Human Reproduction, Vol.36, No.5, pp.

1213–1229, 2021
Advance Access Publication on February 12, 2021 doi:10.1093/humrep/deab010

ORIGINAL ARTICLE Early pregnancy

Hereditary thrombophilia and

recurrent pregnancy loss: a systematic
review and meta-analysis
Xiaoling Liu1, Yan Chen1, Changxiang Ye1, Dexiu Xing1, Rong Wu1,
Fang Li1, Lizhang Chen1,2,*, and Tingting Wang1,3,*

Downloaded from https://academic.oup.com/humrep/article/36/5/1213/6133739 by guest on 10 April 2023

1
Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Hunan 410078, China
2
Hunan Provincial Key Laboratory of Clinical Epidemiology, Changsha, Hunan 410078, China 3National Health Commission Key
Laboratory for Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital, Hunan 410008, China

*Correspondence address: Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University,
110 Xiangya Road, Changsha, Hunan 410078, China. Tel/ Fax: 0731-84805414; E-mail: liche4005@126.com (L.C.); National Health
Commission Key Laboratory for Birth Defect Research and Prevention, Hunan Provincial Maternal and Child Health Care Hospital 53
Xiangchun Road, Changsha, Hunan 410008, China. Tel: 15273188582; Fax: 0731-84332158; E-mail: wangting91123@126.com (T.W.)

Submitted on October 24, 2020; resubmitted on December 31, 2020; editorial decision on January 8, 2021

STUDY QUESTION: Is there an association between hereditary thrombophilia in pregnant women and risk of recurrent pregnancy loss
(RPL)?
SUMMARY ANSWER: Pregnant women with hereditary thrombophilia have an increased risk of RPL, especially for pregnant women
with the G1691A mutation of the factor V Leiden (FVL) gene, the G20210A mutation of the prothrombin gene (PGM), and deficiency of
protein S (PS).
WHAT IS KNOWN ALREADY: Prior studies have suggested that pregnant women with hereditary thrombophilia have a higher risk of
RPL, however, the results are inconsistent; furthermore, a complete overview is missing. This lack of information is an obstacle to the risk
assessment of RPL in pregnant women with hereditary thrombophilia. A comprehensive meta-analysis on the relation between hereditary
thrombophilia and the risk of RPL is needed.
STUDY DESIGN, SIZE, DURATION: A systematic review and meta-analysis was performed using observational studies published in
English before 1 April 2020 to evaluate the relation between hereditary thrombophilia and risk of RPL.
PARTICIPANTS/MATERIALS, SETTING, METHODS: Relevant studies were identified from PubMed, Web of Science, and
EMBASE searches and complemented with perusal of bibliographies of retrieved articles. The exposure of interest was hereditary throm-
bophilia, including FVL mutation, PGM, deficiency of antithrombin (AT), deficiency of protein C (PC), and deficiency of PS. The overall risk
estimates were pooled using random effects models. Subgroup and sensitivity analyses were carried out to explore possible sources of het-
erogeneity and assess the robustness of the results.
MAIN RESULTS AND THE ROLE OF CHANCE: A total of 89 studies involving 30 254 individuals were included. Results showed that
women with FVL mutation (odds ratio (OR): 2.44, 95% CI: 1.96–3.03), PGM (OR: 2.08, 95% CI: 1.61–2.68), or deficiency of PS (OR: 3.45,
95% CI: 1.15–10.35) had higher risks of developing RPL. Compared with the reference group, there was no observed relation between a
deficiency in AT or PC and RPL (all P > 0.05). Heterogeneity in the risk estimates of RPL was partially explained by geographic region, defi-
nitions of RPL, types of RPL, and controlled confounders. Sensitivity analyses validated the robustness of the findings.
LIMITATIONS, REASONS FOR CAUTION: Only 39 of the included studies controlled for one or more confounders, and the hetero-
geneity across all included studies was high. Based on the data available, we cannot determine whether this association is confounded by
other potential risk factors of RPL.
WIDER IMPLICATIONS OF THE FINDINGS: This systematic review and meta-analysis show a possible association between hereditary
thrombophilia and an increased risk of RPL, suggesting that testing for hereditary thrombophilia should be considered in individuals with RPL.
STUDY FUNDING/COMPETING INTEREST(S): The study was funded by the Hunan Provincial Key Research and Development
Program (Grant number: 2018SK2062) and National Natural Science Foundation Program (Grant number: 81973137). There are no con-
flicts of interest.

C The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved.
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1214
REGISTRATION NUMBER: N/A.
Key words: meta-analysis / hereditary thrombophilia / recurrent pregnancy loss / factor V Leiden / prothrombin / antithrombin / pro-
tein C / protein S
..
Introduction
As an important obstetric issue, recurrent pregnancy loss (RPL) affects
approximately 1  5% of couples (El Hachem et al., 2017; Garrido-
Gimenez and Alijotas-Reig, 2015). RPL can be a painful experience for
women and their partners, both physically and mentally. For many
couples trying to have children, miscarriage represents the loss of a
child along with the destruction of their expectations and hopes for
the child. Experiencing loss and grief is common for patients.
Therefore, it is not surprising that women and their partners are upset
and anxious during their subsequent pregnancies. In severe cases, RPL
may lead to infertility, which can be a major blow to parents who long
for the company of children and can even be a trigger for depression.
RPL is a complex disease involving the interaction of genetic factors
and environmental factors. Although multiple causes of RPL have been
identified, such as thrombophilia, endocrinological factors, environmen-
tal and psychological factors, male factors, and genetic factors (El
Hachem et al., 2017; Hong and Marren, 2018), more than 50% of
cases remain unexplained (Garrido-Gimenez and Alijotas-Reig, 2015;
Santos et al., 2017; Hong and Marren, 2018).
Evidence suggests that pregnant women with hereditary thrombo-
philia might be at a higher risk of RPL when compared with the refer-
ence group (Mitriuc et al., 2019). Considering that hereditary
thrombophilia in pregnant women might be common (hereditary
thrombophilia is present in 5 out of every 100 people in the general
population (MacCallum et al., 2014)) and RPL is frequent, even mod-
est risks could result in a significant burden of disease. However, evi-
dence for a relationship between hereditary thrombophilia and RPL is
still discordant owing to the deviations in sample size, ethnicity, and
other aspects in the few studies performed (Fakhr-Eldeen et al., 2017;
Wolski et al., 2017; Bigdeli et al., 2018; Jusic et al., 2018; Peres
Wingeyer et al., 2019). In this case, using integrated methods (such as
meta-analysis) to assess the data provided in the scientific literature
would be helpful to determine the association between hereditary
thrombophilia and risk of RPL.
During the past decade, two relevant meta-analyses without any
geographic restriction have been performed (Gao and Tao, 2015;
Sergi et al., 2015). They both found that pregnant women with heredi-
tary thrombophilia, compared with the references, had a significantly
higher risk of RPL. However, those analyses were not exhaustive, as
only one type of hereditary thrombophilia was reported in each of
them. For example, Sergi et al. only assessed the risk of early RPL in
pregnant women with the G1691A mutation of the factor V Leiden
(FVL) gene (Sergi et al., 2015), whereas in the meta-analysis performed
by Gao et al., only the association between the G20210A mutation of
the prothrombin gene (PGM) and RPL was evaluated (Gao and Tao,
2015). Furthermore, several high-quality studies were published after
these two meta-analyses and reported different results (Fakhr-Eldeen
et al., 2017; Wolski et al., 2017; Bigdeli et al., 2018; et al., 2018; Jusic
et al., 2018; Peres Wingeyer et al., 2019; Nassour-Mokhtari et al.,
2020; Yengel et al., 2020). Other types of hereditary thrombophilia,
Liu et al.
.. such as deficiency of antithrombin (AT), deficiency of protein C (PC),
.. and deficiency of protein S (PS), have also been reported as risk fac-
..
.. tors of RPL (Hansda and Roychowdhury, 2012; Hossain et al., 2013;
.. Patil et al., 2015). However, relevant results were discrepant and no
..
.. related meta-analysis was performed; such an information deficit is a
.. hindrance to assessing the risk of RPL in pregnant women with heredi-
..
.. tary thrombophilia.
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..
.. Therefore, the objective of this study was to perform a renewed
.. and comprehensive meta-analysis of the relation between hereditary
..
.. thrombophilia and risk of RPL.
..
..
..
..
.. Materials and methods
..
..
.. Search strategy
..
.. We performed the present meta-analysis following the Preferred
.. Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)
..
.. statement (Shamseer et al., 2015). Two authors independently identi-
.. fied studies published in English prior to 1 April 2020, that reported
..
.. data on RPL for pregnant women with and without hereditary throm-
..
.. bophilia. PubMed, Web of Science, and EMBASE were systematically
.. searched. The following search terms were applied in combination:
..
.. inherited thrombophilia, thrombophilia, thrombophilic, hypercoagu-
.. lable, activated protein C resistance, APCR, antithrombin deficiency,
..
.. protein C deficiency, protein S deficiency, hypercoagulabil, factor V,
.. factor V Leiden, factor 5 Leiden, FVL, factor II, prothrombin, poly-
..
.. morphism, mutation, variant, PGM, PGV, G20210A, and G1691A;
..
.. pregnancy, trimester, gestational, pregnant, conception, preconception,
.. pre-conception, pre-pregnancy, pre-pregnancy, prenatal, pre-natal,
..
.. perinatal, peri-natal, antepartum, ante-partum, antenatal, and ante-
.. natal; complication, problem, difficult, disorder, outcome, fetal, fetal,
..
.. fetus, fetus, embryo, loss, death, demise, resorption, pregnancy loss,
.. miscarriage, abortion, stillbirth, stillborn, livebirth, and live birth.
..
.. Reference lists of all reviews related to the topic and included studies
.. were manually searched for additional potentially eligible studies.
..
..
..
.. Exposure and outcomes
..
.. The key exposure variable was the presence of hereditary thrombo-
.. philia, including FVL mutation, PGM, deficiency of AT, deficiency of PC,
..
.. and deficiency of PS. The FVL mutation causes a coagulation defect of
.. factor V, inherited as a dominant autosomal trait, with G > A substitu-
..
.. tion at nucleotide 1691 located on chromosome 1q23 (the heterozy-
..
.. gote genotype of FVL mutation is GA and homozygote genotype is AA).
.. The PGM results in a coagulation defect of factor II, inherited as a
..
.. dominant autosomal trait, with G > A substitution at nucleotide 20210
.. located on chromosome 11, the 11b11-Q12 position (heterozygote
..
.. genotype of PGM is GA and homozygote genotype is AA). The defi-
.. ciency of AT is a result of over 250 distinct mutations of the AT gene,
..
. located on chromosome 1q23-25, inherited as a dominant autosomal
Hereditary thrombophilia and recurrent pregnancy loss
..
trait. The deficiency of PC arises from more than 160 distinct muta-
tions of the PC gene, inherited as a dominant autosomal disorder, lo-
cated on chromosome 2 (2q13-14). The deficiency of PS arises from
over 130 autosomal dominant mutations of the gene located on chro-
mosome 3q11.2 (Zoller et al., 1999; Mitriuc et al., 2019).
The outcome of interest was RPL, including early RPL and late RPL.
RPL was defined as two or more pregnancy losses (Hong and Marren,
2018). Early RPL was defined as pregnancy losses before the 13th
week of pregnancy, whereas late RPL was defined as pregnancy losses
after the 13th week of pregnancy.
Inclusion and exclusion criteria
For the screening of title and abstract, we intentionally enlarged the
criteria of inclusion to obtain any related study. First, studies would be
considered for inclusion if they reported on the association between
hereditary thrombophilia and the risk of RPL and were published in
English. Then, full texts of the selected studies were reviewed. Studies
were included if they: were observational in design; included women
as study population; had at least two groups (one with hereditary
thrombophilia and one without hereditary thrombophilia); or showed
sufficient information to allow for accurate risk estimates and the cor-
responding 95% CIs to be computed. Studies were excluded if they:
were reviews, case reports, letter to the editor, or abstracts; were
without controls or with control groups that included men or infants
except for separate data on women; provided unclear or incomplete
data; or were redundant publications. If there was more than one
study from the same population, only the most comprehensive or
most recent published one was included.
Data abstraction
Two reviewers independently abstracted the following data from each
study using a self-designed form for data abstraction: the first author,
year of publication, geographic region, study design, types of thrombo-
philia, types of RPL, average age of case and control, definitions of
RPL, causes of RPL (presented as ‘exclusion of known causes of RPL’),
sample size, distribution of genotypes, confounding factors controlled
for, and risk estimates with their corresponding 95% CIs (the adjusted
CIs were extracted if available). Any disagreements were resolved by
discussion or settled by a third reviewer.
Quality assessment
The Newcastle Ottawa scale recommended by the Agency for
Healthcare Research and Quality was used to evaluate the quality of
articles. Eight major criteria were assessed including adequate definition
of case, representativeness of the case, selection of control, definition
of control, comparability between case and control, ascertainment of
exposure, consistency of the method of ascertainment for case and
control, and non-response rate. With a total score of 9, the higher the
score, the better the quality.
Statistical analysis
Odds ratio (OR) was used as the measure of the association between
hereditary thrombophilia and RPL. Random-effects model meta-
analysis was used to calculate the pooled ORs and 95% CIs
(Borenstein et al., 2010). Heterogeneity was evaluated by the chi-
1215
.. square test (P < 0.10 represented statistically significant heterogeneity)
.. and I2 statistic (I2 > 75% implied an extremely high degree of hetero-
..
.. geneity, 51–75% implied a high degree of heterogeneity, 26–50% im-
... plied a moderate-degree of heterogeneity, and  25% implied a low
.. degree of heterogeneity) (Higgins and Thompson, 2002; Higgins et al.,
..
.. 2003). The Chi-square test was used to estimate whether the variance
.. among studies was caused by chance and the I2 statistic was used to
..
.. estimate the proportion of total variation in prevalence evaluations
.. owing to statistical heterogeneity instead of sampling error. Egger’s line
..
.. regression test was used to examine the existence of publication bias
.. across studies included (P < 0.05 indicated statistically significant differ-
..
.. ences) (Egger et al., 1997). Subgroup analyses were carried out to de-
.. tect possible sources of heterogeneity according to different
..
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.. categories: geographic region (e.g. Africa, Asian, Europe, Latin
..
.. America, North America, Middle East), definitions of RPL (e.g. two or
.. more pregnancy losses, three or more pregnancy losses), types of RPL
..
.. (e.g. pregnancy losses before the 13th week of pregnancy, pregnancy
.. losses after the 13th week of pregnancy), controlled confounders (e.g.
..
.. control one or more confounders, no control for confounders), types
.. of genetic variation (homozygote, heterozygote), and exclusion of
..
.. known causes of RPL (yes, no). Sensitivity analysis was performed to
.. evaluate the robustness of the results of the meta-analysis by repeating
..
.. the meta-analysis after the exclusion of each included study. All the
.. statistical analyses were conducted by RevMan version 5.3 (The
..
.. Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen,
.. Denmark) and R version 3.4.1 (The R Foundation for Statistical
..
.. Computing).
..
..
..
..
.. Results
..
..
.. Selection and characteristics of the studies
..
.. The search strategy and manual retrieval yielded a total of 3046
..
.. articles. Of these, 2054 articles were left after eliminating the duplicate
.. publication, 1711 of them were excluded after screening the title and
..
.. abstracts, and 254 of them were excluded after screening the full text.
.. As a consequence, 89 articles remained (Ridker et al., 1998; Brenner
..
.. et al., 1999; Kutteh et al., 1999; Souza et al., 1999; Foka et al., 2000;
.. Kupferminc et al., 2000; Murphy et al., 2000; Wramsby et al., 2000;
..
.. Younis et al., 2000; Pickering et al., 2001; Pihusch et al., 2001; Rai
.. et al., 2001; Reznikoff-Etievan et al., 2001; Dilley et al., 2002; Finan
..
.. et al., 2002; Pauer et al., 2003; Dossenbach-Glaninger et al., 2004;
.. Aksoy et al., 2005; Glueck et al., 2005; Krause et al., 2005; Mahjoub
..
.. et al., 2005; Mtiraoui et al., 2005; Sehirali et al., 2005; Behjati et al.,
.. 2006; Lindqvist et al., 2006; Sottilotta, G et al., 2006; Zammiti et al.,
..
.. 2006; Altintas et al., 2007; Sotiriadis et al., 2007; Bellver et al., 2008;
..
.. D’Uva et al., 2008; Glueck et al., 2008; Hopmeier et al., 2008;
.. Mougiou et al., 2008; Vora et al., 2008; Ayadurai et al., 2009; Biron-
..
.. Andréani et al., 2009; Ciacci et al., 2009; Ivanov et al., 2009;
.. Kurzwinska et al., 2009; Mukhopadhyay et al., 2009; Pasquier et al.,
..
.. 2009; Hussein et al., 2010; Kovac et al., 2010; Mitic et al., 2010;
.. Mohamed et al., 2010; Yenicesu et al., 2010; Abu-Asab et al., 2011;
..
.. Bagheri et al., 2011; Klai et al., 2011; Serrano et al., 2011; Settin et al.,
.. 2011; Dissanayake et al., 2012; Hansda and Roychowdhury, 2012;
..
.. Karata et al., 2012; Mierla et al., 2012; Skrzypczak et al., 2012; Torabi
.. et al., 2012; Yildiz et al., 2012; Barlik et al., 2013; Baumann et al.,
1216
..
2013; Hossain et al., 2013; Kaur et al., 2013; Kazerooni et al., 2013;
Parand et al., 2013; Teremmahi et al., 2013; Zonouzi et al., 2013;
Dutra et al., 2014; Isaoglu et al., 2014; Pietropolli et al., 2014; Babker
and Gameel, 2015; Kashif et al., 2015; Lino et al., 2015; Patil et al.,
2015; Sharma et al., 2015; Farahmand et al., 2016; Gonçalves et al.,
2016; Khaniani et al., 2016; Chatzidimitriou et al., 2017; Elgari et al.,
2017; Fakhr-Eldeen et al., 2017; Wolski et al., 2017; Bigdeli et al.,
2018; Jusic et al., 2018; Kardi et al., 2018; Ahangari et al., 2019; Peres
Wingeyer et al., 2019; Nassour-Mokhtari et al., 2020; Yengel et al.,
2020) (Fig. 1).
The characteristics of the 89 included studies are shown in the
Supplementary Data (Supplementary Table SVI). The studies were
published between 1998 and 2020, involving a total of 30 254 partici-
pants. Of the observational studies included here, one was cohort in
design and 88 were case-control. The average age of cases and con-
trols was 23.0–48.0 and 23.6–49.0 years, respectively. Among the
studies, 34 were conducted in Europe, 20 in the Middle East, 16 in
Asia, eight in Africa, six in Latin America, and five in North America.
Various definitions of RPL were used; specifically, 48 studies used two
or more pregnancy losses as the definition, whereas the others used
three or more pregnancy losses. In total, 58 studies only included
unexplained RPL, and 31 studies did not exclude RPL caused by other
known causes. With regard to the time of RPL, 67 studies specified
the time ranges, such as ‘within 10th week of pregnancy’. Accordingly,
29 studies assessed the association between hereditary thrombophilia
and early RPL (before 13 weeks gestation) and nine studies assess he-
reditary thrombophilia and later RPL (after 13 weeks gestation). A total
of 39 studies controlled for one or more confounders, such as age,
ethnicity, smoking, etc.
Among all included studies, 81 studies evaluated the relation be-
tween FVL mutation and RPL, 64 studies evaluated the relationship be-
tween PGM and RPL, seven studies evaluated the relation between
deficiency of AT and RPL, nine studies evaluated the relation between
deficiency of PC and RPL, and 10 studies evaluated the relation be-
tween deficiency of PS and RPL. All studies included here were of me-
dium or high quality.
The relation between FVL mutation
and RPL
The risk estimation of RPL associated with FVL mutation is summarized
in Fig. 2. The ORs for the association reported by included studies
ranged from 0.10 to 89.84. Analysis of pooled data from 81 studies in-
dicated a significant association between FVL mutation and RPL (OR:
2.44, 95% CI: 1.96–3.03). A high-degree of statistical heterogeneity
was obtained (I2 ¼ 70%, P < 0.001). The Egger’s line regression test
did not show a potential publication bias (t ¼ 0.796, P ¼ 0.429).
Sensitivity analysis was performed by repeating the meta-analysis after
the exclusion of each included study; results showed that exclusion of
any single study did not materially alter the risk estimate of RPL associ-
ated with FVL mutation (ORs ranged between 2.35 and 2.50)
(Supplementary Table SI).
Subgroup analysis for the pooled risk estimates of RPL associated
with FVL mutation is shown in Table V. After subgroup analyses, the
variables including geographic region and types of RPL were shown to
be associated with the between-study heterogeneity. The differences
for risk of RPL associated with FVL mutation were significant for
Liu et al.
.. different geographic regions (test for subgroup differences (TSD): I2 ¼
.. 70%, P ¼ 0.005) and types of RPL (TSD: I2 ¼ 83%, P ¼ 0.020). When
..
.. stratified by geographic region, positive associations between FVL mu-
... tation and RPL were found in studies conducted in Africa (OR: 7.26,
.. 95% CI: 3.78–13.93), Asia (OR: 2.64, 95% CI: 1.59–4.40), Europe
..
.. (OR: 1.75, 95% CI: 1.31–2.32), and the Middle East (OR: 2.69, 95%
.. CI: 1.86–3.90), rather than studies conducted in Latin America (OR:
..
.. 1.97, 95% CI: 0.99–3.93), and North America (OR: 1.79, 95% CI:
.. 0.61–5.22). Compared to the reference group, the risk of early RPL
..
.. (OR: 1.69, 95% CI: 1.18–2.41) and late RPL (OR: 5.07, 95% CI:2.22–
..
.. 11.57) were significantly higher among pregnant women with the FVL
.. mutation.
..
..
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.. The relation between PGM and RPL
..
.. The risk estimation of PGM associated with RPL is summarized in
..
.. Fig. 3. The ORs for the association reported by included studies
..
.. ranged from 0.11 to 36.70. Analysis of pooled data from 64 studies in-
.. dicated a significant association between PGM and RPL (OR: 2.08,
..
.. 95% CI: 1.61–2.68). An intermediate-degree of statistical heterogene-
.. ity was obtained (I2 ¼ 42%, P < 0.001). The Egger’s line regression
..
.. test did not show a potential publication bias (t ¼ 1.187, P ¼ 0.240).
.. Sensitivity analysis was performed by repeating the meta-analysis after
..
.. the exclusion of each included study; results showed that exclusion of
.. any single study did not materially alter the risk estimate of RPL associ-
..
.. ated with PGM (ORs ranged between 2.00 and 2.18) (Supplementary
..
.. Table SII).
.. Subgroup analysis of the pooled risk estimates of RPL associated
..
.. with PGM is shown in Table II. After subgroup analyses, the variables
.. including geographic region (TSD: I2 ¼ 0%, P ¼ 0.910), definitions of
..
.. RPL (TSD: I2 ¼ 0%, P ¼ 0.530), types of RPL (TSD: I2 ¼ 8%,
.. P ¼ 0.300), types of PGM (TSD: I2 ¼ 0%, P ¼ 0.550), controlled con-
..
.. founders (TSD: I2 ¼ 0%, P ¼ 0.890) and causes of RPL (TSD: I2 ¼
.. 50%, P ¼ 0.160) were not shown to be associated with the between-
..
.. study heterogeneity.
..
..
.. The relation between deficiency of at and
..
.. RPL
..
.. The risk estimation of RPL associated with deficiency of AT is summa-
..
.. rized in Fig. 4. The ORs for the association reported by included stud-
.. ies ranged from 0.11 to 3.02. Analysis of pooled data from seven
..
.. studies showed no significant association between deficiency of AT
.. and RPL (OR: 0.83, 95% CI: 0.29–2.36). A low-degree of statistical
..
.. heterogeneity was obtained (I2 ¼ 12%, P ¼ 0.340). The Egger’s line re-
.. gression test did not show a potential publication bias (t ¼ 0.248,
..
.. P ¼ 0.814). Sensitivity analysis was performed by repeating the meta-
.. analysis after the exclusion of each included study; results showed that
..
.. exclusion of any single study did not materially alter the risk estimate
..
.. of RPL associated with a deficiency of AT (ORs ranged between 0.60
.. and 1.51) (Supplementary Table SIII).
..
.. Subgroup analysis for the pooled risk estimates of RPL associated
.. with deficiency of AT is shown in Table III. After subgroup analyses,
..
.. the variable controlled confounders was shown to be associated with
.. the between-study heterogeneity. The differences for risk of RPL asso-
..
.. ciated with deficiency of AT were significant for different controlled
.. confounders (TSD: I2 ¼ 74%, P ¼ 0.050). When stratified by
Hereditary thrombophilia and recurrent pregnancy loss 1217

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Figure 1. Flow diagram of articles included in a systematic review of an association between hereditary thrombophilia and re-
current pregnancy loss: PRISMA statement. FVL, the G1691A mutation of the factor V Leiden gene; PGM, the G20210A mutation of the pro-
thrombin gene; AT, antithrombin; PC, protein C; PS, protein S; RPL, recurrent pregnancy loss.

..
controlled confounders, no significant association was observed be- .. studies showed no significant association between deficiency of PC
tween deficiency of AT and RPL, neither in studies controlling for one .. and RPL (OR: 1.98, 95% CI: 0.97–4.04). A low-degree of statistical
..
or more confounders (OR: 1.83, 95% CI: 0.52–6.39) nor in studies .. heterogeneity was obtained (I2 ¼ 0%, P ¼ 0.560). The Egger’s line re-
controlling for none (OR: 0.26, 95% CI: 0.06–1.17). .. gression tests did not show a potential publication bias (t ¼ 1.295,
..
.. P ¼ 0.236). Sensitivity analysis was performed by repeating the meta-
.. analysis after the exclusion of each included study; results showed that
The relation between deficiency of PC and ..
.. exclusion of any single study did not materially alter the risk estimate
RPL .. of RPL associated with a deficiency of PC (ORs ranged between 1.68
..
The risk estimation of RPL associated with deficiency of PC is summa- .. and 2.96) (Supplementary Table SIV).
rized in Fig. 5. The ORs for the association reported by included stud- .. Subgroup analysis for the pooled risk estimates of RPL associated
..
ies ranged from 0.34 to 17.75. Analysis of pooled data from nine . with deficiency of PC is shown in Table IV. After subgroup analyses,
1218 Liu et al.

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Figure 2. Forest plot of the association between risk of RPL and FVL mutation in women.
Hereditary thrombophilia and recurrent pregnancy loss 1219

Table I Subgroup analyses for the association between FVL mutation and RPL.

Subgroup No. of studies OR (95% CI) I2 (%) P-value for Test for subgroup differences
heterogeneity
v2 P I2 (%)
............................................................................................................................................................................................................................
Geographic region 16.90 0.005 70
Africa 7 7.26 (3.78, 13.93) 62 0.020
Asian 15 2.64 (1.59, 4.40) 49 0.020
Europe 31 1.75 (1.31, 2.32) 54 <0.001
Latin America 5 1.97 (0.99, 3.93) 0 0.420
North America 5 1.79 (0.61, 5.22) 74 0.004
Middle East 18 2.69 (1.86, 3.90) 63 <0.001

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Definitions of RPL 1.35 0.250 26
2 45 2.15 (1.66, 2.79) 57 <0.001
3 36 2.78 (1.97, 3.91) 75 <0.001
Types of RPL 5.73 0.020 83
Early RPL 26 1.69 (1.18, 2.41) 74 <0.001
Late RPL 9 5.07 (2.22, 11.57) 81 <0.001
Types of FVL 0.53 0.470 0
FVL homozygote 23 2.76 (1.34, 5.71) 60 <0.001
FVL heterozygote 44 2.07 (1.57, 2.72) 65 <0.001
Controlled confounders 1.32 0.250 24
One or more 37 2.81 (2.07, 3.81) 52 <0.001
None 44 2.19 (1.62, 2.95) 77 <0.001
Exclusion of known causes of RPL 3.32 0.070 70
Yes 54 2.80 (2.20, 3.56) 65 <0.001
No 27 1.81 (1.21, 2.70) 69 <0.001

RPL, recurrent pregnancy loss; FVL, the G1691A mutation of the factor V Leiden gene; OR, odds ratio.

..
the variables including geographic region (TSD: I2 ¼ 0%, P ¼ 0.800), .. shown to be associated with the between-study heterogeneity. The
definitions of RPL (TSD: I2 ¼ 58%, P ¼ 0.120), types of RPL (TSD: I2 .. differences for risk of RPL associated with deficiency of PS were signifi-
..
¼ 0%, P ¼ 0.690), controlled confounders (TSD: I2 ¼ 63%, P ¼ 0.100), .. cant for different definitions of RPL (TSD: I2 ¼ 76%, P ¼ 0.040) and
and causes of RPL (TSD: I2 ¼ 31%, P ¼ 0.230) were not shown to be
.. controlled confounders (TSD: I2 ¼ 88%, P ¼ 0.005). When stratified
..
associated with the between-study heterogeneity. .. by definitions of RPL, a positive association between deficiency of PS
.. and RPL was found in studies with two or more losses as the defini-
..
The relation between deficiency of PS and .. tion of RPL (OR: 6.94, 95% CI: 2.08–23.18), rather than in studies
..
RPL .. with three or more losses as the definition of RPL (OR: 0.91, 95% CI:
.. 0.19–4.27). When stratified by controlled confounders, a positive as-
The risk estimation of RPL associated with a deficiency of PS is sum- ..
.. sociation between deficiency of PS and RPL was found in studies that
marized in Fig. 6. The ORs for the association reported by included .. controlled for one or more confounders (OR: 5.99, 95% CI: 2.14–
studies ranged from 0.22 to 47.77. Analysis of pooled data from 10
..
.. 16.75), rather than in studies that did not control for any confounders
studies indicated a significant association between deficiency of PS and .. (OR: 0.34, 95% CI: 0.06–1.85).
..
RPL (OR: 3.45, 95% CI: 1.15–10.35). A high-degree of statistical het- ..
erogeneity was obtained (I2 ¼ 59%, P ¼ 0.009). The Egger’s line re- ..
gression test did not show a potential publication bias (t ¼ 0.649, ...
.. Discussion
P ¼ 0.535). Sensitivity analysis was performed by repeating the meta- ..
analysis after the exclusion of each included study; results showed that
.. Our meta-analysis, including 89 studies with 30 254 individuals, sug-
..
exclusion of any single study did not materially alter the risk estimate .. gested that hereditary thrombophilia was associated with RPL. Overall,
..
of RPL associated with deficiency of PS (ORs ranged between 2.55 .. FVL mutation, PGM and a deficiency of PS may increase the risk of RPL
and 4.53) (Supplementary Table SV). .. by 2.44-fold, 2.08-fold, and 3.45-fold, respectively. Compared with the
..
Subgroup analysis for the pooled risk estimates of RPL associated .. reference group, the available evidence did not support a positive as-
with deficiency of PS is shown in Table I. After subgroup analyses, the .. sociation between deficiency of AT or deficiency of PC and RPL (all
..
variables including definitions of RPL and controlled confounders were . P > 0.05). To the best of our knowledge, this study is the most up-to-
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Liu et al.

Figure 3. Forest plot of the association between risk of RPL and PGM in women.
1220
Hereditary thrombophilia and recurrent pregnancy loss 1221

Table II Subgroup analyses for the association between PGM and RPL.

Subgroup No. of studies OR (95% CI) I2 (%) P-value for Test for subgroup differences
heterogeneity
v2 P I2 (%)
............................................................................................................................................................................................................................
Geographic region 1.49 0.910 0
Africa 7 4.53 (0.93, 22.06) 76 <0.001
Asian 7 1.64 (0.57, 4.72) 30 0.200
Europe 28 1.93 (1.38, 2.70) 36 0.030
Latin America 5 1.77 (0.45, 6.93) 42 0.140
North America 2 1.95 (0.43, 8.92) 3 0.310
Middle East 15 2.25 (1.47, 3.44) 39 0.060

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Definition of RPL 0.40 0.530 0
2 33 2.23 (1.54, 3.22) 54 <0.001
3 31 1.89 (1.34, 2.68) 22 0.140
Type of RPL 1.09 0.300 8
Early RPL 22 2.03 (1.32, 3.13) 52 0.003
Late RPL 5 3.21 (1.53, 6.76) 0 0.880
Type of PGM 0.35 0.550 0
PGM homozygote 8 2.33 (0.87, 6.26) 0 1.000
PGM heterozygote 38 1.69 (1.17, 2.45) 51 <0.001
Controlled confounders 0.02 0.890 0
One or more 27 2.12 (1.43, 3.15) 41 0.010
None 37 2.05 (1.46, 2.87) 42 0.005
Exclusion of known causes of RPL 2.02 0.160 50
Yes 43 2.34 (1.78, 3.08) 34 0.020
No 21 1.52 (0.90, 2.58) 45 0.010

PGM, the G20210A mutation of the prothrombin gene.

date and comprehensive meta-analysis evaluating the relation between

.. association between PGM and RPL. Instead, Robertson et al. (ORearly
..
hereditary thrombophilia and RPL; this study could provide useful in- .. RPL ¼ 2.70, ORlate RPL ¼ 8.60; all P < 0.05) and Rey et al. (ORRPL ¼
..
formation for both affected women and clinicians, and help to guide .. 2.05, P < 0.05) had observed an increased risk of RPL among PGM
clinical management and advocacy efforts. .. carriers, which was consistent with our findings. Furthermore, a meta-
..
By comprehensive meta-analysis of 81 case-control studies, we .. analysis conducted in 2015 with 37 case-control studies also indicated
found that FVL mutation may be significantly associated with risk of .. a significant association between PGM and RPL (ORRPL ¼ 1.81,
..
RPL; the findings were consistent with the results of previous meta- .. P < 0.05) (Gao and Tao, 2015).
analyses performed by Rey et al. (ORRPL ¼ 3.04, P < 0.05),
.. In addition to the FVL mutation and PGM, in the present meta-
..
Kovalevsky et al. (ORRPL ¼ 2.00, P < 0.05), Dudding and Attia .. analysis an increased risk of RPL was also detected in pregnant women
(ORearly RPL ¼ 1.80, P < 0.05), Kist et al. (ORRPL ¼ 2.16, P < 0.05),
.. with a deficiency in PS. To the best of our knowledge, this was the
..
Bradley et al. (ORRPL ¼ 2.02, P < 0.05), Sergi et al. (ORearly RPL ¼ .. first time that the association between deficiency of PS and RPL was
..
1.68, P < 0.05), and Kamali et al. (ORRPL ¼ 2.22, P < 0.05) (Rey et al., .. assessed by using integrated methods. However, considering the lim-
2003; Dudding and Attia, 2004; Kovalevsky et al., 2004; Kist et al., .. ited number of included studies (10 studies) and substantial between-
..
2008; Bradley et al., 2012; Sergi et al., 2015; Kamali et al., 2018). .. study heterogeneity, the result should be interpreted with caution.
Similar results were found in the analyses of the association between .. Furthermore, the associations between deficiency of AT as well as de-
PGM and RPL. However, in light of previous meta-analyses, the find-
... ficiency of PC and risk of RPL were quantitatively analyzed using the
..
ings seemed to be discordant, which was probably owing to the rela- .. meta-analysis method, and neither deficiency of AT nor deficiency of
tively small sample size in the previous meta-analyses. Specifically,
.. PC was found to be associated with risk of RPL (all P > 0.05).
..
meta-analyses performed by Ghee et al., Kovalevsky et al., Robertson .. Although deficiencies of AT, deficiencies of PC, and deficiencies of PS
..
et al., and Rey et al. included merely six, seven, seven, and nine stud- .. have been shown to have relatively higher thrombogenic potential
ies, respectively (Ghee and Burrows, 2002; Rey et al., 2003; .. (Middeldorp, 2016; Mitriuc et al., 2019; Pearson-Stuttard et al., 2019),
..
Kovalevsky et al., 2004; Robertson et al., 2006). With the minimum .. there are fewer studies on their association with RPL owing to their
number of studies, Ghee et al. (ORRPL ¼ 1.90, P > 0.05) and .. potentially lower prevalence in pregnant women (the prevalence of
..
Kovalevsky et al. (ORRPL ¼ 2.00, P > 0.05) did not detect a significant . deficiencies of AT, PC, and PS in the general population are evaluated
1222 Liu et al.

Figure 4. Forest plot of the association between risk of RPL and deficiency of AT in women.

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Table III Subgroup analyses for the association between deficiency of AT and RPL.

Subgroup No. of studies OR (95% CI) I2 (%) P-value for Test for subgroup differences
heterogeneity
v2 P I2 (%)
............................................................................................................................................................................................................................
Geographic region 0.99 0.800 0
Africa 1 0.52 (0.02, 13.02) – –
Asian 4 0.87 (0.17, 4.31) 49 0.120
Europe 1 3.02 (0.12, 74.87) – –
Latin America 1 0.34 (0.01, 8.78) – –
Definition of RPL 1.56 0.210 36
2 3 1.67 (0.43, 6.51) 0 0.570
3 4 0.45 (0.10, 2.10) 17 0.310
Type of RPL 0.06 0.810 0
Early RPL 1 2.12 (0.24, 18.34) – –
Late RPL 1 3.09 (0.36, 26.87) – –
Controlled confounders 3.82 0.050 74
One or more 4 1.83 (0.52, 6.39) 0 0.740
None 3 0.26 (0.06, 1.17) 0 0.410
Exclusion of known causes of RPL 0.47 0.490 0
Yes 5 1.36 (0.39, 4.82) 0 0.790
No 2 0.45 (0.03, 8.02) 73 0.050

AT, antithrombin.

to be 0.02–0.20%, 0.2–1.5%, and 0.03–1.3%, respectively (Mitriuc .. Rey et al. (2003) (ORearly RPL ¼ 2.01, ORlate RPL ¼ 7.83), Kovalevsky
..
et al., 2019)). More research is needed to clarify the relations even .. et al. (2004) (ORearly RPL ¼ 1.60, ORlate RPL ¼ 2.70), Robertson et al.
though it may take a long time to achieve that goal.
.. (2006) (ORearly RPL ¼ 1.91, ORlate RPL ¼ 4.12), and Kist et al. (2008)
..
Meanwhile, by performing the subgroup analyses, we found that .. (ORearly RPL ¼ 1.85, ORlate RPL ¼ 2.28) (Rey et al., 2003; Kovalevsky
geographic region might have a significant influence on the association
.. et al., 2004; Robertson et al., 2006; Kist et al., 2008). With regard to
..
between hereditary thrombophilia and RPL. These distinct outcomes .. PGM, we found that the relation between PGM and late RPL seems to
seemed to correlate with ethnic heterogeneity. The previous two
.. be stronger than that between PGM and early RPL; however, the dif-
..
meta-analyses also indicated that different regions or race might influ- .. ference was not statistically significant.
ence the relation between hereditary thrombophilia and RPL
.. Based on a large sample size, we obtained a more convincing result.
..
(Kovalevsky et al., 2004; Gao and Tao, 2015). In addition, our results .. However, some limitations must be noted. The first potential limita-
..
showed that the relation between FVL mutation and late RPL was .. tion of the present meta-analysis was the high heterogeneity across in-
stronger than that between FVL mutation and early RPL, which was .. cluded studies. That is not surprising considering the variation in
..
consistent with the findings of previous meta-analyses performed by .. characteristics of populations and study design. Fortunately, subgroup
Hereditary thrombophilia and recurrent pregnancy loss 1223

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Figure 5. Forest plot of the association between risk of RPL and deficiency of PC in women.

Table IV Subgroup analyses for the association between deficiency of PC and RPL.

Subgroup No. of studies OR (95% CI) I2 (%) P-value for Test for subgroup differences
heterogeneity
v2 P I2 (%)
............................................................................................................................................................................................................................
Geographic region 1.67 0.800 0
Africa 1 1.61 (0.22, 11.70) – –
Asian 4 2.98 (0.80, 11.03) 44 0.150
Europe 2 3.18 (0.35, 29.00) 0 0.970
Latin America 1 0.34 (0.01, 8.78) – –
The Middle East 1 2.00 (0.22, 18.44) – –
Definition of RPL 2.38 0.120 58
2 5 3.93 (1.28, 12.08) 0 0.480
3 4 1.25 (0.50, 3.15) 0 0.830
Type of RPL 0.15 0.690 0
Early RPL 1 9.04 (1.20, 68.31) – –
Late RPL 1 5.04 (0.62, 40.95) – –
Controlled confounders 2.69 0.100 63
One or more 7 3.39 (1.30, 8.82) 0 0.700
None 2 1.02 (0.35, 2.97) 0 0.600
Exclusion of known causes of RPL 1.46 0.230 31
Yes 6 3.17 (1.12, 8.96) 0 0.530
No 3 1.32 (0.50, 3.49) 0 0.550

PC, protein C.

..
analyses in this study have identified several main heterogeneity mod-
... hereditary thrombophilia and RPL. Out of the 89 included studies,
erators including geographic region, definitions of RPL, types of RPL, .. only 39 studies controlled for one or more confounders, such as age,
and controlled confounders. In addition, the variables including mater- .. ethnicity. The overlap between the confounders controlled across
..
nal age, health condition, complications, and exposure to environmen- .. these studies was also limited. Given that many studies included in this
tal pollutants might contribute to the heterogeneity, considering the .. meta-analysis have not controlled for the key confounders of RPL, it is
..
underlying mechanisms involved in the relation between hereditary .. possible that the increased risks detected in this study are partially due
thrombophilia and risk of RPL. However, we could not acquire suffi- .. to differences in these risk factors of RPL between pregnant women
..
cient information to examine this hypothesis. .. with hereditary thrombophilia and the reference groups. Further re-
The second potential limitation was that significant unmeasured con-
.. search is needed to establish whether hereditary thrombophilia inde-
..
founders might be involved in the observed relation between . pendently increases the risk of RPL.
1224 Liu et al.

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Figure 6. Forest plot of the association between risk of RPL and deficiency of PS in women.

Table V Subgroup analyses for the association between deficiency of PS and RPL.

Subgroup No. of studies OR (95% CI) I2 (%) P-value for Test for subgroup differences
heterogeneity
v2 P I2 (%)
............................................................................................................................................................................................................................
Geographic region 6.95 0.140 42
Africa 1 0.22 (0.01, 4.32) – –
Asian 4 7.86 (1.08, 57.43) 74 0.009
Europe 3 3.61 (1.06, 12.29) 0 0.570
Latin America 1 0.69 (0.11, 4.45) – –
The Middle East 1 10.37 (0.59, 182.46) – –
Definition of RPL 4.13 0.040 76
2 6 6.94 (2.08, 23.18) 53 0.060
3 4 0.91 (0.19, 4.27) 28 0.240
Type of RPL 0.37 0.540 0
Early RPL 1 9.04 (1.20, 68.31) – –
Late RPL 1 22.00 (2.95, 164.05) – –
Controlled confounders 8.04 0.005 88
One or more 8 5.99 (2.14, 16.75) 44 0.080
None 2 0.34 (0.06, 1.85) 0 0.730
Exclusion of known causes of RPL 0 0.940 0
Yes 7 3.53 (0.90, 13.95) 63 0.010
No 3 3.22 (0.36, 29.05) 64 0.060

PS: protein S.

..
In addition, only published studies were included, which might lead .. English (Robertson et al., 2006). What is more, Egger’s line regression
to the omission of some important unpublished studies that meet our .. tests did not find a potential publication bias in any of our analyses.
..
inclusion criteria in the literature search. Furthermore, the studies in- .. The strength of the present meta-analysis is that the large sample
cluded in this review were limited to those published in English, which .. size of 30 254 individuals from all included studies is helpful for en-
..
might also lead to potential publication bias. However, these would be .. hancing statistical power to provide more precise and reliable risk esti-
unlikely to change our overall conclusions owing to the magnitude and .. mates. Compared with previous meta-analyses, our study is more
..
consistency of the associations we observed. Excluding non-English .. comprehensive. Several related meta-analyses that have been per-
studies might not have a significant impact on the results, as high-
.. formed just focused on one or two particular kinds of hereditary
..
quality research in obstetrics and gynecology is usually published in .. thrombophilia, such as FVL mutation or/and PGM (Ghee and Burrows,
.
Hereditary thrombophilia and recurrent pregnancy loss 1225

..
2002; Dudding and Attia, 2004; Kovalevsky et al., 2004; Robertson ..
..
Authors’ roles
et al., 2006; Kist et al., 2008; Bradley et al., 2012; Gao and Tao, 2015;
.. Study concept and design: L.C. and T.W.. Acquisition, analysis, or in-
Sergi et al., 2015; Kamali et al., 2018) or were confined to a certain ..
group of people, such as the Iranian population (Kamali et al., 2018), ... terpretation of data: X.L., Y.C., C.Y., D.X., R.W. and F.L. Statistical
or was limited to a certain period of pregnancy such as first trimester .. analysis: X.L. and Y.C. Drafting of the manuscript: X.L. Critical revision
.. of the manuscript for important intellectual content: L.C., T.W. and
(Sergi et al., 2015). Moreover, in order to identify relevant studies as ..
completely as possible, a comprehensive and detailed search strategy .. X.L. Obtained funding: L.C.. Administrative, technical, or material sup-
.. port: L.C.. Study supervision: L.C. and T.W.
was used at the start of this study. Then, a set of more rigorous selec- ..
tion criteria was used in the screening of the selected studies. Finally,
..
..
more recent studies were included, which ensures that our results .. Funding
were more applicable to present practices.
..
.. The study was funded by the Hunan Provincial Key Research and
Our finding of an association between hereditary thrombophilia and ..
future risk of RPL has significant implications for clinical management
.. Development Program (grant number: 2018SK2062) and National
..

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and health policy. Pregnant women with hereditary thrombophilia are .. Natural Science Foundation Program (grant number: 81973137).
..
at a higher risk of RPL, suggesting that testing for hereditary thrombo- ..
philia should be considered in these women. It is worth nothing, how- .. Conflict of interest
..
ever, that the decision should be made in a clinic context taking into .. None declared.
account all other variables such as ethnicity, and the frequency and ..
..
timing of miscarriage onset. For pregnant women diagnosed with he- ..
reditary thrombophilia, anticoagulant therapy may be helpful for im- ..
..
proving the pregnancy outcomes and reducing the occurrence of RPL. .. References
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