www.thelancet.com Vol 368 August 12, 2006 601
Raj Rai, Lesley Regan
Many human conceptions are genetically abnormal and end in miscarriage, which is the commonest complication of
pregnancy. Recurrent miscarriage, the loss of three or more consecutive pregnancies, aff ects 1% of couples trying to
conceive. It is associated with psychological morbidity, and has often proven to be frustrating for both patient and
clinician. A third of women attending specialist clinics are clinically depressed, and one in fi ve have levels of anxiety
that are similar to those in psychiatric outpatient populations. Many conventional beliefs about the cause and
treatment of women with recurrent miscarriage have not withstood scrutiny, but progress has been made. Research
has emphasised the importance of recurrent miscarriage in the range of reproductive failure linking subfertility and
late pregnancy complications and has allowed us to reject practice based on anecdotal evidence in favour of evidence-
Miscarriage, the commonest complication of pregnancy,
is the spontaneous loss of a pregnancy before the fetus
has reached viability. The term therefore includes all
pregnancy losses from the time of conception until
24 weeks of gestation. Although 15% of clinically
recognised pregnancies miscarry, total reproductive losses
are closer to 50% (fi gure 1).1–3 There are two types of
miscarriage: sporadic and
miscarriage aff ects about 1% of couples.4 By contrast, at
least 25% and probably as many as 50% of all women
experience one or more sporadic miscarriages, usually
due to random fetal chromosomal abnormalities,4–6 the
risk of which rises with increasing maternal age.7
Recurrent miscarriage, defi ned as three or more
consecutive pregnancy losses, is part of a range of
reproductive disorders sharing a common underlying
cause (fi gure 2).4–6 Many clinicians defi ne recurrent
miscarriage as two or more losses; this increases the
scale of the problem from 1% to 5% of all couples trying
to conceive.8 Evidence suggests that defects in the depth
and quality of implantation lead to adverse outcomes in
all three trimesters of pregnancy. However, several
features suggest that recurrent miscarriage is a distinct
clinical entity: (1) a woman’s risk of miscarriage is
directly related to the outcomes of previous preg-
nancies,9–12 (2) the observed incidence of recurrent mis-
carriage (1%) is much higher than that expected by
chance alone (0·34%),13 (3) unlike sporadic miscarriage,
recur rent miscarriage tends to occur even if the fetus
has a normal chromosome complement,4,14 and (4) recur-
rent miscarriage tends to aff ect women with specifi c
reproductive characteristics15–18 (table 1).
Reproductive behaviour in our society has changed;
many women now choose to delay childbearing.
According to UK census data the number of babies born
to mothers aged 35 years or more doubled between 1985
and 2001—from 8% to 16% of total births. Although no
comparable fi gures are available for miscarriages, it is
logical to conclude that the rate of miscarriage has also
increased. A large prospective register linkage study has
shown that maternal age at conception is a strong,
independent risk factor for miscarriage,12 due to an
increase in chromosomally abnormal conceptions
(fi gure 3).4,19 The risk of fetal loss increases steeply after
the age of 35 years, rising from 9% at 20–24 years to 75%
at 45 years and older (table 2).12 The chance of a successful
pregnancy in women aged 40 years or more is poor, with
risks of miscarriage, ectopic pregnancy, or stillbirth
becoming much higher than in women in their 30s.12
Reproductive history is an independent predictor of
future pregnancy outcome. Primigravidae and women
with a history of livebirths have a lower risk of miscarriage
in their next pregnancy than women whose most recent
pregnancy ended in miscarriage.10 However, women who
have had previous livebirths are not precluded from
recurrent miscarriage.16,17 Both
prospective10,12 studies have shown that the risk of a
further miscarriage increases after each successive
pregnancy loss, reaching 45% after three consecutive
pregnancy losses. The increased risk is partly explained
by the fact that women who miscarry tend to embark on
subsequent pregnancies at progressively later ages.
Most investigations into the eff ects of environmental
exposure on pregnancy have concentrated on the rate of
sporadic miscarriage rather than recurrent miscarriage.
The results are confl icting—biased by diffi culties in
controlling for confounding factors and the lack of accurate
Lancet 2006; 368: 601–11
Department of Obstetrics and
Gynaecology, St Mary’s
Campus, Imperial College
London, Mint Wing, South
Wharf Road, London W2 1PG,
UK (R Rai MD, Prof L Regan MD)
Prof Lesley Regan
Search strategy and selection criteria
We searched the Cochrane Library (Issue 2, 2006), MEDLINE
(1990– March 2006), and EMBASE (1990–March 2006) with
the search terms: “miscarriage”, “recurrent miscarriage”,
“abortion” or “recurrent abortion”, alone and in combination
with “epidemiology”, “diagnosis”, “treatment”,
“immunology”, “reproductive immunology”, “assisted
conception”, “IVF”, “progesterone”, “aspirin”, “heparin”,
“steroids”, “IVIG”, and “intravenous immunoglobulin”. We
searched the reference lists of articles identifi ed by this search
for further studies. Only articles published in English were
www.thelancet.com Vol 368 August 12, 2006
data on exposure or toxin dose. However, some
environmental factors have been shown to aff ect pregnancy
outcomes. Cigarette smoking has an adverse eff ect on
trophoblast function and is associated with a dose-
dependent increased risk of miscarriage.20 Cocaine use
confers an independent risk of pregnancy loss.21 Alcohol
has adverse eff ects on fertility and fetal development: even
moderate consumption of 3–5 units per week has been
shown to heighten the risk of miscarriage.22 Caff eine
consumption is also associated with a dose-dependent risk
of miscarriage, which increases when intake exceeds
300 mg (three cups) of coff ee daily.23 Some types of
occupational exposure, such as working with visual display
units, do not seem to intensify the risk of miscarriage,24 but
the evidence for adverse eff ects of anaesthetic gases on
surgical workers is contradictory.25 The likelihood of
miscarriage might also rise if either non-steroidal anti-
infl ammatory drugs or some antidepressant drugs are
used during the periconceptual period.26,27 In the UK,
obesity now aff ects 20% of the female population, and
evidence suggests that obesity is a risk factor for infertility,28
miscarriage,16,29 and late pregnancy complications.30
Causes of recurrent miscarriage
Historically, recurrent miscarriage has been attributed to
either genetic, structural, infective, endocrine, immune,
or unexplained causes. Thrombophilic disorders are now
thought to play a part in the cause of recurrent pregnancy
loss, which widens the scope of investigations and
management options for recurrent miscarriage.
Fetal aneuploidy is the most important cause of
miscarriage before ten weeks’ gestation.31 At least 50–60%
of all miscarriages are associated with cytogenetic
abnormalities, the most frequent being trisomy, followed
by polyploidy and monosomy X.4,5,32,33 Most human
aneuploidies arise from errors in the fi rst meiotic division
of the oocyte, which is initiated prenatally and is not
complete until ovulation. An increased rate of sperm
chromosome abnormalities has also been reported in
couples with recurrent miscarriage,34 but only 7% of fetal
trisomies have been shown to arise from paternal meiotic
errors.35 Despite the recognised association between
advancing maternal age and fetal aneuploidy, little is
known about the underlying mechanisms. One hypothesis
is that women have a limited oocyte pool, and that
increasing age results in a relative scarcity of oocytes at
optimum stages of maturation.36 Thus women who have
lost at least one trisomic fetus have been reported to have
a diminished ovarian reserve and to enter the menopause
at an earlier age than those with no such history.37,38 Some
women with recurrent miscarriage might be more prone
to heterotrisomy—ie, recurrence of a diff erent trisomy
after a trisomic pregnancy.39 One screening study of
couples with recurrent miscarriage undergoing in-vitro
fertilisation showed that they had more abnormal embryos
than an age-matched control group with no history of
In about 4% of couples with recurrent miscarriage one
partner carries either a balanced reciprocal translocation,
in which there is an exchange of two terminal segments
from diff erent chromosomes, or a Robertsonian trans-
location, in which there is centric fusion of two acrocentric
chromosomes.16 Carriers of a balanced reciprocal trans-
location are phenotypically normal, but 50–70% of their
gametes and hence embryos are unbalanced, because of
abnormal segregation at meiosis. The reproductive risk
conferred by chromosome rearrangements is dependent
Number reaching stage
Figure 1: Number of conceptions expected to reach each stage of pregnancy1
Prematurity Early miscarriage
1st trimester2nd trimester3rd trimester
Figure 2: Range of adverse pregnancy outcomes
IUGR=intrauterine growth restriction.
Number of women
Conception delays/fertility investigations
Late miscarriage (second trimester)
Stillbirth or neonatal death
Abortion for fetal abnormality
Pregnancy complicated by prematurity or fetal
Table 1: Reproductive characteristics associated with poor pregnancy
prognosis and recurrent miscarriage15
www.thelancet.com Vol 368 August 12, 2006 603
on the type of rearrangement and whether it is carried by
the woman or her male partner.41 The livebirth rate in
couples with a structural chromosome abnormality who
conceive spontaneously is higher (50–65%)42 than that
currently achieved after in-vitro fertilisation and
preimplantation genetic screening, which is 29% per
oocyte retrieval and 38% per embryo transfer.43
Transcervical embryoscopy has shown that aneuploid
embryos have disordered growth and development (such
as anencephaly and facial and limb dysplasia), and that
similar abnormalities are found in up to 18% of euploid
pregnancies ending in miscarriage.44
The frequency of congenital uterine abnormalities
(uterine septae and bicornuate uterus) in the general
population is unknown, but in women with recurrent
miscarriage it has been reported to be between 1·8% and
37·6%.45–47 This wide range refl ects diff erences in diagnostic
criteria and the imaging techniques used. A retrospective
review of patients with uncorrected abnormalities suggests
that they undergo high rates of miscarriage and preterm
delivery.45 However, the benefi ts of surgical correction
(open or hysteroscopic) on pregnancy outcome have not
yet been assessed by a randomised trial.
Uterine fi broids are present in up to 30% of women, but
their eff ect on reproductive outcome is controversial.48
Most studies report that implantation failure after in-vitro
fertilisation is linked to either intramural or submucosal
fi broids, but this fi nding could indicate publication bias.
The mechanism or mechanisms by which fi broids could
cause early pregnancy loss are unclear. Traditionally,
researchers have postulated that uterine fi broids have a
mechanical or space-occupying eff ect that impedes
embryonic implantation. The expression of HOX10, a gene
that controls diff erentiation and is involved in implantation,
has now been shown to be lower in uteri with fi broids than
in those without.49
A diagnosis of cervical incompetence, based on a
history of late miscarriage preceded by spontaneous
rupture of membranes or painless cervical dilatation, is
frequently cited as a cause of midtrimester recurrent
miscarriage.16,50 However, no objective tests can reliably
identify women with cervical weakness in the non-
pregnant state. A Cochrane review identifi ed no
conclusive evidence that prophylactic cervical cerclage
reduces the risk of recurrent midtrimester miscarriage.51
Therefore, the value of serial ultrasound assessments of
cervical shortening and the insertion of a rescue cerclage
for prevention of late miscarriage and preterm delivery
are questionable.52,53 In our experience, the success of
cerclage is determined by detailed clinical history,
treatment of coexistent thrombophilic disorders and
prophylactic antibiotics. More important is the skill and
experience of the surgeon, and their ability to bury the
suture material under the vaginal mucosa to keep
vaginal discharge to a minimum.54 Abdominal cerclage
has been advocated for selected women with previous
failed vaginal cerclage. However, a systematic review
comparing the two techniques concluded that although
abdominal cerclage might reduce perinatal death, it is
associated with a higher risk of serious operative
Infective causes of recurrent miscarriage remain
speculative. For any infective agent to be implicated, it
must be capable of persisting in the genital tract undetected
and must cause few maternal symptoms. Because
toxoplasmosis, rubella, cytomegalovirus, herpes, and
listeria infections do not meet these criteria, routine
screening for these diseases has now been abandoned.56
The evidence for bacterial vaginosis as a cause of early
miscarriage secondary to endometritis is inconsistent,57,58
but the presence of bacterial vaginosis during the fi rst
trimester of pregnancy has been repeatedly reported as a
risk factor for late miscarriage and early preterm birth.59
One randomised controlled trial in a low-risk obstetric
population showed that the risk of late miscarriage and
preterm birth is reduced by screening women for bacterial
vaginosis in early pregnancy and treating with oral
clindamycin.60 However, investigators in no less than eight
randomised trials concluded that there is no benefi t in
screening and treating all pregnant women for bacterial
vaginosis to prevent preterm birth. By contrast, the
Cochrane review suggested that detection and treatment of
bacterial vaginosis early in pregnancy might prevent
preterm delivery in women with a history of preterm
Figure 3: Proportion of miscarriages due to fetal aneuploidy by maternal age
Age (years) Total number of pregnanciesMiscarriage rate
Table 2: Miscarriage rates stratifi ed by maternal age at conception11
www.thelancet.com Vol 368 August 12, 2006
Endocrine disturbances have been postulated to cause
recurrent miscarriage, but few reports withstand scrutiny.
Well controlled diabetes is not a risk factor for recurrent
miscarriage.62,63 A meta-analysis reported an association
between the presence of thyroid autoantibodies, a history
of one or two miscarriages, and the outcome of the next
pregnancy.64 However, no association is found if analysis
is restricted to those with recurrent miscarriage.64,65
Prolactin has a role in both ovulation and endometrial
maturation. Hyperprolactinaemia is reported to cause
recurrent miscarriage, and treatment with bromocriptene,
which suppresses prolactin secretion by the anterior
pituitary, signifi cantly reduces the rate of miscarriage.66
Lack of expression of endometrial prolactin during the
luteal phase of the menstrual cycle has also been associated
with recurrent miscarriage.67
Possible links between polycystic ovaries, the various
endocrinopathies associated with polycystic ovarian
syndrome, and recurrent miscarriage have been
investigated for the past three decades. The prevalence of
polycystic ovaries is signifi cantly higher in women with
recurrent miscarriage (40%) than in women with an
uncomplicated reproductive history (22%).68 However,
ovarian morphology per se is not predictive of the outcome
of future pregnancies without treatment.68 A placebo-
controlled randomised controlled trial reported that
suppression of high endogenous luteinising hormone
does not improve the rate of livebirths.69
Attention is now focused on the connection between
polycystic ovarian syndrome, insulin resistance, and
pregnancy loss. Insulin resistance is common in women
with recurrent miscarriage, and has been associated with
an increased rate of miscarriage.70,71 The mechanism might
include impairment of the fi brinolytic response, which is
important in the tissue remodelling that accompanies
embryonic implantation.72 Plasma concentrations of fi brin
are aff ected by the 4G/5G polymorphism in the
plasminogen activator inhibitor (PAI1) gene promoter.
Homozygosity for the 4G/4G polymorphism, which is
associated with hypofi brinolysis, is recorded signifi cantly
more often in women with polycystic ovaries and a history
of recurrent miscarriage than in women with normal
ovarian morphology.73 The fact that there is an insulin
response element in the promoter region of the PAI-1 gene
lends support to the hypothesis that hyperinsulinaemia is
associated with impairment of fi brinoylyis, which in turn
is associated with miscarriage.
From a traditional immunological perspective, survival
of the semiallogenic fetus is dependent on suppression
of the maternal immune response. However, although
lymphocyte function changes during pregnancy, no
generalised suppression of the maternal immune
response has been recorded. Indeed, randomised
therapeutic studies have refuted the usefulness of the
concept of immunising a mother (eg, with paternal
white blood cells) to prevent rejection of her genetically
dissimilar fetus.74,75 The contemporary understanding of
interaction between the maternal immune system and
fetal antigens.76 Interest centres on the link between
natural killer cells and reproductive failure. Natural
killer cells are lymphocytes, and are part of the innate
immune system. Peripheral blood and the uterine
mucosa each contain natural killer cells, but the cells
have important phenotypic and functional diff erences
in each location.77
The temporal and spatial distribution of natural killer
cells in the uterine mucosa suggests they contribute to
control of trophoblast invasion. Women with recurrent
miscarriage have more natural killer cells in their uterine
mucosa than controls and those with the highest levels
have a correspondingly high rate of miscarriage in
subsequent pregnancies without treatment.78–80 No
association between the levels of natural killer cells in
peripheral blood and in the uterine mucosa has been
recorded, and levels of natural killer cells in peripheral
blood are not predictive of pregnancy outcome in women
with unexplained recurrent miscarriage. Therefore, the
value of testing women with recurrent miscarriage for
levels of natural killer cells in peripheral blood is therefore
Natural killer cells in uterine mucosa contribute to the
cytokine response at the maternal-fetal interface. This
cytokine response is generally characterised either as a
T-helper-1 (Th-1) type (with production of interleukin 2,
interferon, and tumour necrosis factor α [TNFα]) or a
T-helper-2 (Th-2) type (with interleukins 4, 6, and 10).
Normal pregnancy might be the result of a Th-2 type
cytokine response, in which blocking antibodies mask fetal
trophoblast antigens from immunological recognition by a
maternal Th-1 cell-mediated cytotoxic response.82 By
contrast, women with recurrent miscarriage tend to
produce a predominantly Th-1 type response both in the
period of embryonic implantation and during pregnancy.83–86
These fi ndings support the view that disturbances of the
immune tolerance of the fetus could contribute to recurrent
miscarriage. We need to investigate (1) the subgroup of
women with recurrent miscarriage who produce a
dominant Th-1 cytokine profi le at the maternal-fetal
interface during pregnancy and (2) immunomodulatory
interventions designed to promote Th-2 dominance.
Some studies show high levels of various autoantibodies
in women with recurrent miscarriage,87,88 but this
association has not been conclusively proved. Prospective
data on pregnancy outcomes for women with or without
autoantibodies are also confl icting—but most studies
suggest there is no association.65,89–92 One placebo-controlled
randomised study showed that the use of steroids to
suppress autoantibody titres does not improve the livebirth
rate, and moreover can increase the risk of preterm
posits a cooperative
www.thelancet.com Vol 368 August 12, 2006 605
Antiphospholipid syndrome is the most important
treatable cause of recurrent miscarriage. Anti phospho-
lipid antibodies are a family of about 20 anti bodies that
are directed against phospholipid binding plasma
proteins. They include lupus anticoagulant and anti-
cardiolipin antibodies. Antiphospholipid syndrome was
originally defi ned as the association between anti-
phospholipid antibodies and either recurrent mis-
carriage, thrombosis, or thrombocytopenia.94 The clinical
criteria now used to diagnose antiphospholipid syn-
drome are shown in the panel.95 The prevalence of
antiphospholipid syndrome in women with recurrent
miscarriage is 15%;96,97 women with the syndrome have a
miscarriage rate of 90% in subsequent untreated
pregnancies.98 Various treatments—including aspirin,
steroids, intravenous immunoglobulin and heparin—
have been used in attempts to improve the pregnancy
outcome of women with antiphospholipid syndrome.
However, a meta-analysis shows that only a combination
of heparin and aspirin can signifi cantly improve the
livebirth rate in women with recurrent miscarriage and
antiphospholipid syndrome (fi gure 4).99 This treatment
enhances pregnancy outcome by 54%, to achieve a
livebirth rate of over 70% in women with the
syndrome.100,101 Although one trial did not show a benefi t
in adding heparin to aspirin,102 it included several
women with low positive titres for anticardiolipin
antibodies, who were randomly assigned to treatment
at a late stage when pregnancy outcome was more likely
to be successful. Furthermore, nearly 25% of participants
in this study switched treatment groups. Traditionally,
pregnancy loss associated with antiphospholipid
antibodies has been ascribed to thrombosis and
infarction of the uteroplacental vasculature.103–105
However these fi ndings are neither universal nor
specifi c to antiphospholipid syndrome,106,107 and have
been challenged by advances in our understanding of
early pregnancy development and the biology of
antiphospholipid antibodies. In-vitro studies show that
antiphospholipid antibodies interfere with the signal
transduction mechanisms controlling endometrial cell
decidualisation;108 promote trophoblast apoptosis;109
decrease trophoblast fusion;109–112 and impair trophoblast
invasion.107,113 The eff ects of antiphospholipid antibodies
on trophoblast function are reversed in vitro by low-
Pregnancy is a hypercoaguable state.117,118 The evolutionary
advantage of such a change in haemostasis is to
counteract the inherent instability associated with
haemochorial placentation, which is unique to human
beings. The fi rst studies of the prevalence of coagulation
abnormalities in women with a history of adverse
pregnancy outcome appeared in the mid-1990s.119,120
Three common thrombophilic mutations were identifi ed:
Factor V (Leiden) G1691A; factor II (prothrombin)
G20210A and methylene tetrahydrofolate reductase
C677T. Since then, many publications have reported that
individual coagulation defects are either as frequent or
more frequent in women with recurrent miscarriage
than they are in controls.
Data on the frequency of genetic thrombophilia are
compromised by the small size of individual studies,
stratifi cation bias and poor matching of cases and
controls due to racial heterogeneity. Nonetheless, two
meta-analyses have confi rmed an association between
recurrent miscarriage and gene mutations in Factor
V Leiden and prothrombin.121,122 There are few prospective
data on the outcome of untreated pregnancies in women
with genetic thrombophilic defects. The largest
published study of 19 women with unexplained fi rst
trimester recurrent miscarriage, who were heterozygous
for the Factor V Leiden mutation, showed that they had
a signifi cantly lower rate of livebirth (37·5%) than a
control group of 100 women with recurrent miscarriage,
who had the normal Factor V genotype (69·5%; odds
ratio 3·75, 95% CI 1·3–10·9).123 However, women with
the Factor V Leiden mutation were not precluded from
having an uncomplicated
Additional comorbid disorders probably diff erentiate
between these outcomes, and multiple risk factors
increase the likelihood of adverse pregnancy outcomes
in carriers of weakly prothrombotic genotypes.124 Indeed
one European cohort study identifi ed a 14-fold increased
Panel: Criteria for diagnosis of antiphospholipid
● Three or more consecutive unexplained miscarriages
before 10th week of gestation
● One or more unexplained deaths of a morphologically
normal fetus at 10 weeks’ gestation or older
● One or more premature births of a morphologically
normal fetus at 34 weeks’ gestation or younger associated
with severe pre-eclampsia or placental insuffi ciency
0 1·01·0 2·03·0 4·0
vs aspirin or placebo
Aspirin vs placebo
or usual care
Figure 4: Meta-analysis of treatments for pregnancy loss associated with
www.thelancet.com Vol 368 August 12, 2006
risk of stillbirth in patients with combined thrombophilic
Since individual genetic thrombophilic defects have
little value in predicting pregnancy outcome, so-called
global markers of haemostatic function are used to
assess women with recurrent miscarriage. These tests
have shown that women with recurrent miscarriage are
in a prothrombotic state outside of pregnancy.125–128
Research suggests that the prothrombotic state not only
results in an exaggerated haemostatic response during
pregnancy, leading to thrombosis of the uteroplacental
vasculature and subsequent fetal loss,119,129,130 but also
confers a risk of ischaemic heart disease in later life.131
In-vitro studies in mice suggest that thrombosis is
not the only mechanism for reproductive failure in
women with thrombophilic defects. Murine trophoblast
cells express many glycoproteins that promote (tissue
factor) and inhibit (thrombomodulin) coagulation.
Isermann and colleagues132 reported that fetal loss in
thrombomodulin-defi cient embryos is caused by tissue-
factor-initiated activation of the blood coagulation
cascade at the fetomaternal interface. The blood
coagulation cascade leads to excess generation of
thrombin, which then (a) signals through protease-
activated receptors to promote trophoblast apoptosis
and (b) stimulates production of fi brinogen split
products which also accelerate apoptosis of the
In about two-thirds of fi rst trimester miscarriages
there is histological evidence of premature onset of
maternal blood fl ow into the intervillous space
throughout the placenta.133,134 This blood fl ow leads to a
state of oxidative stress which is associated with
trophoblast apoptosis. This fi nding is independent of
the fetal karyotype.135–137 Some cases of recurrent
miscarriage are associated with defi ciencies in either
glucose-6-phosphate dehydrogenase or nitric oxide
synthase, which are enzymes involved in the metabolism
of reactive oxygen species.138–140
Management options and therapeutic
The treatment of couples with recurrent miscarriage has
traditionally been based on anecdotal evidence, personal
bias, and the results of small uncontrolled studies.141 As our
knowledge of early pregnancy development increases, it is
incumbent on us to embrace evidence-based practice. Data
on which to base such practice is being generated by newly
established clinics, dedicated to recurrent miscarriage,
which are able to recruit patients to clinical trials of
suffi cient power to establish how well a treatment works in
a trial setting. These clinics aim to identify an underlying
cause of recurrent miscarriage, to conduct prospective
randomised controlled trials of suffi cient power to
determine the best possible treatment regimens, and to
avoid use of treatments with no proven benefi t. Our
investigative protocol for assessing couples with recurrent
miscarriage is shown in table 3. When assessing the
eff ectiveness of any intervention, it is important to
recognise that at least 35% of couples with a history of
three consecutive miscarriages have lost pregnancies
purely by chance alone, secondary to sporadic fetal
aneuploidy. Such couples have a 75% chance of a successful
pregnancy next time with no therapeutic intervention
responses, such as anxiety, depression, denial, anger,
marital disruption, and a sense of loss and inadequacy.
Various psychosocial factors infl uence the immune
system, and it has been proposed that a so-called
miscarriage.142 Certainly, stress induces miscarriage in
mice,143 and raised levels of CD8+ T cells, TNFα and
tryptase-positive mast cells have been reported in the
endometriums of women with sporadic miscarriage and
can induce pronounced emotional
is involved in
Parental peripheral blood karyotype
Early follicular-phase follicule stimulating hormone
Pelvic ultrasound scan
Antiphospholipid antibodies (lupus anticoagulant+IgG and IgM anticardiolipin antibodies)
4% of couples have an abnormal karyotype. Make a referral for genetic counselling
Assessment of ovarian reserve
To determine uterine anatomy and ovarian morphology
15% of women have antiphospholipid syndrome. Treatment with aspirin+heparin signifi cantly
improves livebirth rate
Associated with recurrent miscarriage. Thromboprophylaxis reported to improve outcome
Associated with recurrent miscarriage. Thromboprophylaxis reported to improve outcome
Factor V Leiden and prothrombin gene mutations
Global assessment of haemostasis activated protein C resistance and thromboelastography
Table 3: Protocol for investigation of recurrent miscarriage
Level of evidenceReferences
Intervention of benefi t
Aspirin+heparin for antiphospholipid syndrome
Metformin for women with insulin resistance
Heparin for women with thrombophilic defects
Intervention of no benefi t
Progesterone supplementation after positive pregnancy test
Aspirin for “unexplained” reccurent miscarriage
Embryo aneuploidy screening
Table 4: Evidence level for given intervention in management of recurrent miscarriage
www.thelancet.com Vol 368 August 12, 2006 607
a high stress score.139 Moreover, a signifi cant association
between baseline depressive symptoms and subsequent
miscarriage has been identifi ed.144,145 Several non-
randomised studies have reported that psychological
support in early pregnancy decreases the miscarriage rate
in women with so-called unexplained mis carriage.146–148
Progesterone is secreted mainly by the corpus luteum,
which is formed in the ovary after rupture of an ovarian
follicle at the time of ovulation. Because progesterone
induces secretory changes in the endometrium which
are essential for implantation of the embryo, it has been
suggested that some cases of miscarriage might be due
to inadequate secretion of progesterone, either in the
postovulatory phase of the menstrual cycle or in early
pregnancy. Hence progestational agents have been used,
beginning in the early fi rst trimester of pregnancy, in an
attempt to prevent miscarriage. Two meta-analyses of the
use of progesterone showed that it did not reduce the
miscarriage rate for women with sporadic miscarriage.149,150
However, a subgroup analysis of women with recurrent
miscarriage suggests that progesterone use in the fi rst
trimester might be of benefi t.150,151 This could be explained
by progesterone’s immunomodulatory actions in shifting
the proinfl ammatory Th-1 cytokine response to a more
favourable Th-2 response.152
Insulin-sensitising agents, such as metformin, have
been reported to reduce hyperinsulinaemia, reverse the
endocrinopathy of polycystic ovarian syndrome, and
normalise endocrine, metabolic, and reproductive
function. Small retrospective studies show that use of
metformin during pregnancy is associated with a
reduction in the miscarriage rate in women with
polycystic ovarian syndrome.153,154 However, the eff ect of
metformin remains to be tested in a large, prospective,
placebo-controlled study of a well defi ned cohort of
women with recurrent miscarriage.
Aspirin off ers a thromboprophylactic eff ect by inhibiting
platelet aggregation. But two studies have reported that
aspirin does not improve the livebirth rate in women
with unexplained recurrent miscarriage.155,156 Although
the use of aspirin and other non-steroidal anti-
infl ammatory agents prior to conception has been
associated with a high miscarriage rate,26,157 these studies
were method ologically weak—one investigated fewer
than 20 pregnancies.153 Both a case-controlled study158 and
a meta-analysis159 have reported a two-fold to three-fold
increased risk of fetal gastroschisis in mothers taking
aspirin during the fi rst trimester of pregnancy, further
emphasising the dangers of empirical therapy for women
with recurrent miscarriage. Aspirin has not yet been
demonstrated to be benefi cial for women in whom a
thrombophilic defect has been identi fi ed as the cause of
their pregnancy failures.
Heparin, and the structurally related heparin sulphate,
are typically classed as thromboprophylactic agents, but
have other properties which act at the fetomaternal
interface. Heparin can bind to antiphospholipid
antibodies and can also antagonise the action of the Th-
1 cytokine interferon gamma, thereby protecting the
trophoblast and maternal vascular endothelium from
damage in early pregnancy. Later in pregnancy, when
the intervillous circulation has been established, heparin
helps to ameliorate the risk of placental fi brin deposition,
thrombosis, and infarction. A prospective placebo-
controlled study would be needed to establish the
effi cacy of heparin in the treatment of women with
recurrent miscarriage of unknown cause.160
Some women with recurrent miscarriage are being given
intravenous immunoglobulin, anti-TNFα drugs, and
glucocorticoids to dampen a so-called excessive immune
response. These interventions are not based on evidence,
and furthermore could potentially cause morbidity.161
Intravenous immunoglobulin is a pooled-blood product
and is associated with anaphylactic response, fever,
fl ushing, muscle pains, nausea, and headache.162 Anti-
TNFα agents have been linked with the development of
lymphoma, granulomatous diseases such as tuberculosis,
demyelinating disease, congestive cardiac failure, and
syndromes similar to systemic lupus erythematosus.163
Although TNFα is viewed mainly as a cytokine, and as a
trigger for a maternal immune response to fetal antigens,
it has other roles in antiapoptotic signalling pathways
and regulation of cell proliferation. Studies in TNFα
knock-out mice also suggest that TNFα might aff ect
embryo development and help to prevent structural
abnormalities (which might not become apparent until
later infant life).164 Glucocorticoids during pregnancy are
associated with a risk of preterm delivery secondary to
rupture of membranes and the development of pre-
eclampsia and gestational diabetes.93
Embryo aneuploidy screening
Aneuploidy is the most common cause of miscarriage.
In-vitro fertilisation allows preimplantation embryos to
be screened for aneuploidy, using fl uorescent in-situ
hybridisation. Although the embryo aneuploidy rate is
higher in women with recurrent miscarriage than in age-
matched controls,40 aneuploidy screening and the
replacement of chromosomally normal embryos does
not improve the rate of livebirths.165 Moreover, women
with recurrent miscarriage aged less than 37 years only
had a 26% livebirth rate after in-vitro fertilisation and
aneuploidy screening. By contrast, after spontaneous
conception the livebirth rate is 75%.17,18,147
www.thelancet.com Vol 368 August 12, 2006
Maternal age at conception and previous reproductive
history are strong and independent risk factors for
miscarriage. The chance of a successful pregancy in a
woman aged 40 years or more is poor. The demonstration
that some women with recurrent miscarriage are in a
prothrombotic state outside of pregnancy has
emphasised the role of haemostatic pathways in early
pregnancy development and the value of anticoagulant
treatment in the management of recurrent miscarriage.
Advances in reproductive immunology, endocrinology,
and genetics have enabled a more multidisciplinary
approach to studying and treating couples with
recurrent miscarriage. The high chance of a successful
pregnancy in couples with no identifi able cause for
recurrent miscarriage coupled with the paucity of data
from randomised trials mean that clinicians should
resist the use of empirical treatments which might
deliver no benefi t or might even cause harm. Instead,
patients with recurrent miscarriage should be recruited
to adequately powered placebo-controlled studies,
especially as the value of psychological support in
improving pregnancy outcome has been shown in
Confl ict of interest statement
We declare that we have no confl ict of interest.
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