ORIGINAL INVESTIGATION

Evaluation of the Association Between Hereditary

Thrombophilias and Recurrent Pregnancy Loss
A Meta-analysis
George Kovalevsky, MD; Clarisa R. Gracia, MD; Jesse A. Berlin, ScD;
Mary D. Sammel, ScD; Kurt T. Barnhart, MD, MSCE

Background: Recurrent pregnancy loss (RPL) is a sig-
nificant clinical problem. Recently, thrombophilias have
been implicated as a possible cause. Factor V Leiden (FVL)
and prothrombin gene (G20210A) mutations are the most
common types of hereditary thrombophilias, but are usu-
ally undiagnosed because most carriers are asymptom-
atic. The relationship between FVL, G20210A, and RPL
has been investigated with conflicting results. This study
analyzed existing data to determine whether an associa-
tion exists.
firmed by means of fixed- and random-effects meta-
analyses models.
Results: The combined odds ratios for the association
between RPL and FVL and between RPL and G20210A
were 2.0 (95% confidence interval, 1.5-2.7; P⬍.001) and
2.0 (95% confidence interval, 1.0-4.0; P = .03), respec-
tively. Similar results were produced by the logistic re-
gression and both fixed- and random-effects meta-
analysis models.

Methods: A systematic review of the literature was per-
formed. Only case-control studies that defined RPL as 2
or more pregnancy losses in the first or second trimes-
ter and that confirmed mutations by DNA analysis were
included. Sixteen studies were selected for the FVL meta-
analysis and 7 for the G20210A analysis. Stratified and
multivariate logistic regression analyses were per-
formed with the use of aggregate data. Results were con-
Conclusions: Carriers of FVL or prothrombin gene mu-
tations have double the risk of experiencing 2 or more
miscarriages compared with women without thrombo-
philias. Hereditary thrombophilias may be an unrecog-
nized cause of RPL. We recommend testing for these mu-
tations in women with RPL.
Arch Intern Med. 2004;164:558-563

From the Division of
Reproductive Endocrinology
and Infertility, Department of
Obstetrics and Gynecology
(Drs Kovalevsky, Gracia, and
Barnhart), and Center for
Clinical Epidemiology and
Biostatistics (Drs Kovalevsky,
Berlin, Sammel, and Barnhart),
University of Pennsylvania
Medical Center, Philadelphia.
Dr Kovalevsky is now with
CONRAD, Department of
Obstetrics and Gynecology,
Eastern Virginia Medical
School, Norfolk. The authors
have no relevant financial
interest in this article.
R
ECURRENT PREGNANCY LOSS
(RPL), defined as 2 or more
spontaneous abortions, af-
fects approximately 5% of
women of reproductive
age.1 Although several causes of RPL have
been established, more than 50% of cases
remain unexplained. This is a challeng-
ing dilemma for both patients and physi-
cians.1 Recently, thrombophilias have been
suggested as a possible cause of RPL.2-8 He-
reditary thrombophilias are a group of ge-
netic disorders of blood coagulation re-
sulting in a hypercoagulable state, which
in turn can result in abnormal placenta-
tion. Early in pregnancy this may mani-
fest as spontaneous loss.9-10 In later preg-
nancy, thrombophilias have been associated
with complications such as preeclampsia,
intrauterine growth restriction, placental
abruption, and stillbirth.11-15
Most carriers of the mutation will not
develop any clinical signs and remain un-
diagnosed because these conditions result
in a small absolute risk of clinically signifi-
cant thrombosis. However, when carriers
are exposed to additional risk factors, such
as pregnancy or possibly oral contracep-
tives, the risk of life-threatening throm-
botic events is significantly increased and
may become clinically evident.16-17
The 2 most common causes of heredi-
tary thrombophilias are factor V Leiden
(FVL) and prothrombin gene (G20210A)
mutations.18 Factor V Leiden is a point mu-
tation (G1691A) that results in an altered
factor V, which is resistant to inactivation
by protein C. This results in a hypercoagu-
lable state with a 5- to 10-fold risk of throm-
bosis in heterozygotes and an 80-fold risk
in homozygotes.17 Factor V Leiden is re-
sponsible for 20% to 40% of isolated throm-
botic events and 40% to 45% of familial
thrombophilias. Its prevalence in the United
States is estimated to be between 3% and
7%, with the highest frequency in whites.18-20
Many studies have investigated the rela-
tionship between FVL and RPL, and the ma-
jority found an association, with odds ra-
tios ranging from 0.5 to 18.21-43

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 The G20210A mutation affects 1% to 4% of the US
population. Its prevalence is highest among whites of
Southern European decent. This mutation is associated
with a 20% to 50% rise in prothrombin plasma lev-
els.44-45 Affected women have a 3-fold increased risk of
venous thrombosis, and a higher chance of myocardial
infarction and cerebral thrombosis than noncarri-
ers.16,46,47 Studies of G20210A have also shown conflict-
ing associations with RPL.32,33,35,38,39,41,48,49
Since the association between hereditary thrombo-
philias and RPL has not been conclusively established,
most women with RPL are not tested for these muta-
tions unless they have a personal or family history of
thrombosis. Because most carriers are otherwise asymp-
tomatic, the diagnosis would usually be missed. Prelimi-
nary studies of thrombophylaxis during pregnancy in car-
riers suggest that treatment may significantly improve
pregnancy outcome.9,50-51 Thus, by identifying heritable
thrombophilias in young women, we might potentially
prevent miscarriages, as well as serious maternal and neo-
natal complications.
Our objective was to evaluate the relationship be-
tween RPL and these 2 common thrombophilias. To do
so, we conducted a comprehensive meta-analysis of the
existing data. We believe that this was the best ap-
proach to address this controversial issue because col-
lecting prospective data would be exceedingly difficult,
given the relatively low prevalence of both the risk fac-
tor (thrombophilia) and the outcome (RPL). Further-
more, many of the previous studies lacked power to de-
tect a small, but clinically important, association.
METHODS
STUDY SELECTION
We conducted a systematic review of the literature to identify
studies exploring the relationship between FVL or G20210A
and RPL. An English-language MEDLINE search using Ovid
and PubMed (1966-2002) was performed with the use of vari-
ous combinations of the following terms: thrombophilia, factor
V Leiden, prothrombin, G20210A, miscarriage, abortion, and preg-
nancy loss. Pertinent studies were also identified from article
bibliographies.
Inclusion criteria required that RPL be defined as 2 or more
losses in the first 2 trimesters of pregnancy, and that muta-
tions be identified by DNA analysis (polymerase chain reaction).
Studies that did not provide control subjects were excluded. If
a study as a whole did not meet inclusion criteria, but a subset
of the subjects qualified, only the subset was included. The search
yielded 34 relevant studies. Among articles addressing FVL, 17
met inclusion criteria. Of these, 16 were case-control studies
and 1 was a retrospective cohort. Because of the major differ-
ence in design, the cohort study was excluded from analysis.
Seven articles investigating G20210A met inclusion criteria; all
were case-control studies. All studies excluded women with a
history of thrombosis and those previously diagnosed as hav-
ing a hereditary thrombophilia. Two of us (G.K. and C.R.G.)
performed the literature search, reviewed the articles, and ab-
stracted the data independently. All differences were resolved
by consensus.
DATA EXTRACTION
The data were abstracted by means of a standardized spread-
sheet. The information extracted from each study consisted of
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the number of cases and controls with and without each mu-
tation, mean age of cases and controls, minimum number of
losses (2 or 3), race (whites only or mixed), and whether sub-
jects were excluded on the basis of an evaluation for other causes.
When possible, data were recorded separately for women with
pregnancy losses exclusively in the first trimester and for those
with losses in both the first and second trimesters.
STATISTICAL ANALYSIS
All analyses were performed with Stata (version 6.0; Stata Corp,
College Station, Tex). Rather than assigning arbitrary quality
scores to this set of studies with similar designs, we analyzed
the associations between outcome and relevant variables that
we were able to extract.52 Data were entered as the aggregate
number of cases or controls with or without the mutation in
each study. Independent analyses were carried out for the 2 mu-
tations. The association between presence of mutation and RPL
was evaluated by means of multiple techniques: crude bivari-
ate analysis, analysis stratified by study, logistic regression, and
meta-analysis of weighted averages. The multivariate logistic
regression model was constructed by means of indicator vari-
ables for the individual studies. The meta-analysis was per-
formed with both fixed-effects and random-effects models. This
approach involved computing weighted averages of the study-
specific log odds ratios.
The degree of among-study heterogeneity was investi-
gated and possible sources were examined. First, the analysis
was stratified by study and an overall test of among-study het-
erogeneity was performed. Then, interactions between the pres-
ence of mutation and aggregate-level covariates (ie, mean age,
race, minimum number of losses, and exclusion based on other
causes) were evaluated by likelihood-ratio tests. To estimate
the influence of various factors on the association of interest,
we also performed analyses stratified by race, trimester of RPL,
minimum number of losses, and whether other causes of RPL
were excluded. Finally, to further assess among-study hetero-
geneity, weighted random-effects meta-regression models of the
log odds ratios were fitted by means of the “metareg” proce-
dure in Stata. Covariates were added to the model individually
and in all possible combinations.
As one large study contributed approximately half of the
cases to the FVL analysis, we decided a priori to perform the
complete analysis with and without this study. Publication
bias was assessed with both Begg and Egger tests and funnel
plots.53
RESULTS
FVL MUTATION
The 16 individual studies included in the analysis are sum-
marized in Table 1, and the odds ratios (ORs) are de-
picted in Figure 1. Table 2 summarizes the ORs pro-
duced by each method. The initial bivariate analysis of
the association between the FVL mutation and RPL pro-
duced a crude OR of 2.1 (95% confidence interval [CI],
1.6-2.7; P⬍.001). However, significant among-study het-
erogeneity was observed when the analysis was strati-
fied by study (Breslow and Day test of homogeneity,
P =.03). Nevertheless, this result was confirmed by the
logistic regression model, while attempting to control for
among-study variation. Furthermore, both fixed-effects
and random-effects meta-analyses also reproduced this
estimate (fixed effects: OR, 2.0; 95% CI, 1.5-2.6; P⬍.001;
random effects: OR, 2.2; 95% CI, 1.4-3.3; P⬍.001).
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 Table 1. Summary of Studies Included in the Analysis

Age, y
No. of Minimum White Unexplained
Source Cases/Controls Cases Controls No. of Losses Trimester Only Only OR (95% CI)
Factor V Leiden
Balasch et al,31 1997 55/50 31.8 34.4 2 First No Yes 0.9 (0.1-14.9)
Dizon-Townson et al,42 1997 40/25 33.0 31.0 3 First and second Yes Yes ND*
Grandone et al,30 1997 27/118 31.0 35.0 2 First Yes Yes 1.8 (0.3-9.9)
Metz et al,29 1997 100/85 NA NA 3 First and second No No 1.7 (0.4-7.2)
Ridker et al,36 1998 206/437 NA NA 3 First and second Yes Yes 2.2 (1.1-4.5)
Pauer and Neesen,43 1998 84/87 32.9 NA 2 First and second No Yes 1.2 (0.4-3.2)
Souza et al,41 1999 56/384 29.6 24.3 3 First and second No No 4.8 (1.3-17.7)
Kutteh et al,32 1999 50/50 33.6 34.3 3 First and second Yes No 0.5 (0.04-5.6)
Tal et al,37 1999 78/125 31.4 30.7 2 First and second No Yes 4.4 (1.7-11.1)
Hashimoto et al,28 1999 52/55 NA NA 3 First No Yes ND*
Foka et al,33 2000 80/100 33.0 35.0 2 First and second Yes No 5.5 (1.8-17.4)
Wramsby et al,38 2000 84/69 NA NA 3 First and second No No 6.1 (1.3-28.2)
Younis et al,40 2000 78/139 30.0 30.7 2 First and second No Yes 3.9 (1.6-9.7)
Rai et al,34 2001 904/150 34.0 33.0 3 First Yes No 0.8 (0.4-1.5)
Raziel et al,35 2001 36/40 34.0 33.5 2 First and second Yes Yes 3.8 (0.7-20.2)
Pihusch et al,39 2001 102/128 35.0 32.0 2 First and second Yes Yes 0.9 (0.3-2.3)
Total or mean 2032/2042 32.4 32.2 2.5 8 Yes, 8 no 10 Yes, 6 no
Prothrombin Gene (G20210A)
Pickering et al,49 1998 122/66 35.0 31.0 3 First and second No Yes 0.7 (0.2-3.3)
Kutteh et al,32 1999 50/50 33.6 34.3 3 First and second Yes Yes 1.0 (0.06-16.4)
Souza et al,41 1999 56/384 29.6 24.3 3 First and second No No 3.5 (0.6-19.7)
Foka et al,33 2000 80/100 33.0 35.0 2 First and second Yes No 4.7 (0.9-23.3)
Wramsby et al,38 2000 84/69 NA NA 3 First and second No No 0.8 (0.2-4.2)
Raziel et al,35 2001 36/40 34.0 33.5 2 First and second Yes Yes 2.3 (0.2-26.4)
Pihusch et al,39 2001 102/128 35.0 32.0 2 First and second Yes Yes 6.5 (0.8-56.9)
Total or mean 530/837 33.4 31.7 2.6 4 Yes, 3 no 4 Yes, 3 no

Abbreviations: CI, confidence interval; NA, not available; ND, not determined; OR, odds ratio.
*Could not be calculated because none of the cases or controls had the mutation.

Balasch et al,31 1997 Table 2. Combined Odds Ratios for Association

Grandone et al,30 1997 Between Factor V Leiden and Prothrombin Mutations
Metz et al,29 1997 and Recurrent Pregnancy Loss
Pauer and Neesen,43 1998
Ridker et al,36 1998
Kutteh et al,32 1999 Prothrombin
Souza et al,41 1999 Factor V Gene
Tal et al,37 1999 Leiden (G20210A)
Foka et al,33 2000
Younis et al,40 2000
Wramsby et al,38 2000
OR 95% CI OR 95% CI
Raziel et al,35 2001 Crude bivariate analysis 2.1 1.6-2.7 2.5 1.3-4.7
Rai et al,34 2001
Pihusch et al,39 2001
Adjusted stratified analysis* 2.0 1.5-2.7 2.0 1.0-4.0
Logistic regression* 2.2 1.6-2.9 2.2 1.1-4.3
Combined Fixed-effects meta-analysis 2.0 1.5-2.6 1.9 0.96-3.9
0.3 1.0 2.2 5.0 10.0 20.0 Random-effects meta-analysis 2.2 1.4-3.3 1.9 0.96-3.9
Odds Ratio (Log Scale)
Abbreviations: CI, confidence interval; OR, odds ratio.
Figure 1. Association of factor V Leiden mutation and recurrent pregnancy *Analysis performed while adjusted for among-study heterogeneity.
loss. The center of each box indicates the odds ratio (OR) for each study;
error bars, confidence intervals (CIs); dotted vertical line, calculated
combined OR; and rhombus, the combined CI. If the CIs were very wide, ity by the weighted meta-regression model (P =.14). In
they were truncated at 0.29 and 21.0. The size of the box is proportional to fact, none of the covariates was found to be a significant
the weight given to the study in the meta-analysis model. The combined ORs
and CIs were calculated using the random-effects meta-analysis technique. source of heterogeneity by this method.
Subgroup analyses confirmed that race produced sta-
tistically significant variation in the strength of the main
These models also confirmed the presence of sig- association (Table 3). We also found that limiting the
nificant among-study heterogeneity (P = .02). When we analysis to women with exclusively first-trimester losses
attempted to identify a likely source for the heterogene- weakened the association (OR, 1.6; 95% CI, 1.2-2.2;
ity, we found that the only covariate that showed a sig- P=.002). Despite these stratifications, the association be-
nificant interaction with the presence of FVL mutation tween FVL and RPL remained significant in all of the sub-
was race (likelihood ratio test, P = .005). However, race groups. We also found that greater age was associated
was not shown to be a significant source of heterogene- with higher risk. Finally, tests for publication bias did

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 Table 3. Associations Between Factor V Leiden
and Prothrombin Mutations With RPL Pickering et al,49 1998
When Examined Within Subgroups
Kutteh et al,32 1999

Prothrombin Souza et al,41 1999

Factor V Gene Foka et al,33 2000
Leiden (G20210A)
Wramsby et al,38 2000
OR 95% CI OR 95% CI
Pihusch et al,39 2001
No. of miscarriages
ⱖ3 2.1 1.5-3.0 1.6 0.7-3.7 Raziel et al,35 2001
ⱖ2 2.5 1.7-3.6 4.5 1.5-13.3
Time of miscarriages Combined
First trimester only 1.6 1.2-2.2 3.4 1.5-8.0 0.3 1.0 1.9 5.0 10.0 20.0
First and second trimesters 2.7 2.0-3.7 2.2 1.1-4.4 Odds Ratio (Log Scale)
Race
White only 1.5 1.1-2.2 3.4 1.3-9.1 Figure 2. Association of prothrombin mutation and recurrent pregnancy
loss. The center of each box indicates the odds ratio (OR) for each study;
Other races included 3.4 2.2-5.1 1.8 0.7-4.4
error bars, confidence intervals (CIs); dotted vertical line, calculated
Other causes combined OR; and rhombus, the combined CI. If the CIs were very wide,
Unexplained only 2.1 1.5-3.0 1.9 0.7-5.2 they were truncated at 0.29 and 21.0. The size of the box is proportional to
Other causes not excluded 2.3 1.5-3.5 3.0 1.3-6.8 the weight given to the study in the meta-analysis model. The combined ORs
and CIs were calculated using the random-effects meta-analysis technique.
Abbreviations: CI, confidence interval; OR, odds ratio; RPL, recurrent
pregnancy loss.
cally significant variation in the strength of the associa-
not detect any significant bias (Begg test, P = .78; Egger tion (Table 3). The association between G20210A and
test, P=.47). RPL remained positive in all of the subgroups, although
The complete analysis was repeated with exclusion statistical significance was not achieved in all strata. Spe-
of the study by Rai et al.34 Stratification by study could no cifically, a significant association was not found in stud-
longer reject the null hypothesis of homogeneity (Bres- ies where RPL was defined as 3 or more losses, races other
low and Day test, P=.26). The adjusted OR increased to than white were included, and only unexplained losses
2.5 (95% CI, 1.8-3.4; P⬍.001). This result was corrobo- were included. Finally, tests for publication bias did not
rated by the logistic regression model (OR, 2.6; 95% CI, detect any significant bias (Begg test, P=.89; Egger test,
1.9-3.5; P⬍.001) and both meta-analysis models (fixed ef- P =.71).
fects: OR, 2.5; 95% CI, 1.8-3.4; P⬍.001; random effects:
OR, 2.5; 95% CI, 1.7-3.7; P⬍.001). Neither the interac- COMMENT
tion tests nor the meta-regression analyses yielded any sig-
nificant findings. Thus, exclusion of the study by Rai et al Recurrent pregnancy loss is a devastating condition, both
eliminated significant among-study heterogeneity. medically and emotionally. While most cases remain un-
explained, inherited thrombophilias have recently been
G20210A MUTATION implicated as a potential cause. The FVL and G20210A
mutations, the two most common inherited thrombo-
The 7 studies included in the analysis are summarized philias, have been investigated and have shown incon-
in Table 1, and ORs are given in Table 2 and Figure 2. sistent results. By performing a meta-analysis, we estab-
The initial analysis of the association between the lished an association between FVL mutation and RPL,
G20210A mutation and RPL produced a crude OR of 2.5 with a cumulative OR of 2. In other words, carriers of
(95% CI, 1.3-4.7; P = .004), and the analysis stratified by the FVL mutation have double the risk of RPL when com-
study resulted in a Mantel-Haenszel adjusted OR of 2.0 pared with noncarriers. This association was confirmed
(95% CI, 1.0-4.0; P=.03). No significant among-study het- by several methods of analysis.
erogeneity was observed (Breslow and Day test of ho- Carriers of the G20210A mutation also were found
mogeneity, P= .51). The association between G20210A to have double the risk of RPL when compared with non-
and RPL in the logistic regression model, while adjust- carriers. However, while the magnitude of the associa-
ing for the influence of among-study variation, was not tion between G20210A and RPL remained similar in all
substantially different from the adjusted OR. Both fixed- methods of analysis, statistical significance was depen-
effects and random-effects meta-analyses achieved a simi- dent on the technique of analysis. This may be due to a
lar result; however, the statistical significance became bor- smaller sample size in the G20210A group; only 7 stud-
derline. These models also confirmed the absence of ies met the inclusion criteria for this analysis.
among-study heterogeneity (P=.44). Consistent with the Inclusion and exclusion criteria are a critical part
absence of significant heterogeneity, both the interac- of a meta-analysis and can substantially affect results. We
tion analyses and the meta-regression models found that chose to be conservative in our study selection, which
no factors significantly influenced the association be- likely underestimated the discovered association. A num-
tween G20210A and RPL. ber of articles investigating FVL from the Israeli collabo-
The subgroup analyses demonstrated that stratifi- rators were excluded because they included third-
cation by each of the variables also yielded no statisti- trimester miscarriages in their definition of RPL, and the

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necessary information for the subset of women who met
our criteria could not be extracted.4,5,12,24 The ORs in these
publications ranged from 4 to 18. Similarly, the cohort
study, which was excluded on the basis of design differ-
ences, found an OR of 2.5.26 Thus, inclusion of these stud-
ies in our analysis would have only strengthened the as-
sociation between FVL and RPL.
Notably, the disproportionately large study by Rai
et al34 showed no association (OR, 0.8). This study con-
tributed 45% of the FVL-positive RPL cases to our analy-
sis and was the cause of significant among-study hetero-
geneity. Nevertheless, we found a significant association
between FVL and RPL both with and without inclusion
of this study. One possible reason for the null effect in
this study is that women with RPL of known causes were
included in their analysis. In fact, 20.7% of the cases in
this study were diagnosed as having antiphospholipid an-
tibodies. When we repeated the analysis without this
study, a stronger association was observed (OR, 2.5; 95%
CI, 1.8-3.4).
We stratified our analysis by using several descrip-
tive variables in an attempt to estimate their influence
on the main association (Table 3). We found that race
had a significant influence on the association between
FVL and RPL; studies recruiting only white women dem-
onstrated a weaker association than those with mixed
populations. This effect was reversed in the G20210A
analysis, but the difference was not statistically signifi-
cant. Also in the FVL analysis, limiting the data to women
with first-trimester RPL appeared to weaken the asso-
ciation, while such an effect was not found in the G20210A
analysis. It would not be surprising to find that the as-
sociation is weakened in the first trimester because ab-
normal fetal karyotype has been consistently shown to
be responsible for most of these losses,1 thus resulting
in a lower prevalence of losses caused by abnormal pla-
centation. On the other hand, we are not aware of any
reason why race may have influenced the association. It
is possible that selection bias was present in studies that
did not recruit the cases and controls from populations
with equal prevalence of the mutation. However, in in-
terpreting these results, it is important to remember that
the analysis was performed on data composed of aggre-
gate values from studies, and not on data from indi-
vidual subjects. Such analyses are vulnerable to ecologi-
cal bias, and further investigation of these factors is
needed. Most importantly, the association between FVL
and RPL remained significant in all subgroups, while the
association between G20210A and RPL remained sig-
nificant in most and borderline in the rest.
Our study focused on women with RPL, but it is
likely that hereditary thrombophilias are also a cause of
isolated pregnancy losses. Carriers of these mutations ex-
hibit highly variable phenotypic expression, with most
having no clinically discernible abnormalities. With re-
spect to pregnancy losses, only a fraction of carriers will
develop RPL, while most will experience no losses or pos-
sibly a single loss with an otherwise normal reproduc-
tive history. Since women who have a single early preg-
nancy loss are not commonly tested, and hereditary
thrombophilias are usually clinically silent, the true cause
of the miscarriage thus remains undiagnosed. Clearly, the
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effect of thrombophilias on isolated pregnancy loss de-
serves further research.
In addition to pregnancy loss, there is evidence that
hereditary thrombophilias are associated with severe com-
plications in late pregnancy and with increased risk of
venous thrombosis during pregnancy, post partum, and
in users of oral contraceptives.11-15 The role of thrombo-
philias in all aspects of reproduction should be closely
examined. As the clinical implications of inherited throm-
bophilias on pregnancy and women’s health become bet-
ter understood, a comprehensive cost-effectiveness analy-
sis will be essential to assess the benefits of screening all
women of reproductive age.
For testing to be truly beneficial, effective treat-
ment of carriers is needed. Thrombophylaxis has been
shown to be valuable in preventing recurrent thrombo-
sis in carriers, and preliminary evidence from case se-
ries suggests that it also may help to prevent miscar-
riages and improve neonatal and maternal outcomes in
pregnancy.50,51 However, clinical trials are necessary to
establish the safety and efficacy of treatment before wide-
spread application is instituted.
In summary, our meta-analyses have demon-
strated a strong association between RPL and the FVL
mutation and shown a probable association between RPL
and the G20210A mutation. Given the clinical implica-
tions and the relatively high prevalence of these muta-
tions, we recommend testing women with RPL for their
presence. Until the efficacy of thrombophylaxis for RPL
is proved, anticoagulation of carriers should be consid-
ered on an individual basis.
Accepted for publication April 28, 2003.
This study was presented in part at the meeting of the
American Society of Reproductive Medicine; October 15,
2002; Seattle, Wash.
Corresponding author: George Kovalevsky, MD,
CONRAD Clinical Research Center, 601 Colley Ave, Nor-
folk, VA 23507.
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