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CLINICAL OBSTETRICS AND GYNECOLOGY
Volume 59, Number 3, 509–523
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
Immunologic
Abnormalities,
Treatments, and
Recurrent Pregnancy
Loss: What Is Real and
What Is Not?
NATHALIE F. WANG, MD,* ASTRID M. KOLTE, MD,*
ELISABETH C. LARSEN, MD, PhD,*
HENRIETTE S. NIELSEN, MD, DMSc,*
and OLE B. CHRISTIANSEN, MD, DMScw
*Recurrent Pregnancy Loss Clinic, Rigshospitalet, Copenhagen
University Hospital, Copenhagen, Denmark; and w Department of
Obstetrics and Gynecology, Aalborg University Hospital and Clinical
Institute, Aalborg University, Aalborg, Denmark
Abstract: Recurrent pregnancy loss, depending on the
definition, affects 1% to 3% of women aiming to
have a child. Little is known about the direct causes
of recurrent pregnancy loss, and the condition is
considered to have a multifactorial and complex
pathogenesis. The aim of this review was to summarize
the evaluation and the management of the condition
with specific emphasis on immunologic biomarkers
identified as risk factors as well as current immunologictreatmentoptions.Thereviewalsohighlightsand
discusses areas in need of further research.
Key words: autoantibodies, antiphospholipid antibodies, NK cells, HLA, miscarriage, recurrent pregnancy
loss
Correspondence: Ole B. Christiansen, MD, DMSc,
Recurrent Pregnancy Loss Clinic, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100
Copenhagen, Denmark. E-mail: olbc@rn.dk
The authors declare that they have no disclosures.
CLINICAL OBSTETRICS AND GYNECOLOGY
/
Introduction
Recurrent pregnancy loss (RPL) is traditionally defined as 3 or more consecutive
pregnancy losses before gestational week
20,1 althoughitis sometimes defined as only
2 consecutive losses. Depending on the
definition used, it affects 1% to 3% of all
couples aiming to have a child. Approximately half of the pregnancy losses are due
to embryonal aneuploidy, often occurring
as a random event, but with increased
incidence with advanced maternal age.2
In the vast majority of the cases, no
documented cause of miscarriage can be
found although a series of endocrine,
thrombophilic, and immunologic risk factorsforpregnancyloss have beenidentified.
VOLUME 59
/
NUMBER 3
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SEPTEMBER 2016
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510
Wang et al
In this review, we will not use the term
‘‘causes’’ of pregnancy loss as the only
documented cause of pregnancy loss is
lethal embryonal malformations often
caused by chromosomal abnormality. Biomarkers significantly associated with
pregnancy loss or RPL will instead be
entitled ‘‘risk factors’’ reflecting our conviction that RPL in most instances is a
multifactorial condition, which occurs
only if a woman (or couple) has several
risk factors.3
In this article, we will provide an overview of the scientific evidence for immune
aberrationsinvolvedinthepathogenesisof
RPL. We will discuss about which biomarkers related to immune function are
candidates for further research or can
already be used in clinical practice. Furthermore, we will review the current status
of immunologic treatments used for patients with RPL. Proposed mechanisms of
action and documentation of efficacy will
be highlighted.
Diagnostic Tests
Research on immunologic biomarkers
associated with RPL has focused on measurements of autoantibodies, natural killer
(NK) cells in the blood or the uterus,
cytokines in the blood or the decidual
tissue, and investigations of classic and
nonclassic human leukocyte antigen
(HLA) polymorphisms in patients or couples with RPL. An assessment of the
clinical value of these tests is provided
in Table 1.
AUTOANTIBODIES
It has previously been shown that women
with various autoimmune diseases have an
increased risk of pregnancy loss, especially
in early and late gestation.3 In systemic
lupus erythematosus (SLE), this increased
risk is associated with the presence of
antiphospholipid antibodies (APLs) such
as lupus anticoagulant (LAC) and anticardiolipin antibodies (ACA). APLs are
also associated with an increased risk of
venous and arterial thrombosis. APLs are
often found in RPL patients without
clinical signs of SLE and are associated
with an increased thrombosis risk and a
highriskoffurtherpregnancylosses.4 Only
high titers of ACA, especially IgG, seem to
be important. APLs are often classified as
acquired thrombophilia factors due to the
increased thrombosis risk. In this review,
APLs will be considered primarily as a sign
of breakage of the immunologic autotoleranceofthewoman.Thisisemphasizedby
the observation of numerous other autoantibodies in many women with APLs.
Clinical hyperthyroidism or hypothyroidism is strongly associated with the
presence of thyroid autoantibodies. Thyroid autoantibodies are found in 5% to
15% of women of reproductive age, but in
the majority of these cases, they are not
associated with thyroid dysfunction. The
most prevalent thyroid autoantibody is
thyroid peroxidase antibody. A considerable number of studies have found
an increased prevalence of thyroid autoantibodies in RPL patients and a metaanalysis of relevant case-control studies
found that the antibodies are associated
with RPL with an odds ratio (OR) of 2.3
(95% CI, 1.5-3.5).5
Antinuclear antibodies (ANA) can be
detected in a series of autoimmune diseases
including SLE. In a review from 1996,6 10
out of 12 case-control studies found
an increased prevalence of ANA in
RPL patients. In the 4 relevant studies
published subsequently, 2 found a significantly increased prevalence of ANA in
RPL patients compared with controls.7,8
However, in most studies, a positive ANA
does no predict the pregnancy outcome.
It remains to be elucidated whether
the association between APLs, antithyroid
antibodies, and ANA and RPL reflects a
directly harmful impact of the autoantibodies on placental development and vascularization and embryonic development
orwhethertheirpresenceisratheramarker
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Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
Immunology and Recurrent Pregnancy Loss
TABLE 1.
511
Biomarkers With Putative Diagnostic Value in RPL
Associated
With RPL
Biomarker
Autoantibodies
Antiphospholipid
+++
antibodies
Thyroid antibodies
+++
Antinuclear antibodies + +
Soluble immune biomarkers
Peripheral blood
+
cytokines
Mannose-binding lectin + +
Immune cells
Peripheral blood NK-cell +
subsets
Peripheral blood NK
+
cytotoxicity
Endometrial NK cells
?
Prognostic
Value
Needed Research
++
+
?
Standardization of assays and cut-off values
Prognostic studies in untreated patients
Prognostic studies in untreated patients
Prognostic studies in untreated patients
?
More sensitive and reliable methods
+
More studies
?
Establishment of reference values in different phases
of the menstrual cycle or pregnancy
Establishment of reference values in different phases
of the menstrual cycle or pregnancy
Establishment of reference values in different phases
of the menstrual cycle
Standardization of methods
Suitable control samples (aneuploid missed
miscarriages?)
Establishment of reference values in different phases
of the menstrual cycle
Standardization of methods
?
?
Decidual NK cells
?
–
Peripheral blood Treg
cells
?
?
+
+
More studies
?
?
HLA class II
++
+
HLA-C, HLA-G
+
?
Studies using up-to-date techniques
Clear definition of criteria for allele sharing
Larger studies
Studies homogenous with regard to reproductive
history and ethnicity
Larger studies
Studies homogenous with regard to reproductive
history and ethnicity
Genetic biomarkers
Mannose-binding lectin
gene polymorphism
HLA sharing
HLA indicates human leukocyte antigen; NK, natural killer; RPL, recurrent pregnancy loss; ?, undetermined.
of an increased predisposition to breakage
of immunologic autotolerance. A direct
pathophysiological link between the presenceofautoantibodiesinRPLpatientsand
fetal death has not yet been documented
convincingly. The production of autoantibodies may be a result of RPL in
geneticallypredisposedwomensinceintrauterine retention of necrotic tissue in case
of a missed miscarriage may expose hidden
(cryptic) autoantigens on fetal or trophoblast cells to the mother’s immune system.
A known genetic predisposing factor is
the HLA-DRB1*03 allele, which is associated both with the production of ACA,
antithyroid antibodies, and ANA and
with the risk of RPL.9,10
Screening for LAC, ACA should be
undertaken in RPL patients primarily
because there may be treatments
available for these patients although
there is some controversy. Screening for
thyroid peroxidase antibodies, ANA, and
anti-ds-DNA should be undertaken in
RPL patients primarily because the presence of the antibodies impacts the prognosis negatively. It is also a sign of
breakage of general autotolerance pointing toward an immunologic background
for pregnancy losses.
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512
Wang et al
CYTOKINES
Cytokines are signal molecules secreted
from immune cells (especially T lymphocytes), which bind to receptors on other
cells, resulting in the stimulation or the
inhibition of function. Cytokines are often
categorized as either T-helper (Th) type 1
cytokines, which promote T-lymphocyte
cytotoxicity and inflammation, and Th
type 2 cytokines, which promote antibody
production and decrease inflammation.
Typical Th1 cytokines are tumor necrosis
factor (TNF)-a, interferon (IFN)-g, and
interleukin (IL)-2, whereas IL-4 and IL-10
are characteristic Th2 cytokines. An imbalance in Th1/Th2 cytokines has been
associated with adverse pregnancy outcomes including RPL.11
Research into the role of cytokines in
RPL is complicated by several factors: (1)
levels and functions of cytokines change
from day to day during implantation and
early pregnancy; (2) blood lymphocyte
cytokine secretion or cytokine concentrations in the blood may be completely
different from that in the uterus; and (3)
the measurement of cytokines in endometrial biopsies or washings or in decidual
tissue is subject to technical and methodological difficulties.
TNF-a is a potent proinflammatory
cytokine and may be a good marker for
systemic inflammation. High plasma
TNF-a levels are reported to increase the
risk of miscarriage in RPL patients,12 and
high TNF-a and TNF-a/IL-10 ratios characterize women with euploid compared
with aneuploid miscarriage.13 Also, lymphocytes from RPL patients who later go
on to miscarry produce more TNF-a than
those of women who have live births.14
Finally, patients with RPL after a birth
(secondary RPL patients) have significantly higher plasma levels of TNF-a in
earlypregnancythanpatientswithnoprior
live birth (primary RPL patients).15 These
observations suggest that a high systemic
inflammatory state in early pregnancy
increases the risk of miscarriage and that
secondary RPL is particularly associated
with a proinflammatory state.
Plasma levels or the in vitro production
of many cytokines are partly determined
by polymorphisms in the genes encoding
the cytokines and their promoters. Therefore, if abnormal cytokine profiles play a
role in RPL, it may be reflected in the
cytokine gene polymorphisms carried by
the women. However, a review concluded
that no cytokine gene polymorphism is
convincingly associated with RPL.16 The
measurement of cytokines in plasma or
endometrial biopsies is in our view useful
only in the context of research, and still has
no place in clinical practice.
MANNOSE-BINDING LECTIN (MBL)
MBL is a plasma protein produced in the
liver. Plasma levels exhibit large interindividualvariationsthataremainlygenetically
determined. MBL is a part of the so-called
lectin-dependent pathway of complement
activation. Furthermore, by enhancing
phagocytosis, MBL can aid in clearing
apoptotic cells, debris, and immune
complexes that would otherwise prompt
inflammatory processes. The result of
MBL deficiency in pregnancy may therefore be enhanced proinflammatory processes at the fetomaternal interface and is thus
expected to increase the risk of miscarriage. Indeed, MBL deficiency was found to
be associated with RPL in previous casecontrol studies17,18 and was also associated
with a significantly poorer prognosis.18
Plasma levels of MBL are determined
by polymorphisms in several loci of the
MBL2 gene. Genetic polymorphisms associated with low (<100 ng/L) MBL levels
have been reported with increased frequency in RPL patients and in particular
in those experiencing unexplained late
fetal death.19 The measurement of MBL
levels or the related genetic polymorphism
is still uncommon in the RPL setting, but
we believe that there is sufficient evidence
to consider it in the screening program as
low levels are associated with a poor
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Immunology and Recurrent Pregnancy Loss
prognosis,18 and it is often a relief for the
patientstobeinformedthattheyhavearisk
factor for which they cannot be blamed.
NK CELLS
In the search for immunologic aberrations
in RPL patients, there has been much focus
on NK cells. NK cells are a part of the
innate immune system, and in contrast
to T lymphocytes, they can recognize and
react against cells infected by intracellular microorganisms or cells undergoing malignant transformation without
prior sensitization against target antigens.
This reaction can result in the killing of the
cells (cytotoxicity) or in the secretion of
specific cytokines. There has been considerable interest in NK cells in RPL due to 3
observations: (1) the composition of NK
cells in the endometrium and the decidual
tissue is unique: >90% of the lymphocytes
in the luteal-phase endometrium and early
pregnancydecidualtissuearelow-cytotoxicity, high-cytokine-producing NK cells
carrying a high density of the CD56
surface marker (CD56bright),20 whereas in
the peripheral blood, almost all NK cells
carry the CD16 surface marker, which is
associated with high cytotoxicity and low
cytokine production; (2) the major HLA
molecules expressed on trophoblast subsets, HLA-G and HLA-C, can act as
ligands for the 3 kinds of activating or
inhibitory receptors found on NK cells in
the uterus21,22; and (3) studies on NK-celldeficient and T-cell-deficient transgenic
mice with a high fetal loss rate show that
therestorationofNKcellsbybonemarrow
transplantation results in a normal fetal
loss rate.23
Investigations of NK cells in RPL can be
divided into flow-cytometric analyses or
tests of NK cell cytotoxicity of peripheral
blood lymphocytes before or during pregnancy and studies of NK cells in prepregnancy endometrial biopsies or in decidual
tissues from missed miscarriages and elective abortions.
513
Because of the easy availability, studies
on the peripheral blood are dominant. The
majority of the larger studies found that
the percentage of CD56+ cells in the
peripheral blood taken before pregnancy
is significantly higher in RPL women than
in controls.24–27 Other studies did not
confirm this observation.28,29 A flaw in
many of the studies is that most of the
women with RPL women were nulliparous
and most controls were multiparous.30 A
previous successful pregnancy can induce
permanent changes in lymphocyte subsets
including NK cells.31
Most of the studies on prepregnancy
blood samples26,32–34 found significantly
increased NK-cell cytotoxicity in RPL
patientscomparedwithcontrols.Onelarge
study, however, did not find such a
difference.35
Aoki et al36 reported that RPL patients
with high peripheral blood NK-cell cytotoxicity before pregnancy had a significantly higher rate of miscarriage in the
next pregnancy compared with those with
lower NK-cell cytotoxicity (71% vs. 20%).
Subsequent smaller studies found higher
or similar NK-cell cytotoxicity in patients
with a subsequent euploid miscarriage
compared with those with a live birth.
Importantly, in a recent large prospective
study, high NK-cell cytotoxicity before
pregnancy had no impact on subsequent
miscarriage rates after adjustment for
recognized risk factors for miscarriage.37
It has been questioned whether endometrial NK-cell subsets reflect those in the
peripheral blood. This is due to the fact that
frequencies of NK-cell subsets in the endometrium and the peripheral blood are
extremely different. A series of studies investigated NK cells in endometrial biopsies
taken in nonpregnant cycles by immunohistochemistry or flow cytometry of homogenized tissue. The former technique is prone to
subjective evaluation and the latter is flawed
because the tissue undergoes enzymatic
digestion, which influences marker expression.Furthermore,endometriallymphocyte
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514
Wang et al
numbers fluctuate hugely in the the menstrual cycle, and therefore the exact timing
of biopsies is extremely crucial,38 but this
has rarely been reported. Lachapelle et al39
found that the CD56bright NK-cell subset
was significantly lower in RPL patients
than in control, whereas other studies40–42
found that the frequency of CD56+ (or
unspecified NK cells) cells was significantly
higher in RPL than in controls. In 2 studies,43,44 no difference was found in NK-cell
subsets in the endometrium between RPL
patients and controls. Importantly, no relationship between the CD56+ NK-cell
count in the endometrium and the subsequent pregnancy outcome was found in a
study by Tuckerman et al.42
Some studies compared NK-cell subsets
in the decidual tissue from missed miscarriages of RPL patients with normal women
having an elective termination and reported differences in the NK-cell composition between the 2 groups.45,46 As the
tissue in the former case is often necrotic
and inflamed and the tissue in the latter is
fresh and vital, these studies provide limited valid information.
Because peripheral blood NK-cell subsets do not reflect conditions in the uterus
and the largest studies found no prognostic
significance of NK-cell cytotoxicity, the
benefitofmeasuringperipheralbloodNKcell parameters in clinical practice is
limited and it cannot be used to select
RPL patientsfor immunologictreatments.
The measurement of uterine NK cells,
although in theory a better approach, is
also unfit for clinical practice due to
methodological problems.
T-REGULATORY (TREG) CELLS
The fetoplacental unit is often entitled the
fetoplacental allograft because it is similar
to the transplantation of an organ from an
allogeneic donor. In case of a transplantation, the allograft can avoid rejection only
by intensive immunosuppressive therapy.
A priori, it must be presumed that the
maternal immune system would make
efforts to reject the fetoplacental unit that
carries paternal alloantigens. One of the
mechanisms thought to be important for
establishing immunologic tolerance to alloantigens and autoantigens and the fetoplacental allograft is Treg lymphocytes.
After being activated by tolerogenic
antigen-presenting cells (APCs), Tregs
can suppress the formation and the
effector function of T-cell-mediated
immune responses that could otherwise
induce alloimmunity and autoimmunity
and rejection of pregnancy tissues.
Studies on T-cell-deficient transgenic
mice strains demonstrate that lymphocytes with the Treg phenotype CD4+ ,
CD25+ , Foxp3+ are important for implantation and successful pregnancy in
allogeneic crossings.47 In an elegant study,
the elimination of CD4+ , CD25+ cells
induced fetal resorption in allogeneic, but
not in syngeneic, mated mice.48 The role
Tregs play in human pregnancy and especially in RPL is still not clarified as relevant
studies are small and sparse. Kwiatek
etal49 recentlyreportedthatthepercentage
of Tregs in the peripheral blood at the time
of miscarriage is significantly lower in
women with RPL than in women with
normalpregnanciesatthesamegestational
age. In women without RPL, those who
miscarried had significantly lower frequencies of CD4+ , CD25+ cells in the
peripheral blood and decidual tissue than
those with normal pregnancies.50
A hypothesis that integrates data from
animal and human research regarding the
role of Tregs in normal and adverse
pregnancy is intriguing.51 Increasing plasma estrogen levels in the follicular phase
cause the Treg pool in the blood or regional
lymph nodes to expand. It also causes
increased uterine expression of chemokines, resulting in the recruitment of
T cells to the uterus. Male antigens and
cytokines in the seminal fluid in the vagina
recruit tolerogenic APCs to the uterus and
regional lymph nodes. Here, the APCs
activate local Tregs that suppress harmful
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Immunology and Recurrent Pregnancy Loss
T-cell immunity toward alloantigens on
the embryo and trophoblast. The hypothesis is attractive because it introduces
adaptive cellular immunity to the pathogenesis of adverse pregnancy outcomes
such as RPL. In contrast to NK-cellmediated immunity, an important feature
of adaptive immunity is immunologic
memory, which is stored in memory T
cells. Clinical observations such as the
traditionally claimed rarer occurrence of
preeclampsia in a second pregnancy with
the same husband or the negative prognostic impact of a first-born boy in women
with secondary RPL52 can potentially be
explained by mechanisms where tolerance
or harmful immunity has developed in the
first ongoing pregnancy and is remembered by memory T cells.
The measurement of Tregs in adverse
pregnancies in humans is still in its infancy,
and should for the time being be undertaken only in the context of research.
Although there is significant potential in
measuring Tregs, there is a severe obstacle
for truly evaluating their impact on the
pregnancy outcome. Subsets of most importance are probably (as in mice) located
in regional lymph nodes draining the
uterus, which are difficult to access in
humans.
IMMUNOGENETIC BIOMARKERS
All proteins directly participating in immune interactions or expressed on immune
cells are coded by genes that are often
polymorphic. This may occur as singlenucleotide polymorphisms or as small
additions or deletions of chromosomes
that may include several genes, termed
copy-number variations (CNVs). Such
polymorphisms may give rise to decreased
orincreasedproteinproduction,whichcan
lead to alterations in immune interactions
that can sometimes lead to disease.
Using genome-wide screening, gene alterations that affect gene function can be
assigned to specific immunologic or metabolic pathways. In a recent study, CNVs
515
that rearrange genes in pathways of ‘‘innate immune signaling,’’ ‘‘complement
cascade,’’ or ‘‘interaction of Fc g receptors
with antigen-bound IgG’’ were found
more often in RPL patients than in fertile
controls.53 The result was highly significant. This suggests that genetic disruption
of the immune function may be important
in the pathogenesis of RPL.
Genome-wide screening studies are important for research purposes, but their
value is still limited when assessing the
backgroundforRPLinindividualcouples.
The investigation of specific genetic polymorphisms of importance for immune
function with a documented impact on
the risk of RPL or new pregnancy loss
after RPL could theoretically be useful.
However, do such genetic polymorphisms
exist?
In a previous section, we discussed the
association between genetic polymorphisms in the MBL2 gene associated with
MBL deficiency and RPL. This association has been documented in several independent studies. We believe that
investigation of MBL genetics will be
potentially helpful, especially in cases with
second-trimester RPL or extreme preterm
birth.19,54
Numerous studies have investigated
HLAs and RPL. The HLA region comprises several genetic loci located on chromosome 6 and it contains the most
polymorphic genes known in humans.
Depending on the genetic distance
between the various HLA loci, the alleles
of the genes in each locus display a stronger
or weaker linkage disequilibrium. This
means that alleles in different loci are
inherited together more or less often than
expected by chance. This is an important
concept when studies of HLA polymorphisms in RPL and other disorders are
evaluated.
HLA molecules play an important role
in the adaptive and the innate immune
system. In the adaptive immune system,
CD8+ T lymphocytes can exert cytotoxic
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516
Wang et al
reactions against cells carrying class I
HLA molecules, especially HLA-A and
HLA-B, both of which play an important
role in transplantation immunology. Class
II HLA molecules (HLA-DR and HLADQ) carried primarily on APCs present
antigenic peptides on Th (CD4+) lymphocytes, which can initiate both humeral
and cellular immune reactions. An individual’s 2 sets of class II HLA alleles
determine the repertoire of antigens that
he/she can be immunized against easily.
Class II alleles are therefore (sometimes
strongly) associated with most autoimmune diseases as these diseases are caused
by adverse reactions against self-antigens.
NK cells, which belong to the innate
immune system, react against all cells not
carrying HLA molecules. They can also
react against or interact with cells carrying
specific HLA molecules; NK receptors can
be inhibited or activated by HLA-C and
HLA-G ligands.
Because of the different ways in which
HLA can influence immune reactions,
studies of HLA in RPL can be divided
into 3 main categories: studies of HLA
allele incompatibility (sharing) between
partners with RPL; studies of HLA allele
prevalence in women with RPL; and
studies of HLA-C and HLA-G alleles in
couples with RPL. All 3 kinds of studies
have been evaluated in a recent metaanalysis.55
Increased HLA compatibility between
spouses was originally thought to decrease
the probability of the mother adequately
reacting immunologically to the fetus and
producing so-called blocking antibodies.
The meta-analysis55 reported that allele
sharing in the HLA-B, HLA-DR, and
HLA-DQ loci was more frequent in RPL
than in control couples. However, the
results should be interpreted with caution
due to the obsolete serological techniques
used for HLA determination in most of
these older studies.
Studies of HLA allele frequencies in
RPL patients and controls have focused on
alleles in HLA class II loci: HLA-DRB1 or
HLA-DQB1. A meta-analysis of relevant
case-controlstudies,allusingmodernPCR
techniques, found that HLA-DRB1*04
and HLA-DRB1*15 alleles were significantly increased in RPL patients. HLADRB1*03 also tended to be found more
often in patients than in controls.55 However, we are convinced that HLADRB1*03 may be the strongest HLA class
II RPL susceptibility allele in whites. In a
large case-control study,10 which was only
partly included in the meta-analysis, we
found that this allele was highly significantly increased in RPL patients. Furthermore, the prevalence increased with an
increased number of previous miscarriages. A reason why the HLA-DRB1*03
allele was not significantly increased in
RPL patients in the meta-analysis55 might
be that 4 of the included studies were in
Japanese women. In Japan, the HLADRB1*03 allele is very rare. Studies of
associations between HLA polymorphisms and disease susceptibility should
always be restricted to specific ethnic
groups.
Studies assessing the impact of maternal
carriage of specific HLA class II alleles on
future pregnancy outcomes provide information that can be useful in counseling
regarding the prognosis. Among patients
with RPL after a birth (secondary RPL),
the birth of a boy before the miscarriages is
significantly more prevalent than the
birth of a girl (61% vs. 39%). Patients with
a first-born boy also prospectively exhibit
a significantly lower chance of a second
live birth.52 Among RPL patients with
a first-born boy, maternal carriage of
one of the alleles, HLA-DRB1*15, HLADQB1*0501/2, and HLA-DRB3*0301,
reduces the chance of a live birth by 22%
compared with patients not carrying these
alleles.56 These alleles (HY-restricting
class II HLA alleles) are known to present
peptides derived from male-specific proteins (HY antigens) to Th cells. In transplantation immunology, carriage of the
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Immunology and Recurrent Pregnancy Loss
alleles predisposesonetograft-versus-host
disease after sex-mismatched bone-marrow transplantation. On the basis of these
data56 and supported by the study of antiHY antibodies in RPL patients,57 our
hypothesis is that Th lymphocytes from
women carrying HY-restricting class II
HLAalleles mayrecognizeHYantigenson
the fetoplacental unit in their first ongoing
pregnancy with a boy. This initiates a series
of harmful immune reactions targeting the
fetoplacental unit in the subsequent pregnancies, ultimately leading to RPL. More
research confirming this mechanism of
RPL is still needed.
In the section about NK cells, we discussed the relationship between specific
KIR receptor polymorphisms, HLA, and
RPL. HLA-C alleles can be divided into C1
and C2 groups according to a genetic
dimorphism of the segment of the HLAC molecule that can bind KIRs. C1 allotypes are ligands that inhibit KIR2DL2/3
and activate KIR2DS2, whereas C2 allotypes are ligands for the inhibitory
KIR2DL1 and activating KIR2DS1. Hiby
et al58 reported that the combination of a
woman carrying the KIR genes that
are primarily inhibitory and a man carrying C2 allotypes is more frequent among
RPL than among control couples. It was
suggested that this combination of mainly
inactivating KIR genes in a woman and
their ligands in the parents results in
decidual NK-cell inhibition. This may lead
to insufficient secretion of specific cytokines at the fetomaternal interface, resulting in defective trophoblast proliferation
and invasion and subsequent RPL. In
contrast, another large study found that
maternal carriage of the inhibitory
KIR2DL1 in combination with C2 homozygosity in both partners was found significantly more often in controls than in
RPL women, whereas maternal carriage of
the activating KIR2DS2 in conjunction
with C1 homozygosity in partners was
found significantly more often in RPL
patients.59 Thus, the 2 studies yielded
517
completely opposite results regarding the
role of maternal KIR genes and parental
HLA-C allotypes. In several studies, no
association between parental C2 allotypes
and RPL was detected.55,60
Another set of studies have investigated
HLA-G polymorphisms inRPL.HLA-Gis
a nonclassic HLA gene, which exhibits
much less polymorphism than classic
HLA genes. It is highly expressed in extravillous trophoblast cells in contrast to all
other HLA genes. It can also be detected in
plasma in the form of soluble HLA-G. In
RPL research, there has been considerable
interest in a 14-base-pair-long insertion/
deletion dimorphism in exon 8 of the HLAG gene, which may affect the transcription
of the gene. There seems to be an association between low levels of soluble HLA-G
in the plasma and homozygosity for the
HLA-G14 bp insertion.61 Soluble HLA-G
can modulate NK-cell function in vitro.62
Two recent meta-analyses found that
the HLA-G14 base-pair insertion frequency
was significantly increased in RPL with
ORs 1.27 (1.04-1.55) and 1.47 (1.13-1.91),
respectively.63,64 As the HLA-G14 basepair insertion is in strong positive linkage
disequilibrium with the HLA-DRB1*03
allele,65 it remains unclear as to whether
the HLA-G gene insertion or HLA-DRB
*03 is the main RPL susceptibility gene.
More research into the role of classic
and nonclassic HLA genes in RPL should
be carried out. As the association between
the pregnancy outcome and HLA polymorphisms in women is weak and results of KIR/
HLA investigations are indecisive, HLA
determination in couples with RPL still has
no place in clinical practice. An exception
may be women with RPL after a first-born
boy, where HLA class II investigations
may be useful when counseling patients.
Immunologic Treatments
As reviewed in previous sections, there is
considerable evidence that immune aberrations play a role in the pathogenesis of
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518
Wang et al
RPL. As a consequence, it is logical to test
various immunologic treatment options in
these patients.
In this article, we focus on treatments
directly targeting immune factors or interactions such as allogeneic lymphocyte
immunization (ALT), intravenous immunoglobulin (IvIg), prednisone, and growth
factors. In contrast, we will not evaluate
heparin, aspirin, and progesterone, which
are also used in RPL treatment and may
have immunomodulatory properties.
These treatments are reviewed elsewhere
in this symposium.
Immunomodulatory treatments have
been tested in RPL patients selected (1)
due to RPL and positive tests for 1 or more
immunologic biomarkers suggested to
identify patients with a specific immune
etiology and (2) RPL, but negative testing
for immunologic and thrombophilia biomarkers (referred to as idiopathic RPL).
It is important to note that the chance of
live birth without any treatment is at least
55%after3and46%after4miscarriages.66
Accordingly, success rates for treatments
should be substantially above these percentages to prove efficient. Furthermore,
TABLE 2.
it cannot be ruled out that any intervention
will improve the pregnancy success rate
due to a placebo effect. Therefore, only
prospective studies with random allocation
to treatment against placebo (optimal) or
no treatment or treatment as usual (less
optimal) are informative, and only such
studies will be reviewed here (Table 2).
Several treatment studies have been
performed in RPL patients selected due
to positivity for autoantibodies or high
NK-cell numbers, but only 2 were randomized, including a placebo-treated group.
Laskin et al67 carried out a large placebo-controlledRCTofprednisone andlowdose aspirin in women with RPL and
positivity for ACA, LAC, ANA, antiDNA, or antilymphocyte antibodies. This
is a subset of patients with serological signs
of breakage of immune tolerance, and
they may, in theory, benefit the most from
immunomodulation therapy. A 9% higher
live birth rate was found in the treatment
group, but this was not significantly different from that of controls. The treated
patients had a significantly higher risk of
preterm birth (62% vs. 12%) and a higher
risk of diabetes and hypertension. The
Immunologic Treatments Tested in RPL
Treatment
EffectonLiveBirth Rate Adverse Effects
Suggested Research
Prednisone
Nonsignificant
increase
Allogeneic lymphocyte
therapy
Nonsignificant
increase
Large studies administering
moderate doses of
prednisone
Better studies with attention
toward methodology and
adverse effects. Must
include long-term followup
Intravenous
immunoglobulin
G-CSF
Preterm birth, diabetes,
and hypertension
Neonatal alloimmune
thrombocytopenia
Production of red blood
cell antibodies
Transfer of infectious
agents
Hematological
malignancies?
Borderline significant Headache and skin rash
increase in
secondary RPL
Significant increase
Flu-like symptoms
Leukocytemia
More studies especially in
secondary RPL
More studies
G-CSF indicates granulocyte colony-stimulating factor; RPL, recurrent pregnancy loss.
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Immunology and Recurrent Pregnancy Loss
authors therefore concluded that prednisone should not be given to RPL patients. It
is worth remembering that very high doses
of prednisone (40 to 50 mg/d) were used for
the duration of the pregnancy, which explains the high rate of preterm birth. In an
RCT of RPL patients selected due to
endometrial NK-cell density Z5%, Tang
et al68 found a 20% higher live birth rate
in patients allocated to 8 weeks of prednisone in early pregnancy compared with
placebo. This was, however, not significant
due to small numbers. Although prednisone did not increase the live birth rate
significantly, the 2 RCTs point toward a
potential beneficial effect. A new study
administering lower doses of prednisone
to RPL patients before pregnancy and in
the first trimester (optimally selected due
to the presence of biomarkers suggesting
immune activation) should be carried out.
A larger number of RCTs have been
conducted in RPL patients with idiopathic RPL. Two immunomodulatory
treatments, ALT and IvIg, have been
tested in a sufficient number of RCTs to
allow the performance of systematic reviews and meta-analyses. The theory for
using ALT was that RPL patients lack
antipaternal antibodies or blocking antibodies that protect the fetus against rejection. Therefore, ALT and the subsequent
production of these antibodies could be
beneficial.69 The updated Cochrane systematicreviewontheefficacyofALTfound
the OR for live birth in ALT-treated
patients to be 1.23 in RCTs using
paternal lymphocytes and 1.39 in RCTs
using third-party lymphocytes compared
with placebo.70 Combining results from all
ALT trials irrespective of the source of
the lymphocytes, the OR for live birth
after ALT was 1.34 (95% CI, 0.83-2.15).71
Many of the included RCTs do not meet
the current criteria for methodological
quality, the impact of antipaternal antibodies is unclear,72 and, last but not
least, treatment with allogeneic cells raises
serious safety concerns. There is a
519
substantial risk of neonatal alloimmune
thrombocytopenia and production of red
blood cell antibodies,73 some risks of transferring infectious agents, and in theory
an increased long-term risk of hematological malignancies. Therefore, we cannot
recommend that ALT should be used in
clinical practice. If further RCTs on ALT
are carried out, they should be conducted
using strict methodological rigor, precautions to diminish risks of adverse alloimmunization, and they should include
long-termfollow-up of mothers and babies.
IvIg is known to reduce symptoms in
many autoimmune and inflammatory diseases. IvIg has been tested in 11 RCTs
involving idiopathic RPL patients; 9 of
them comparing IvIg with placebo and 2
RCTs comparing IvIg with other treatments. The most recent systematic review
and meta-analysis of IvIg in RPL74 included all relevant RCTs and found in all
included patients an RR of 0.92 (95% CI,
0.75-1.12) for no live birth after IvIg. In
patients with secondary RPL, a subset that
in previous RCTs seemed to benefit the
most from IvIg,75 the RR for no live birth
after IvIg was 0.77 (0.58-1.02; P = 0.06),
which can be translated into a borderline
significant benefit of IvIg in secondary
RPL. IvIg is not labeled for use in RPL and
must still be considered investigational for
the purpose.
Adverse events such as headache and
skin rash were more frequent in IvIgtreated patients compared with placebotreated patients. There was no difference in
the incidence of severe adverse events. A
trial sequential analysis in the review concluded that even with meta-analyses, studies are underpowered. More RCTs are
needed to make definitive conclusions
about the efficacy of IvIg in RPL. Given
the expense and the potential for adverse
events, IVIG cannot be recommended for
clinical use in women with RPL.
Growth factors such as granulocytemacrophage colony-stimulating factor
and granulocyte colony-stimulating factor
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520
Wang et al
(G-CSF) may promote trophoblast
growth and improve the pregnancy outcome. One small RCT tested the efficacy of
G-CSF injections before pregnancy and in
early pregnancy in patients with 4 or more
miscarriages, with a pregnancy loss despite
IvIg treatment.76 There was a significantly
increased live birth rate in the G-CSFtreated patients compared with placebo.
OthersimilarRCTsareneededtoassessthe
efficacy of this treatment before implementation in clinical practice.
Conclusions
Overall, there are 3 main arguments for
immunologicdisturbancesplayingarolein
RPL: (1) the general knowledge that whenever allogeneic tissue is introduced into an
organism, immune reactions develop, and
if not abolished, rejection will occur; (2) the
observation that a series of autoimmune
diseasesandautoantibodiesarefoundwith
increased prevalence in RPL; and (3) the
observation that women with RPL have an
increased risk of atherosclerotic cardiovascular diseases probably attributable to
a chronic proinflammatory state.77,78
In our view, not one but several disturbances or disruptions of pathways relatingtoimmuneinteractionscontributeto
many cases of RPL.3 The reproductive
process is too importantto be vulnerableto
the disruption of only 1 immunologic
pathway. We think that disturbances in
severalimmunepathways(causedbySNPs
or CNVs) in conjunction with immunizing
events in previous pregnancies, such as a
substantial transfer of fetal antigens (cells)
into the maternal circulation, can promote
proinflammatory reactions or breakage of
autotolerance. This will predispose one to
RPL and other adverse pregnancy outcomes and ultimately lead to atherosclerotic or autoimmune disease.77,78
The complexity of the pathogenesis of
RPL is a challenge for future research in the
area. It is further complicated by the fact that
almosthalfofallmiscarriagesinRPLwomen
are due to embryonal aneuploidy. We find it
importantthatresearchersacknowledgethis
complexity when carrying out future research on immunologic and nonimmunologic risk factors of RPL. It may also help if
the management of RPL is centralized in a
few dedicated clinics to improve patient care
and possibilities for research.
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