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PGMJ Online First, published on February 13, 2015 as 10.1136/postgradmedj-2014-132672
1
High Obstetric Risk Unit,
Obstetric Department, Vall
dHebrn University Hospital,
Universitat Autnoma,
Barcelona, Spain
2
Systemic Autoimmune Disease
Unit, Department of Internal
Medicine I, Vall dHebrn
University Hospital, Barcelona,
Spain
3
Department of Medicine,
Faculty of Medicine, Universitat
Autnoma, Barcelona, Spain
Correspondence to
Dr Carmen Garrido-Gimnez,
High Obstetric Risk Unit, Vall
dHebrn University Hospital,
Passeig Vall dHebron
119-129, Barcelona 08035,
Spain; carmengagi@hotmail.
com, cgarrido@vhebron.net
Received 4 March 2014
Revised 12 January 2015
Accepted 25 January 2015
To cite: Garrido-Gimenez C,
Alijotas-Reig J. Postgrad
Med J Published Online
First: [ please include Day
Month Year] doi:10.1136/
postgradmedj-2014-132672
CopyrightC, Article
Garrido-Gimenez author
et al. Postgrad
Med J 2015;0:112.
Review
Recurrent miscarriage: causes, evaluation
and management
Carmen Garrido-Gimenez,1 Jaume Alijotas-Reig2,3
ABSTRACT
Recurrent miscarriage is frustrating for the physician and
a heartbreaking experience for the patient.
Approximately 5% of couples trying to conceive have
two consecutive miscarriages. Despite a thorough study
of patients, the aetiology of this common obstetric
complication is unknown in 50% of cases. Known
causes include abnormal chromosomes, endocrinological
disorders and uterine abnormalities. Although
antiphospholipid antibodies have been demonstrated in
miscarriages, the role played by alloimmune mechanisms
remains unclear. New immunological approaches such as
natural killer cells, regulatory T cells, tumour necrosis
factor , cell-derived microparticles, leptin, certain
glycoproteins and cytokines should be considered. The
management of thyroid diseases and immunological
disorders is continuously evolving. Several genetic
diagnostic procedures such as parental karyotyping and
preimplantation genetic screening should probably not
be used routinely. Antiphopholipid syndrome and some
recurrent miscarriage-related endocrinological disorders
can be effectively treated. Finally, new therapeutic
approaches and the pleiotropic effects of old ones have
led to improved fetalmaternal outcomes.
INTRODUCTION
Recurrent miscarriage is one of the most frustrating
and difcult areas in reproductive medicine, since
the aetiology is often unknown and evidence-based
diagnostic and treatment strategies are scarce.
Recurrent miscarriage is classically dened as the
loss of three or more consecutive pregnancies
before the 20th week of gestation (molar, ectopic
and biochemical pregnancies are not included),
with or without previous live births. However,
many experts consider two consecutive losses suf-
cient for diagnosis, and suggest an assessment after
each loss with a thorough evaluation after three or
more losses.1
The current classication of poor pregnancy out-
comes is shown in gure 1. Recurrent miscarriage
can be considered a primary or secondary process,
depending on whether a live birth has occurred at
some time. No specic term has been coined to
describe women with non-consecutive pregnancy
losses interspersed with normal pregnancies.
Couples suffering recurrent miscarriage mainly
want to know the cause and the risk of further
recurrence. General aetiological categories of recur-
rent miscarriage include genetic, endocrine, ana-
tomical, immunological, thrombophilic and
environmental factors (box 1). When evaluating a
patient, the physician should be aware of the
current classication, determine the nature of previ-
ous pregnancy losses, and collect all possible risk
(or their employer)
2015. Produced
doi:10.1136/postgradmedj-2014-132672 by BMJ Publishing Group Ltd under licence.
factors. However, despite thorough investigation,
no cause can be found in up to 50% of cases.2
Nevertheless, the prognosis for a successful future
pregnancy is generally good: the overall live birth
rates after normal and abnormal diagnostic evalua-
tions for recurrent miscarriage are 77% and 71%,
respectively.3
A wealth of information has accumulated on this
topic. However, this article aims to propose a
correct assessment of couples with recurrent mis-
carriage and summarise the evidence of evaluation
and management rather than provide an update on
current understanding of the topic.
SEARCH STRATEGY AND SELECTION CRITERIA
Data for this review were obtained through a com-
prehensive literature search using the relevant key-
words (miscarriage or recurrent miscarriage,
abortion or recurrent abortion, recurrent fetal
loss, recurrent in-vitro fertilisation failure; alone or
in combination with: idiopathic, spontaneous,
diagnosis, treatment immunology, autoanti-
bodies, antiphospholipid antibodies, aspirin, low
molecular weight heparin, intravenous immuno-
globulin, progesterone parental cell inmunisation,
thrombophilia, treatment) to identify articles pub-
lished in English from Medline, PubMed and The
Cochrane Library (2000January 2014). The initial
search identied more than 5000 articles using the
keywords (some were found in duplicate). We par-
ticularly selected randomised controlled studies or
meta-analyses when possible, followed by prospect-
ive, matched or non-matched casecontrol, cohort
studies and reviews. Short cohort studies, short
reports, brief reports, editorials, opinion papers and
letters to the editor were excluded. Finally, only 271
studies on recurrent miscarriage were considered
adequate and were nally collected and discussed.
Some relevant articles before 2000 focusing on
general concerns about recurrent miscarriage were
also included. Finally, following journal policy, 100
articles were selected for this review using our clinical
and scientic judgement after a hard and accurate
review and discussion between CG-G and JA-R.
AETIOLOGY OF AND RISK FACTORS FOR
RECURRENT MISCARRIAGE
Epidemiological factors
Miscarriage occurs in up to 1520% of apparently
normal couples and becomes recurrent in 23% of
these couples.3 The risk of fetal loss rises steeply
after the age of 35 years,4 from 9.5% at 2024
years to 76% at 45 years and older. In clinical prac-
tice, the chances of a successful pregnancy in
women 40 years are poor, when risks of
1
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Review
Figure 1 Spectrum of poor pregnancy outcomes. PE, pre-eclampsia; pPE, puerperal pre-eclampsia; SGA, small for gestational age; w, weeks.
miscarriage, pre-eclampsia, ectopic pregnancy and stillbirth
increase.5
Reproductive history is known to be an independent pre-
dictor of future pregnancy outcome. Primigravidae and women
with a history of live births have a lower risk of miscarriage in
their next gestation than those whose most recent pregnancy
ended in miscarriage.3 Nevertheless, women with a history of
live births may still miscarry in future gestations; however, the
prognosis for successful pregnancy is better with secondary
recurrent miscarriage. Interestingly, it has been demonstrated
that the risk of further miscarriage increases after each succes-
sive pregnancy loss, reaching 4550% after three consecutive
losses,6 and the prognosis worsens with increasing maternal age.
Fortunately, 90% of women who have had one miscarriage sub-
sequently have a normal pregnancy and a healthy baby; 50
60% are able to have a healthy baby after two miscarriages.
Even a woman who has had three miscarriages in a row still has
an approximately 40% chance of having a successful pregnancy
the fourth time.
Gestational age at the time of pregnancy loss should be con-
sidered, since recurrent miscarriage typically occurs at a similar
gestational age in consecutive pregnancies.7 Most women with
recurrent miscarriage have early losses, a signicant proportion
of which are due to chromosomal aneuploidies, although these
are less common than in sporadic miscarriages.8 Few women
with recurrent miscarriage have late miscarriages, which are
often attributable to other causes and are rarely due to chromo-
somal aberrations. Furthermore, late pregnancy complications,
including fetal growth restriction, preterm labour and pre-
eclampsia, are associated with recurrent miscarriage.9
Genetic abnormalities
Genetic factors are the most common cause of early spontan-
eous miscarriage (5060%). However, it is important to distin-
guish between the genetic abnormalities in parents and the
genetic alterations of the conceptus.
Parental chromosomal rearrangements
In approximately 24% of couples with recurrent miscarriage,
one partnermore often the womanwill have a genetically
balanced structural chromosome rearrangement, the most
common being a balanced translocation (60% reciprocal and
40% Robertsonian, involving two homologous or non-
homologous acrocentric chromosomes).10 Chromosome inver-
sions are also associated with a higher risk of miscarriage,11 and
2 Garrido-Gimenez C, et al. Postgrad Med J 2015;0:112. doi:10.1136/postgradmedj-2014-132672
the risk of miscarriage is inuenced by the size and genetic
content of the rearranged chromosomal segments.
The likelihood of a subsequent live birth in couples with an
abnormal karyotype and recurrent miscarriage is poorer than in
couples with normal chromosomes (66% vs 78%);12 however,
an abnormal karyotype might not be the cause of the recurrent
miscarriage, and parental karyotype is not particularly predictive
of a subsequent pregnancy.13 Recently, many genetic poly-
morphisms14 and genes responsible for impaired cyclic decidua-
lisation of the endometrium,15 apoptosis and inammatory
processes16 have also been found to be associated with recurrent
miscarriage, and this is an active area of investigation.
Furthermore, the sperm of male partners in recurrent miscar-
riage appears to have a higher incidence of DNA damage and
worse motility.17 Although increased numbers of sperm chromo-
some abnormalities have been described in couples with recur-
rent miscarriages, only 7% of fetal trisomies have been shown
to be associated with paternal meiotic errors.18 Interestingly, the
live birth rate in couples with structural chromosome abnormal-
ities who conceive spontaneously is higher (5065%) than that
currently achieved after in vitro fertilisation (IVF) and preim-
plantation genetic screening (2938%) per embryo transfer.19
Abnormal embryonic karyotypes
Fetal aneuploidy is the leading cause of spontaneous miscarriage
in the rst 10 weeks of gestation. At least 50% of all miscarriages
are probably associated with cytogenetic abnormalitiestrisomy,
polyploidy and monosomy X.20 In couples with recurrent mis-
carriage, chromosomal abnormalities of the embryo account for
3057%. Evidence shows that the higher the number of miscar-
riages, the less probable it is that they are related to chromosomal
anomalies, so conceptus chromosomal abnormalities are more
common in sporadic miscarriages than in recurrent miscar-
riage.21 A low proportion of these women have late recurrent
miscarriages, usually before weeks 1516, and chromosomal
aberrations as a cause are rare.
Endocrine abnormalities
Endocrine dysfunction may account for 1520% of all cases of
recurrent miscarriage. Mild endocrine disease is not associated
with recurrent miscarriage; however, poorly controlled diabetes
mellitus and signicant thyroid dysfunction have been associated
with recurrent miscarriage.22
Thyroid autoimmunity is also linked to recurrent miscarriage,
including those that are euthyroid. Interestingly, women with
high levels of anti-thyroid antibodies do not suffer more
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Review

The role of other hormonal abnormalities remains controver-

Box 1 Risk factors for recurrent miscarriage sial. Convincing evidence is lacking that elevated prolactin levels
or a luteal phase defect are associated with recurrent miscar-
riage. However, it has been shown that bromocriptine and
1. Chromosomal and gene disorders
cabergoline may signicantly reduce the rate of miscarriage in
2. Endocrine abnormalities
some women with recurrent miscarriage.28
Diabetes/thyroid dysfunctions
Prolactin disorders
Anatomical factors
Polycystic ovary syndrome
Congenital uterine malformations are detected in approximately
Luteal phase insufciency
1015% of women with recurrent miscarriage. The most
Androgen disorders
common congenital uterine malformation associated with recur-
3. Anatomical factors
rent miscarriage is septate uterus (gure 2) (35%), which is due
Congenital anomalies
to vascular insufciency in the septum.29 The longer the septum,
Uterine broids
the worse the prognosis. Conversely, women with arcuate uterus
Ashermans syndrome
tend to miscarry more often in the second trimester, so the con-
Defective endometrial receptivity
tribution in recurrent miscarriage is controversial.30
4. Immunological disorders
Regarding broids, submucous leiomyomata that deform the
Autoimmune disorders
endometrial cavity can impede normal implantation and cause
Thyroid dysfunctions
recurrent miscarriage.31 However, the relationship between mis-
Coeliac disease
carriage and intramural and subserous myomas remains the
Antiphospholipid antibodies and antiphospholipid
subject of debate.32 33
syndrome
Classically, adenomyosis was not associated with infertility;
Positivity for other autoantibodies
however, recent studies point to an immunological mechanism
Reproductive autoimmune failure syndrome
by which adenomyosis might interfere with successful embryo
Alloimmune factors (maternalfetal tolerance)
implantation and could cause recurrent miscarriage.34 35
Regulatory T cell and natural killer (NK) cell
Whether Ashermans syndrome/intrauterine synechiae, endo-
dysfunctions
metrial polyps and endometriosis contribute to recurrent mis-
proinammatory cytokine network
carriage remains controversial.36
(immunodystrophism)
Cervical insufciency is a recognised cause of late recurrent
5. Inherited thrombophilic disorders
miscarriage, although the true incidence is unknown. Women at
Antithrombin and protein C/S deciency
risk include those with a history of cervical trauma (eg, conisa-
Factor II, factor V Leiden and MTHFR mutations
tion), collagen disorders, or congenital anomalies of the uterus/
Other gene mutations related to clot pathway proteins
cervix.
(ie, 4G/4G plasminogen activator inhibitor)
6. Infectious diseases (rarely)
Immune factors
Bacterial
Antiphospholipid syndrome (APS)
Viral
APS refers to the association of aPLs with venous and/or arterial
7. Miscellaneous factors
thrombosis, and with embryofetal morbidity. It manifests in 5
Environmental/exercise/stress
15% of women with recurrent miscarriage, and is associated
Placental abnormalities
with other obstetric complications such as preterm delivery,
Medical illness
intrauterine growth restriction, early pre-eclampsia, HELLP syn-
Male factors
drome and subchorionic haematoma/placental abruption.37 38 It
Toxic habits
should be noted that obstetric APS refers to women with only
8. New risk factors
obstetric aPL-related complaints and no history of current
Circulating cell-derived microparticles
thrombotic events at the time of diagnosis.39 In cases of recur-
Leptin
rent miscarriage related to aPLs, placental injury produces
Human chorionic gonadotropin (hCG)
inammatory and prothrombotic changes that involve tropho-
Glycodelin
blasts and endothelial and blood cells.40
NK cells
To be considered to have APS, patients must full the cur-
NK cell receptors (NK-KIRs, NKG).
rently accepted Sydney criteria41 (box 2). Although Gris et al42
suggested that anticardiolipin antibodies (aCLs) might be
miscarriages than those with low antibody concentrations.23 24 dropped from the laboratory battery, others have shown that all
An apparent interaction between antiphospholipid antibodies categories dened in the Sydney criteria are needed to avoid a
(aPLs) and anti-thyroid antibodies in the risk of recurrent mis- false-negative APS diagnosis.43 More recently, several authors
carriage has been reported.25 Vitamin D levels have been found have argued in favour of exibility and/or extending clinical and
to be lower in women with thyroid autoimmunity, and this de- laboratory categories.44 45 Several ongoing studies should help
ciency is linked to infertility and miscarriage.26 to clarify this topic in the near future.
Between 8% and 10% of women with recurrent miscarriage
have polycystic ovary syndrome (PCOS), which is also related to Alloimmune dysfunction
hyperandrogenaemia, obesity and hyperinsulinaemia.22 The During pregnancy, the maternal immune system must undergo
underlying mechanisms of recurrent miscarriage related to changes to tolerate the semi-allogeneic conceptus. Since mater-
obesity and insulin resistance may include impairment of the nal alloreactive lymphocytes are not fully depleted during preg-
brinolytic response, a leading player in the tissue remodelling nancy, local and/or systemic mechanisms have to play a key role
that accompanies embryonic implantation.27 in altering the immune response. An altered Th1/Th2 cytokine

Garrido-Gimenez C, et al. Postgrad Med J 2015;0:112. doi:10.1136/postgradmedj-2014-132672 3

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Figure 2 Septate uterus shown on
transvaginal three-dimensional
volumetric ultrasound in sagittal (A)
and coronal (B) plane. The arrow
indicates the septate area itself. Image
courtesy of Juan Jos Gmez Cabeza,
Department of Gynecology, Vall
dHebrn University Hospital.
balance with Th2 predominance has been observed, indicating a
possible mechanism for determining fetal survival in the
womb.46 However, studies conducted in genetically decient
Box 2 Revised classication criteria for the
antiphospholipid antibody syndrome (Sydney criteria)*
Clinical criteria (one or more)
1. Vascular thrombosis: one or more objectively conrmed
episodes of arterial, venous or small-vessel thrombosis
occurring in any tissue organ.
2. Pregnancy morbidity:
(a) one or more unexplained deaths of a morphologically
normal fetus (documented by ultrasound or by direct
examination) at or beyond the 10th week of gestation; OR
(b) one or more premature births of a morphologically
normal neonate before the 34th week of gestation because
of (i) eclampsia, pre-eclampsia dened according to
standard denitions or (ii) placental insufciency; OR
(c) three or more unexplained consecutive spontaneous
abortions before the 10th week of gestation, with maternal
anatomical or hormonal abnormalities and paternal and
maternal chromosomal causes excluded.
Laboratory criteria (one or more, present on two or more
occasions at least 12 weeks apart)
1. Lupus anticoagulant, detected according to the guidelines of
the International Society on Thrombosis and Haemostasis.
2. Anticardiolipin antibody of IgG and/or IgM isotype, in serum
or plasma, present in medium or high titre (>40 GPL or
MPL, or >99th centile), measured by a standardised ELISA
method.
3. Antibody to 2-glycoprotein I of IgG and/or IgM isotype, in
serum or plasma in titres (>99th centile), measured by a
standardised ELISA method according to recommended
procedures.
*See Miyakis et al.41
In studies of populations of women who have more than one type of
pregnancy morbidity, investigators are strongly encouraged to stratify
groups of women as listed in (a), (b), (c).
Patients with antiphospholipid syndrome should be classied into
one of the following laboratory categories: I, more than one
laboratory criterion present; IIa, LA present alone; IIb,
anticardiolipin antibodies present alone; IIc, anti-2-glycoprotein I
antibody alone.
4 Garrido-Gimenez C, et al. Postgrad Med J 2015;0:112. doi:10.1136/postgradmedj-2014-132672
mice unable to secrete Th2 cytokines have not always reported
miscarriages, suggesting that the former is not essential for a
normal pregnancy.47 Thus, alloreactive Th1 cells must be differ-
ently blocked or regulated, for instance, by regulatory T cells
(Tregs).
Modications in different T cell subsets, particularly CD4
+CD25+FoxP3+ Tregs, are essential to maintain maternal
fetal immune tolerance.48 49 Treg sensitisation from paternal
antigens at the maternalfetal interface is currently believed to
avoid fetal allo-rejection by creating a tolerant microenviron-
ment particularly characterised by the expression of interleukin
10, transforming growth factor and indoleamine 23 deoxy-
genase.48 50 Similarly, it has been proposed that progesterone,
human chorionic gonadotropin (-hCG) and human placental
growth hormone may modulate maternal tolerance to fetal
paternal antigens, perhaps by means of a reduction in uterine
natural killer (NK) cell activity, expanding Tregs, or both. Some
authors have reported on the role played by different NK cell
receptors, particularly killer cell immunoglobulin-like receptors
(KIRs), their relationship with human leucocyte antigen C and
fetalmaternal tolerance, and their possible pharmacological
modulation.51 52
Other immunological factors
A correlation between maternal coeliac disease and recurrent
miscarriage has been shown53; patients with proven coeliac
disease should already be on a gluten-free diet.54 Thus, screen-
ing for antibody to transglutaminase IgA isotype in the recurrent
miscarriage population could be warranted. However, in our
clinical practice and after many years of testing women with
recurrent miscarriage for coeliac disease, no data supporting
that relationship have been obtained (unpublished results).
Inherited thrombophilic disorders
There is a large and contradictory literature on the association
between maternal inherited thrombophilia and recurrent miscar-
riage. However, current studies have generally reported an asso-
ciation particularly for late fetal loss. The presumed mechanism
seems to be the thrombosis of the uteroplacental circulation.
The most prevalent polymorphisms are the heterozygous
variant of factor V Leiden and the abnormal heterozygous pro-
thrombin gene (G20210A).55 Recurrent miscarriage has also
been related to the presence of other mutations, such as 4G/5G
plasminogen activator inhibitor and the homozygosity for methy-
lenetetrahydrofolate reductase (MTHFR). The association with
other deciencies such as protein C or protein S is still debated.56
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Box 3 Suggested regimens for the treatment of APS in
pregnancy*
(A) Women with APS without previous thrombosis and recurrent
early ( pre-embryonic or embryonic) miscarriage: LDA together
with either prophylactic unfractionated heparin (50007500 IU
SC/12 h) or LMWH (enoxaparin, tinzaparin, bemiparin or
dalteparin, in usual prophylactic doses SC/24 h) (Grade 1B).
After delivery, postpartum thromboprophylaxis with warfarin or
better, LMWH, is indicated for 6 weeks.
(B) Women with APS without previous thrombosis and isolated
or recurrent fetal death (more than 10 weeks gestation) or
previous early delivery (<34 weeks gestation) due to early
severe pre-eclampsia or placental insufciency: LDA plus
prophylactic or intermediate-unfractionated heparin (7500
10 000 IU SC every 12 h, or every 812 h adjusted to maintain
the mid-interval aPTT 1.5 times the control mean) or LMWH
(usual low or intermediate prophylactic doses, eg, enoxaparin
40 mg or 60 mg SC/24 h). After delivery, postpartum
thromboprophylaxis with warfarin or better, LMWH, is indicated
for 6 weeks.
(C) Women with APS and previous thrombosis: LDA plus
therapeutic unfractionated heparin (SC every 812 h adjusted to
maintain the mid-interval aPTT or heparin concentration
anti-factor Xa activity in the therapeutic range) or LMWH
(therapeutic dose, ie, enoxaparin 1 mg/kg SC, or dalteparin
100 U/kg SC/12 h, or enoxaparin 1.5 mg/kg/day SC, or
dalteparin 200 U/kg/day SC). After delivery, thromboprophylaxis
(secondary) with warfarin or LMWH (therapeutic dose) is
indicated for life.
*Modied from Bates et al.66
Lactation is not a contraindication to warfarin or heparin use.
Women without a lupus anticoagulant in whom the aPTT is normal
can be monitored with the aPTT. Women with lupus anticoagulant
should be monitored with anti-factor Xa activity.
Need for dose adjustments over the course of pregnancy remains
controversial. Some experts argue that, in the absence of better
evidence, it is prudent to monitor anti-factor Xa LMWH concentrations
46 h after injection, with dose adjustment to maintain a therapeutic
anti-factor Xa concentration (0.61.1 U/mL) if a twice-daily regimen is
used, and slightly higher if a once-daily regimen is chosen.
APS, antiphospholipid syndrome; aPTT, activated partial thromboplastin
time; LDA, low-dose aspirin; LMWH, low-molecular-weight heparin; SC,
subcutaneously.
It has also been reported that the presence of combined thrombo-
philic disorders increases the rate of recurrent miscarriage, par-
ticularly late miscarriage. Finally, no studies associating recurrent
miscarriage with paternal thrombophilia have been reported.
Infective agents
Infectious diseases are rarely a cause of early miscarriage. No
factual association has been found between bacterial and viral
organisms and recurrent miscarriage, although Chlamydia,
Mycoplasma, Ureaplasma, Listeria, Toxoplasma, Rubella, cyto-
megalovirus, herpes virus and parvoviruses have been associated
with spontaneous miscarriage.57
Lifestyle and environmental factors
The effects of environmental exposure on pregnancy, particu-
larly in recurrent miscarriage, remain a matter of debate, since
Garrido-Gimenez C, et al. Postgrad Med J 2015;0:112. doi:10.1136/postgradmedj-2014-132672
Review
some confounding factors render it difcult to obtain reliable
data. Cigarette smoking, alcohol and moderate-to-heavy caffeine
and cocaine use58 59 may be associated with sporadic miscar-
riages; however, the relationship between these factors and
recurrent miscarriage is unclear.
No high-quality evidence exists supporting a relationship
between recurrent miscarriage and occupational factors, stress
or low-level exposure to most environmental chemicals.2
Obesity (body mass index >29.9 kg/m2) is associated with a
higher rate of miscarriage; its relationship with recurrent miscar-
riage, however, remains uncertain.60 Exercise does not appear
to increase the rate of recurrent miscarriage.61
New risk factors: circulating microparticles, glycoproteins
and leptin
Circulating microparticles represent subcellular elements for cell
signalling and intercellular communication in inammation and
thrombosis, and are believed to induce coagulation. They are
increased during pregnancy and in complicated pregnancy disor-
ders.62 Recent studies found a correlation between circulating
microparticles, including trophoblastic ones, and recurrent
miscarriage.
Some proteins appear to be downregulated in patients who
have early recurrent miscarriages. Examples include hCG, glyco-
delin (glycoproteins secreted in high amounts by the trophoblast
or the decidualised endometrium mainly during the rst trimes-
ter of pregnancy), and galectin-1 expression in the syncytiotro-
phoblast.63 Furthermore, low serum leptin levels were observed
in women suffering spontaneous miscarriage in the rst trimes-
ter of pregnancy.64 The promising results of preliminary studies,
as mentioned previously, showing the role played by the diverse
KIRs expressed by NK cells in recurrent miscarriage and in
recurrent IVF failure require further assessment.52 65
EVALUATION AND MANAGEMENT OF RECURRENT
MISCARRIAGE
Couples suffering recurrent miscarriage need empathy, since for
them this is a traumatic experience. Evaluation can be frustrat-
ing and difcult because the aetiology may not be established.
Couples should be (table 2) informed that the prognosis of
recurrent miscarriage is favourable, even without any interven-
tion,72 although most couples do not accept the conservative
approach.
First, a complete medical history should be obtained, with
special attention paid to personal or family history of throm-
bosis, poor obstetric outcomes, autoimmune disease or endo-
crinological disorders. The history should include knowledge of
gestational age at fetal loss, since recurrent miscarriage typically
occurs at a similar gestational age in consecutive pregnancies
and the aetiology could vary in early and late miscarriages.
Physical examination should include a general assessment with
attention to signs of endocrinopathy (eg, hirsutism, galactor-
rhoea), autoimmune disease (eg, malar blushing, telangiectasia)
and pelvic organ abnormalities (eg, uterine malformation, cer-
vical laceration). The most useful tests should then be analysed
separately in the evaluation of recurrent miscarriage (tables 1
and 2).
Genetic abnormalities
Genetic counselling is important when a genetic factor is identi-
ed. However, peripheral karyotyping is expensive and does not
always provide valuable information on recurrent miscarriage;
thus, this test could be avoided in many couples, although
current guidelines still recommend parental karyotyping.
5
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Table 1 Proposed evaluation of women with recurrent miscarriage*
Appraisal
Medical history
Ask about gestational age of miscarriage
Assess obstetric history
Assess history of uterine malformations and cervical incompetence
Assess whether the mother has had a fetus or child with an inherited anomaly
Evaluate findings related to APS
Ask whether the patient has a history of thyroid abnormalities, diabetes or
polycystic ovary syndrome
Assess personal or family history of thromboembolic diseases
Physical examination
Perform pelvic and uterine examination
Look for signs of thyroid diseases, diabetes, obesity and hyperandrogenaemia
Look for signs related to systemic autoimmune diseases
Usually recommended test: pros and cons
Sonohysterography and hysterosalpingography
Chromosomal analyses of the couple
Sperm morphology
Sperm DNA studies
Chromosomal analyses of products of conception
Preimplantation genetic screening in IVF
aPL panel according to Sydney recommendations
Inherited thrombophilic disorders
Not recommended laboratory tests
Progesterone levels in previous luteal phase, atypical aPLs, anti-Mllerian hormone,
anti-paternal cytotoxic antibodies, HLA class I/II screening, cytokine numbering and
ratios, NK cells and NK KIRs.
*Modified from Alijotas-Reig and Garrido-Gimenez67 and Branch et al.10
aCL, anticardiolipin antibody; aPL, antiphospholipid antibody; APS, antiphospholipid syndrome; 2GPI, 2-glycoprotein I; FISH, fluorescent in situ hybridisation; HLA, human leucocyte
antigen; IVF, in vitro fertilisation; KIR, killer cell immunoglobulin-like receptor; NK cells, natural killer cells; TSH, thyroid-stimulating hormone.
In couples with recurrent miscarriage, some experts recom-
mend conceptus karyotype analysis, albeit controversial, since it
can offer useful information73that is, an aneuploid conceptus
indicates a better chance of success in a subsequent pregnancy.74
Preimplantation genetic screening of biopsied blastomeres
during IVF has not shown any improvement in clinical out-
comes,19 and thus its use is debateable in couples with recurrent
6 Garrido-Gimenez C, et al. Postgrad Med J 2015;0:112. doi:10.1136/postgradmedj-2014-132672
Comments/recommendations
Pre-embryonic and embryonic are the most common type of recurrent miscarriage.
The aetiology may differ from cases of losses occurring later.
Poor obstetric outcomes, such as early and late miscarriage, pre-eclampsia, stillbirth
and prematurity, are major predictors of subsequent pregnancy risk complications.
Previous obstetric complications such as miscarriage, preterm labour or breech
presentation may suggest uterine malformation or cervical incompetence.
Congenital abnormalities raise the possibility of a parental chromosomal abnormality.
Features include thrombosis, fetal death, pre-eclampsia and other poor obstetric
outcomes, livedo reticularis, thrombocytopenia and autoimmune diseases.
Consider overt clinical and subclinical forms of hypothyroidism. Do not contemplate
cases of subclinical thyroid hyperfunction. Be aware in cases of recurrent miscarriage
and TSH ranging from 2.5 to 4.5 IU.
Venous thromboembolic history, mainly in young people and in uncommon locations,
may be related to inherited thrombophilias and/or APS.
Standard manual pelvic examination cannot rule out cervical abnormalities.
Complete physical examination.
Some skin signs that accompany normal gestation (eg, malar blushing, facial
pigmentation, alopecia, hand erythema, telangiectasia or carpal tunnel syndrome)
may be difficult to differentiate from those related to systemic or rheumatic diseases.
MRI and hysteroscopy are more informative but more expensive and invasive,
respectively. Both screening tests are increasingly being used. Transvaginal ultrasound
is useful in cases of short or incompetent cervix.
Parental karyotyping is expensive and does not always provide valuable information.
Furthermore, treatment options are limited and do not surpass results of spontaneous
conception. Parental karyotyping would be performed in couples with recurrent
miscarriage where testing of products of conception shows unbalanced structural
chromosomal abnormalities.
Although frequently recommended, sperm morphology analyses do not appear to be
predictive of further miscarriages.
Data regarding the relationship between miscarriages and DNA sperm fragmentation
in IVF cycles are contradictory. Routine testing for sperm ploidy (FISH or DNA
fragmentation) is not recommended.
Conceptus karyotyping test is a matter of debate. Aneuploid conceptus indicates a
favourable outcome of further pregnancy. Mosaicisms may be difficult to evaluate.
Abnormalities in conceptus karyotyping would support chromosomal testing in the
couple.
This screening genetic test, using FISH, does not improve the live birth rate and
should probably not be recommended.
Lupus anticoagulant test is reported as positive or negative. aCLs are expressed in
GPL and MPL units according to a standardised test. Anti-2GPI antibodies are
measured in arbitrary, non-standardised units (AU). Clinical criteria apart, APS is
diagnosed when tests at least 12 weeks apart are repeatedly positive. Other aPLs such
as antiprothrombin/antiphosphatidylserine or anti-domain I anti-2GPI antibodies and
IgA isotype are not yet considered classification laboratory criteria.
Uncertain value in pre-embryonic and embryonic losses, mainly referring to factor V
Leiden. Test should be performed out of pregnancy, especially for protein S levels.
Overall, these tests are not systematically recommended. These parameters may be
tested only for clinical research reasons in monographic units.
miscarriage, except in those who are carriers of Robertsonian
translocations involving chromosome 21.
Endocrine abnormalities
Routine screening for diabetes mellitus should be limited to
women with clinical manifestations of the disease. Neither
routine screening nor medical treatment of thyroid dysfunctions
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Table 2 Some evidence-based guidelines for diagnosis and management of recurrent miscarriage
Evidence Grade of
Statement level recommendation

APS is the leading cause of RM 2a B

All women with recurrent first-trimester miscarriage and all women with one or more second-trimester miscarriage should be 2a B
screened before pregnancy for aPLs
There is insufficient evidence to support the relationship between thyroid autoimmunity and RM in euthyroid women 4 C
Cytogenetic analysis should be performed on products of conception of the third and subsequent consecutive miscarriage(s) 4 D
Parental peripheral blood karyotyping of both partners should be performed in couples with RM where testing of products of 4 D
conception reports unbalanced structural chromosomal abnormality
If karyotyping results of the product of conception are abnormal, the outcome of further pregnancies will improve 4 C
Sperm morphology analyses, fluorescent in situ hybridisation and DNA fragmentation are not recommended, since they do not 2a B
appear to be predictive of further miscarriages
All women with recurrent first-trimester miscarriage and all women with one or more second-trimester miscarriages should have 2b B
a pelvic ultrasound to assess uterine anatomy
Suspected uterine anomalies may require further investigation to confirm the diagnosis, using hysteroscopy, laparoscopy or 2b B
three-dimensional pelvic ultrasound
Women with second-trimester miscarriage should be screened for inherited thrombophilia including factor V Leiden, factor II 2a B
gene mutation and protein S
Pregnant women with APS should be considered for treatment with low-dose aspirin plus heparin to prevent further miscarriage 1a A
Neither corticosteroids* nor intravenous immunoglobulin therapy improve the live birth rate of women with recurrent 1b A
miscarriage associated with aPLs compared with other treatment modalities
Preimplantation genetic screening with in vitro fertilisation treatment in women with unexplained recurrent miscarriage does not 2a B
improve live birth rates
There is insufficient evidence to assess the effect of uterine septum resection in women with RM to prevent further miscarriage 3 C
In women with a singleton pregnancy and a history of one second-trimester miscarriage attributable to cervical factors, 1b A
ultrasound-indicated cerclage could be offered if cervical length 25 mm is detected by transvaginal scan before 24 weeks of
gestation
Preliminary evidence shows that the effect of progesterone supplementation in pregnancy may prevent a further miscarriage in 2b B
women with RM
Immunotherapy, active or passive, in women with previous unexplained recurrent miscarriage does not improve the live birth 1b A
rate
There is insufficient evidence to evaluate the effect of heparin in pregnancy to prevent miscarriage in women with recurrent 4 C
first-trimester miscarriage associated with inherited thrombophilia
Heparin therapy during pregnancy may improve the live birth rate of women with second-trimester miscarriage associated with 1b A
inherited thrombophilia
Treatment of women with RM suffering from overt hyperthyroidism or overt hypothyroidism does improve further pregnancy 2a B
outcomes
Women with unexplained RM have an excellent prognosis for future pregnancy outcome without pharmacological intervention if 2a B
offered supportive care alone (tender loving care) in the setting of a dedicated early pregnancy assessment unit
From diverse listed papers, mainly: Branch et al,10 Franssen et al,19 Haas and Ramsey68; Porter et al69; Practice Committee of American Society of Reproductive Medicine1;
Royal College of Obstetricians and Gynaecologist.70
*A recent controlled study reported benefits in the group treated with low-dose prednisolone for 810 weeks (Bramham et al71).
aPL, antiphospholipid antibody; APS, antiphospholipid syndrome; RM, recurrent miscarriage.

in euthyroid pregnant women is recommended.75 However,
thyroid antibodies should be evaluated in women with recurrent
miscarriage, including those with aPLs, since there is an apparent
interaction between them.25 76 Women with overt hypothyroid-
ism or hyperthyroidism obviously require treatment, but this is
less clear for women with subclinical hypothyroidism and
thyroid autoimmunity.77 To date, the only prospective rando-
mised controlled trial evaluating treatment in euthyroid women
with positive thyroid antibodies was performed by Negro et al,78
showing a statistically signicant reduction in miscarriages in
women who received levothyroxine. Furthermore, thyroid-
stimulating hormone (TSH) levels should be kept below 2.53
IU, as one study concluded that there is a higher incidence of mis-
carriage when TSH levels are above this range.79 The treatment
of subclinical hyperthyroidism during pregnancy is currently
considered to be unwarranted, since it is not associated with
adverse pregnancy outcomes.
The use of metformin for women with anovulatory PCOS
showed no benet with respect to enhancing either fertility or
live birth rates; thus, its routine use is not recommended.80
No clear evidence exists to support the routine use of exogen-
ous progesterone supplementation during the rst trimester to
prevent miscarriage. However, although randomised studies in
this setting are lacking, there appears to be evidence of benet
in women with a history of recurrent miscarriage.68 A large ran-
domised, double-blind, placebo-controlled multicentre trial
(PROMISE; http://www.medscinet.net/promise) is currently
underway to assess the benet of progesterone supplementation
in women with unexplained recurrent miscarriage.
Data supporting an association between alterations in prolac-
tin levels and recurrent miscarriage are lacking; however, in
cases of detected hyperprolactinaemia, it may be appropriate to
treat with cabergoline or bromocriptine.28
Anatomical factors
Gynaecological ultrasound is recommended in women with
recurrent miscarriage, since it is an available, non-invasive and
cost-effective method for detecting uterine disorders, while the
systematic use of hysteroscopy, CT, MRI or hysterosalpingogra-
phy is not justied.

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Figure 3 Suggested management of patients with recurrent miscarriage. G-CSF, granulocyte colony-stimulating factor; IVIG, intravenous
immunoglobulin; LDA, low-dose aspirin; LMWH, low-molecular-weight heparin; PCOS, polycystic ovary syndrome; TNF-, tumour necrosis factor .
*Do not use between 5th and 12th week of gestation. Adapted from Alijotas-Reig and Garrido-Gimenez.67

In patients with recurrent miscarriage and structural uterine
malformations, re-establishing the normal anatomy seems to
improve gestational prognosis.81 Observational studies found an
improvement in gestational outcomes in patients with uterine
septum following hysteroscopic metroplasty.82 Furthermore, it
seems that myomectomy of submucous leiomyomata before con-
ception reduces the rate of miscarriage;33 however, it is less
clear when broids do not distort the uterine cavity.83 The clin-
ical management of miscarriage in patients with Ashermans
syndrome/intrauterine synechiae or uterine polyps is controver-
sial, and there is no conclusive evidence that surgical treatment
reduces the risk of miscarriage.36
For women with late recurrent miscarriage or three or more
early preterm births who have risk factors for cervical insuf-
ciency, cervical cerclage is indicated. Measurement of cervical
length with transvaginal ultrasound during pregnancy could
detect patients with a short cervix (<25 mm) before 24 weeks,
and vaginal progesterone administration or cervical pessary
could reduce the risk of late miscarriage or preterm birth.84
Immune factors
Women with recurrent miscarriage should also be tested for
lupus anticoagulant, aCLs and 2-glycoprotein I antibodies
(IgG/IgM isotypes) using standard assays. The tests should be
performed twice, 12 weeks apart, since transient positive levels
can be due to infections or drugs and spontaneously revert to
normal.43
The recommended therapy in women with aPL/APS-related
recurrent miscarriage consists of prophylactic low-molecular-weight
heparin (LMWH) plus low-dose aspirin (LDA), which was found to
be superior to treatment with LDA alone (74.2% vs 55.8% live
birth rate)66 85 (box 3). The use of LMWH is preferable because of
its greater safety and efcacy compared with unfractionated
heparin; however, unfractionated heparin remains an acceptable
alternative. In cases of refractory obstetric APS (2025% of cases),
promising results have been obtained with the addition of hydroxy-
chloroquine or low-dose prednisolone to standard treatment.71
Similarly, other therapeutic regimens have been proposed, such as
vitamin D, fondaparinux or pentoxifylline;86 however, they should
be tested in well-designed clinical trials before their general use is
approved.
Inherited thrombophilic disorders
Routine testing for inherited thrombophilias in women with
recurrent miscarriages is not currently recommended. Screening
may be clinically justied when a history of thromboembolism
with no risk factors, such as surgery or late recurrent miscar-
riages, does exist.70
Consensus on whether or not to treat cases of recurrent mis-
carriage with associated congenital thrombophilia using aspirin,
heparin or both is lacking.87
Infective agents
Routine cervical cultures, vaginal evaluation for bacterial vagin-
osis, and toxoplasmosis serology are not useful in the evaluation
of recurrent miscarriage in otherwise healthy women. Although
some authors, including a Cochrane review,88 support them,
these screening tests are currently not recommended.
Unexplained recurrent miscarriage
If no cause for recurrent miscarriage is established, a lifestyle
modication should be recommended. Epidemiological studies
suggest that lifestyle modications can increase fertility, although
they have not been denitively tested in randomised trials.
These modications include eliminating toxic habits and caf-
feine, following a well-balanced diet, and reducing body mass
index in obese women.89

8 Garrido-Gimenez C, et al. Postgrad Med J 2015;0:112. doi:10.1136/postgradmedj-2014-132672

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Furthermore, there seems to be a rationale for the use of a
combination of LDA and prophylactic heparin in the treatment
of unexplained recurrent miscarriage.67 Several trials have
emphasised the benet of LMWH,90 although some studies
found no advantages of its use.91 Despite this, and taking into
account its probable benet and small potential risk, LMWH
could be considered an experimental drug for patients with
recurrent miscarriages until further conclusive data from con-
trolled clinical trials become available.
Although no alloimmune mechanism has been proven to cause
recurrent miscarriage, some immune-modulating therapies have
been used to treat these women. However, systematic reviews have
consistently found no benecial effect of immunotherapy for treat-
ing unexplained recurrent miscarriage. Therapy with paternal
leucocyte immunisation and intravenous immunoglobulins
(IVIGs) has been used in this eld, but results have been controver-
sial.69 92 Anti-tumour necrosis factor (anti-TNF-) drugs may
offer a novel, safe and effective approach, but evidence is still
scarce.93 Furthermore, the combination of heparin with IVIGs or
anti-TNF- inhibitor seems to improve live birth rates;94 however,
further controlled trials are required to conrm these optimistic
results. Data on the effectiveness of granulocyte colony-stimulating
factor in the treatment of both unexplained recurrent miscarriage
and recurrent in vitro implantation failure are now available.95 96
However, the paucity of well-designed studies does not support
the use of these therapies in routine clinical practice.
Main messages
Approximately 5% and 23% of couples trying to conceive
have, respectively, two or three consecutive miscarriages.
Recurrent miscarriage typically occurs at a similar gestational
age in consecutive pregnancies.
Systematic parental karyotyping, karyotype screening of the
conceptus and preimplantation genetic screening are not
recommended.
Routine screening for thyroid dysfunction is recommended. If
subclinical hypothyroidism is detected, levothyroxine
treatment must be offered.
Assessment of uterine anatomy with pelvic ultrasound is
widely recommended.
The benets of myomectomy (for non-submucous myomas) and
metroplasty are uncertain, and more information is required
before a surgical therapeutic approach can be recommended.
Testing for lupus anticoagulant, anticardiolipin,
anti-2-glycoprotein I and anti-thyroid autoantibodies is
recommended.
Currently, women with unexplained recurrent miscarriage,
particularly in the rst trimester, should not be tested for
inherited thrombophilia.
Patients with antiphospholipid syndrome must be
treated with low-dose aspirin (LDA) plus
low-molecular-weight heparin (LMWH). In refractory
cases, drugs such as hydroxychloroquine or low-dose
prednisone are being tested, but preliminary results are
controversial.
It seems reasonable to use prophylactic LMWH in
combination with LDA for patients with recurrent
miscarriage. Currently, immunotherapy and glucocorticoids
are not yet recommended as treatments for unexplained
recurrent miscarriage.
Garrido-Gimenez C, et al. Postgrad Med J 2015;0:112. doi:10.1136/postgradmedj-2014-132672
Review
Glucocorticoids have several anti-inammatory effects,
including suppression of NK cell number and activity in the
endometrium; however, the high rate of adverse effects (eg, ges-
tational diabetes and hypertension) renders their use for recur-
rent miscarriage controversial (gure 3).97 98
SUMMARY
Recurrent miscarriage can be evaluated after two clinical pregnancy
losses. Assessment of recurrent miscarriage focuses on medical
history, physical examination and recommended laboratory tests;
however, up to 50% of cases will not have a clearly dened aeti-
ology. The prognosis of subsequent pregnancies is generally good
even without treatment, and patients should be informed that solid
evidence is lacking to support several commonly used interventions
and treatments for recurrent miscarriage.
Current research questions
Could patients with recurrent miscarriage and elevated
circulating microparticle levels benet from
low-molecular-weight heparin and/or low-dose aspirin
during pregnancy?
What is the role of the complement pathway, uterine Tregs and
natural killer cells, killer cell immunoglobulin-like receptors,
and cytokines in unexplained recurrent miscarriage?
What is the most accurate thromboprophylaxis schedule for
women with inherited thrombophilia and recurrent
rst-trimester miscarriage?
Can immunotherapy, particularly maternal sensitisation with
paternal-derived cells and treatment with granulocyte
colony-stimulating factor, be an effective treatment for
recurrent miscarriage?
Key references
Alijotas-Reig J, Garrido-Gimenez C. Current concepts and
new trends in the diagnosis and management of
recurrent miscarriage. Obstet Gynecol Surv
2013;68:44566.
American College of Obstetricians and Gynecologists. ACOG
practice bulletin. Management of recurrent pregnancy loss.
Number 24, February 2001. Int J Gynaecol Obstet
2002;78:17990.
Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia,
antithrombotic therapy, and pregnancy. In: Antithrombotic
therapy and prevention of thrombosis, 9th ed: American
College of Chest Physicians Evidence-Based Clinical Practice
Guidelines. Chest 2012;141:e691S736S.
Branch DW, Gibson M, Silver RM. Clinical practice. Recurrent
miscarriage. N Engl J Med 2010;363:17407.
Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for
recurrent miscarriage. Cochrane Database Syst Rev 2006;2:
CD000112.
Royal College of Obstetricians and Gynaecologists. The
investigation and treatment of couples with recurrent
rst-trimester and second-trimester miscarriage. Green-top
Guidelines No 17, April 2011.
9
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Review
Self assessment questions
1. Which of the following statements regarding miscarriage is
false?
A. Approximately 5% of couples trying to conceive have
two consecutive miscarriages, and approximately 2% of
couples have three or more consecutive losses.
B. The aetiology is not established in up to 50% of cases.
C. The term early miscarriage means involuntary
pregnancy loss before the 12th week of gestation.
D. The American Society for Reproductive Medicine 2008
expert committee denes recurrent miscarriage as the
loss of three or more failed pregnancies.
2. Which of the following statements regarding recurrent
miscarriage is false?
A. Genetic factors are the most common cause (50% and
60%) of early spontaneous miscarriages, and
translocations are the most common types of structural
abnormality.
B. The higher the number of miscarriages, the more
probable they are related to chromosomal anomalies.
C. Preimplantation genetic screening of biopsied
blastomeres during IVF has not produced any
improvement in clinical outcomes.
D. Parental karyotyping is expensive and does not always
provide valuable information on recurrent miscarriage.
3. Which of the following statements regarding the aetiology of
recurrent miscarriage is true?
A. Women with diabetes mellitus have more miscarriages,
regardless of metabolic control.
B. In cases of detected hyperprolactinaemia, it may be
appropriate to give treatment with cabergoline or
bromocriptine.
C. Subclinical hyperthyroidism is associated with increased
risk of recurrent miscarriage, so treatment of these
patients is recommended.
D. Women with high levels of anti-thyroid antibodies suffer
more miscarriages than those with low concentrations
of antibodies.
4. Which of the following statements regarding immunology of
recurrent miscarriage is false?
A. Antiphospholipid syndrome (APS) is diagnosed in
15-20% of women with recurrent miscarriage.
B. Alloimmune factors may play a role in recurrent
miscarriage.
C. Women with antiphospholipid antibody-related obstetric
morbidity should be treated with metformin.
D. The combination of low-dose aspirin (LDA) plus prophylactic
heparin increases fetalmaternal outcomes in recurrent
miscarriage related to antiphospholipid antibody positivity.
5. Which of these statements regarding the future treatment of
women with recurrent miscarriage is true?
A. Hydroxychloroquine and low-dose prednisolone plus
low-molecular-weight heparin (LMWH) may have
success in the treatment of refractory obstetric APS.
B. The recommended therapy in women with recurrent
miscarriage related to APS is prophylactic LMWH plus
LDA plus granulocyte colony-stimulating factor.
C. Currently, treatment with human chorionic gonadotropin
shows clear benets compared with a placebo group.
D. Therapy with paternal leucocyte immunisation is the new
approved treatment for idiopathic recurrent miscarriage
10 Garrido-Gimenez C, et al. Postgrad Med J 2015;0:112. doi:10.1136/postgradmedj-2014-132672
Acknowledgements We thank Ms Christine OHara for reviewing and correcting
the style and grammar of the manuscript. An extensive review by us67 on this topic
Current concepts and new trends in the diagnosis and management of recurrent
miscarriage was published in Obstetrical and Gynecological Survey in 2013; the
present paper is published with permission of the publishers.
Contributors CG-G and JA-R contributed to the conception and design of this
research, drafting the article and critically revising it, and nal approval of the
version to be published.
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES
1 Practice Committee of the American Society for Reproductive Medicine. Denitions
of infertility and recurrent pregnancy loss: a committee opinion. Fertil Steril
2013;99:638.
2 Simpson JL. Causes of fetal wastage. Clin Obstet Gynecol 2007;50:1030.
3 Rai R, Regan L. Recurrent miscarriage. Lancet 2006;368:60111.
4 Grande M, Borrell A, Garcia-Posada R, et al. The effect of maternal age on
chromosomal anomaly rate and spectrum in recurrent miscarriage. Hum Reprod
2012;27:310917.
5 Nybo Andersen AM, Wohlfahrt J, Christens P, et al. Maternal age and fetal loss:
population based register linkage study. BMJ 2000;320:74888.
6 Regan L, Braude PR, Trembath PL. Inuence of past reproductive performance on
risk of spontaneous abortion. BMJ 1989;299:5415.
7 Heuser C, Dalton J, Macpherson C, et al. Idiopathic recurrent pregnancy loss recurs
at similar gestational ages. Am J Obstet Gynecol 2010;203:343.e15.
8 Rubio C, Pehlivan T, Rodrigo L, et al. Embryo aneuploidy screening for unexplained
recurrent miscarriage: a minireview. Am J Reprod Immunol 2005;53:15965.
9 Li M, Huang SJ. Innate immunity, coagulation and placenta-related adverse
pregnancy outcomes. Thromb Res 2009;124:65662.
10 Branch DW, Gibson M, Silver RM. Clinical practice. Recurrent miscarriage. N Engl J
Med 2010;363:17407.
11 Meza-Espinoza JP, Anguiano LO, Rivera H. Chromosomal abnormalities in couples
with reproductive disorders. Gynecol Obstet Invest 2008;66:23740.
12 Sugiura-Ogasawara M, Aoki K, Fujii T, et al. Subsequent pregnancy outcomes in
recurrent miscarriage patients with a paternal or maternal carrier of a structural
chromosome rearrangement. J Hum Genet 2008;53:6228.
13 Carp H, Guetta E, Dorf H, et al. Embryonic karyotype in recurrent miscarriage with
parental karyotypic aberrations. Fertil Steril 2006;85:44650.
14 Huang JY, Su M, Lin SH, et al. A genetic association study of NLRP2 and NLRP7
genes in idiopathic recurrent miscarriage. Hum Reprod 2013;28:112734.
15 Salker M, Teklenburg G, Molokhia M, et al. Natural selection of human embryos:
impaired decidualization of endometrium disables embryo-maternal interactions and
causes recurrent pregnancy loss. PLoS One 2010;5:e10287.
16 Su MT, Lin SH, Chen YC. Genetic association studies of angiogenesis- and
vasoconstriction-related genes in women with recurrent pregnancy loss: a systematic
review and meta-analysis. Hum Reprod Update 2011;17:80312.
17 Brahem S, Mehdi M, Landolsi H, et al. Semen parameters and sperm DNA
fragmentation as causes of recurrent pregnancy loss. Urology 2011;78:7926.
18 Robinson WP, Bernasconi F, Lau A, et al. Frequency of meiotic trisomy depends on
involved chromosome and mode of ascertainment. Am J Med Genet
1999;84:3442.
19 Franssen MT, Musters AM, van der Veen F, et al. Reproductive outcome after PGD
in couples with recurrent miscarriage carrying a structural chromosome abnormality:
a systematic review. Hum Reprod Update 2011;17:46775.
20 Fritz B, Hallermann C, Olert J, et al. Cytogenetic analyses of culture failures by
comparative genomic hybridisation (CGH)-Re-evaluation of chromosome aberration
rates in early spontaneous abortions. Eur J Hum Genet 2001;9:53947.
21 Kwinecka-Dmitriew B, Zakrzewska M, Latos-Bieleska A, et al. Frequency of
chromosomal aberrations in material from abortions. Ginekol Pol
2010;81:896901.
22 Arredondo F, Noble LS. Endocrinology of recurrent pregnancy loss. Semin Reprod
Med 2006;24:339.
23 Abalovich M, Mitelberg L, Allami C, et al. Cinical hypothyroidism and thyroid
autoimmunity in women with infertility. Gynecol Endocrinol 2007;23:27983.
24 Kaprara A, Krassas GE. Thyroid autoimmunity and miscarriage. Hormones (Athens)
2008;7:294302.
25 De Carolis C, Greco E, Guarino MD, et al. Anti-thyroid antibodies and
antiphospholipid syndrome: evidence of reduced fecundity and of poor pregnancy
outcome in recurrent spontaneous aborters. Am J Reprod Immunol 2004;52:2636.
26 Twig G, Shina A, Amital H, et al. Pathogenesis of infertility and recurrent pregnancy
loss in thyroid autoimmunity. J Autoimmun 2012;38:J27581.
27 Carrington B, Rai R, Regan L. Polycistic ovaries, insulin resistance, hypobrinolysis
and recurrent miscarriage. J Soc Gynecol Investig 2005;12:20 (abstr).
 Downloaded from http://pmj.bmj.com/ on February 16, 2015 - Published by group.bmj.com
28 Hajder M, Hajder E, Dervisefendic M, et al. Prolactinomas in infertile women:
clinical and endocrine characteristics before and after 24 months of treatment with
bromocriptine. Med Arh 2013;67:1814.
29 Saravelos SH, Cocksedge KA, Li TC. Prevalence and diagnosis of congenital uterine
anomalies in women with reproductive failure: a critical appraisal. Hum Reprod
Update 2008;14:41529.
30 Sugiura-Ogasawara M, Ozaki Y, Katano K, et al. Uterine anomaly and recurrent
pregnancy loss. Semin Reprod Med 2011;29:51421.
31 Bajekal N, Li TC. Fibroids, infertility and pregnancy wastage. Hum Reprod Update
2000;6:61420.
32 Casini ML, Rossi F, Agostini R, et al. Effects of the position of broids on fertility.
Gynecol Endocrinol 2006;22:1069.
33 Saravelos SH, Yan J, Rehmani H, et al. The prevalence and impact of broids and
their treatment on the outcome of pregnancy in women with recurrent miscarriage.
Hum Reprod 2011;26:32749.
34 Maheshwari A, Gurunath S, Fatima F, et al. Adenomyosis and subfertility: a
systematic review of prevalence, diagnosis, treatment and fertility outcomes. Hum
Reprod Update 2012;18:37492.
35 Tremellen KP, Russell P. The distribution of immune cells and macrophages in the
endometrium of women with recurrent reproductive failure. II: adenomyosis and
macrophages. J Reprod Immunol 2012;93:5863.
36 Prez-Medina T, Bajo-Arenas J, Salazar F, et al. Endometrial polyps and their
implication in the pregnancy rates of patients undergoing intrauterine insemination:
a prospective, randomized study. Hum Reprod 2005;20:16325.
37 Alijotas-Reig J, Vilardell-Tarres M. Is obstetric antiphospholipid syndrome a primary
nonthrombotic, proinammatory, complement-mediated disorder related to
antiphospholipid antibodies? Obstet Gynecol Surv 2010;65:3945.
38 Galarza-Maldonado C, Kourilovitch MR, Prez-Fernndez OM, et al. Obstetric
antiphospholipid syndrome. Autoimmun Rev 2012;11:28895.
39 Alijotas-Reig J, Ferrer-Oliveras R; EUROAPS Study Group. The European Registry on
Obstetric Antiphospholipid Syndrome (EUROAPS): a preliminary rst year report.
Lupus 2012;21:7668.
40 Coulam CB, Faulk WP, McIntyre JA. Immunotherapy for recurrent spontaneous
abortion and its analogies to treatment for cancer. Am J Reprod Immunol
1991;25:11419.
41 Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an
update of the classication criteria for denite antiphospholipid syndrome (APS).
J Thromb Haemost 2006;4:295306.
42 Gris JC, Qur I, Sanmarco M, et al. Antiphospholipid and antiprotein syndromes in
non-thrombotic, non-autoimmune women with unexplained recurrent primary early
foetal loss. The Nmes Obstetricians and Haematologists StudyNOHA. Thromb
Haemost 2000;84:22836.
43 Boffa MC, Boinot C, De Carolis S, et al. Laboratory criteria of the obstetrical
antiphospholipid syndrome. Data from a multicentric prospective European women
cohort. Thromb Haemost 2009;102:258.
44 Rajewski M, Skrzypczak J. Frequency of antiphospholipid antibodies and
antiphospholipid syndrome in women with recurrent miscarriages. Ginekol Pol
2011;82:328.
45 Danza A, Ruiz-Irastorza G, Khamashta M. Antiphospohlipid syndrome in obstetrics.
Best Pract Res Clin Obstet Gynaecol 2012;26:6576.
46 Paust S, Cantor H. Regulatory T cells and autoimmune disease. Immunol Rev
2005;204:195207.
47 Zenclussen AC, Gerlof K, Zenclussen ML, et al. Abnormal T cell reactivity against
paternal antigens in spontaneous abortion: adoptive transfer of pregnancy of
pregnancy-induced CD4+CD25+ T regulatory cells prevent fetal rejection in a
murine abortion model. Am J Pathol 2005;166:81122.
48 Williams Z. Inducing tolerance to pregnancy. N Engl J Med 2012;367:115961.
49 Rowe JH, Ertelt JM, Xin L, et al. Pregnancy imprints regulatory memory that sustains
anergy to fetal antigen. Nature 2012;490:1026.
50 Alijotas-Reig J. Immunological puzzle related to recurrent miscarriage: overview.
Curr Immunol Rev 2009;5:17586.
51 Tang AW, Alrevic Z, Quenby S. Natural killer cells and pregnancy outcomes in
women with recurrent miscarriage and infertility: a systematic review. Hum Reprod
2011;26:197180.
52 Hiby SE, Regan L, Lo W, et al. Association of maternal killer-cell
immunoglobulin-like receptor and parental HLA-C genotypes with recurrent
miscarriage. Hum Reprod 2008;23:9726.
53 Kumar A, Meena M, Begum N, et al. Latent celiac disease in reproductive
performance of women. Fertil Steril 2011;95:9227.
54 Tursi A, Giorgetti G, Brandimarte G, et al. Effect of gluten-free diet on pregnancy
outcome in celiac disease patients with recurrent miscarriages. Dig Dis Sci
2008;53:29258.
55 Mierla D, Szmal C, Neagos D, et al. Association of prothrombin (A20210G) and
factor V Leiden (A506G) with recurrent pregnancy loss. Maedica (Buchar)
2012;7:2226.
56 Davenport WB, Kutteh WH. Inherited thrombophilias and adverse pregnancy
outcomes: a review of screening patterns and recommendations. Obstet Gynecol
Clin North Am 2014;41:13344.
Garrido-Gimenez C, et al. Postgrad Med J 2015;0:112. doi:10.1136/postgradmedj-2014-132672
Review
57 Nigro G, Mazzocco M, Mattia E, et al. Role of infections in recurrent spontaneous
abortion. J Matern Fetal Neonatal Med 2011;24:9839.
58 Rasch V. Cigarette, alcohol, and caffeine consumption: risk factors for spontaneous
abortion. Acta Obstet Gynecol Scand 2003;82:1828.
59 Ness RB, Grisso JA, Hirshinger N, et al. Cocaine and tobacco use and the risk of
spontaneous abortion. N Engl J Med 1999;340:3339.
60 Boots C, Stephenson MD. Does obesity increase the risk of miscarriage in
spontaneous conception: a systematic review. Semin Reprod Med 2011;
29:50713.
61 American College of Obstetricians and Gynecologists. ACOG practice bulletin.
Management of recurrent pregnancy loss. Number 24, February 2001. Int J
Gynaecol Obstet 2002;78:17990.
62 Alijotas-Reig J, Palacio-Garcia C, Farran-Codina I, et al. Circulating cell-derived
microparticles in women with pregnancy loss. Am J Reprod Immunol
2011;66:199208.
63 Jeschke U, Toth B, Scholz C, et al. Glycoprotein and carbohydrate binding protein
expression in the placenta in early pregnancy loss. J Reprod Immunol
2010;85:99105.
64 Kratzch J, Hckel M, Kiess W. Leptin and pregnancy outcome. Curr Opin Obstet
Gynecol 2000;12:5015.
65 Makrigiannakis A, Petsas G, Toth B, et al. Recent advances in understanding
immunology of reproductive failure. J Reprod Immunol 2011;90:96104.
66 Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia, antithrombotic
therapy, and pregnancy. In: Antithrombotic therapy and prevention of thrombosis,
9th ed: American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines. Chest 2012;141:e691S736S.
67 Alijotas-Reig J, Garrido-Gimenez C. Current concepts and new trends in the
diagnosis and management of recurrent miscarriage. Obstet Gynecol Surv
2013;68:44566.
68 Haas DM, Ramsey PS. Progestagen for preventing miscarriage. Cochrane Database
Syst Rev 2013;10:CD003511.
69 Porter TF, LaCoursiere Y, Scott JR. Immunotherapy for recurrent miscarriage.
Cochrane Database Syst Rev. 2006;(2):CD000112.
70 Royal College of Obstetricians and Gynaecologists. The investigation and treatment
of couples with recurrent rst-trimester and second-trimester miscarriage. Green-top
Guidelines No. 17, April 2011.
71 Bramham K, Thomas M, Nelson-Piercy C, et al. First-trimester low-dose
prednisolone in refractory antiphospholipid antibody-related pregnancy loss. Blood
2011;117:694851.
72 Lund M, Kamper-Jorgensen M, Nielsen HS, et al. Prognosis for live birth in women
with recurrent miscarriage: what is the best measure of success? Obstet Gynecol
2012;119:3743.
73 Carp H, Toder V, Aviram A, et al. Karyotype of the abortus in recurrent miscarriage.
Fertil Steril 2001;75:67882.
74 Ogasawara M, Aoki K, Okada S, et al. Embryonic karyotype of abortuses in relation
to the number of previous miscarriages. Fertil Steril 2000;73:3004.
75 Stagnaro-Green A, Abalovich M, Alexander E, et al., American Thyroid Association
Taskforce on Thyroid Disease During Pregnancy and Postpartum. Guidelines of the
American Thyroid Association for the diagnosis and management of thyroid disease
during pregnancy and postpartum. Thyroid 2011;21:1081125.
76 Abbassi-Ghanavati M. Thyroid autoantibodies and pregnancy outcomes. Clin Obstet
Gynecol 2011;54:499505.
77 Vissenberg R, van den Boogaard E, van Wely M, et al. Treatment of thyroid
disorders before conception and in early pregnancy: a systematic review. Hum
Reprod Update 2012;18:36073.
78 Negro R, Formoso G, Mangieri T, et al. Levothyroxine treatment in euthyroid
pregnant women with autoimmune thyroid disease: effects on obstetrical
complications. J Clin Endocrinol Metab 2006;91:258791.
79 Benhadi N, Wiersinga WM, Reitsma JB, et al. Higher maternal TSH levels in
pregnancy are associated with increased risk for miscarriage, fetal or neonatal
death. Eur J Endocrinol 2009;160:98591.
80 Palomba S, Falbo A, Orio F Jr, et al. Effect of preconceptional metformin on
abortion risk in polycystic ovary syndrome: a systematic review and meta-analysis of
randomized controlled trials. Fertil Steril 2009;92:164658.
81 Grimbizis GF, Camus M, Tarlatzis BC. et al Clinical implications of uterine
malformations and hysteroscopic treatment results. Hum Reprod Update
2001;7:16174.
82 Pace S, Cipriano L, Pace G, et al. Septate uterus: reproductive outcome after
hysteroscopic metroplasty. Clin Exp Obstet Gynecol 2006;33:11012.
83 Pritts EA, Parker WH, Olive DL. Fibroids and infertility: an updated systematic review
of the evidence. Fertil Steril 2009;91:121523.
84 Goya M, Pratcorona L, Merced C, et al. Cervical pessary in pregnant women with a
short cervix (PECEP): an open-label randomised controlled trial. Lancet
2012;379:18006.
85 Mak A, Cheung MW, Cheak AA, et al. Combination of heparin and aspirin is
superior to aspirin alone in enhancing live births in patients with recurrent
pregnancy loss and positive anti-phospholipid antibodies: a meta-analysis of
randomized controlled trials and meta-regression. Rheumatology 2010;49:2818.
11
 Downloaded from http://pmj.bmj.com/ on February 16, 2015 - Published by group.bmj.com

Review

86 Alijotas-Reig J. Treatment of refractory obstetric antiphospholipid syndrome: the state of 96 Wrfel W, Santjohanser C, Hirv K, et al. High pregnancy rates with administration
the art and new trends in the therapeutic management. Lupus 2013;22:617. of granulocyte colony-stimulating factor in ART-patients with repetitive implantation
87 de Jong PG, Goddijn M, Middeldorp S. Antithrombotic therapy for pregnancy loss. failure and lacking killer-cell immunoglobulin-like receptors. Hum Reprod
Hum Reprod Update 2013;19:65673. 2010;25:21512.
88 Brocklehurst P, Hannah M, McDonald H. Interventions for treating bacterial 97 Silver RM, Branch DW, Scott JR. Prednisone and aspirin in women with recurrent
vaginosis in pregnancy. Cochrane Database Syst Rev. 2000;2:CD000262. fetal loss. N Engl J Med. 1997;337:162930.
89 Benammar A, Sermondade N, Faure C, et al. Nutrition and miscarriages: a literature 98 Laskin CA, Bombardier C, Hannah ME, et al. Prednisone and aspirin in women with
review. Gynecol Obstet Fertil 2012;40:1629. autoantibodies and unexplained recurrent fetal loss. N Engl J Med
90 Badawy AM, Khiary M, Sherif LS, et al. Low-molecular weight heparin in patients with 1997;337:14853.
recurrent early miscarriages of unknown aetiology. J Obstet Gynaecol 2008;28:2804.
91 Kaandorp S, Di Nisio M, Goddijn M, et al. Aspirin or anticoagulants for treating
recurrent miscarriage in women without antiphospholipid syndrome. Cochrane
Database Syst Rev 2009;21:CD004734.
92 Nonaka T, Takakuwa K, Ooki I, et al. Results of immunotherapy for patients with
unexplained primary recurrent abortions--prospective non-randomized cohort study. Answers
Am J Reprod Immunol 2007;58:5306.
93 Clark DA. Anti-TNFalpha therapy in immune-mediated subfertility: state of the art.
J Reprod Immunol 2010;85:1524. 1. D.
94 Winger EE, Reed JL. Treatment with tumor necrosis factor inhibitors and intravenous 2. B.
immunoglobulin improves live births rates in women with recurrent spontaneous
abortion. Am J Reprod Immunol 2008;60:816. 3. B.
95 Scarpellini F, Sbracia M. Use of granulocyte colony-stimulating factor for the 4. C.
treatment of unexplained recurrent miscarriage: a randomised controlled trial. Hum 5. A.
Reprod 2009;24:27038.

12 Garrido-Gimenez C, et al. Postgrad Med J 2015;0:112. doi:10.1136/postgradmedj-2014-132672

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Recurrent miscarriage: causes, evaluation

and management
Carmen Garrido-Gimenez and Jaume Alijotas-Reig

Postgrad Med J published online February 13, 2015

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