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PGMJ Online First, published on February 13, 2015 as 10.1136/postgradmedj-2014-132672
Review

Recurrent miscarriage: causes, evaluation


and management
Carmen Garrido-Gimenez,1 Jaume Alijotas-Reig2,3
1
High Obstetric Risk Unit, ABSTRACT factors. However, despite thorough investigation,
Obstetric Department, Vall Recurrent miscarriage is frustrating for the physician and no cause can be found in up to 50% of cases.2
dHebrn University Hospital,
Universitat Autnoma,
a heartbreaking experience for the patient. Nevertheless, the prognosis for a successful future
Barcelona, Spain Approximately 5% of couples trying to conceive have pregnancy is generally good: the overall live birth
2
Systemic Autoimmune Disease two consecutive miscarriages. Despite a thorough study rates after normal and abnormal diagnostic evalua-
Unit, Department of Internal of patients, the aetiology of this common obstetric tions for recurrent miscarriage are 77% and 71%,
Medicine I, Vall dHebrn complication is unknown in 50% of cases. Known respectively.3
University Hospital, Barcelona,
Spain causes include abnormal chromosomes, endocrinological A wealth of information has accumulated on this
3
Department of Medicine, disorders and uterine abnormalities. Although topic. However, this article aims to propose a
Faculty of Medicine, Universitat antiphospholipid antibodies have been demonstrated in correct assessment of couples with recurrent mis-
Autnoma, Barcelona, Spain miscarriages, the role played by alloimmune mechanisms carriage and summarise the evidence of evaluation
Correspondence to remains unclear. New immunological approaches such as and management rather than provide an update on
Dr Carmen Garrido-Gimnez, natural killer cells, regulatory T cells, tumour necrosis current understanding of the topic.
High Obstetric Risk Unit, Vall factor , cell-derived microparticles, leptin, certain
dHebrn University Hospital, glycoproteins and cytokines should be considered. The
Passeig Vall dHebron
management of thyroid diseases and immunological SEARCH STRATEGY AND SELECTION CRITERIA
119-129, Barcelona 08035, Data for this review were obtained through a com-
Spain; carmengagi@hotmail. disorders is continuously evolving. Several genetic
com, cgarrido@vhebron.net diagnostic procedures such as parental karyotyping and prehensive literature search using the relevant key-
preimplantation genetic screening should probably not words (miscarriage or recurrent miscarriage,
Received 4 March 2014 be used routinely. Antiphopholipid syndrome and some abortion or recurrent abortion, recurrent fetal
Revised 12 January 2015 loss, recurrent in-vitro fertilisation failure; alone or
Accepted 25 January 2015 recurrent miscarriage-related endocrinological disorders
can be effectively treated. Finally, new therapeutic in combination with: idiopathic, spontaneous,
approaches and the pleiotropic effects of old ones have diagnosis, treatment immunology, autoanti-
led to improved fetalmaternal outcomes. bodies, antiphospholipid antibodies, aspirin, low
molecular weight heparin, intravenous immuno-
globulin, progesterone parental cell inmunisation,
thrombophilia, treatment) to identify articles pub-
INTRODUCTION lished in English from Medline, PubMed and The
Recurrent miscarriage is one of the most frustrating Cochrane Library (2000January 2014). The initial
and difcult areas in reproductive medicine, since search identied more than 5000 articles using the
the aetiology is often unknown and evidence-based keywords (some were found in duplicate). We par-
diagnostic and treatment strategies are scarce. ticularly selected randomised controlled studies or
Recurrent miscarriage is classically dened as the meta-analyses when possible, followed by prospect-
loss of three or more consecutive pregnancies ive, matched or non-matched casecontrol, cohort
before the 20th week of gestation (molar, ectopic studies and reviews. Short cohort studies, short
and biochemical pregnancies are not included), reports, brief reports, editorials, opinion papers and
with or without previous live births. However, letters to the editor were excluded. Finally, only 271
many experts consider two consecutive losses suf- studies on recurrent miscarriage were considered
cient for diagnosis, and suggest an assessment after adequate and were nally collected and discussed.
each loss with a thorough evaluation after three or Some relevant articles before 2000 focusing on
more losses.1 general concerns about recurrent miscarriage were
The current classication of poor pregnancy out- also included. Finally, following journal policy, 100
comes is shown in gure 1. Recurrent miscarriage articles were selected for this review using our clinical
can be considered a primary or secondary process, and scientic judgement after a hard and accurate
depending on whether a live birth has occurred at review and discussion between CG-G and JA-R.
some time. No specic term has been coined to
describe women with non-consecutive pregnancy
losses interspersed with normal pregnancies. AETIOLOGY OF AND RISK FACTORS FOR
Couples suffering recurrent miscarriage mainly RECURRENT MISCARRIAGE
want to know the cause and the risk of further Epidemiological factors
recurrence. General aetiological categories of recur- Miscarriage occurs in up to 1520% of apparently
rent miscarriage include genetic, endocrine, ana- normal couples and becomes recurrent in 23% of
To cite: Garrido-Gimenez C,
Alijotas-Reig J. Postgrad
tomical, immunological, thrombophilic and these couples.3 The risk of fetal loss rises steeply
Med J Published Online environmental factors (box 1). When evaluating a after the age of 35 years,4 from 9.5% at 2024
First: [ please include Day patient, the physician should be aware of the years to 76% at 45 years and older. In clinical prac-
Month Year] doi:10.1136/ current classication, determine the nature of previ- tice, the chances of a successful pregnancy in
postgradmedj-2014-132672 ous pregnancy losses, and collect all possible risk women 40 years are poor, when risks of

Garrido-Gimenez
CopyrightC, Article
et al. Postgrad Med J 2015;0:112.
author doi:10.1136/postgradmedj-2014-132672
(or their employer) 2015. Produced by BMJ Publishing Group Ltd under licence. 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 the risk of miscarriage is inuenced by the size and genetic
increase.5 content of the rearranged chromosomal segments.
Reproductive history is known to be an independent pre- The likelihood of a subsequent live birth in couples with an
dictor of future pregnancy outcome. Primigravidae and women abnormal karyotype and recurrent miscarriage is poorer than in
with a history of live births have a lower risk of miscarriage in couples with normal chromosomes (66% vs 78%);12 however,
their next gestation than those whose most recent pregnancy an abnormal karyotype might not be the cause of the recurrent
ended in miscarriage.3 Nevertheless, women with a history of miscarriage, and parental karyotype is not particularly predictive
live births may still miscarry in future gestations; however, the of a subsequent pregnancy.13 Recently, many genetic poly-
prognosis for successful pregnancy is better with secondary morphisms14 and genes responsible for impaired cyclic decidua-
recurrent miscarriage. Interestingly, it has been demonstrated lisation of the endometrium,15 apoptosis and inammatory
that the risk of further miscarriage increases after each succes- processes16 have also been found to be associated with recurrent
sive pregnancy loss, reaching 4550% after three consecutive miscarriage, and this is an active area of investigation.
losses,6 and the prognosis worsens with increasing maternal age. Furthermore, the sperm of male partners in recurrent miscar-
Fortunately, 90% of women who have had one miscarriage sub- riage appears to have a higher incidence of DNA damage and
sequently have a normal pregnancy and a healthy baby; 50 worse motility.17 Although increased numbers of sperm chromo-
60% are able to have a healthy baby after two miscarriages. some abnormalities have been described in couples with recur-
Even a woman who has had three miscarriages in a row still has rent miscarriages, only 7% of fetal trisomies have been shown
an approximately 40% chance of having a successful pregnancy to be associated with paternal meiotic errors.18 Interestingly, the
the fourth time. live birth rate in couples with structural chromosome abnormal-
Gestational age at the time of pregnancy loss should be con- ities who conceive spontaneously is higher (5065%) than that
sidered, since recurrent miscarriage typically occurs at a similar currently achieved after in vitro fertilisation (IVF) and preim-
gestational age in consecutive pregnancies.7 Most women with plantation genetic screening (2938%) per embryo transfer.19
recurrent miscarriage have early losses, a signicant proportion
of which are due to chromosomal aneuploidies, although these Abnormal embryonic karyotypes
are less common than in sporadic miscarriages.8 Few women Fetal aneuploidy is the leading cause of spontaneous miscarriage
with recurrent miscarriage have late miscarriages, which are in the rst 10 weeks of gestation. At least 50% of all miscarriages
often attributable to other causes and are rarely due to chromo- are probably associated with cytogenetic abnormalitiestrisomy,
somal aberrations. Furthermore, late pregnancy complications, polyploidy and monosomy X.20 In couples with recurrent mis-
including fetal growth restriction, preterm labour and pre- carriage, chromosomal abnormalities of the embryo account for
eclampsia, are associated with recurrent miscarriage.9 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
Genetic abnormalities
common in sporadic miscarriages than in recurrent miscar-
Genetic factors are the most common cause of early spontan-
riage.21 A low proportion of these women have late recurrent
eous miscarriage (5060%). However, it is important to distin-
miscarriages, usually before weeks 1516, and chromosomal
guish between the genetic abnormalities in parents and the
aberrations as a cause are rare.
genetic alterations of the conceptus.
Endocrine abnormalities
Parental chromosomal rearrangements Endocrine dysfunction may account for 1520% of all cases of
In approximately 24% of couples with recurrent miscarriage, recurrent miscarriage. Mild endocrine disease is not associated
one partnermore often the womanwill have a genetically with recurrent miscarriage; however, poorly controlled diabetes
balanced structural chromosome rearrangement, the most mellitus and signicant thyroid dysfunction have been associated
common being a balanced translocation (60% reciprocal and with recurrent miscarriage.22
40% Robertsonian, involving two homologous or non- Thyroid autoimmunity is also linked to recurrent miscarriage,
homologous acrocentric chromosomes).10 Chromosome inver- including those that are euthyroid. Interestingly, women with
sions are also associated with a higher risk of miscarriage,11 and high levels of anti-thyroid antibodies do not suffer more

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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

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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 mice unable to secrete Th2 cytokines have not always reported
possible mechanism for determining fetal survival in the miscarriages, suggesting that the former is not essential for a
womb.46 However, studies conducted in genetically decient normal pregnancy.47 Thus, alloreactive Th1 cells must be differ-
ently blocked or regulated, for instance, by regulatory T cells
(Tregs).
Box 2 Revised classication criteria for the Modications in different T cell subsets, particularly CD4
antiphospholipid antibody syndrome (Sydney criteria)* +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
Clinical criteria (one or more) avoid fetal allo-rejection by creating a tolerant microenviron-
1. Vascular thrombosis: one or more objectively conrmed ment particularly characterised by the expression of interleukin
episodes of arterial, venous or small-vessel thrombosis 10, transforming growth factor and indoleamine 23 deoxy-
occurring in any tissue organ. genase.48 50 Similarly, it has been proposed that progesterone,
2. Pregnancy morbidity: human chorionic gonadotropin (-hCG) and human placental
(a) one or more unexplained deaths of a morphologically growth hormone may modulate maternal tolerance to fetal
normal fetus (documented by ultrasound or by direct paternal antigens, perhaps by means of a reduction in uterine
examination) at or beyond the 10th week of gestation; OR natural killer (NK) cell activity, expanding Tregs, or both. Some
(b) one or more premature births of a morphologically authors have reported on the role played by different NK cell
normal neonate before the 34th week of gestation because receptors, particularly killer cell immunoglobulin-like receptors
of (i) eclampsia, pre-eclampsia dened according to (KIRs), their relationship with human leucocyte antigen C and
standard denitions or (ii) placental insufciency; OR fetalmaternal tolerance, and their possible pharmacological
(c) three or more unexplained consecutive spontaneous modulation.51 52
abortions before the 10th week of gestation, with maternal
anatomical or hormonal abnormalities and paternal and
maternal chromosomal causes excluded. Other immunological factors
Laboratory criteria (one or more, present on two or more A correlation between maternal coeliac disease and recurrent
occasions at least 12 weeks apart) miscarriage has been shown53; patients with proven coeliac
1. Lupus anticoagulant, detected according to the guidelines of disease should already be on a gluten-free diet.54 Thus, screen-
the International Society on Thrombosis and Haemostasis. ing for antibody to transglutaminase IgA isotype in the recurrent
2. Anticardiolipin antibody of IgG and/or IgM isotype, in serum miscarriage population could be warranted. However, in our
or plasma, present in medium or high titre (>40 GPL or clinical practice and after many years of testing women with
MPL, or >99th centile), measured by a standardised ELISA recurrent miscarriage for coeliac disease, no data supporting
method. that relationship have been obtained (unpublished results).
3. Antibody to 2-glycoprotein I of IgG and/or IgM isotype, in
serum or plasma in titres (>99th centile), measured by a Inherited thrombophilic disorders
standardised ELISA method according to recommended There is a large and contradictory literature on the association
procedures. between maternal inherited thrombophilia and recurrent miscar-
riage. However, current studies have generally reported an asso-
*See Miyakis et al.41 ciation particularly for late fetal loss. The presumed mechanism
In studies of populations of women who have more than one type of seems to be the thrombosis of the uteroplacental circulation.
pregnancy morbidity, investigators are strongly encouraged to stratify The most prevalent polymorphisms are the heterozygous
groups of women as listed in (a), (b), (c). variant of factor V Leiden and the abnormal heterozygous pro-
Patients with antiphospholipid syndrome should be classied into thrombin gene (G20210A).55 Recurrent miscarriage has also
one of the following laboratory categories: I, more than one been related to the presence of other mutations, such as 4G/5G
laboratory criterion present; IIa, LA present alone; IIb, plasminogen activator inhibitor and the homozygosity for methy-
anticardiolipin antibodies present alone; IIc, anti-2-glycoprotein I
lenetetrahydrofolate reductase (MTHFR). The association with
antibody alone.
other deciencies such as protein C or protein S is still debated.56

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some confounding factors render it difcult to obtain reliable


Box 3 Suggested regimens for the treatment of APS in data. Cigarette smoking, alcohol and moderate-to-heavy caffeine
pregnancy* and cocaine use58 59 may be associated with sporadic miscar-
riages; however, the relationship between these factors and
recurrent miscarriage is unclear.
(A) Women with APS without previous thrombosis and recurrent
No high-quality evidence exists supporting a relationship
early ( pre-embryonic or embryonic) miscarriage: LDA together
between recurrent miscarriage and occupational factors, stress
with either prophylactic unfractionated heparin (50007500 IU
or low-level exposure to most environmental chemicals.2
SC/12 h) or LMWH (enoxaparin, tinzaparin, bemiparin or
Obesity (body mass index >29.9 kg/m2) is associated with a
dalteparin, in usual prophylactic doses SC/24 h) (Grade 1B).
higher rate of miscarriage; its relationship with recurrent miscar-
After delivery, postpartum thromboprophylaxis with warfarin or
riage, however, remains uncertain.60 Exercise does not appear
better, LMWH, is indicated for 6 weeks.
to increase the rate of recurrent miscarriage.61
(B) Women with APS without previous thrombosis and isolated
or recurrent fetal death (more than 10 weeks gestation) or
New risk factors: circulating microparticles, glycoproteins
previous early delivery (<34 weeks gestation) due to early
and leptin
severe pre-eclampsia or placental insufciency: LDA plus
Circulating microparticles represent subcellular elements for cell
prophylactic or intermediate-unfractionated heparin (7500
signalling and intercellular communication in inammation and
10 000 IU SC every 12 h, or every 812 h adjusted to maintain
thrombosis, and are believed to induce coagulation. They are
the mid-interval aPTT 1.5 times the control mean) or LMWH
increased during pregnancy and in complicated pregnancy disor-
(usual low or intermediate prophylactic doses, eg, enoxaparin
ders.62 Recent studies found a correlation between circulating
40 mg or 60 mg SC/24 h). After delivery, postpartum
microparticles, including trophoblastic ones, and recurrent
thromboprophylaxis with warfarin or better, LMWH, is indicated
miscarriage.
for 6 weeks.
Some proteins appear to be downregulated in patients who
(C) Women with APS and previous thrombosis: LDA plus
have early recurrent miscarriages. Examples include hCG, glyco-
therapeutic unfractionated heparin (SC every 812 h adjusted to
delin (glycoproteins secreted in high amounts by the trophoblast
maintain the mid-interval aPTT or heparin concentration
or the decidualised endometrium mainly during the rst trimes-
anti-factor Xa activity in the therapeutic range) or LMWH
ter of pregnancy), and galectin-1 expression in the syncytiotro-
(therapeutic dose, ie, enoxaparin 1 mg/kg SC, or dalteparin
phoblast.63 Furthermore, low serum leptin levels were observed
100 U/kg SC/12 h, or enoxaparin 1.5 mg/kg/day SC, or
in women suffering spontaneous miscarriage in the rst trimes-
dalteparin 200 U/kg/day SC). After delivery, thromboprophylaxis
ter of pregnancy.64 The promising results of preliminary studies,
(secondary) with warfarin or LMWH (therapeutic dose) is
as mentioned previously, showing the role played by the diverse
indicated for life.
KIRs expressed by NK cells in recurrent miscarriage and in
*Modied from Bates et al.66 recurrent IVF failure require further assessment.52 65
Lactation is not a contraindication to warfarin or heparin use.
Women without a lupus anticoagulant in whom the aPTT is normal EVALUATION AND MANAGEMENT OF RECURRENT
can be monitored with the aPTT. Women with lupus anticoagulant MISCARRIAGE
should be monitored with anti-factor Xa activity. Couples suffering recurrent miscarriage need empathy, since for
Need for dose adjustments over the course of pregnancy remains them this is a traumatic experience. Evaluation can be frustrat-
controversial. Some experts argue that, in the absence of better ing and difcult because the aetiology may not be established.
evidence, it is prudent to monitor anti-factor Xa LMWH concentrations Couples should be (table 2) informed that the prognosis of
46 h after injection, with dose adjustment to maintain a therapeutic recurrent miscarriage is favourable, even without any interven-
anti-factor Xa concentration (0.61.1 U/mL) if a twice-daily regimen is tion,72 although most couples do not accept the conservative
used, and slightly higher if a once-daily regimen is chosen. approach.
APS, antiphospholipid syndrome; aPTT, activated partial thromboplastin First, a complete medical history should be obtained, with
time; LDA, low-dose aspirin; LMWH, low-molecular-weight heparin; SC, special attention paid to personal or family history of throm-
subcutaneously.
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
It has also been reported that the presence of combined thrombo-
occurs at a similar gestational age in consecutive pregnancies
philic disorders increases the rate of recurrent miscarriage, par-
and the aetiology could vary in early and late miscarriages.
ticularly late miscarriage. Finally, no studies associating recurrent
Physical examination should include a general assessment with
miscarriage with paternal thrombophilia have been reported.
attention to signs of endocrinopathy (eg, hirsutism, galactor-
rhoea), autoimmune disease (eg, malar blushing, telangiectasia)
Infective agents and pelvic organ abnormalities (eg, uterine malformation, cer-
Infectious diseases are rarely a cause of early miscarriage. No vical laceration). The most useful tests should then be analysed
factual association has been found between bacterial and viral separately in the evaluation of recurrent miscarriage (tables 1
organisms and recurrent miscarriage, although Chlamydia, and 2).
Mycoplasma, Ureaplasma, Listeria, Toxoplasma, Rubella, cyto-
megalovirus, herpes virus and parvoviruses have been associated Genetic abnormalities
with spontaneous miscarriage.57 Genetic counselling is important when a genetic factor is identi-
ed. However, peripheral karyotyping is expensive and does not
Lifestyle and environmental factors always provide valuable information on recurrent miscarriage;
The effects of environmental exposure on pregnancy, particu- thus, this test could be avoided in many couples, although
larly in recurrent miscarriage, remain a matter of debate, since current guidelines still recommend parental karyotyping.

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Table 1 Proposed evaluation of women with recurrent miscarriage*


Appraisal Comments/recommendations

Medical history
Ask about gestational age of miscarriage Pre-embryonic and embryonic are the most common type of recurrent miscarriage.
The aetiology may differ from cases of losses occurring later.
Assess obstetric history Poor obstetric outcomes, such as early and late miscarriage, pre-eclampsia, stillbirth
and prematurity, are major predictors of subsequent pregnancy risk complications.
Assess history of uterine malformations and cervical incompetence Previous obstetric complications such as miscarriage, preterm labour or breech
presentation may suggest uterine malformation or cervical incompetence.
Assess whether the mother has had a fetus or child with an inherited anomaly Congenital abnormalities raise the possibility of a parental chromosomal abnormality.
Evaluate findings related to APS Features include thrombosis, fetal death, pre-eclampsia and other poor obstetric
outcomes, livedo reticularis, thrombocytopenia and autoimmune diseases.
Ask whether the patient has a history of thyroid abnormalities, diabetes or Consider overt clinical and subclinical forms of hypothyroidism. Do not contemplate
polycystic ovary syndrome cases of subclinical thyroid hyperfunction. Be aware in cases of recurrent miscarriage
and TSH ranging from 2.5 to 4.5 IU.
Assess personal or family history of thromboembolic diseases Venous thromboembolic history, mainly in young people and in uncommon locations,
may be related to inherited thrombophilias and/or APS.
Physical examination
Perform pelvic and uterine examination Standard manual pelvic examination cannot rule out cervical abnormalities.
Look for signs of thyroid diseases, diabetes, obesity and hyperandrogenaemia Complete physical examination.
Look for signs related to systemic autoimmune diseases 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.
Usually recommended test: pros and cons
Sonohysterography and hysterosalpingography 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.
Chromosomal analyses of the couple 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.
Sperm morphology Although frequently recommended, sperm morphology analyses do not appear to be
predictive of further miscarriages.
Sperm DNA studies 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.
Chromosomal analyses of products of conception 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.
Preimplantation genetic screening in IVF This screening genetic test, using FISH, does not improve the live birth rate and
should probably not be recommended.
aPL panel according to Sydney recommendations 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.
Inherited thrombophilic disorders 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.
Not recommended laboratory tests
Progesterone levels in previous luteal phase, atypical aPLs, anti-Mllerian hormone, Overall, these tests are not systematically recommended. These parameters may be
anti-paternal cytotoxic antibodies, HLA class I/II screening, cytokine numbering and tested only for clinical research reasons in monographic units.
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- miscarriage, except in those who are carriers of Robertsonian
mend conceptus karyotype analysis, albeit controversial, since it translocations involving chromosome 21.
can offer useful information73that is, an aneuploid conceptus
indicates a better chance of success in a subsequent pregnancy.74 Endocrine abnormalities
Preimplantation genetic screening of biopsied blastomeres Routine screening for diabetes mellitus should be limited to
during IVF has not shown any improvement in clinical out- women with clinical manifestations of the disease. Neither
comes,19 and thus its use is debateable in couples with recurrent 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, No clear evidence exists to support the routine use of exogen-
thyroid antibodies should be evaluated in women with recurrent ous progesterone supplementation during the rst trimester to
miscarriage, including those with aPLs, since there is an apparent prevent miscarriage. However, although randomised studies in
interaction between them.25 76 Women with overt hypothyroid- this setting are lacking, there appears to be evidence of benet
ism or hyperthyroidism obviously require treatment, but this is in women with a history of recurrent miscarriage.68 A large ran-
less clear for women with subclinical hypothyroidism and domised, double-blind, placebo-controlled multicentre trial
thyroid autoimmunity.77 To date, the only prospective rando- (PROMISE; http://www.medscinet.net/promise) is currently
mised controlled trial evaluating treatment in euthyroid women underway to assess the benet of progesterone supplementation
with positive thyroid antibodies was performed by Negro et al,78 in women with unexplained recurrent miscarriage.
showing a statistically signicant reduction in miscarriages in Data supporting an association between alterations in prolac-
women who received levothyroxine. Furthermore, thyroid- tin levels and recurrent miscarriage are lacking; however, in
stimulating hormone (TSH) levels should be kept below 2.53 cases of detected hyperprolactinaemia, it may be appropriate to
IU, as one study concluded that there is a higher incidence of mis- treat with cabergoline or bromocriptine.28
carriage when TSH levels are above this range.79 The treatment
of subclinical hyperthyroidism during pregnancy is currently Anatomical factors
considered to be unwarranted, since it is not associated with Gynaecological ultrasound is recommended in women with
adverse pregnancy outcomes. recurrent miscarriage, since it is an available, non-invasive and
The use of metformin for women with anovulatory PCOS cost-effective method for detecting uterine disorders, while the
showed no benet with respect to enhancing either fertility or systematic use of hysteroscopy, CT, MRI or hysterosalpingogra-
live birth rates; thus, its routine use is not recommended.80 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 alternative. In cases of refractory obstetric APS (2025% of cases),
malformations, re-establishing the normal anatomy seems to promising results have been obtained with the addition of hydroxy-
improve gestational prognosis.81 Observational studies found an chloroquine or low-dose prednisolone to standard treatment.71
improvement in gestational outcomes in patients with uterine Similarly, other therapeutic regimens have been proposed, such as
septum following hysteroscopic metroplasty.82 Furthermore, it vitamin D, fondaparinux or pentoxifylline;86 however, they should
seems that myomectomy of submucous leiomyomata before con- be tested in well-designed clinical trials before their general use is
ception reduces the rate of miscarriage;33 however, it is less approved.
clear when broids do not distort the uterine cavity.83 The clin-
ical management of miscarriage in patients with Ashermans
Inherited thrombophilic disorders
syndrome/intrauterine synechiae or uterine polyps is controver-
Routine testing for inherited thrombophilias in women with
sial, and there is no conclusive evidence that surgical treatment
recurrent miscarriages is not currently recommended. Screening
reduces the risk of miscarriage.36
may be clinically justied when a history of thromboembolism
For women with late recurrent miscarriage or three or more
with no risk factors, such as surgery or late recurrent miscar-
early preterm births who have risk factors for cervical insuf-
riages, does exist.70
ciency, cervical cerclage is indicated. Measurement of cervical
Consensus on whether or not to treat cases of recurrent mis-
length with transvaginal ultrasound during pregnancy could
carriage with associated congenital thrombophilia using aspirin,
detect patients with a short cervix (<25 mm) before 24 weeks,
heparin or both is lacking.87
and vaginal progesterone administration or cervical pessary
could reduce the risk of late miscarriage or preterm birth.84
Infective agents
Routine cervical cultures, vaginal evaluation for bacterial vagin-
Immune factors
osis, and toxoplasmosis serology are not useful in the evaluation
Women with recurrent miscarriage should also be tested for
of recurrent miscarriage in otherwise healthy women. Although
lupus anticoagulant, aCLs and 2-glycoprotein I antibodies
some authors, including a Cochrane review,88 support them,
(IgG/IgM isotypes) using standard assays. The tests should be
these screening tests are currently not recommended.
performed twice, 12 weeks apart, since transient positive levels
can be due to infections or drugs and spontaneously revert to
normal.43 Unexplained recurrent miscarriage
The recommended therapy in women with aPL/APS-related If no cause for recurrent miscarriage is established, a lifestyle
recurrent miscarriage consists of prophylactic low-molecular-weight modication should be recommended. Epidemiological studies
heparin (LMWH) plus low-dose aspirin (LDA), which was found to suggest that lifestyle modications can increase fertility, although
be superior to treatment with LDA alone (74.2% vs 55.8% live they have not been denitively tested in randomised trials.
birth rate)66 85 (box 3). The use of LMWH is preferable because of These modications include eliminating toxic habits and caf-
its greater safety and efcacy compared with unfractionated feine, following a well-balanced diet, and reducing body mass
heparin; however, unfractionated heparin remains an acceptable index in obese women.89

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Furthermore, there seems to be a rationale for the use of a Glucocorticoids have several anti-inammatory effects,
combination of LDA and prophylactic heparin in the treatment including suppression of NK cell number and activity in the
of unexplained recurrent miscarriage.67 Several trials have endometrium; however, the high rate of adverse effects (eg, ges-
emphasised the benet of LMWH,90 although some studies tational diabetes and hypertension) renders their use for recur-
found no advantages of its use.91 Despite this, and taking into rent miscarriage controversial (gure 3).97 98
account its probable benet and small potential risk, LMWH
could be considered an experimental drug for patients with
SUMMARY
recurrent miscarriages until further conclusive data from con-
Recurrent miscarriage can be evaluated after two clinical pregnancy
trolled clinical trials become available.
losses. Assessment of recurrent miscarriage focuses on medical
Although no alloimmune mechanism has been proven to cause
history, physical examination and recommended laboratory tests;
recurrent miscarriage, some immune-modulating therapies have
however, up to 50% of cases will not have a clearly dened aeti-
been used to treat these women. However, systematic reviews have
ology. The prognosis of subsequent pregnancies is generally good
consistently found no benecial effect of immunotherapy for treat-
even without treatment, and patients should be informed that solid
ing unexplained recurrent miscarriage. Therapy with paternal
evidence is lacking to support several commonly used interventions
leucocyte immunisation and intravenous immunoglobulins
and treatments for recurrent miscarriage.
(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 Current research questions
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 Could patients with recurrent miscarriage and elevated
factor in the treatment of both unexplained recurrent miscarriage circulating microparticle levels benet from
and recurrent in vitro implantation failure are now available.95 96 low-molecular-weight heparin and/or low-dose aspirin
However, the paucity of well-designed studies does not support during pregnancy?
the use of these therapies in routine clinical practice. 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
Main messages
women with inherited thrombophilia and recurrent
rst-trimester miscarriage?
Approximately 5% and 23% of couples trying to conceive Can immunotherapy, particularly maternal sensitisation with
have, respectively, two or three consecutive miscarriages. paternal-derived cells and treatment with granulocyte
Recurrent miscarriage typically occurs at a similar gestational colony-stimulating factor, be an effective treatment for
age in consecutive pregnancies. recurrent miscarriage?
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 Key references
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Acknowledgements We thank Ms Christine OHara for reviewing and correcting


Self assessment questions 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
1. Which of the following statements regarding miscarriage is present paper is published with permission of the publishers.
false? Contributors CG-G and JA-R contributed to the conception and design of this
A. Approximately 5% of couples trying to conceive have research, drafting the article and critically revising it, and nal approval of the
version to be published.
two consecutive miscarriages, and approximately 2% of
couples have three or more consecutive losses. Competing interests None.
B. The aetiology is not established in up to 50% of cases. Patient consent Obtained.
C. The term early miscarriage means involuntary Provenance and peer review Not commissioned; externally peer reviewed.
pregnancy loss before the 12th week of gestation.
D. The American Society for Reproductive Medicine 2008
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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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