the blood vessels supplying the placenta. This number is at its peak in early pregnancy but declines at parturition. [1]


Can I get tested to check the level of my NK cells?

It is possible to have tests to measure your level of NK cells. This is not usually available on the NHS, although some women have told is that they have had these tests through their NHS recurrent miscarriage clinic. Some fertility clinics offer tests, but not all. If they do, you will have to pay for it. This can be expensive and will vary from clinic to clinic.

Before deciding whether or not to have tests, it’s important to know that there are some issues with these tests:

  • There is a lack of evidence about the exact role that NK cells have in causing miscarriage.
  • There are no official guidelines for what ‘normal’ NK cell activity is.
  • It is difficult to measure the ideal level of NK cells and when an imbalance can cause infertility and miscarriage.
  • Specialists have different opinions about how to do these tests and report the results – as there are no official guidelines, doctors will interpret the results based on their clinic’s ‘normal’ range and their clinical and professional experience.
  • The level of uNK cells is different in each menstrual cycle so having a single test may not give a clear picture.

Testing may involve peripheral NK cell testing. This is a blood test that measures the percentage and quantity of NK cells in the bloodstream. However, these cells are different to uNK cells. Therefore, some clinics do uNK testing, which is similar to an endometrial scratch. This involves scratching the lining of the womb (the endometrium) to test the tissue for NK cell activity.


NK Cells in Miscarriage

It's hard to dispute that NK cells are elevated in women who have recurrent miscarriages since numerous studies have found this to be true. Researchers have even suggested that elevated NK cells could be behind as many as one-third of all unexplained miscarriages.

Scientists have fleshed out a few mechanisms in which elevated NK cells could terminate an otherwise viable pregnancy, usually promoting the idea that a disordered immune system causes the cells to attack the pregnancy.

At least one study has found evidence that NK cells in the uterus attack cells from the pregnancy in cases of spontaneous miscarriage, although it's unclear what those results mean.  

Some researchers have even looked at the chromosomes of the miscarried pregnancy to determine whether the NK cells were elevated because of the body's natural response to a chromosomally abnormal pregnancy. The researchers discovered that women with elevated NK cells were potentially more likely to miscarry a chromosomally normal baby in their next pregnancy.

If true, elevated NK cells are causing viable pregnancies to miscarry, reducing elevated NK cells should lead to a reduced risk of miscarriage. Studies have looked at the use of both corticosteroids (such as prednisolone) and IV immunoglobulins (IV gammaglobulin) for those with a history of recurrent miscarriage.  

A few studies have found that these treatments, especially IV immunoglobulins may increase the chance that participants will carry their next pregnancy to term.   Researchers recommend that further studies should be done to understand the risks and benefits of these treatments.


Links to Infertility/Miscarriage

What’s the possible connection between uterine natural killer cells and getting (and maintaining) pregnancy? The quick but truthful answer is we don’t really know (yet). The original theory was that having “too many” uterine natural killer cells could lead to a woman’s immune system rejecting and “attacking” an embryo.

The uterine NK cells would identify the fetal cells as “foreign” invaders and mark them for death. This theory was proposed to explain unexplained infertility, recurrent miscarriage, and repeated failed IVF implantation. It was based on the assumption that uterine natural killer cells acted like the ones that circulate in the bloodstream.

Many fertility experts now recognize that this is inaccurate. Uterine natural killer cells do not attack the embryo. They also do not behave the same as the NK cells in the bloodstream.

Uterine natural killer cells never come into direct contact with the fetal cells—they only have direct access to placental cells.

Also, uterine natural killer cells have significantly less of the “bright” cell attachment that can lead to cell death. Despite being put into the same immunological class of cells, they have different roles and capabilities. All that said, this doesn’t mean that uterine natural killer cells may not be a cause for fertility problems.

Uterine NK cells absolutely are vital to the development of a healthy endometrium and placental development. We know that uterine NK cells are the primary immune cells present in the uterus. We also know they make up over 30 percent of the endometrial cells developed during the luteal phase. Whether and how uterine NK cell activity contributes to infertility, IVF failure, and miscarriage is unclear.


HOW TO INCREASE NATURAL KILLER CELLS

The enhancement of NK cell function can be accomplished in a variety of ways. For the purposes of this review, we break down the strategies into three major categories:

  1. Targeting inhibitory signaling pathways and negative regulators of NK cell activating signaling pathways,
  2. Manipulation of inhibitory/activating receptors expressed by NK cells,
  3. Cytokine-mediated activation and expansion of natural killer cells. This review will highlight the scientific progress in these 3 areas and discuss how these different strategies are currently impacting NK cell-mediated immunotherapy.


Uterine natural killer cells: To protect and to nurture

Dorothy K. Sojka, Rheumatology Division Box 8045, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110.

Rheumatology Division, Washington University School of Medicine, St. Louis, Missouri

Rheumatology Division, Washington University School of Medicine, St. Louis, Missouri

Rheumatology Division, Washington University School of Medicine, St. Louis, Missouri

Dorothy K. Sojka, Rheumatology Division Box 8045, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110.

Rheumatology Division, Washington University School of Medicine, St. Louis, Missouri

Rheumatology Division, Washington University School of Medicine, St. Louis, Missouri

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Abstract

During the course of pregnancy, the maternal-fetal interface is tightly regulated and undergoes dynamic changes that promote the successful development of the semi-allogeneic fetus. In response to embryo implantation, the uterus remodels with maternal immune cells occupying the maternal-fetal interface and uterine natural killer (uNK) cells becoming the most prominent leukocyte. Recently, uNK cells have been discovered to be heterogeneous, including conventional NK and tissue-resident NK cells. Here, we will review the recent advances in uNK cell biology and discuss their functional mechanisms which protect and nurture the growing fetus.


INTRODUCTION

Natural killer (NK) cells play an important part in the innate immune system and were first defined functionally by their ability to kill certain tumors and virally infected cells without a requirement for major histocompatibility complex restriction or previous immunization [1]. NK cells produce immunoregulatory cytokines that contribute to the early host defense against several types of viruses, bacteria, and parasites. In humans, ∼10% of peripheral blood lymphocytes are NK cells [2], which can be defined phenotypically by the expression of CD56 and the absence of CD3, and NK cells fall into two distinct subsets according to their surface density of CD56. The majority of NK cells in human blood has low CD56 expression (CD56 dim ) and expresses high levels of Fc receptor for immunoglobulin G (IgG FcγR)III (CD16) and CD57 [3]. A small subset of blood NK cells (∼10%) expresses high levels of CD56 (CD56 bright ), low or no CD16, and lack CD57 expression. Uterine NK (uNK) cells account for a large percentage of leukocytes in the human endometrium (EM) and have similar expression of CD56, CD16, and CD57 as the CD56 bright blood NK cell subset [3, 4].

The human uterine EM is a complex mucosal tissue that has a unique immune cell component that is regulated by sex hormones throughout the menstrual cycle [5, 6]. The EM must be prepared to respond to potential pathogen challenges yet be able to control immune cell responses to allow the development of a semi-allogeneic fetus. In the nonpregnant state, there is a tightly controlled influx, spatial compartmentalization, and regulation of immune cells [7, 8]. The EM contains macrophages, NK cells, T cells, B cells, and neutrophils in contact with a variety of stromal and epithelial cells. The interplay among these different cell types and their roles in defense against pathogen invasion in this specialized tissue are poorly understood. Unlike the murine uterus, uNK cells in the human uterus are found in large numbers spread throughout the EM with increasing numbers as the menstrual cycle progresses [91011].

NK cells express receptors for monocyte-derived cytokines (monokines) and can produce several cytokines in response to monokine stimulation. NK cells from peripheral blood have been shown to produce interferon-γ (IFN-γ), granulocyte macrophage-colony stimulating factor, interleukin (IL)-10, IL-13, and tumor necrosis factor-β, and there is evidence that CD56 bright NK cells are the major producers of cytokines by NK cells in response to monokines [12]. In contrast, CD56 dim NK cells are more cytotoxic against tumor cells and produce smaller amounts of cytokines upon monokine stimulation than CD56 bright NK cells [121314].

Members of the transforming growth factor-β (TGF-β) family are powerful, immunoregulatory agents that act on a range of different target cells [15161718]. TGF-β proteins are produced as inactive precursors that can bind to extracellular matrix and cell-surface proteins, where they are activated [19]. Low pH conditions can activate latent TGF-β, but the mechanisms that regulate TGF-β activation remain unclear. TGF-β has been demonstrated to have activating and inhibitory effects on many parts of the human immune system, including cellular cytotoxicity, proliferation, cytokine production, and differentiation [20]. TGF-β1 can inhibit proliferation of T cells [15, 16], decrease antigen presentation [17], inhibit macrophage activity [18], and suppress cytotoxic activity, cytokine production, and proliferation in peripheral blood NK cells [21]. However, stimulatory effects from TGF-β, such as murine T cell proliferation [22] and IL-2 release from human effector cells [23, 24], have been reported.

In this study, we examined phenotype and function of uNK cells in the EM of nonpregnant women. In situ and in vitro analyses show that uNK cells have a unique phenotype compared with blood NK cells. We show that isolated human uNK cells produce cytokines and that these can be suppressed in a dose-dependent manner by TGF-β1. In addition, we demonstrate that neutralizing endogenous TGF-β promotes IFN-γ production by uNK cells. Taken together, these results indicate that local TGF-β-mediated inhibition is a mechanism that regulates NK cell-derived cytokine production in the human EM.


Role of Uterine Natural Killer Cells and Interferon γ in Placental Development

Large granular lymphocytes migrate in large numbers to the pregnant uteri of a wide variety of mammalian species 1. These cells, also known as granulated metrial gland cells in rodents and endometrial granulocytes in primates, will for the purposes of this review all be referred to as uterine (u)NK cells. uNK cells are bone marrow�rived leukocytes, but their immediate precursors may migrate from the spleen. Cells expressing a similar panel of activation antigens are found in the spleens of pregnant but not nonpregnant mice, and only splenocytes derived from pregnant donors can populate the uteri of uNK-deficient recipients during pregnancy 1 2. The signals that regulate migration of uNK to the uterus are not known. Homing precedes implantation in rodents and primates, so it is unlikely that the fetus plays a direct role. Circumstantial evidence implicates ovarian steroids and uterine decidualization, a metaplastic process that modifies the placental implantation site during pregnancy 3. Mice lacking genes for chemokines known to attract NK cells at other sites show no defects in uNK localization 1. After migration, uNK cells proliferate, differentiate, and accumulate in large numbers in specific areas of the uterus between days 2.5 and 12 of murine pregnancy (implantation occurs on day 4 and delivery on day 19). After day 12, uNK cells undergo extensive apoptosis (as defined by morphology and TdT tailing) and are dramatically decreased in number and activation through the remainder of pregnancy 4 5 6. uNK granules contain lytic molecules such as perforin and granzymes A and B, matrix components including osteopontin, and vasoactive factors such as inducible nitric oxide synthase (iNOS) and endothelial (e)NOS 6 7 8. Factors expressed in the uterus that are either bound by or otherwise implicated in the regulation of uNK cells include IL-15 9, decidual prolactin-related peptide B 10, and IFN-γ. uNK cells can also be activated to secrete a variety of cytokines including GM-CSF, CSF-1, leukemia inhibitory factor, TGF-㬡, TNF-α, and most importantly for the purposes of this discussion, IFN-γ 8.

What is the justification for assigning uterine large granular lymphocytes to the NK lineage? Murine uNK cells express Thy 1.1, asialo-GM1, IL-15Rα, and at least two members of the CD94/NKG2 C-type lectin–like family of class I MHC receptors, NKR-P1 (NK1.1) and Ly49G2 (LGL-1), and can lyse YAC-1 target cells 5 6. Human uNK cells express CD56 (polysialylated neural cell adhesion molecule), members of the CD94/NKG2 and killer inhibitory receptor (KIR)2D class I MHC receptor families, and can lyse K562 target cells 11 12. Despite having these typical phenotypic and functional characteristics, some doubt persists as to whether uNK cells truly belong to the NK lineage. Part of the controversy is inherent to the definition of NK cells. In the absence of any one lineage specific marker, NK cells are essentially defined in negative terms, i.e., cells of appropriate phenotype and function that lack surface CD3/TCR molecules and show no molecular evidence of Ig/TCR rearrangement 9. Lineage diagrams depict an early separation of T lymphocytes and NK cells before expression of the recombinase activating genes RAG-1 and RAG-2. These definitions raise a more specific problem for uNK cells, the presence of an overlapping population of uterine large granular lymphocytes that express γ/δ TCRs. A significant fraction of CD56 + human uNK cells either express γ/δ TCRs or can acquire γ/δ TCRs in culture 13. Based on these observations plus the unusually high expression of RAG-1 and RAG-2 in CD56 + human uNK cells 14, it has been suggested that the human uterus could represent a site of extrathymic maturation for γ/δ T cells analogous to cryptopatches in the small intestine. A corresponding population of murine γ/δ T cells has also been isolated, but their exact phenotype and localization within the pregnant uterus has not been studied 15. Some evidence suggests that these cells may regulate pregnancy viability in early gestation (day 5.5𠄸.5) and produce cytokines in response to trophoblast antigens later in pregnancy (day 14�) 16 17. Whether these cells are distinct from uNK cells is unknown. However, as virtually all uterine CD45 + leukocytes in the vicinity of the placenta are by morphologic and immunophenotypic criteria typical uNK cells, it is difficult to accommodate a substantial independent population of γ/δ T cells 6 18. On balance, it seems reasonable at this point to assign uterine large granular lymphocytes to the NK lineage, realizing that their taxonomy may change as further data becomes available.

The recognition that uterine large granular lymphocytes are probably NK cells coincided with the finding that invasive trophoblasts in rodents and primates express class I MHC molecules 11 18. These observations both occurred at a time of heightened interest in the mechanisms by which a semiallogeneic fetus might survive in the histoincompatible mother. It had previously been thought that trophoblasts lacked MHC expression, making them ineffective targets for a classical allogeneic response. The paired observations that invasive trophoblasts express class I MHC antigens and that uNK cells are prevalent in the pregnant uterus led to the formulation of a hypothesis that has remained pervasive in the field over the past decade: that trophoblasts resist NK lysis by expressing class I MHC molecules (later shown to the consequence of NK𠄼lass I MHC-specific KIR) and that recognition of trophoblasts by NK cells elicits the secretion of cytokines that both enhance placental growth and modulate local allogeneic responses (Th2 deviation). It is no exaggeration to state that the number of reviews, editorials, conference reports, and commentaries reiterating this hypothesis has far exceeded the number of studies that have directly tested it. Unfortunately, while heuristically satisfying, the uNK trophoblast class I MHC hypothesis has not been particularly useful thus far in explaining either normal placental development or reproductive disorders such as abortion, growth retardation, preeclampsia, and fetal loss.

Careful morphologic assessment of normal and abnormal pregnancies is a powerful tool to evaluate hypotheses regarding uNK function, and problems with the trophoblast class I MHC hypothesis are readily apparent. Most of the problems relate to the fact that for most of pregnancy, uNK cells and trophoblasts are not in close temporal or anatomic proximity to one another. Murine uNK cells accumulate before implantation away from the implanting conceptus and eventually concentrate in the metrial gland, a structure located deep within the uterine musculature 19. The metrial gland is never infiltrated by trophoblasts but rather surrounds large uterine arteries that supply the placenta 18. Only late in pregnancy after extensive apoptosis and downregulation of both activation antigens and lytic activity do uNK cells come in contact with trophoblasts in the decidua basalis. Even at this stage, the majority of uNK cells are in the metrial gland. Similarly, human uNK cells are primarily clustered around endometrial glandular epithelium and small arteries away from trophoblasts 20. The most intriguing observations relating to uNK function come from rats and hamsters, rodent species that, unlike the mouse, have deeply implanting placentas with uterine arteries that are remodelled by invading trophoblastic cells (discussed below). In these species, it has been shown that uNK cells infiltrate the walls of uterine arteries before their invasion by trophoblasts 21. Earlier in rat pregnancy, uNK cells appear to have second distinct role: infiltration of endometrial epithelium surrounding the implantation cylinder immediately before its incorporation into the endometrial vasculature and long before contact with placental trophoblasts 22. The weight of the anatomic evidence does not support a primary or direct role for uNK cells interacting with trophoblasts but rather suggests a role for uNK in the modification of uterine blood vessels and endometrial epithelium away from the zones of trophoblast invasion and placental morphogenesis.

Eschewing the trophoblast class I MHC hypothesis, Croy et al. 1 have over the past 10 years pursued an alternative genetic approach supplemented by careful morphologic analysis. This group has focused on two questions: What defects would be seen in pregnancies derived from mothers without uNK cells, and What manipulations would be required overcome uNK deficiency and restore normal morphology? Answering these questions was initially hampered by the lack of an appropriate model of uNK deficiency. Studies with SCID mice argued against a substantial role for adaptive immunity in placental morphology and pregnancy outcome. beige/beige mice with defective NK lytic activity also had essentially normal pregnancies, as did doubly mutant SCID/beige mice 8. Subsequent analysis of many immunodeficient mouse strains revealed two with absent uNK cells, tg𻔦 females having an insertional mutation involving multiple copies of the human CD3E gene and mice doubly mutant for p56 lck and IL-2Rβ. Six well defined pregnancy abnormalities were described in these animals: absence of uNK cells, no metrial gland, decreased placental size, increased fetal loss, decidual edema, and most importantly an arteriopathy involving the large maternal arteries supplying the placenta. This arteriopathy was characterized by hypertrophy of the muscular media and narrowing of the vascular lumen (defective vascular remodeling). All six defects were corrected by transplantation of normal bone marrow just before pregnancy. The results of the study by Ashkar et al. in this issue provide further insights into the etiology and mechanisms of uNK deficiency arteriopathy 23. For this study, a third uNK-deficient mouse, doubly mutant for RAG-2 and the common cytokine γ receptor subunit, was used. These mice received either bone marrow transplants from donors lacking key uNK-regulatory molecules or daily cytokine infusions to define the minimum requirements for restoration of normal morphology. Three conclusions emerged. First, low levels of endogenous (non–uNK-derived) IFN-γ are required to maintain decidual integrity at day 12� of pregnancy. Second, higher levels of IFN-γ, normally derived from uNK but substituted for by daily infusions of IFN-γ, are needed for vascular remodelling (day 10�). Third, an intact IFN-γ signal transduction pathway is required in donor cells for normal uNK (and metrial gland) development. However, donors lacking IFN-γ signal transduction function were still able to appropriately remodel uterine arteries, suggesting that the uNK abnormalities observed in these mice did not interfere with the availability of IFN-γ.

Vascular remodelling is a relatively recent concept now believed to occur in a variety of situations characterized by inadequate perfusion or increased vascular demand 24. Mediated by changes in local cytokines, growth factors, vasoregulatory substances, matrix components, and matrix proteases, this process culminates in permanent structural alterations, including thinning of the vascular muscle wall and with luminal dilatation, which increase local perfusion. Although unfamiliar to many immunologists, vascular remodelling has been of considerable recent interest in reproductive biology. It has long been known that maternal arteries supplying the human placenta are invaded by fetal trophoblasts, which replace the muscular media with a fibrinoid matrix, leading to increased blood flow 21. Recent data have shown that this trophoblast-dependent process is preceded by a trophoblast-independent phase of vascular remodelling 25. As shown most convincingly by Ashkar et al. 23, trophoblast-independent remodelling of uterine arteries in rodents appears to be uNK dependent. Although human uNK cells have not yet been implicated in vascular remodelling, it is notable that �% of human uNK cells cluster around uterine arteries undergoing vascular remodelling 20. Recent data has shown that decreased oxygen tension leads to impaired trophoblast differentiation and trophoblast-dependent arterial remodelling, both of which are characteristic of the human pregnancy disorder preeclampsia 26. In light of these recent data, the following hypothesis is suggested. Defects in early vascular remodelling related to uNK dysfunction lead to local hypoxia, which retards trophoblast differentiation and inhibits trophoblast-dependent vascular remodelling. The resulting reduction in uteroplacental perfusion would then increase the risk of preeclampsia and related pregnancy disorders such as growth retardation and unexplained fetal loss. The uNK-deficient murine model, although lacking the trophoblast-dependent vascular remodelling component, supports such a model and implicates uNK-derived IFN-γ as a possible mediator.

With regard to future investigation, three obvious questions stand out: the relationship of murine uNK to γ/δ T cells throughout gestation and their relative functionality, the downstream pathways mediating murine IFN-γ�pendent vascular remodelling, and the relationship of human uNK cells to abnormal vascular remodelling in preeclampsia and related disorders.


Treatments for implantation failure or recurrent loss

There are several lines of treatment for embryo Implantation

Immunotherapy

Immunotherapies are treatments that suppress the immune system or more specifically Natural Killer Cells

Natural killer cells are immune cells that have different roles. The classic NK cell is the peripheral blood or pbNK cell, which "kill" infected cells, while the nontraditional uterine or uNK cell is less about the killing and more about supporting implantation. Read more about it on my blog NK cells in IVF

Natural killer cells are immune cells that have different roles. The classic NK cell is the peripheral blood or pbNK cell, which "kill" infected cells, while the nontraditional uterine or uNK cell is less about the killing and more about supporting implantation. Read more about it on my blog NK cells in IVF

For more details, check out my post on NK cells in IVF (opens in new tab)

Generally, immunotherapies don’t have good supporting evidence: the HFEA gives this a red light – no evidence that the treatment is safe and effective. However, as with all things on this blog, your mileage may vary so ask your doctor what they think.

A very high quality research article that summarizes all the available data for a particular subject at the time. They identify all the risks for bias and describe the quality of the evidence (ie. very poor, poor, moderate, high) to give a good idea of how the data should be evaluated. Read more in the Cochrane Handbook.

Intralipids

Emulsified fat that is delivered by IV. Believed to reduce the activity of Natural Killer Cells

Natural killer cells are immune cells that have different roles. The classic NK cell is the peripheral blood or pbNK cell, which "kill" infected cells, while the nontraditional uterine or uNK cell is less about the killing and more about supporting implantation. Read more about it on my blog NK cells in IVF

  • 1 RCT found no difference in chemical pregnancy rate, but an increased live birth rate (Dakhly et al. 2016)
  • 1 retrospective study found no difference in live birth rates in women with recurrent losses with increased Natural Killer Cells

Natural killer cells are immune cells that have different roles. The classic NK cell is the peripheral blood or pbNK cell, which "kill" infected cells, while the nontraditional uterine or uNK cell is less about the killing and more about supporting implantation. Read more about it on my blog NK cells in IVF

Prednisone (prednisolone)

Predisone is a glucocorticoid that functions as an anti-inflammatory and immunosuppressive drug. It is used to enhance Implantation

  • Some studies showed increased success while others showed no benefit: controversial
  • Inconsistent protocols makes interpretation difficult (prednisone, methylprednisone, etc.)
  • May act in suppressing blood vessel development

Embryo glue

Embryo glue contains hyaluronic acid or HA which is believed to make embryos more “sticky” to attach to the Endometrium

A very high quality research article that summarizes all the available data for a particular subject at the time. They identify all the risks for bias and describe the quality of the evidence (ie. very poor, poor, moderate, high) to give a good idea of how the data should be evaluated. Read more in the Cochrane Handbook.

  • Increase in live birth, pregnancy rate, and multiples (expected since HA will allow more than 1 embryo to stick in multiple transfers)
  • Not stage specific – works for Cleavage stage

Endometrial scratch

An endometrial scratch is where a device is inserting into the uterus to “scratch” the Endometrium

A very high quality research article that summarizes all the available data for a particular subject at the time. They identify all the risks for bias and describe the quality of the evidence (ie. very poor, poor, moderate, high) to give a good idea of how the data should be evaluated. Read more in the Cochrane Handbook.

A very high quality research article that summarizes all the available data for a particular subject at the time. They identify all the risks for bias and describe the quality of the evidence (ie. very poor, poor, moderate, high) to give a good idea of how the data should be evaluated. Read more in the Cochrane Handbook.

A very high quality research article that summarizes all the available data for a particular subject at the time. They identify all the risks for bias and describe the quality of the evidence (ie. very poor, poor, moderate, high) to give a good idea of how the data should be evaluated. Read more in the Cochrane Handbook.

A recent large RCT (1300+ women) found no increase in pregnancy rates or miscarriage with the endometrial scratch (Lensen et al 2019) – you can read more about this study here.

Related posts:

9 thoughts on “Complete guide to embryo implantation and implantation failure”

Thank you for this very detailed post. I’ve been learning about implantation and everything ivf-related and have learned a lot from your site. The information is much more in-depth and scientific
without being overly so, and very well-organized. So many other sites just have very basic information, and it is essentially regurgitations of what I’ve already read. Your posts are very original and do fill a niche! I’ve really enjoyed your content and just wanted to share my feedback!

I am a 44 year old female who froze her eggs at 37-38. I have one day 7 blastocyst embryo that has a grade of 4 BB. Sent for genetic testing and initially came back quality insufficient. My doc said the blastocyst seemed dark and disorganized after thawing for re-biopsy. He gave me a 1% chance of having a chromosomally normal embryo. The embryo came back chromosomally normal 46 chromosomes XY. Now he wants me to do ERA test. I have never been pregnant. Anything else that could help implantation? Is ERA worth it? What are my chances of healthy live birth?

So much useful information!
Thank you for sharing with us!
And for providing not only the possible factors for failed implantation but some treatments as well!
Thanks.

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