Recurrent Miscarriage (RM) is defined as three or more consecutivespontaneous abortions1. It affects 1% of child-bearing population2. Aetiologies include parental chromosomal abnormalities,uterine anomalies, antiphospholipid syndrome, endometrial infections, endocrine( luteal phase defect, thyroid dysfunction, uncontrolled diabetes mellitus ), inherited thrombophilias and alloimmune causes3,4,5 but only first three are universally accepted3,5. A cause can be identified in 50% of patients6; but, unknown in the remainder3. Natural killer (NK) cells ‘Immunological cause’ for unexplained RM has been proposed.
PBNK-Cells constitute 10% of lymphocytes. Their prototypic cell surface antigens are CD16 and CD56. CD16 receptor is responsible for NK-mediated antibody-dependent cellular cytotoxicity.CD56 is expressed on essentially all NK cells7.Based on intensity of CD56 expression, majority (90%) of PBNK cells are CD56dim and express high levels of CD16 and 10% are CD56bright and express low levels or no CD168. CD56dim cells are more cytotoxic, whereas the CD56bright subset is the main source of NK-cell derive immunoregulatory cytokines8.
NK-cellActivating Receptors include CD16 and killer-Inhibitory-Receptor (KIR) 2DS9. Interaction with IgG for CD16 and human leukocyte antigen (HLA)-C for KIR2DS transduce activating signals through transmembrane proteins10.
NK-cells Inhibitory Receptors interact with major histocompatibility complex (MHC)-I-bearingtargets and deliver inhibitory signals to NK-cells. Such receptors have been recently identified and consist of KIRs, which recognize mainly HLA-A, HLA-B, and HLA-C expressed on any host cell and CD94/NKG2 receptor, which recognizes the non-classical MHC-molecule HLA-E11.
During normal human pregnancyPBNK-cells particularly CD16+ subset decreasein number12,13 and lytic activity with increase of inhibitory receptors reaching a maximum in third month of gestation, with decline to basal levels by end of pregnancy14.
The changes are result of Progesterone direct action on PBNK-cells and/or through promoting Th2 cytokine and Progesterone-Induced-Binding-Factor production by T-cells15. It also facilitates PBNK-cell homing to endometrium, via inducing homing-receptors on PBNK-cells and addressins-receptors on endometrium. Regulation may occur throughdirect actions of oestrogen on ER-β in PBNK-cells or progesterone via an as yet unidentified receptor. Hormonal regulation abnormalities may underlie the changes occurring in the NK-cell populationin RM.
NK-cells have characteristic ability to lysetarget cells without prior sensitization and without restriction by HLA-antigens. The four functions are antiviral;anti-neoplastic, hematopoiesis regulation and graft-vs.-leukemia effect16. PBNK-cells express few cytokines; however when induced express granulocyte-macrophage-colony-stimulating-factor(GM-CSF), macrophage-CSF(M-CSF),IL-3, IFN-γ, TNF-α, and TNF-ß17,18,19. TNF-α induces apoptosisand IFN-γ induces additional immune response16. NK-cell function is mainly regulated by IL-2 and IFN-γ.IL-2 causes both NK-cell proliferation and enhanced cytotoxicity.IFN-γ augments NK cytolytic activity. Both cytokines act synergistically to augment NK cytotoxicity 16.
Leukocytes account for 10% of stromal cells in proliferative phase, 20% in secretory phase, and 30%in early pregnancy-decidua20.Uterine-NK-cells (large granulated lymphocytes)comprise over 70% of endometrial leukocytes in first-trimester-decidua20,25.
uNK-cells resemble PBNK-cells as they express CD56 as well as the killer activatory and inhibitoryreceptors but lack expression of other typical NK markers suchas CD16 or CD5721. In contrast to PBNK-cells, uNk-cells express CD69, an early activation marker 22,23. uNK are KIR+, CD69+, CD62L–,whereas CD56bright PBNK-cells are KIR–, CD69–,and CD62L+24. uNK-cells during pregnancy decrease expression of activation markers CD69, HLA-DR, leukocyte-function-associatedantigen-1 and CD45RA26 and express one or more inhibitory receptors in early pregnancy27.
Given the high levels of CD56 expression in uNK, it has been suggested that they derive from CD56bright PBNK-cells.
Data on uNK-cells numbers in second trimester are conflicting20. uNK-cells numbers decrease at term28.
uNK-cells originate from bone marrow, may enter endometrium via peripheral circulation ‘direct trafficking’23 or self-renew in-situ as 40% are proliferative20 with up-regulation genes 29 or uNK-cell precursors may be recruited from the spleen30.
Studies suggest that uNK-cells are hormonally regulated15. Progesterone was suggested as uNK-cells numbers increase in mid-luteal phase. uNK-cells do not express progesterone receptors but do express prolactin receptor31, oestrogen receptor-β and glucocorticoid receptors32. uNK-cells may be regulated by direct action of oestrogen on its receptor or progesterone via an as yet undiscovered receptor. Alternatively, uNK-cells could be regulated by an indirect mechanism whereby progesterone acts on endometrial T-cells and stromal cells, affecting Vascular-Endothelial-Growth-Factor and Macrophage-Inhibitory-Protein-1β to enhance recruitment of uNK-cells to the uterus, as well as acting through prolactin, via interleukin-15, to increase proliferation and differentiation of uNK-cells15 and production of cytokines and other molecules that support placental and trophoblast development and promote local immunomodulation15.
Perivascular location of uNK-cells may reflect trafficking from peripheral circulation33,34,35 or a role in decidualization of stroma20 or remodelling of the spiral arteries28 or promoting angiogenesis34,35. uNK-cells express GFs that are critical in angiogenesis, including VEGF29, PlaGF, angiopoeitin2 and NKT533. Activated uNK-cells secrete IFN-γ involved in development of spiral arteries36.
HLA-G expression is unique to invading cytotrophoblast. uNK-cells express receptors for HLA-G37. uNK-cells position in early pregnancy and their ability to express KIRs for HLA-G suggests that uNK-cells are involved in the regulation of trophoblast invasion and maternal-trophoblast signalling during early pregnancy. However, HLA-C is the dominant ligand for uNK-cell KIRs and recent evidence suggests that combinations of maternal KIRs on uNK-cells combined with specific polymorphisms for fetal HLA-C may be unfavourable to trophoblast cell invasion38.
In contrast to CD56+ CD16+ NK-cells, CD56+ CD16- NK-cells are potent secretors of cytokines but have low cytolytic ability and cytokine production is therefore another function of these cells.The precise function of CD56+ cells in the endometrium and decidua remains speculative.
In normal pregnancy cell-mediated Th1-immunity towardtrophoblast cells is suppressed. RM is associated with Th1 immunity, for which NK-cells are partly responsible39. Th1-immunity against trophoblast is inhibited by addition of progesterone to in-vitro PBMC/trophoblast co-cultures40. Preconceptional PBNK-cellactivity is increased in women with unexplained RM compared with controls41. PBNK-cell numbersdo not correlate with levels of NK-cell cytotoxicity42. PBNK-cell numbers and activity can fluctuatewith exercise and time ofday43,44. Increase in PBNK-cellnumbers and/or activity in luteal or early pregnancy of women with RM41,45 is of concern but additional studies are needed to confirm these findings.
CD69, an early activation marker, was significantly higher on PBNK-cells in women with RM or infertility of uncertain etiology compared with controls46. This Phenotype difference was significant across all subsets of NK cells studied (CD56dim, CD56bright,CD16neg). Compared with controls, women with RM did show significant decrease inexpression of KIR CD94/NKG2. Phenotypic changes are apparent in PBNK-cells in women with RM, which may account for their increasedactivity46.
It is assumed PBNK-cells and uNK-cells are similar. It is speculated that women with RM and infertility have abnormalities in uNK-cell function. It has been implied that these are discernible from analysis of PBNK-cells45,46,50.
The role of PBNK-cells in implantation failure has been questioned51,52. Firstly, utNK-cells are different from PBNK-cells as discussed earlier and examination of PBNK-cells will not tell us what is happening in the uterus. Secondly >12% NK cells in women with infertility or miscarriage has been arbitrarily defined as abnormally raised and used as an indication for treatment47even though percentage of CD56+ PBNK-cells in normal healthy individuals varies from 5%- 29%48 and affected by sex, ethnicity, stress, and age. Thirdly, PBNK-cells activity is measured by a range of assays and the results will vary in different laboratories. The most commonly used in-vitro assay is cytotoxicity, which may not have much relevance to PBNK-cells function in-vivo49. Certainly, in viral infection, PBNK-cells function mainly by producing cytokines. Furthermore, uNK-cells have much lower cytolytic activity than PBNK-cells. Thus, no clinically relevant information is gained from studying either the percentage or cytotoxicity of PBNK-cells in women with pregnancy failure.
Women with RM have an endometrial factor contributing to the pregnancy losses53.
There is likely no difference in the percentageof total uNK-cells in women with RMcompared with women without RM54,55. Using flow-cytometry CD16–CD56bright NK-cells were decreased and CD16+CD56dim NK-cells were increased in luteal-endometrium from women who had RM54 which may have important functional implications in women with RM. Immuno-histochemistry detected increased numbers of CD56+cells in midluteal-endometrium in RM compared with fertile controls56,57,58. Increased uNK-cells in women withRM were predictive of and associated with miscarriage in subsequent pregnancy57,58.
Previous live birth does not reduces uNK-cells to <5%58. Women with RM, luteal phase defect ‘LPD’ may be involved53, however; increased numbers of uNK-cells in RM were thought to be independent of LPD59. Detailed genetic study found no association between polymorphisms or numbers of KIRs on uNK-cells and RM60.
uNK-cells in RM were thought to be either hostile to invading trophoblast, or facilitating implantation of abnormal blastocysts leading to clinical presentation of RM61. It is doubtful that high numbers of uNk-cells are harmful to the trophoblast as uNk-cells are needed for normal pregnancy to occur, at least in mice62. uNK-cells are more likely to facilitate implantation being more numerous in deciduas from chromosomally abnormal miscarriages / RM than in chromosomally normal miscarriages /RM63,64.
Endometrial CD56+ cells in peri-implantation endometrium did not appear to have any useful prognostic value on the outcome of a subsequent pregnancy65 and questions the usefulness of measurement of uNK-cell numbers into routine clinical practice.
A recent study suggested that increased endometrial uNK-cell density noted in recurrent reproductive failure contributes to increased preimplantation angiogenesis leading to early maternal circulation and miscarriage by final common pathway of excessive oxidative stress66.
In recurrent IVF failure ‘with recurrent implantation failure’ preimplantation endometrium did show higher numbers of uNK-cells67,68, but high numbers of uNK-cells are more likely part of a complex array of immune and vascular abnormalities68.
In spite of the exact mechanism of unexplained RM is lacking; progesterone,heparin, aspirin, hCG, prednisone, Anti-TNF-alpha, leukocyte immunization, and IVIGare advocated69,70,71.
Progesterone treatment ‘early in pregnancy’ has beneficial effectin women with RM72. Women with Th1 immunity to trophoblastcan be treated effectively with progesteronebeginning 3d after ovulation70. Progesterone,can inhibit Th1 cytokine release and reduce embryotoxicity bytrophoblast-activated PBMC cultures from women with RM40. Ovarian stimulation with gonadotropins and progesteronein women with unexplained infertility results in a decrease in Th1 CD4+ cells, NK-cells, and NK-cellactivity73, with decrease inthe levels of plasma IFN-γ and IL-2 and an increase in TGF-ß173; higher numbers of successful pregnancies, however, remains to be determined through RCTs.
Heparin ‘anticoagulant’ suppresses NK-cell cytotoxicity74,75 and antagonizes IFN-γ action by inhibiting its bindingto the cell surface76,77.
It is interesting that Progesterone and Heparin two of the most commonly used the rapiesin RM affect NK-cell function.
Preconceptional prednisolone produced life birth in a woman with 10 miscarriages when given intrauterine78 and in a woman with elevated uNK-cells with 19 consecutive miscarriages 79. Prednisolone from day1-day21 reduces high numbers of uNK-cells in preimplantation endometrium in RM58. Prednisolone for 3 days reduces peripheral NK cell numbers80. A RCT of prednisolone for 4-weeks prior to ET reduced miscarriage rates (18 versus 23%)81.
A retrospective study of prednisolone and aspirin given for 5 weeks prior to IVF and ET found an apparent improvement in pregnancy rates in women with a possible autoimmune aetiology to their subfertility82. Prednisolone given at egg collection or ET did not improve pregnancy rates83,84. While immunomodulation of preimplantation endometrium-decidua opens new avenues for treatment of RM, RCTs are needed before prednisolone is used to treat RM52.
Immunotherapy for RM is controversial85,86,87,88.
Paternal Leukocyte immunizationand IV Immunoglobulins, have been tried as different approaches of immunomodulationto down-regulate the maternal immune response to the embryo.
Antipaternal lymphocytotoxic antibodies were proposed as a cause of RM89, but were found to be more prevalent in fertile couple90,91 with conclusion that antipaternal lymphocytotoxic antibodies have no effect on subsequent pregnancy outcome91,92.
Paternal Leukocyte immunization is based on the beneficial effects that donor or third party leukocytes have on allograft rejection in transplant patients and evidence that it may decrease the number circulating NK-cells in women with recurrent pregnancy loss93. Studies suggested small treatment benefit ‘8-10% improvement in live birth rate’ weighed against costs and risks including injection site reaction, myalgia, platelets and erythrocyte alloimunization94. Large RCT found no evidence that paternal Leukocyte immunization was effective in the treatment of unexplained RM95 and meta-analysis concluded the same87.
Maternal blocking antibody theory of RM presume maternal failure to recognize and respond to fetal antigens ‘mother and father are too anti-genically similar’ by production of blocking antibodies leaving the embryo exposed to a lethal cell-mediated immune rejection96. However HLA sharing does not predict pregnancy outcome and testing has no clinical utility97,98.
IV-Immunoglobulins regarded as immunosuppressive were proposed to treat and are prepared from pooled immunoglobulins. The treatment is costly, require multiple infusions during pregnancy and could transmit viruses and cause anaphylaxis99. IVIG has been tried with apparent success in a small number of women with recurrent implantation failure and a high degree of HLA similarity between the parents100.
Randomised trials of IVIG in treatment of unexplained RM failed to demonstrate improved outcome85,94,87. However, RCTs of this approach are needed to substantiate the efficacy of IVIG.
There is no convincing evidencethat reproductive failure occurs as a result of immune rejection. Contemporary concepts in reproductive immunology now emphasise the cooperative nature of the interaction between thematernal immune system and the feto-placental unit in governing pregnancy outcome101.
Abnormal response auto or alloimmune response has been postulated to underlie some cases of ‘unexplained’ infertility, IVF failure and RM. Despite little evidence, a variety of immune tests and treatments for reproductive failure have been introduced into clinical practice.
Measurement of PBNK-cell numbers or activity as a surrogate marker of events at the maternal–fetal interface is inappropriate. A recent large UK study reported PBNK-cell levels in predicting IVF cycle outcome to be ‘little better than tossing a coin’102.
Several studies linked RM with raised uNK-cell number in a preconception cycle and that these levels may be decreased with prednisolone58. However, an association between uNK cell number and function has not been demonstrated.
Autoantibody screening for lupus anticoagulant and anticardiolipin antibodies, are important treatable cause of recurrent miscarriage103. These two antibodies are increased among those with infertility and implantation failure following IVF-ET. However, a meta-analysis reports no relationship between LA and aCL status and implantation or clinical pregnancy rate among those undergoing IVF104. In IVF antiphosphotidyl ethanolamine and serine may be of more relevance than LA and aCL.
Alloimmune testing is not helpful with arguments against increased sharing of HLA between partners can lead to RM is well established105. Production of blocking antibody occurs after 28 weeks of gestation and successful pregnancies can occur despite failure of production of blocking antibody.
Meta-analyses confirmed aspirin combined with heparin significantly increases live-birth rate among those with antiphospholipid syndrome106; the routine use of peri-implantation glucocorticoids does not increase the live-birth rate among those undergoing IVF107; white cell immunisation does not increase live-birth rate among those with RM105 and IVIG does not improve live birth rate among those with unexplained RM108.
There are no published data that anti-TNF agents infliximab and etanercept use improve IVF outcome. Anti-TNF-alpha agents can cause lymphomas, granulomatous and demyelinating disease.
Glucocorticoids during pregnancy may be associated with gestational diabetes, pre-eclampsia and rupture of membranes with preterm delivery52,109.
With the exception of aPL testing in RM, there is little evidence to support any particular test or immunomodulatory treatment in investigation and treatment of couples with reproductive failure.
We should protect our patients with reproductive failure, who are vulnerable, from the exploitation by those pedalling new tests and treatments that have little scientific validity52.
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