Number and function of uterine natural killer cells in recurrent miscarriage and implantation failure: a systematic review and meta-analysis

Abstract

BACKGROUND Uterine natural killer cells (uNK) are the most abundant lymphocytes found in the decidua during implantation and in first trimester pregnancy. They are important for early placental development, especially trophoblast invasion and transformation of the spiral arteries. However, inappropriate uNK function has been implicated in reproductive failure, such as recurrent miscarriage (RM) or recurrent implantation failure (RIF). Previous studies have mainly focussed on peripheral NK cells (pNK), despite the well-documented differences in pNK and uNK phenotype and function. In recent years, there has been an explosion of studies conducted on uNK, providing a more suitable representation of the immune environment at the maternal–foetal interface. Here, we summarize the evidence from studies published on uNK in women with RM/RIF compared with controls. OBJECTIVE AND RATIONALE The objectives of this systematic review and meta-analysis are to evaluate: differences in uNK level in women with RM/RIF compared with controls; pregnancy outcome in women with RM/RIF stratified by high and normal uNK levels; correlation between uNK and pNK in women with RM/RIF; and differences in uNK activity in women with RM/RIF compared with controls. SEARCH METHODS MEDLINE, EMBASE, Web of Science and Cochrane Trials Registry were searched from inception up to December 2020 and studies were selected in accordance with PRISMA guidelines. Meta-analyses were performed for uNK level, pregnancy outcome and uNK/pNK correlation. Narrative synthesis was conducted for uNK activity. Risk of bias was assessed by ROBINS-I and publication bias by Egger’s test. OUTCOMES Our initial search yielded 4636 articles, of which 60 articles were included in our systematic review. Meta-analysis of CD56+ uNK level in women with RM compared with controls showed significantly higher levels in women with RM in subgroup analysis of endometrial samples (standardized mean difference (SMD) 0.49, CI 0.08, 0.90; P = 0.02; I2 88%; 1100 women). Meta-analysis of CD56+ uNK level in endometrium of women with RIF compared with controls showed significantly higher levels in women with RIF (SMD 0.49, CI 0.01, 0.98; P = 0.046; I2 84%; 604 women). There was no difference in pregnancy outcome in women with RM/RIF stratified by uNK level, and no significant correlation between pNK and uNK levels in women with RM/RIF. There was wide variation in studies conducted on uNK activity, which can be broadly divided into regulation and receptors, uNK cytotoxicity, cytokine secretion and effect of uNK on angiogenesis. These studies were largely equivocal in their results on cytokine secretion, but most studies found lower expression of inhibitory receptors and increased expression of angiogenic factors in women with RM. WIDER IMPLICATIONS The observation of significantly increased uNK level in endometrium of women with RM and RIF may point to an underlying disturbance of the immune milieu culminating in implantation and/or placentation failure. Further research is warranted to elucidate the underlying pathophysiology. The evidence for measuring pNK as an indicator of uNK behaviour is sparse, and of limited clinical use. Measurement of uNK level/activity may be more useful as a diagnostic tool, however, a standardized reference range must be established before this can be of clinical use.

Transcriptomic analysis of mid‐secretory endometrium reveals essential immune factors associated with pregnancy after single euploid blastocyst transfer

“…Meanwhile, a significant increase in Th1 cell abundance supported the theory of a correlation between dominance of the Th1 cytokine profile and reproductive failures 49 . The inappropriate abundance of uNK cells has long been implicated in reproductive failure, 33 except for one study that reported no association between the number of uNK cells and successful implantation 50 . Regarding the relationship between the abundance of uNK cells and reproductive outcomes, both decreased and increased levels of uNK cells in the peri‐implantation endometrium have been reported to contribute to reproductive failures such as RIF when compared to fertile controls 38,51 .…”

“…The hub genes GZMB , FYN , and ITGB2 were involved in the ‘Natural killer cell mediated cytotoxicity’ (Figure 3E), indicating that downregulation of these genes might affect NK cell‐mediated cytotoxicity in the non‐pregnant group. Peripheral NK cell cytotoxicity has been reported to be associated with reproductive failures 33,34 . However, how the dysregulated genes ( GZMB/FYN/ITGB2 ) affect embryo implantation by modulating the cytotoxicity of endometrial NK cells requires further mechanistic studies.…”

Local immune recognition of trophoblast in early human pregnancy: controversies and questions

“…Blood tests to measure NK cell numbers or function do not provide any information about the uNK cells that are distinctive to the uterine mucosa and are probably involved in establishing the physiological maternal–placental boundary. Another test in use does measure numbers of uNK cells in secretory phase endometrium, but this requires invasive biopsies 203 . Because uNK cell numbers normally greatly increase after ovulation, and they are not uniformly distributed in the endometrium, these are not robust assays 204 .…”

The peripheral and decidual immune cell profiles in women with recurrent pregnancy loss

“…A recent systematic review has shown that there was no significant difference between dNK subtypes although subgroup analysis revealed notably higher total CD56 + uterine NK cells in RPL patients compared with HDs using endometrial specimens from the mid-luteal phase only. However, this observation was not successfully replicated by testing decidual tissue in first-trimester pregnancy ( 41 ). These results were in contrast to our study where we observed a decreased abundance of CD56 hi dNK cells in RPL patients, including HLA-DR + CD56 hi and CD11c - CD62L - CD56 hi dNK cells.…”