Professional Documents
Culture Documents
Fertility Clinic 4071 and f Department of Clinical Biochemistry, Rigshospitalet, Copenhagen; b Institute of Social Medicine,
University of Copenhagen, Copenhagen, Denmark; c Instituto Valenciano de Infertilidad, Valencia, Spain; d Department of
Obstetrics and Gynecology, McMaster University, Hamilton, Ontario, Canada; e Department of Immunology and Molecular
Pathology, Division of Infection and Immunity, University College London; h Division of Biomedical Sciences, Sheffield
Hallam University, Sheffield; i Biomedical Research Unit, Jessop Hospital for Women, Sheffield, United Kingdom; g Division
of Reproductive Endocrinology and Immunology, Department of Obstetrics and Gynecology, University of Tennessee,
Memphis, Tennessee; and j IVF Clinic, Department of Obstetrics and Gynaecology, University of Bonn, Bonn, Germany
Objective: To give an overview of currently used investigations and treatments offered to women with recurrent
pregnancy loss (RPL) and, from an evidence-based point of view, to evaluate the usefulness of these interventions.
Design: Ten experts on epidemiologic, genetic, anatomic, endocrinologic, thrombophilic, immunologic, and
immunogenetic aspects of RPL discussed methodologic problems threatening the validity of research in RPL
during and after an international workshop on the evidence-based management of RPL.
Conclusion(s): Most RPL patients have several risk factors for miscarriage, and an extensive investigation for all
major factors should always be undertaken. There is an urgent need for agreement concerning the thresholds for
detecting what is normal and abnormal, irrespective of whether laboratory tests or uterine abnormalities are
concerned. A series of lifestyle factors should be reported in future studies of RPL because they might modify
the effect of laboratory or anatomic risk factors. More and larger randomized controlled trials, including trials of
surgical procedures, are urgently needed, and to achieve this objective multiple centers have to collaborate.
Current meta-analyses evaluating the efficacy of treatments of RPL are generally pooling very heterogeneous
patient populations and treatments. It is recommended that future meta-analyses look at subsets of patients and
treatment protocols that are more combinable. (Fertil Steril 2005;83:82139. 2005 by American Society for
Reproductive Medicine.)
Key Words: Abortion, anticardiolipin, HLA-G, recurrent miscarriage, uterine fibroids, recurrent pregnancy loss
0015-0282/05/$30.00
doi:10.1016/j.fertnstert.2004.12.018
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struations in the past as early miscarriages. More miscarriages might also be reported owing to the womans wish to
be offered investigations and treatment. Only 71% of miscarriages reported by non-RPL women in a questionnaire
could be verified in hospital records (4).
Biochemical pregnancies (pregnancies documented only
by a positive urine or serum hCG test) constitute a considerable proportion of some RPL patients previous pregnancy
history. Some of these pregnancies might be spontaneous
resorbed ectopic pregnancies or very early implantation failures due to genetically abnormal embryos, according to
currently available tools. The etiologies of recurrent biochemical pregnancies might thus be different from those of
clinical pregnancy losses. Thus, inclusion of patients with a
large proportion of biochemical pregnancies in clinical studies of RPL would be expected to diminish the estimate of a
maternal risk factor in case control studies and the treatment
effect in controlled clinical trials.
Many studies have included women with only two previous miscarriages, which often might be a chance phenomenon caused by de novo fetal chromosome abnormalities
rather than a recurrent maternal factor (5). Including women
with only two early miscarriages in the study will in most
cases dilute the estimate of the risk factor (in case control
and cohort studies) or the treatment effect in controlled
clinical trials. This is supported by findings that the frequency of many immunologic risk factors (6, 7) and the
possible effect of immunotherapy increases (8) and the frequency of chromosomally abnormal abortions declines (9)
with the number of previous pregnancy losses.
Ascertainment Bias. Ascertainment bias occurs when patients referred to clinics with special interests are deliberately or unconsciously selected because of that clinical feature on which the clinics interest is focused. Such patients
therefore are not representative of the general RPL population. For example, RPL patients investigated in clinics with
expertise in coagulation and antiphospholipid antibodies
might comprise an excess of women with antiphospholipid
antibodies (10) because referring centers preferentially refer
patients who in addition to obstetric problems also have
suffered thromboembolic episodes or expressed lupus-like
symptoms.
Incorrect RPL Diagnosis. Women can be diagnosed erroneously as having RPL owing to faulty recall of the pregnancy
history, classification of biochemical pregnancies as miscarriages, and the investigators failure to adhere to the generally accepted criteria for RPL.
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Christiansen et al.
that progressed beyond the first trimester. Therefore, unreliable results can be produced if blood samples from pregnant
RPL patients are compared with samples from women who
are not pregnant or in a different stage of pregnancy.
Ascertainment bias often occurs when controls are sampled. Normal women are difficult to sample; therefore,
individuals consulting the hospital for reasons other than
RPL are often used as controls. Ascertainment of controls by
this method is often biased or subject to confounding. The
controls might differ from the RPL patients by the occurrence of a disorder that can affect the variable being evaluated, or they might differ by social class or by potential
hazardous exposures (tobacco, alcohol, caffeine, medicine).
Testing Procedures. Testing is often done during and immediately after miscarriage. Miscarriage might induce an
inflammatory reaction and endocrine changes that locally or
systemically can affect immunologic variables, such as cytokines (15, 16) or antibodies. Abnormal findings after miscarriage therefore might be the result of miscarriage rather
than its cause (17). It is therefore important to be careful in
establishing causality from abnormal findings in samples
taken during and just after miscarriage. The best evidence for
causality comes from samples taken remote from miscarriage.
In many studies, numerous statistical comparisons are
carried out without information being given concerning the
prior hypothesis being tested. Defining statistical significance as a P value .05 will result in every 20th statistical
comparison being significant by chance. Without a clearly
defined prior hypothesis, statistically significant post hoc
findings should not be overstated. Multiple statistical testing
should use appropriate multiple comparison methods to
avoid incorrect inferences from being drawn.
Cohort Studies: Differential Misclassification
Differential misclassification is an uneven intensity of monitoring of exposure to risk factors or outcomes in the different cohortsa problem often reported in occupational medicine.
Biased intensity of monitoring is also a problem in research in human reproduction. For example, owing to the
standard procedures in most ART clinics of measuring serum -hCG 14 days after ET, more biochemical pregnancies
will be registered in cohorts of ART patients compared with
women who conceive spontaneously.
An example of the impact of biased intensity of monitoring of pregnancy outcomes comes from the comparison of
two cohorts of RPL patients who were found suitable and
agreed to participate in placebo-controlled trials of treatment
with intravenous Ig in Sweden (18) and Denmark (19). In the
first trial, the patients were included in the trial in the next
pregnancy when fetal heart action could be demonstrated by
ultrasound in gestational weeks 6 8. In the second trial, the
patients had to call the trial center as soon as a pregnancy test
Fertility and Sterility
assessed separately because the risk of subsequent miscarriage among these groups varies (1): [1] the primary RPL
group consists of women with three or more consecutive
miscarriages with no pregnancy progressing beyond 20
weeks gestation, [2] the secondary RPL group consists of
women who have had three or more miscarriages following
a pregnancy that progressed beyond 20 weeks gestation,
which might have ended in live birth, stillbirth, or neonatal
death, and [3] the tertiary RPL group, which has not been
well characterized or studied, consists of women who have
had at least three miscarriages that are not consecutive but
are interspersed with pregnancies that have progressed beyond 20 weeks gestation (and might have ended in live
birth, stillbirth, or neonatal death).
From these three different groups, it is evident that the
study population being evaluated should be clearly specified
because the prognosis for a successful outcome undoubtedly
will be influenced by the group being selected. The current
approach of lumping all three groups together will not allow
the effect of the experimental intervention to be detected
easily. In the Cochrane meta-analysis of the effect of immunotherapy in RPL (21), studies that are very heterogenous
are combined in a common meta-analysis including patients
with both primary and secondary RPL. Because there are
strong indications that allogeneic lymphocyte immunization
might only have a beneficial effect in women with primary
RPL, and because intravenous Ig displays its strongest effect
in women with secondary RPL, it is important that metaanalyses of the efficacy of the respective treatments be
undertaken in the relevant patient subgroups.
Untreated Control Group. In many trials of treatments in
RPL, pregnancy outcome in the treated group is compared
with the outcome in a group of historical controls. Such
controls might comprise untreated patients from studies undertaken decades ago in another setting. This method is
likely to produce flawed results because the ascertainment
and the pregnancy-monitoring procedures of the controls
might be very different from those of the treated patients.
Another variation of the use of historical controls is the
comparison of pregnancy outcome of the patients subjected
to the new treatment with the outcome in their previous
untreated pregnancies. This method is often used in studies
of surgical procedures to prevent RPL. However, women
with RPL were sampled because of their previous pregnancy
losses, and some of them might have suffered them merely
by chance. They will still have a very favorable chance of
successful pregnancy without any treatment, owing to a
phenomenon called regression to the mean. In women
included in a trial because of RPL, the accumulated past
pregnancy success rate will often be 10%. Comparing this
low pretreatment success rate with an 85% posttreatment
success rate (e.g., after cerclage) will not require many
patients for obtaining statistical significance (22). However,
by using historical controls, most interventions can be
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Christiansen et al.
In some case series and controlled trials, several pregnancies from the same patients were included. The commonly
used statistical methods, such as the 2 test and t-test, require
that all measurements are independent. Pregnancy outcomes
in the same women are not independent variables; therefore,
inclusions of several pregnancies from the same women
require suitable sophisticated tests.
TABLE 1
Methodologic factors to evaluate in studies of recurrent pregnancy loss.
Factor to evaluate
Ascertainment bias
Selection of controls
Advanced age of patients
Uneven monitoring of two cohorts studied
Historical controls
Poor characterization of miscarriage and
subgroups of RPL
Premature termination after interim analysis
Inclusion after detection of fetal heart action
No exclusion of aneuploid abortuses
Note: RPL recurrent pregnancy loss; CCS case control studies; RCT randomized control trials.
Christiansen. Management of recurrent pregnancy loss. Fertil Steril 2005.
TABLE 2
Potential etiologic factors in the causation of recurrent pregnancy loss.
Factor
Parental genetics
Uterine abormalities
Uncontrolled thyroid disease
Uncontrolled diabetes
Polycystic ovary syndrome
Antithyroid antibodies
Antiphospholipid antibodies
Factor V Leiden mutation
Th1 cytokine bias
Increased NK cell cytotoxicity
Maternal HLA alleles
Parental HLA sharing
Causation of RPL
Definite
Definite
Probable
Probable
Definite
Doubtful
Definite
Definite
Probable
Probable
Probable
Doubtful
Definite
Probable
Probable
Probable
Probable
Doubtful
Probable
Probable
Probable
Probable
Probable
Doubtful
Note: RPL recurrent pregnancy loss; Th1 T helper 1; NK natural killer; HLA human leukocyte antigen.
Christiansen. Management of recurrent pregnancy loss. Fertil Steril 2005.
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Christiansen et al.
FIGURE 1
Figures are illustrating the traditional mono-etiological thinking (pie) and the recommended multifactorial
thinking (column) regarding the pathogenesis of recurrent pregnancy loss. NK-cells natural killer cells;
Th1 cytokine T helper cell type 1 cytokines; MBL mannan-binding lectin; HLA human leukocyte
antigen.
Christiansen et al.
Thyroid Disease
For some years, hyper- or hypothyroidism has been thought
to be associated with RPL. Current evidence seems to suggest that treated thyroid dysfunction is not associated with
RPL (53). A recent study suggested that 2% of women with
a midtrimester loss were found to be hypothyroid (54).
Because measuring TSH is a sensitive and inexpensive tool
to assess thyroid function, it should be considered in the
evaluation of RPL for women with any signs or symptoms of
thyroid dysfunction.
Diabetes Mellitus
Current evidence suggests that well-controlled diabetes mellitus is not associated with RPL (53). In a recent study,
investigators looked at the frequency of insulin resistance in
unselected women who presented to a clinic with a diagnosis
of RPL. Insulin resistance was identified significantly more
frequently in women with RPL when compared with age-,
race-, and body mass indexmatched controls (55).
Hypersecretion of LH
Initial reports suggested that a high level (10 IU/L) of LH
on cycle day 8 was associated with an increased risk of
miscarriage (56). Later studies, however, could not confirm
the impact of high follicular LH on the risk of miscarriage
(57), and the suppression of LH with GnRH analogues did
not affect the miscarriage risk (58).
Polycystic Ovaries
In a recent study (61), the prevalence of polycystic ovaries
(PCO) among women with RPL was reported to be 40.7%
(852 of 2,199), but in another study of 102 women with RPL
who underwent transvaginal ultrasonography, only 8 (7.8%)
had the typical features of PCO (59). In the study by Rai et
al. (61), the live birth rate was similar in women with PCO
(60.9%) and in women with normal ovarian morphology
(58.5%). The above evidence leads to the conclusion that
PCO pathology is not predictive of pregnancy loss among
ovulatory women with RPL who spontaneously conceived.
Christiansen et al.
(11%) in the control group (P.01). The women with unexplained RPL differed from controls, especially with regard
to hyperhomocystinemia, elevated APA or LAC, and the
presence of the factor V Leiden mutation. These results are
in concordance with another study that found that 66% of
RPL patients had at least one thrombophilic defect compared
with 28% of controls; however, in this study an accumulation of thrombophilic defects characterized RPL patients
because at least two defects were found in 21% of patients
and in 5.5% of controls (81). These data suggest that hypercoagulable states might be an important factor in RPL.
A series of 31 relevant studies judged to be of good quality
has now been subjected to meta-analysis, which concluded
that there is an increased prevalence of several acquired and
inherited thrombophilias in populations of women with unexplained RPL compared with women without a history of
adverse pregnancy outcome (82). Factor V Leiden mutation
was weakly associated with early RPL (odds ratio [OR], 2.0;
95% confidence interval [CI], 1.13.6) but strongly associated with late RPL (OR, 7.8; 95% CI, 2.8 21.7). The prothrombin G20210A mutation and protein S deficiency
seemed also to be associated with RPL, but the ORs had very
wide confidence limits owing to small studies, and more
studies are needed to document their association with RPL.
The meta-analysis could not document any association between methylenetetrahydrofolate mutation (a risk factor for
hyperhomocystinemia), protein C, and antithrombin deficiencies.
A second meta-analysis evaluated the association of factor
V Leiden and prothrombin gene mutation G20210A in
women with RPL (83). The combined ORs for the association between RPL and factor V Leiden and between RPL and
G20210A were 2.0 (95% CI, 1.52.7; P.00l) and 2.0 (95%
CI, 1.0 4.0; P.03), respectively.
An unsolved question is whether RPL patients with congenital thrombophilic factors, such as the factor V Leiden
mutation should be treated with heparin and aspirin. There
are no placebo-controlled trials documenting the efficacy of
this treatment in these women. So far, there is only evidence
for the use of heparin and aspirin in APL-positive RPL
patients.
IMMUNE CELLS AND CYTOKINES IN RPL
One of the causes of pregnancy loss is thought to be the
immunologic rejection of the fetus due to a breakdown in the
mechanisms that normally prevent the maternal immune
system from becoming activated by the paternal antigens
expressed on the developing fetus. Recent studies have investigated the role of specific immune cells and molecules in
the cause of repeated miscarriage, by comparing their expression in peripheral blood, endometrium, and decidua of
women with RPL and control women.
Fertility and Sterility
Christiansen et al.
Christiansen et al.
true for both laboratory tests, such as anticardiolipin antibodies (149), and uterine abnormalities. Indeed, only studies
of the impact of various potential risk factors on the outcome
of future, untreated pregnancies in RPL patients can establish what degree of abnormality of a factor should be considered as important for RPL.
It is recommended that examinations in RPL should as a
minimum be carried out according to Table 3 (documentation A) and, in addition, factors with association and prognostic impact documented in studies of adequate size and
quality could be investigated (Table 3, documentation B). A
specific prognosis for the patient can only be given if all risk
factors are investigated. When clinicians encounter a patient
with RPL and several risk factors, it is important to inform
her about all the risk factors and then discuss with her
whether an attempt should be made to treat all risk factors at
the same time or only one of them before or during the next
pregnancy attempt. In many cases, the patient will wish to
have all factors corrected or treated before attempting a
subsequent pregnancy.
As mentioned previously, a number of lifestyle factors,
including obesity, occupation, history of alcohol use, and
caffeine consumption, are important for the risk of miscarriage. Recurrent pregnancy loss is a complex disorder for
which lifestyle factors are expected to modify the effect of
the non-lifestyle (intrinsic) factors previously discussed. The
prevalence of the most important lifestyle factors should be
reported in publications to establish whether groups studied
for the occurrence of non-lifestyle risk factors or pregnancy
outcome are comparable. Some RPL clinics are already
using a structured information sheet for each patient, which
includes a series of lifestyle factors. It is recommended that
investigators doing research in RPL should use a standardized sheet for recovering lifestyle information from patients.
It might be a task for international societies in the field of
fertility and reproduction to design such a standardized
TABLE 3
Recommended investigations of recurrent pregnancy loss patients.
Investigation
Hysterosalpingography or hysteroscopy or sonohysterography
Karyotyping of the couple
Thyroid hormones
Androgens, LH, FSH in patients with irregular menstruations
APTT-/dRVVT/lupus anticoagulant
IgG and IgM anticardiolipin antibodies
Factor V Leiden mutation
Mannan-binding lectin
Maternal HLA-G and HLA-DR types
Documentation
A
A
A
B
A
A
A
B
B
Note: A value documented in many studies; B value suggested in few but large studies; APTT activated partial
thrombin time; dRVVT dilute Russels viper venom time.
Christiansen. Management of recurrent pregnancy loss. Fertil Steril 2005.
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