DOI: 10.1111/tog.

12256 2016;18:91–7
The Obstetrician & Gynaecologist
Review
http://onlinetog.org

Natural killer cells and reproductive health

a b,
Hsu Phern Chong MRCOG PhD, Siobhan M Quenby PhD FRCOG *
a
NIHR Clinical Lecturer and Specialist Registrar in Obstetrics and Gynaecology, Division of Reproductive Medicine, Warwick Medical School,
Clinical Sciences Research Laboratories, Clifford Bridge Road, Coventry CV2 2DX, UK
b
Professor of Obstetrics and Honorary Consultant Obstetrician, Division of Reproductive Medicine, Warwick Medical School, Clinical Sciences
Research Laboratories, Clifford Bridge Road, Coventry CV2 2DX, UK
*Correspondence: Siobhan M Quenby. Email: s.quenby@warwick.ac.uk

Accepted on 22 July 2015

Key content  Counsel women with recurrent pregnancy loss about natural killer
 Uterine and peripheral natural killer cells have distinct functions. cell testing.
 Uterine natural killer cells play an important role in
Ethical issues
decidualisation and implantation. 
 There is evidence to suggest that disorders in uterine natural killer
Investigation and treatment of women with recurrent miscarriage
or recurrent implantation failure is complex. The psychological
cell physiology may lead to reproductive problems, such as
implications of these conditions may result in a myriad of
recurrent miscarriage, recurrent implantation failure and
investigations and treatments of questionable benefit.
pre-eclampsia.
 Current evidence does not support routine testing of uterine Keywords: natural killer cells / recurrent implantation failure /
natural killer cells and more research is needed. recurrent miscarriage
Learning objectives
 Distinguish between peripheral and uterine natural killer cells.

Please cite this paper as: Chong HP, Quenby SM. Natural killer cells and reproductive health. The Obstetrician & Gynaecologist 2016;18:91–7. DOI: 10.1111/
tog.12256

by virtue of their expression of the CD56 and CD16 cell

Introduction
surface antigens (Figure 1). The majority of pNK cells exhibit
A number of maternal physiological adaptations are required CD16 but have fewer CD56 surface antigens; thus they are
to facilitate continuing fetal development and survival. typically described as CD56dim/CD16+. CD16 is responsible
Advances in the field of immunology have furthered our for cell lysis.1 The primary function of pNK cells is to
understanding of these adaptations. For example, expression recognise foreign antigens that are potentially detrimental to
of human leucocyte antigens (HLAs) differs in the placenta the host organism. Recognition of foreign antigens initiates a
and fetus.1,2 This is a highly logical adaptation since the cascade of events that result in the eventual destruction
placenta is the first foreign tissue that comes into contact and/or removal of the foreign antigen.
with the decidua. Additionally, specific alterations in the Vertebrates distinguish native and foreign proteins
behaviour and repertoire of T-lymphocytes contribute to through the expression of a group of cell surface molecules
tolerance of the fetus.3 The purpose of this review is to called HLAs, which are encoded by major histocompatibility
describe the evolution of knowledge concerning a unique complex (MHC) genes.4 Digestion of intracellular proteins
subset of immune cells, uterine natural killer (uNK) cells, in generated by the invading organism results in peptides or
physiological and pathological reproductive states. For the amino acids that bind to specific portions of HLA.4 This type
purposes of this review, we will describe natural killer cells of antigen presentation sensitises natural killer cells and killer
found in the peripheral circulation as peripheral natural killer T-lymphocytes resulting in the activation of cellular (i.e. non-
cells (pNK), and those found in the endometrium as uNK. antibody-related) immunity and, consequently, apoptosis
and cytolysis of the presenting cell. Thus, these molecules
play a critical role in transplantation genetics and are
Origins of uterine natural killer cells
sometimes referred to as ‘transplantation antigens’.
Central to host defence mechanisms, natural killer cells play a HLA-A, HLA-B and HLA-C are responsible for triggering
vital role in the innate immune response. They are subtyped this response and are often referred to as ‘classical’ MHC

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 Natural killer cells and reproductive health

epithelial endometrial cells for implantation.17 Furthermore,

progesterone can also bind directly to the GR on uNK cells.15
Thus, differential regulation of uNK cells in the endometrium
exists and contrasts with that of pNK cells, which remains
unchanged in the proliferative and secretory phases of the
menstrual cycle.
The interest in natural killer cells in pregnancy loss was
borne out of the hypothesis that rejection of the fetus occurs
at the feto-maternal interface, leading to miscarriage or
recurrent implantation failure.18 If natural killer cells have
cytotoxic and cytolytic activity then it was proposed that this
would have an adverse effect on the fetus.
Figure 1. Hallmarks of uterine natural killer (uNK) cells. uNK cells
express CD56 cell surface markers and killer cell immunoglobulin-like
receptors (KIRs). Progesterone acts genomically on the intracellular Physiological response during the
glucocorticoid receptor (GR) as well as the progesterone receptor (P4) menstrual cycle
on surrounding stromal tissue to induce decidualisation. KIRs interact
with extravillous cytotrophoblast human leucocyte antigens. In humans, the endometrium undergoes a transformation
during the secretory phase to become the decidua, which is
capable of sustaining pregnancy. The human endometrium is
molecules.2 They are expressed on all nucleated cells with the unique in being able to undergo spontaneous decidualisation.
exception of extravillous cytotrophoblasts. Natural killer cells Under the influence of progesterone, endometrial stromal
express killer cell immunoglobulin (Ig)-like receptors (KIRs) cells proliferate and secrete cytokines and angiogenic factors
on their cell surface, which recognise and bind to the classical essential for decidualisation (Figure 2). Angiogenic factors
HLAs.2 Non-classical MHC molecules such as HLA-E, HLA- such as vascular endothelial growth factor-A (VEGF-A),
F and HLA-G present extracellular proteins that have been placental growth factor (PlGF) and angiopoietin-1 (Ang-1)
internalised into the cells.5 Both classical and non-classical induce proliferation, maturation and stabilisation of the
HLAs are inherited in a Mendelian fashion, with the entire
haplotype (i.e. combinations of classical and non-classical
HLAs) being inherited from each parent.6
uNK cells were first recognised as a unique cell type
present in abundance during the mid-secretory phase of
women with normal menses, and in the decidua of
terminated pregnancies.7 The cells were described as large
endometrial lymphocytes and were found to express the
CD56bright cell surface antigen.8 They were eventually named
uterine natural killer cells, based on a similar method used to
identify pNK cells.9 In the context of reproductive
physiology, the term ‘uterine natural killer cell’ is a
misnomer; their cytolytic activity is in fact much reduced
because of a lack of CD16.7,10 Instead, uNK cells release a
wide range of cytokines and angiogenic factors that are now
understood to play a critical role in decidualisation,
implantation and recognition of the embryo.11,12
Additionally, binding of HLA-G by the KIR2DL4 receptor
triggers release of pro-inflammatory and pro-angiogenic
cytokines.13 Interestingly, unlike their peripheral Figure 2. Decidualisation in the human endometrium. The human
counterparts, uNK cells lack the progesterone receptor endometrium undergoes spontaneous transformation to one capable
(PR).14 Instead, the actions of progesterone on uNK cells of sustaining a pregnancy (decidualisation). These changes are
are mediated via the glucocorticoid receptor (GR).15 mediated by progesterone. Secretion of angiogenic factors induces
spiral artery remodelling and migration and proliferation of uterine
Progesterone enhances the expression and activity of natural killer (uNK) cells (blue circles) in the endometrial stroma (yellow
11BHSD type 1 in decidualising human endometrial cells). The exact source of uNKs is unknown. Ang-1 = Angiopoietin 1,
stromal cells, thus increasing the conversion of cortisone to IL-15 = interleukin-15, PlGF = placental growth factor, VEGF = vascular
cortisol.16 Cortisol has a direct effect on the preparation of endothelial growth factor.

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 Chong and Quenby

spiral arteries.19 Interleukin-15 (IL-15) messenger RNA of nitric oxide, a potent vasodilator and inhibitor of smooth
(mRNA) activity and protein expression are upregulated in muscle proliferation. Thus, the preferential exchange of
endometrial stromal cells.19 IL-15 binds to IL-15 receptors on nutrients and oxygen in favour of the embryo is facilitated.1
uNK cells, which induces proliferation of the uNK cells.19 As This invasion is not detected by maternal immune cells,
a result, uNK cells are the predominant leucocyte and partly because of the lack of classical HLA molecules as
account for at least 30% of the endometrial stroma during mentioned previously. The extravillous trophoblast consists
the late secretory phase of the menstrual cycle,20 where they of cytotrophoblast cells, interstitial and endovascular
can be found surrounding spiral arteries (but not veins)21 trophoblast cells and placental-bed giant cells.25 They are
and glands. Progesterone binding to GR on uNK cells induces unique because they express only certain types of HLAs:
interferon-gamma (IFNG), which further promotes HLA-C, HLA-E and HLA-G (Figure 3). Binding of the
angiogenesis and uNK cell proliferation.1 Whether classical MHC molecule HLA-C to uNK cells occurs via
increased numbers of uNK cells initiate or are the effect of activating or inhibitory KIRs. Binding of the non-classical
decidualisation is unclear. HLA-E to CD94/NKG receptors on uNK cells is thought to
inhibit uNK cytotoxicity and mediate uNK–trophoblast
interactions.13 Binding of HLA-G to KIR2DL4 on uNK
Physiological response in pregnancy
cells blocks the lytic activity of uNK cells and increases
By undergoing decidualisation, the endometrium becomes pro-angiogenic cytokines.24, 26 Thus, uNK cells may be
receptive to the blastocyst.22 Implantation involves a series of regarded as regulators of the depth of syncytiotrophoblast
cellular processes by which the embryo is embedded into the invasion. The reader is directed to an excellent review and
decidua. The outer cell mass layer of the blastocyst makes illustration of placentation across a selection of mammalian
contact with the epithelial cells of the decidua, then attaches species by Moffett and Loke.24
to and invades the endometrial stroma.23 If successful
implantation occurs, differentiation of the outer cell mass
The role of uNK in reproductive disorders
into trophoblastic cells occurs; they subsequently secrete
human chorionic gonadotrophin (hCG), which is detectable Recurrent miscarriage
in maternal serum.24 As the syncytiotrophoblast progressively The Royal College of Obstetricians and Gynaecologists
invades the endometrial stroma, angiogenic factors, such as (RCOG) defines recurrent miscarriage (RM) as having lost
IFNG, that are secreted by uNK cells activate the production three or more consecutive pregnancies before 24 weeks of

Figure 3. Extravillous cytotrophoblast cells and uNK cell interaction. Extravillous cytotrophoblast (EVT) cells express non-classical human leucocyte
antigens (HLAs), which interact with killer cell immunoglobulin-like receptors (KIRs) found on uterine natural killer (uNK) cells. Consequently uNK
cell cytotoxicity is inhibited and angiogenic cytokine production increases. For example, nitric oxide production is mediated via interferon gamma
(black arrow) produced by uNK cells, resulting in vasodilation and inhibition of smooth muscle proliferation. Thus the depth of syncitiotrophoblast
invasion is regulated. B = blastocyst cavity, CT = cytotrophoblast, GR = glucocorticoid receptor, P4 = progesterone receptor.

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 Natural killer cells and reproductive health

gestation.27 The incidence of RM is estimated to be between distinct entities. However, given the role of uNK cells in
1% and 3%, depending on the definition used.28 The causes decidualisation and implantation, it would seem biologically
of RM are varied and can be categorised into maternal and plausible that uNK cells might have a role in RIF.
fetal causes. Maternal causes include pre-existing medical Nevertheless, a systematic review comparing women with
conditions such as anti-phospholipid syndrome, polycystic RIF versus controls did not identify a difference in pNK or
ovarian syndrome, and uterine causes such as malformations uNK cells in the endometrium.31 Again, study heterogeneity
of the uterus and fibroids. Fetal causes include chromosomal prohibited any meaningful meta-analysis of the study
abnormalities that may be congenital or arise de novo. results.31 Thus, testing for pNK or uNK cells in the context
The interest in natural killer cells as a cause of RM of RIF requires further research in the form of an adequately
stemmed from a growing body of evidence demonstrating powered, prospective, blinded observational study.
natural killer cells as a biosensor of foreign antigens. The
emergence of uNK cell testing was the result of evidence Impaired placentation
demonstrating the crucial role of uNK cells in decidualisation The concept of maternal rejection of paternal antigens is not
and implantation. Alterations in the ‘form, fit and function’ new, and in fact this purported ‘incompatibility’ sparked
of uNK cells were proposed as a mechanism to explain trials investigating paternal leucocyte immunisation. There is
miscarriage in women without pre-existing medical causes, as now clear evidence that this treatment does not increase the
well as those for whom a fetal cause could not be found. pregnancy rate.33 However, some studies have now
In a study of the endometria of women with RM versus demonstrated a plausible link between pre-eclampsia, the
controls, Lachapelle et al.29 identified a decrease in the paternal HLA-C molecule and uNK cells. The MHC
abundance of CD56bright/CD16– cells and an increase in the molecules are coded for by hundreds of alleles, which allow
CD56dim/CD16+ (i.e. pro-cytolytic) cell type. Women with innumerable conformational changes in the peptide-binding
RM had higher uNK cell counts than controls.30 Although a portion. These polygenic and polymorphic changes are
systematic review investigating the role of pNK and uNK cells critical for recognition of the myriad foreign peptides that
in RM failed to identify any differences in RM patients versus challenge the host immune system. Recent evidence suggests
controls, a key finding of this review was the lack of that certain combinations of the paternally derived HLA-C
standardisation for uNK cell estimation in the endometrium. molecule may be associated with pre-eclampsia.6,21 The
Studies included in the systematic review measured pNK by absence of activating KIRs on maternal uNK cells and the
virtue of a total proportion of natural killer cell activity, as HLA-C2 allotype in the fetus have been demonstrated to
determined by flow cytometry or a specialised assay. The increase the incidence of pre-eclampsia.6 It was proposed that
normal range varied from one study to another.31 uNK cells the absence of this activating KIR resulted in impaired
were measured using immunohistochemistry or flow trophoblast invasion and spiral artery remodelling; hallmarks
cytometry. Again, the normal range varied from one study of pre-eclampsia.24
to another. Thus, this review was limited by the significant
heterogeneity of included trials and highlighted a lack of
Management of patients
good quality primary studies. In contrast to uNK cells, pNK
cells have no role in decidualisation or implantation, thus Recurrent miscarriage
testing for pNK cells in RM would appear to be of Women with RM are a diverse population. As such,
little benefit. treatment should be tailored to the cause, if found. For the
majority of women with unexplained RM, supportive
Recurrent implantation failure treatment early in pregnancy will result in a successful
Implantation failure is typically diagnosed when there is pregnancy, although the precise mechanism underpinning
evidence that implantation has not taken place. It is nearly this is unclear. There is no evidence to support measurement
impossible to quantify the incidence of this in spontaneous of pNK cells in women with RM.9 Current evidence does not
conceptions; however, it is a diagnosis that is commonly recommend routine measurement of uNK cells in women
made following assisted reproductive techniques (ART). with RM. This is partly because of a lack of good quality
There is a lack of standardisation in the definition of studies describing a consistent technique for measuring uNK
recurrent implantation failure (RIF). The most commonly cells, and a lack of evidence surrounding effective treatments.
used definition is “three or more failed treatment cycles” Quenby et al.34 demonstrated that treatment with
followed by “two or more failed cycles”.32 An impaired prednisolone reduced the uNK cell count in women with
decidualised response prohibiting implantation is a RM. This randomised controlled trial (RCT) randomised
proposed cause.32 women with RM (where RM was defined as having three or
Some researchers have drawn similarities between patients more lost pregnancies) and a uNK cell count greater than 5%
with RIF and RM, although their definitions would indicate to either treatment with prednisolone or a placebo. However,

94 ª 2016 Royal College of Obstetricians and Gynaecologists

 Chong and Quenby

the effects of treatment with prednisolone were not or more recurrent miscarriages.37 Given the role of uNK cells
significant; this could be explained by the sample size. in spiral artery remodelling, treatment aimed at reducing
Further RCTs involving a larger cohort are required to oxidative stress could reduce the risk of pre-eclampsia.
confirm this. That 57% of women with three or more Certainly, in vitro experiments demonstrated a beneficial
consecutive miscarriages involved in the study did not have effect of antioxidants on syncytiotrophoblasts and spiral
an elevated uNK cell count demonstrates the complex nature artery remodelling.38 However, this failed to translate into
of assessing the role of uNK cells in patients with RM.34 clinical benefit as a large RCT investigating treatment with
Kuroda et al.16 demonstrated a difference in glucocorticoid high-dose vitamin C and E did not demonstrate a reduction
signalling in patients with RM, and a higher proportion in pre-eclampsia, and was associated with a reduction in
of uNK cells close to the luminal epithelium. uNK cells birthweight.39 A systematic review of nine trials confirmed
are normally found in surrounding perivascular cells and that high-dose vitamin C and E supplementation did not
glands in the endometrial stroma.20 Thus, it was proposed reduce the risk of pre-eclampsia.40 This is, in part,
that elevated uNK cells in patients with RM might be a unsurprising as supplementation with these antioxidants
reflection of relative glucocorticoid deficiency in the were only begun from the 20th week of pregnancy, well past
endometrial stroma, rather than a cause. Conversely, the period of spiral artery remodelling.
steroid deficiency could be a reflection of impaired Wong et al.41 investigated the correlation between uNK
decidualisation, in which uNK cells may be directly cell count and pre-eclampsia in 71 women with a history of
involved.13 Treatment with corticosteroids aims to correct RM (three or more lost pregnancies) who subsequently had a
this deficiency and therefore distribution of uNK cells in the live birth. There was no significant difference in the incidence
endometrial stroma. of pre-eclampsia between women with a high uNK cell count
(defined as 13.9% of stromal cells staining positive for
CD56).41 Thus, on balance, screening for gestational
Recurrent implantation failure
hypertension in women with a history of unexplained
A 2012 systematic review demonstrated a beneficial effect of recurrent miscarriage alone is unjustified on the basis of an
endometrial injury inflicted either by hysteroscopy (and/or absence of preventative strategies.
curettage) or by pipelle biopsy in the cycle preceding embryo
transfer.35 The meta-analysis of four RCTs demonstrated a
Current controversies and avenues for
higher cumulative pregnancy rate (risk ratio 1.71 [95% CI
further research
1.40–2.09]). The precise mechanism behind an increase in the
cumulative pregnancy rate is unclear, especially when not all A key gap in the current knowledge of uNK cells relates to
women in the treatment group actually underwent curettage their origin. A number of hypotheses have been proposed.21
or biopsy. However, the meta-analysis of a total of 411 As a small cohort of pNK cells are CD56brightCD16–, it was
patients in the treatment groups with 572 controls did not proposed that these pNK cells migrate into the
demonstrate significant statistical heterogeneity, indicating endometrium.42 It has also been suggested that uNK cells
that the results are unlikely to be influenced by differences are the result of cellular differentiation directly from bone
between the trials. Three of the RCTs included women with marrow stem cells. However, it has not been possible to
two or more unsuccessful cycles.35 One of the RCTs included demonstrate the migration of bone marrow stem cells to the
women with one or more unsuccessful cycles.35 The endometrium. In fact, bone marrow stem cells are not known
proinflammatory response caused simply by to leave their site of origin. A more likely explanation is that
instrumentation of the uterus could result in recruitment uNK cells are derived from a cohort of stem cells residing in
of immune regulatory cells,36 either transiently or the endometrium itself.21 However, this is as yet unproven.
permanently. It is also unclear how long this effect is An area of controversy relates to the method by which
expected to last, given the lack of studies comparing uNK cells are measured.31,43 Commonly described methods
endometrium harvested from one menstrual cycle to the include cell counting using formalin-fixed tissue stained for
next, and beyond. We are unaware of studies investigating CD56 cells and fluorescent activated cell-sorting. The reader
the biochemical or clinical pregnancy rates after delaying will note that a key limitation of both these techniques lies
embryo transfer by more than one cycle following with the availability of a specific antibody for uNK cells.
instrumentation of the uterus. Furthermore, the threshold for normality differs, as does the
way in which uNK cell numbers are estimated by cell
counting in histological sections. Efforts are underway to
Pre-eclampsia
ascertain the most consistent method.
A recently published large observational study demonstrated Because of the complex interactions between the blastocyst
an increased risk of pre-eclampsia in women who had three and the epithelial layer of the endometrium, it is also unclear

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 Natural killer cells and reproductive health

if recurrent miscarriage or implantation failure is the result of Childbirth and has served as an Associate Editor for
aberrant uNK cell migration into the endometrium, or Human Reproduction.
signalling from the abnormal embryo. Evidence in favour of
the latter comes from a study of uNK cells using flow Contribution to authorship
cytometry in missed miscarriages.44 The decidua of HPC wrote the manuscript and CPD questions. SMQ edited
karyotypically abnormal pregnancies demonstrated a higher the manuscript and CPD questions for content accuracy.
uNK cell population than in karyotypically normal Both authors read and approved of the final version of
miscarriages.44 However, given that the endometrium in the manuscript.
one cycle is dissimilar to the next, and no two embryos are
identical, testing this hypothesis would be difficult. In this Acknowledgements
respect, the use of animal models may be useful.45 Dr Hsu Phern Chong is currently funded by an NIHR
Whilst uterine instrumentation appears to improve Clinical Lectureship.
cumulative pregnancy rates, it is unclear if this procedure
results in regulation of the uNK cell population. To our Supporting Information
knowledge, no studies have investigated this directly, since
embryo transfer is undertaken in the cycle immediately after Single Best Answer questions are available for this article at
uterine instrumentation. In this respect, research on the https://stratog.rcog.org.uk/tutorial/tog-online-sba-resource
impact of uterine instrumentation or ‘endometrial scratch
therapy’ on the uNK cell population would be useful. If References
endometrial trauma increases the cumulative pregnancy rate,
then hypothetically, primary endometrial scratch could be 1 Warning JC, McCracken SA, Morris JM. A balancing act: mechanisms by
which the fetus avoids rejection by the maternal immune system.
beneficial for all patients about to embark on ART and Reproduction. 2011;141:715–24.
embryo transfer and not just those experiencing RIF. The 2 Guleria I, Sayegh MH. Maternal acceptance of the fetus: true human
benefits of a successful first cycle cannot be emphasised, given tolerance. J Immunol 2007;178:3345–51.
3 Saito S, Nakashima A, Shima T, Ito M. Th1/Th2/Th17 and regulatory T-cell
the psychological, emotional and financial cost of assisted paradigm in pregnancy. Am J Reprod Immunol 2010;63:601–10.
reproduction.46 Furthermore, where the first cycle is offered 4 Barrett KE, Barman SM, Boitano S, Brooks HL. Ganong’s review of medical
on the National Health Service (NHS), this could represent a physiology, 23rd edition. United States of America: The McGraw Hill
Companies; 2009. p. 726.
significant cost saving to the NHS. However, further research 5 Allen RL. Non-classical immunology. Genome Biol 2001;2:reports4004.
is needed since the procedure can cause discomfort and is not 6 Moffett A, Hiby SE. How does the maternal immune system contribute to
risk free. the development of pre-eclampsia? Placenta 2007;28 Suppl A:S51–6.
7 King A, Wellings V, Gardner L, Loke YW. Immunocytochemical
characterization of the unusual large granular lymphocytes in human
endometrium throughout the menstrual cycle. Hum Immunol
Conclusion 1989;24:195–205.
8 King A, Balendran N, Wooding P, Carter NP, Loke YW. CD3- leukocytes
Advances in molecular biology techniques have furthered our present in the human uterus during early placentation: phenotypic and
knowledge and understanding of uNK cells in the context of morphologic characterization of the CD56++ population. Dev Immunol
reproductive physiology and pathology. The causes of RM 1991;1:169–90.
9 Moffett A, Regan L, Braude P. Natural killer cells, miscarriage, and infertility.
and RIF comprise a spectrum of disorders in which uNK cells BMJ 2004;329:1283–5.
may be partly involved. Future research in the field will 10 Mandelboim O, Malik P, Davis DM, Jo CH, Boyson JE, Strominger JL. Human
benefit women with a history of recurrent miscarriage or CD16 as a lysis receptor mediating direct natural killer cell cytotoxicity. Proc
Natl Acad Sci U S A 1999;96:5640–4.
recurrent implantation failure. Until such a time, uNK cell 11 Manaster I, Mandelboim O. The unique properties of uterine NK cells. Am J
testing should remain within the remit of research trials. Reprod Immunol 2010;63:434–44.
12 Kalkunte S, Chichester CO, Gotsch F, Sentman CL, Romero R, Sharma S.
Evolution of non-cytotoxic uterine natural killer cells. Am J Reprod Immunol
Disclosure of interests 2008;59:425–32.
Professor Quenby is an advisor on several international and 13 King A. Uterine leukocytes and decidualization. Hum Reprod Update
national committees: the European Society for Human 2000;6:28–36.
14 King A, Gardner L, Loke YW. Evaluation of oestrogen and progesterone
Reproduction and Endocrinology Early Pregnancy Special receptor expression in uterine mucosal lymphocytes. Hum Reprod
Interest Group, the Medicines and Healthcare Products 1996;11:1079–82.
Regulatory Agency (MHRA) Expert Advisory Panel for 15 Guo W, Li P, Zhao G, Fan H, Hu Y, Hou Y. Glucocorticoid receptor mediates
the effect of progesterone on uterine natural killer cells. Am J Reprod
Women’s Health, the Scientific Advisory Committee of the Immunol 2012;67:463–73.
Royal College of Obstetricians and Gynaecologists (RCOG), 16 Kuroda K, Venkatakrishnan R, James S,
Sucurovic S, Mulac-Jericevic B,
the RCOG Preterm Labour Clinical Study Group, and the Lucas ES, et al. Elevated periimplantation uterine natural killer cell density
in human endometrium Is associated with impaired corticosteroid
RCOG Early Pregnancy Clinical Study Group. She is signaling in decidualizing stromal cells. J Clin Endocrinol Metab
currently an Associate Editor for BMC Pregnancy and 2013;98:4429–37.

96 ª 2016 Royal College of Obstetricians and Gynaecologists

 Chong and Quenby

17 Michael AE, Papageorghiou AT. Potential significance of physiological and 33 Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage.
pharmacological glucocorticoids in early pregnancy. Hum Reprod Update Cochrane Database Syst Rev 2006;(2):CD000112.
2008;14:497–517. 34 Quenby S, Kalumbi C, Bates M, Farquharson R, Vince G. Prednisolone
18 Aoki K, Kajiura S, Matsumoto Y, Ogasawara M, Okada S, Yagami Y, et al. reduces preconceptual endometrial natural killer cells in women with
Preconceptional natural-killer-cell activity as a predictor of miscarriage. recurrent miscarriage. Fertil Steril 2005;84:980–4.
Lancet 1995;345:1340–2. 35 Potdar N, Gelbaya T, Nardo LG. Endometrial injury to overcome recurrent
19 Plaisier M. Decidualisation and angiogenesis. Best Pract Res Clin Obstet embryo implantation failure: a systematic review and meta-analysis. Reprod
Gynaecol 2011;25:259–71. Biomed Online 2012;25:561–71.
20 Bulmer JN, Morrison L, Longfellow M, Ritson A, Pace D. Granulated 36 Gnainsky Y, Granot I, Aldo PB, Barash A, Or Y, Schechtman E, et al.
lymphocytes in human endometrium: histochemical and Local injury of the endometrium induces an inflammatory response
immunohistochemical studies. Hum Reprod 1991;6:791–8. that promotes successful implantation. Fertil Steril 2010;94:
21 Zhang J, Chen Z, Smith GN, Croy BA. Natural killer cell-triggered vascular 2030–6.
transformation: maternal care before birth? Cell Mol Immunol 2011; 37 Gunnarsdottir J, Stephansson O, Cnattingius S,  Akerud H, Wikstr€ om A-K.
8:1–11. Risk of placental dysfunction disorders after prior miscarriages: a
22 Weimar CHE, Kavelaars A, Brosens JJ, Gellersen B, de Vreeden-Elbertse JMT, population-based study. Am J Obstet Gynecol 2014;211:34.e1–8.
Heijnen CJ, et al. Endometrial stromal cells of women with recurrent 38 Poston L, Raijmakers MTM. Trophoblast oxidative stress, antioxidants and
miscarriage fail to discriminate between high- and low-quality human pregnancy outcome – a review. Placenta 2004;25 Suppl A:S72–8.
embryos. PLoS ONE 2012;7:e41424. 39 Poston L, Briley AL, Seed PT, Kelly FJ, Shennan AH. Vitamin C and vitamin E
23 Wang H, Dey SK. Roadmap to embryo implantation: clues from mouse in pregnant women at risk for pre-eclampsia (VIP trial): randomised
models. Nat Rev Genet 2006;7:185–99. placebo-controlled trial. Lancet 2006;367:1145–54.
24 Moffett A, Loke C. Immunology of placentation in eutherian mammals. Nat 40 Conde-Agudelo A, Romero R, Kusanovic JP, Hassan SS. Supplementation
Rev Immunol 2006;6:584–94. with vitamins C and E during pregnancy for the prevention of preeclampsia
25 Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immunol and other adverse maternal and perinatal outcomes: a systematic review
2002;2:656–63. and metaanalysis. American Journal of Obstetrics and Gynecology.
26 Rouas-Freiss N, Goncalves RM, Menier C, Dausset J, Carosella ED. Direct 2011;204:503.e1-12.
evidence to support the role of HLA-G in protecting the fetus from 41 Wong AWY, Archer B, Mariee N, Li TC, Laird SM. Do uterine natural killer
maternal uterine natural killer cytolysis. Proc Natl Acad Sci U S A cell numbers in peri-implantation endometrium predict hypertensive
1997;94:11520–5. disorder in pregnancy in women with a history of reproductive failure? J
27 Regan L, Backos M, Rai R. Green-top guideline No. 17. The investigation Reprod Immunol 2014;106:34–40.
and treatment of couples with recurrent first-trimester and second trimester 42 van den Heuvel MJ, Xie X, Tayade C, Peralta C, Fang Y, Leonard S, et al. A
miscarriage. London, England: RCOG Press; 2011. review of trafficking and activation of uterine natural killer cells. Am J
28 Larsen EC, Christiansen OB, Kolte AM, Macklon N. New insights into Reprod Immunol 2005;54:322–31.
mechanisms behind miscarriage. BMC Med 2013;11:154. 43 Polanski LT, Barbosa MAP, Martins WP, Baumgarten MN, Campbell B,
29 Lachapelle MH, Miron P, Hemmings R, Roy DC. Endometrial T, B, and NK Brosens J, et al. Interventions to improve reproductive outcomes in
cells in patients with recurrent spontaneous abortion. Altered profile and women with elevated natural killer cells undergoing assisted
pregnancy outcome. J Immunol 1996;156:4027–34. reproduction techniques: a systematic review of literature. Hum Reprod
30 Quenby S, Bates M, Doig T, Brewster J, Lewis-Jones DI, Johnson PM, et al. 2014;29:65–75.
Pre-implantation endometrial leukocytes in women with recurrent 44 Yamamoto T, Takahashi Y, Kase N, Mori H. Role of decidual natural killer
miscarriage. Human Reprod 1999;14:2386–91. (NK) cells in patients with missed abortion: differences between cases with
31 Tang AW, Alfirevic Z, Quenby S. Natural killer cells and pregnancy outcomes normal and abnormal chromosome. Clin Exp Immunol 1999;116:449–52.
in women with recurrent miscarriage and infertility: a systematic review. 45 Oh MJ, Croy BA. A map of relationships between uterine natural killer cells
Hum Reprod 2011;26:1971–80. and progesterone receptor expressing cells during mouse pregnancy.
32 Polanski LT, Baumgarten MN, Quenby S, Brosens J, Campbell BK, Raine- Placenta 2008;29:317–23.
Fenning NJ. What exactly do we mean by ‘recurrent implantation 46 Verhaak CM, Smeenk JMJ, Evers AWM, Kremer JAM, Kraaimaat FW, Braat
failure’? A systematic review and opinion Reprod Biomed Online DDM. Women’s emotional adjustment to IVF: a systematic review of 25
2014;28:409–23. years of research. Hum Reprod Update 2007;13:27–36.

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