Arch Gynecol Obstet
DOI 10.1007/s00404-015-3894-8
REVIEW
Methylenetetrahydrofolate reductase gene polymorphisms
and recurrent pregnancy loss in China: a systematic review
and meta-analysis
Hui Chen1,2 • Xiaorong Yang2 • Ming Lu1,2
Received: 1 April 2015 / Accepted: 14 September 2015
Ó Springer-Verlag Berlin Heidelberg 2015
Abstract
Purpose Recurrent pregnancy loss (RPL) is defined as
two or more consecutive pregnancy losses before the 20th
week of gestation with the same partner. Methylenete-
trahydrofolate reductase (MTHFR) gene polymorphisms
were reported to have an effect on embryonic development
and pregnancy success. To clarify the effects of MTHFR
polymorphisms on the risk of RPL in the Chinese popu-
lation, a meta-analysis was performed.
Materials and methods Related studies were identified
from Medline, Embase, Web of Science, and Chinese
Databases up to March 7th, 2015. We extracted the number
of both C677T and A1298C genotypes in the cases and
controls. Odds ratios (ORs) and 95 % confidence intervals
(95 % CIs) were used to estimate the associations. Data
analysis was performed using Stata 13.1.
Results Sixteen articles involving 1420 RPL cases and
1408 controls were included in this meta-analysis. MTHFR
C677T polymorphism was significantly associated with
RPL risk under dominant (TT ? CT vs. CC; OR 2.10,
95 % CI 1.76–2.50), recessive (TT vs. CC ? CT; OR 2.36,
95 % CI 1.92–2.90), heterozygote (CT vs. CC; OR 1.77,
95 % CI 1.32–2.37), homozygote (TT vs. CC; OR 3.55,
95 % CI 2.76–4.56), and additive (T vs. C; OR 1.83, 95 %
CI 1.64–2.05) model. Sensitivity analyses excluding stud-
ies that deviated from HWE did not change the direction of
effect. For the A1298C mutation, no significant association
& Ming Lu
lvming@sdu.edu.cn; minglusdu@163.com
1
Clinical Epidemiology Unit, Qilu Hospital, Shandong
University, Jinan 250012, China
2
Department of Epidemiology, School of Public Health,
Shandong University, Jinan 250012, China
was found. The Egger’s regression asymmetry test showed
no significant publication bias.
Conclusions Identification of MTHFR C677T mutation
would have some implication for primary prevention of
RPL and screening of high-risk individuals in China. Large
well-designed researches are needed to fully describe the
associations.
Keywords Methylenetetrahydrofolate reductase

Recurrent pregnancy loss
Meta-analysis
Polymorphism
Introduction
Recurrent pregnancy loss (RPL) is a major reproductive
problem affecting approximately 3 % of otherwise healthy
women of reproductive age with significant clinical prob-
lems [1, 2]. According to the American Society for
Reproductive Medicine, RPL has been redefined as two or
more consecutive pregnancy losses before the 20th week of
gestation with the same partner [3]. Until now, various
factors have been identified that influence miscarriage,
including anatomic abnormalities of the genital tract,
structural uterine abnormalities, cytogenetic abnormalities,
nutritional and environmental factors, as well as hormonal
and metabolic factors, which were taken as risk factors for
RPL [1, 4, 5]. The causes of RPL are complicated, and the
exact underlying etiology of up to 50 % of the RPL
patients remains undetermined [6].
Recent studies investigating the pathophysiology of RPL
indicated that elevated level of homocysteine in blood might
be a risk marker of RPL [7–9]. Genetic and environmental
factors are associated with the hyperhomocysteinemia state,
while the single nucleotide polymorphisms (SNPs) of
methylenetetrahydrofolate reductase (MTHFR) gene were
123

reported to be associated with hyperhomocysteinemia [10].
Among the SNPs, C677T and A1298C are the most preva-
lent. MTHFR enzyme plays an important role in one-carbon
metabolism which catalyzes the conversion of 5,10-
methylenetetrahydrofolate into 5-methylenetetrahydrofo-
late, and then provides the single-carbon for homocysteine
in methionine synthesis [7, 11]. Mutations of MTHFR
C677T and A1298C may reduce enzyme activity, and
decrease the conversion of homocysteine into methionine,
leading to accumulation of homocysteine in blood.
The association between the MTHFR gene polymor-
phisms and RPL susceptibility has been widely researched
[12–14], but with inconclusive results. To lessen the impact
of different genetic background, we performed this meta-
analysis to assess the relationship between MTHFR gene
polymorphisms and the risk of RPL among the Chinese
population.
Materials and methods
Search strategy
Studies were identified in the following databases: Med-
line, Embase, Web of Science, VIP (Database of Chinese
Scientific and Technical Periodicals), the China Wanfang
Database, and the China National Knowledge Infrastruc-
ture (CNKI) for relevant studies published in English or
Chinese from the inception to March 7th, 2015. Key words
were as follows: ‘methylenetetrahydrofolate reductase’ or
‘MTHFR,’ ‘polymorphism’ or ‘mutation’ or ‘variant,’
‘Chinese’ or ‘China,’ ‘recurrent miscarriage’ or ‘recurrent
abortion’ or ‘recurrent pregnancy loss’ or ‘recurrent fetal
loss.’ Besides, we reviewed the references of the retrieved
articles to search for further relevant studies. We followed
standard criteria for conducting meta-analyses and report-
ing the results. The article search was performed by two
investigators, independently (Chen and Yang).
Eligibility criteria
Studies satisfying the following criteria were included: (1)
the design of original article was a cohort study or a case–
control study, and the participants were all Chinese; (2)
studies that evaluated the association between the MTHFR
polymorphisms and RPL risk; (3) RPL was defined as the
occurrence of two or more pregnancy losses in the first two
trimesters of pregnancy, and the controls were women with
at least one successful pregnancy; (4) the numbers or
genotype frequencies in cases and controls in each study
must be given in the original study; (5) for duplicates, only
the studies with more complete data and more extensive
123
Arch Gynecol Obstet
interval of enrollment were included; and (6) reviews,
comments, and editorials articles were excluded.
Data extraction and quality assessment
Two reviewers independently performed data extraction
and then checked the results together. The following
information was extracted from the included studies: first
author, publication year, location where the study was
performed, genotype frequencies in cases and controls, and
evidence of Hardy–Weinberg equilibrium (HWE) in
controls.
The quality of the included studies was estimated by the
9-star Newcastle-Ottawa Scale and Agency for Healthcare
Research and Quality (http://www.ohri.ca/programs/clin
ical_epidemiology/oxford.asp, maximum score nine
points). This scale assessed the selection of patient, the
comparability of group, and the quality of the sampling
process.
Statistical analysis
Odds ratios (ORs) with 95 % confidence intervals (CIs)
were calculated to assess the strength of association
between the MTHFR polymorphisms and the risk of RPL
in the Chinese population. Tests for among-study hetero-
geneity were performed using the Higgins I2 statistics [15].
In the presence of substantial heterogeneity (I2 [ 50 %),
the DerSimonian and Laird random effects model (REM)
was adopted; otherwise, we used the fixed effects model
(FEM) as the pooling method. Publication bias was esti-
mated by Egger’s regression asymmetry test [16]. Data
analysis was performed using Stata (version 13.1; Stata
Corporation, College Station, TX,USA) software. All
reported probabilities (p values) were two-sided, and the
values less than 0.05 were considered statistically
significant.
Results
Main characteristics of all the available studies
The primary search generated 406 potentially relevant
studies, and based on the title and/or abstract screening,
382 studies were excluded according to the eligible criteria.
After full document review, 16 articles [17–32] involving
1420 RPL cases and 1408 controls were included in this
meta-analysis. Among the included articles, 16 articles
[17–32] reported the association between MTHFR C677T
gene mutation and RPL risk; and 5 articles [19, 21, 22, 30,
31] demonstrated the association of MTHFR A1298C
Arch Gynecol Obstet

Table 1 Characteristics of studies on the association between MTHFR gene polymorphisms and RPL risk
Gene References Region Pregnancy loss (times) Method Genotypec pa Quality scoreb
polymorphisms
Case Control

MTHFR C677T Wang et al. [17] Shaanxi C2 PCR-RFLP 13:33:16 43:53:23 0.472 7
Song et al. [18] Guangdong C2 PCR-RFLP 36:2:12 40:12:4 0.044 7
Li et al. [19] Shandong C2 PCR-RFLP 16:32:9 25:20:5 0.736 9
Guan et al. [20] Shandong C3 PCR-RFLP 13:59:55 19:73:25 0.007 8
Wang et al. [21] Shanghai C2 PCR-RFLP 49:78:20 43:34:5 0.612 9
Ren et al. [22] Shanxi C2 PCR-RFLP 9:40:22 29:38:26 0.079 8
Wan et al. [23] Shandong C2 PCR-RFLP 6:46:28 19:33:8 0.284 8
Xu et al. [24] Shandong C2 PCR-RFLP 21:48:43 32:50:18 0.842 8
Ma et al. [25] Shanxi C2 PCR-RFLP 12:32:16 19:34:7 0.162 7
Wang et al. [32] Jiangsu C2 PCR-RFLP 36:2:12 89:27:9 0.003 7
Zhang et al. [26] Jilin C2 PCR-RFLP 12:25:19 20:22:8 0.640 7
Zhong et al. [27] Ningxia C3 PCR-RFLP 72:53:16 114:43:3 0.647 7
Wang et al. [28] Shandong C2 PCR-RFLP 18:82:59 28:78:21 0.009 9
Han et al. [29] Beijing C2 PCR-RFLP 10:35:26 25:15:18 \0.001 8
Hu et al. [30] Guangdong C3 PCR-RFLP 29:14:9 11:4:1 0.473 8
Luo et al. [31] Zhejiang C2 PCR-RFLP 40:70:15 60:65:10 0.178 8
MTHFR A1298C Li et al. [19] Shandong C2 PCR-RFLP 33:21:3 29:18:3 0.926 8
Wang et al. [21] Shanghai C2 PCR-RFLP 103:35:10 60:20:2 0.829 9
Ren et al. [22] Shanxi C2 PCR-RFLP 0:17:54 1:6:86 0.037 8
Hu et al. [30] Guangdong C3 PCR-RFLP 33:12:7 12:3:1 0.248 8
Luo et al. [31] Zhejiang C2 PCR-RFLP 82:40:3 78:54:3 0.068 8
a
p value for Hardy–Weinberg equilibrium in control group
b
Assessed by the Newcastle–Ottawa Assessment Scale for case–control studies
c
Genotype for MTHFR C677T, CC: CT: TT; MTHFR A1298C, AA:AC:CC

polymorphism with risk of RPL. The characteristics of
studies included in the meta-analysis are shown in Table 1.
Analysis of the pooled data
Overall, the ORs and 95 % CIs of the association between
MTHFR gene polymorphisms and RPL risk were consid-
ered under dominant, recessive, heterozygote, homozygote,
and co-dominant models (results are shown in Table 2).
MTHFR C677T polymorphism and RPL risk
Sixteen articles [17–32] investigated the association
between the MTHFR C677T gene mutation and the risk of
RPL, which involve 1420 RPL cases and 1408 controls.
The pooled results indicated a significant association
between MTHFR C677T gene polymorphism and the risk
of RPL under dominant (TT ? CT vs. CC; OR 2.10, 95 %
CI 1.76–2.50; Fig. 1a), recessive (TT vs. CC ? CT; OR
2.36, 95 % CI 1.92–2.90), heterozygote (CT vs. CC; OR
1.77, 95 % CI 1.32–2.37), homozygote (TT vs. CC; OR
3.55, 95 % CI 2.76–4.56), and co-dominant (T vs. C; OR
1.83, 95 % CI 1.64–2.05) model. Cumulative meta-analy-
sis was performed based on the publication year of the
included studies under the dominant model, and as studies
accumulated, the pooled results tended stable and signifi-
cant (Fig. 1b).
Sensitivity analysis was performed by omission of five
non-HWE studies [18, 20, 28, 29, 32] (p \ 0.05;
Table 1), and the result was not altered, indicating that
the result of meta-analysis was statistically significant
(the detailed results under different models are shown in
Table 2).
The Egger’s regression asymmetry test indicated no
significant publication bias for the MTHFR C677T poly-
morphism under dominant model (p = 0.580).
MTHFR A1298C polymorphism and RPL risk
For the association between the MTHFR A1298C poly-
morphism and RPL risk, five studies were included, which
involve 453 RPL cases and 376 controls. Among the
included studies, genotype distribution of the controls in
one study [22] was not in agreement with HWE.

123
 Arch Gynecol Obstet

Meta-analysis based on these five studies indicated no
significant association between MTHFR A1298C gene
mutation and RPL susceptibility under dominant
(CC ? AC vs. AA; OR 0.96, 95 % CI 0.69–1.33; Fig. 2),
recessive (CC vs. AA ? AC; OR 0.94, 95 % CI
0.34–2.61), heterozygote (AC vs. AA; OR 0.90, 95 % CI
0.64–1.27), homozygote (CC vs. AA; OR 1.55, 95 % CI
0.68–3.55) or co-dominant (C vs. A; OR 0.91, 95 % CI
0.58–1.41) model.
High heterogeneity was found between studies under
recessive and additive models. When excluded one study
conducted by Ren et al. [22] whose control genotypes were
not in good fitness of HWE, no significant heterogeneity
was found, and pooled analysis showed null association
between MTHFR A1298C gene polymorphism and the risk
of RPL (shown in Table 2).
No significant publication bias was found under domi-
nant model (p = 0.201) using the Egger’s regression
asymmetry test.
Discussion
In the present meta-analysis, 16 studies (16 studies for the
C677T mutation and 5 studies for the A1298C mutation)
were included to perform this review of the association
between the MTHFR gene polymorphisms and the risk of
RPL. Results revealed that the presence of the C677T
mutation of MTHFR gene was associated with RPL sus-
ceptibility in the Chinese population. Pregnancy women
with TT and CT genotypes had an increased risk of RPL
compared to CC genotype (TT ? CT vs. CC, OR 2.10,
95 % CI 1.76–2.50; CT vs. CC, OR 1.77, 95 % CI
1.32–2.37; TT vs. CC, OR 3.55, 95 % CI 2.76–4.56).
However, for the A1298C gene polymorphism, no signifi-
cant association was found with RPL risk among the
Chinese women.
For MTHFR C677T polymorphism, cumulative analysis
was performed in our current study, and as studies joined in
based on publication year, the cumulated results tended to
significant and stable values. Figure 1b shows the trend
lines of MTHFR C677T mutation with RPL risk under
dominant model. We can demonstrate that MTHFR C677T
mutation was associated with the risk of RPL in the Chi-
nese population.
The allele frequency and genotypes of a gene are thought
to be in balance in a large enough population, that is to say,
the genotypes of a gene are in good fitness of HWE law.
Deviation from HWE law was an indication of potential
bias from methodological shortage or genetic factors, when
performing meta-analysis involving studies whose control
genotypes deviated from HWE, misunderstanding might
occur [33]. In the sensitivity analysis of the MTHFR C677T
gene mutation on RPL risk, when excluded studies that

Table 2 ORs and 95 % CIs for

Gene Contrast Group n I2 (%) Model Pooled OR (95 % CI)
recurrent pregnancy loss and the
MTHFR polymorphisms under C677T TT ? CT vs. CC Overall 16 14.5 FEM 2.10 (1.76–2.50)
different models
HWE: yes 11 0 FEM 2.25 (1.83–2.77)
TT vs. CC ? CT Overall 16 9.7 FEM 2.36 (1.92–2.90)
HWE: yes 11 4.8 FEM 2.17 (1.66–2.84)
CT vs. CC Overall 16 51.8 REM 1.77 (1.32–2.37)
HWE: yes 11 0 FEM 1.96 (1.58–2.44)
TT vs. CC Overall 16 0 FEM 3.55 (2.76–4.56)
HWE: yes 11 0 FEM 3.51 (2.55–4.82)
T vs. C Overall 16 0 FEM 1.83 (1.64–2.05)
HWE: yes 11 0 FEM 1.84 (1.60–2.11)
A1298C CC ? AC vs. AA Overall 5 0 FEM 0.96 (0.69–1.33)
HWE: yes 4 0 FEM 0.95 (0.68–1.32)
CC vs. AA ? AC Overall 5 55.8 REM 0.94 (0.34–2.61)
HWE: yes 4 0 FEM 1.55 (0.66–3.63)
AC vs. AA Overall 5 0 FEM 0.90 (0.64–1.27)
HWE: yes 4 0 FEM 0.88 (0.62–1.25)
CC vs. AA Overall 5 0 FEM 1.55 (0.68–3.55)
HWE: yes 4 0 FEM 1.53 (0.65–3.60)
C vs. A Overall 5 57.1 REM 0.91 (0.58–1.41)
HWE: yes 4 14.2 FEM 1.02 (0.77–1.35)
n number of included studies, FEM fixed effects model, REM random effects model, HWE Hardy–
Weinberg equilibrium

123
Arch Gynecol Obstet

Fig. 1 Results of individual

and summary odds ratios (ORs)
with 95 % confidence intervals
(CIs) of recurrent pregnancy
loss (RPL) for the
methylenetetrahydrofolate
reductase (MTHFR) C677T
polymorphism in China under
dominant model. a Results of a
meta-analysis for the MTHFR
C677T polymorphism in the
Chinese population; b Results
of a cumulative meta-analysis
for the MTHFR C677T
polymorphism

deviated from HWE, pooled results were accordant to the
overall population. For A1298C polymorphism, when
excluded one study that not in good fitness of HWE, no
significant between-study heterogeneity existed, and results
were consistent with the overall population.
Previous meta-analyses conducted by Ren et al. [14] and
Wu et al. [12] had investigated the association between
MTHFR polymorphisms and RPL risk. Results indicated
null association of the A1298C mutation on RPL occur-
rence, whereas for the C677T mutation, a significant strong

123

Fig. 2 Results of individual
and summary odds ratios (ORs)
with 95 % confidence intervals study
(CIs) of recurrent pregnancy
loss (RPL) for the
methylenetetrahydrofolate
Li et al. (2004)
reductase (MTHFR) A1298C
polymorphism in China under
Wang et al. (2006)
dominant model
Ren et al. (2007)
Hu et al. (2014)
Luo et al. (2014)
Overall (I−squared = 0.0%, p = 0.572)
association was observed among the Chinese population
but not in any other ethnicities in Ren’s study, and Wu’s
study supported the idea that MTHFR C677T genotype is
associated with increased risk of RPL, except for Cau-
casians. There are studies reporting the genes as ethnicity-
dependent risk factors for some specific diseases, and
genotype distribution varies among different ethnic groups
[34, 35]. Folic acid plays important role in one-carbon
metabolism and DNA synthesis, and in China, for women
of childbearing age, the dietary folate intake was far from
optimal, especially among women living in northern China,
and the percentage of women who actually took folic acid
supplements before and during pregnancy was only around
12 % [36, 37]. A recent study found that preconception
folic acid supplementation use decreased the risk of RPL
[38]. So the folate intake status may be a confounder in our
study, leading to the different conclusions in the Chinese
population and other ethnicities. In this present meta-
analysis, we generated the most eligible studies, and found
a significant relationship between MTHFR C677T poly-
morphism and RPL under five models in Chinese popula-
tion, but not for the A1298C mutation. The results were
largely in line with previous analyses.
C677T and A1298C are two important SNPs for
MTHFR that may affect the level and the activity of
MTHFR enzyme in blood, which play key roles in one-
carbon metabolism and the conversion of homocysteine
into methionine, leading to hyperhomocysteinemia.
Homocysteine may contribute to oxidative stress, arteriolar
constriction, renal dysfunction, and endothelial damage,
and then leading to dysfunction of our body systems [39–
41]. Studies also investigated the effects of lowering
homocysteine levels (with B vitamins) on stroke, cardio-
vascular disease mortality, and found a significant protec-
tive effect [42, 43].
123
Arch Gynecol Obstet
%
OR (95% CI) Weight
1.00 (0.47, 2.17) 18.50
1.19 (0.65, 2.17) 30.30
2.32 (0.09, 57.77) 1.06
1.73 (0.49, 6.12) 6.85
0.72 (0.43, 1.19) 43.30
0.96 (0.69, 1.33) 100.00
.1 .5 1 2 5 20
We should pay attention to the potential limitations of
this meta-analysis. Only five studies investigated the
MTHFR A1298C polymorphism, and the sample size was
not large enough. Thus, they did not have adequate power to
detect the possible association for this polymorphism and
the results may be false. In this study, we just calculated the
genotype information of the cases and controls in the
original articles, whereas potential confounders were
neglected. The interaction between MTHFR polymor-
phisms and different behavioral and environment factors
may influence the susceptibility of RPL, because of the
insufficient information the interactions were not estimated.
Despite the limitations, our study found an increased
risk of RPL for pregnant women with TT and CT geno-
types compared to CC genotype for the MTHFR C677T in
the Chinese population. However, no significant associa-
tion was found between the A1298C polymorphism and
RPL risk. No publication bias was found. Identification of
MTHFR C677T mutation would have some implication for
primary prevention of RPL and screening of high-risk
individuals in China. Large well-designed researches are
needed to fully describe the association between MTHFR
polymorphisms and the risk of RPL.
Compliance with ethical standards
Disclosure The authors declare that there are no conflicts of
interest.
References
1. Regan L, Rai R (2000) Epidemiology and the medical causes of
miscarriage. Bailliere’s Best Pract Res Clin Obstet Gynaecol
14(5):839–854
2. Mukherjee S, Velez Edwards DR, Baird DD, Savitz DA, Hart-
mann KE (2013) Risk of miscarriage among black women and
Arch Gynecol Obstet
white women in a US Prospective Cohort Study. Am J Epidemiol
177(11):1271–1278
3. Practice Committee of the American Society for Reproductive
Medicine (2013) Definitions of infertility and recurrent preg-
nancy loss: a committee opinion. Fertil Steril 99(1):63
4. Li TC, Makris M, Tomsu M, Tuckerman E, Laird S (2002)
Recurrent miscarriage: aetiology, management and prognosis.
Hum Reprod Update 8(5):463–481
5. Garrido-Gimenez C, Alijotas-Reig J (1073) Recurrent miscar-
riage: causes, evaluation and management. Postgrad Med J
2015(91):151–162
6. Simpson JL (2007) Causes of fetal wastage. Clin Obstet Gynecol
50(1):10–30
7. Puri M, Kaur L, Walia GK et al (2013) MTHFR C677T poly-
morphism, folate, vitamin B12 and homocysteine in recurrent
pregnancy losses: a case control study among North Indian
women. J Perinat Med 41(5):549–554
8. Nelen WL, Blom HJ, Steegers EA, den Heijer M, Eskes TK
(2000) Hyperhomocysteinemia and recurrent early pregnancy
loss: a meta-analysis. Fertil Steril 74(6):1196–1199
9. Ozkan Y, Yardim-Akaydin S, Erdem A, Simsek B (2012) Vari-
ability of total thiol compounds, oxidative and nitrosative stress
in uncomplicated pregnant women and nonpregnant women.
Arch Gynecol Obstet 285(5):1319–1324
10. Kumar KS, Govindaiah V, Naushad SE, Devi RR, Jyothy A
(2003) Plasma homocysteine levels correlated to interactions
between folate status and methylene tetrahydrofolate reductase
gene mutation in women with unexplained recurrent pregnancy
loss. J Obstet Gynaecol 23(1):55–58
11. Mao D, Che J, Li K et al (2010) Association of homocysteine,
asymmetric dimethylarginine, and nitric oxide with preeclampsia.
Arch Gynecol Obstet 282(4):371–375
12. Wu X, Zhao L, Zhu H, He D, Tang W, Luo Y (2012) Association
between the MTHFR C677T polymorphism and recurrent pregnancy
loss: a meta-analysis. Genet Test Mol Biomarkers 16(7):806–811
13. Parveen F, Tuteja M, Agrawal S (2013) Polymorphisms in
MTHFR, MTHFD, and PAI-1 and recurrent miscarriage among
North Indian women. Arch Gynecol Obstet 288(5):1171–1177
14. Ren A, Wang J (2006) Methylenetetrahydrofolate reductase
C677T polymorphism and the risk of unexplained recurrent
pregnancy loss: a meta-analysis. Fertil Steril 86(6):1716–1722
15. Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a
meta-analysis. Stat Med 21(11):1539–1558
16. Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in
meta-analysis detected by a simple, graphical test. BMJ (Clin Res
Ed) 315(7109):629–634
17. Wang Y, Li F, Li Y, Xue M, Yu X, Li X (2002) The study on the
relationship between the methylenetetrahydrofolate reductase
C677T mutation and unexplained recurrent pregnancy loss. Chin
J Pract Gynecol Obstet 18(5):291–293
18. Song L, Qi Q, Tian G, She D, Zhang H (2003) Relationship
between methylenetetrahydrofolate reductase gene mutations and
recurrent spontaneous abortion. J Clin Med Bioeng 9(3):246–247
19. Li XM, Zhang YZ, Xu YX, Jiang S (2004) Study on the rela-
tionship of MTHFR polymorphisms with unexplained recurrent
spontaneous abortion. Chin J Med Genet 21(1):39–42
20. Guan LX, Du XY, Wang JX et al (2005) Association of genetic
polymorphisms in plasminogen activator inhibitor-1 gene and
5,10-methylenetetrahydrofolate reductase gene with recurrent
early spontaneous abortion. Chin J Med Genet 22(3):330–333
21. Wang X, Ma Z, Lin Q (2006) Inherited thrombophilia in recur-
rent spontaneous abortion among Chinese women. Int J Gynaecol
Obstet 92(3):264–265
22. Ren J, Han X, Liu X et al (2007) Methylenetetrahydrofolate
reductase gene polymorphism in women with recurrent preg-
nancy loss. Chin J Perinat Med 10(2):80–84
23. Wan J, Liu X, Zhang H, Zhao J, Ma S (2007) Analyzes of sus-
ceptible gene in women with recurrent spontaneous abortions.
Chin J Birth Health Hered 15(7):9–10
24. Xu L, Liu X, Zhang H, Zhao J, Qi Q, Chang Y (2007) Rela-
tionship between three thrombophilic gene mutations and unex-
plained recurrent early spontaneous abortion. Chin J Obstet
Gynecol 42(3):180–183
25. Ma S, Zheng M (2008) The relation of MTHFRC677T gene
polymorphism to recurrent abortion. Health Med Res Pract
5(4):4–5,9
26. Zhang JY, Zuo WJ, Wu GH, Sun HT (2009) Association between
MTHFR gene C677T polymorphism and habitual abortion. J Jilin
Univ Med Ed 35(4):698–701
27. Zhong H, Liu J, Zhu Y et al (2010) Study on correlation between
MTHFR polymorphisms and repeated spontaneous abortion.
J Ningxia Med 32(8):675–676
28. Wang S, Jia Y, Yang D et al (2011) Correlation between M
THFR gene C677 T polymorphism and unexplained recurrent
spontaneous abortion. Matern Child Health Care China
26(9):1385–1387
29. Han H, Shen H, Wang Y, Yu W (2012) Methylenetetrahydrofolate
reductase C677T polymorphism and homocysteine in recurrent
pregnancy loss. J Reprod Contracept 32(7):486–489, 477
30. Hu X, Liang P, Diao L et al (2014) The association of
methylenetetrahydrofolate reductase gene mutation with unex-
plained recurrent miscarriage. Chin J Birth Health Hered
11:87–89
31. Luo L, Chen Y, Wang L et al. (2014) Polymorphisms of genes
involved in the folate metabolic pathway impact the occurrence
of unexplained recurrent pregnancy loss. Reprod sci
22(7):845–851
32. Wang S, Shi X, Shen R, Wang Q, Chen S, Zhang W (2009) The
role of folate metabolism related enzymes gene polymorphisms
on recurrent early spontaneous abortion. Chin J Birth Health
Hered 17(3):12–13
33. Thakkinstian A, McElduff P, D’Este C, Duffy D, Attia J (2005) A
method for meta-analysis of molecular association studies. Stat
Med 24(9):1291–1306
34. Wu CY, Yang M, Lin M, Li LP, Wen XZ (2013) MTHFR C677T
polymorphism was an ethnicity-dependent risk factor for cervical
cancer development: evidence based on a meta-analysis. Arch
Gynecol Obstet 288(3):595–605
35. Chen B, Cao L, Yang P, Zhou Y, Wu XT (2012) Cyclin D1
(CCND1) G870A gene polymorphism is an ethnicity-dependent
risk factor for digestive tract cancers: a meta-analysis comprising
20,271 subjects. Cancer Epidemiol 36(2):106–115
36. Zhao Y, Hao L, Zhang L et al (2009) Plasma folate status and
dietary folate intake among Chinese women of childbearing age.
Matern Child Nutr 5(2):104–116
37. Zeng Z, Zhu J (2010) Low folic acid supplement intake rate
among women in northern China with a high-prevalence of neural
tube defects, 2008. Prev Med 51(3–4):338–339
38. Gaskins AJ, Rich-Edwards JW, Hauser R et al (2014) Maternal
prepregnancy folate intake and risk of spontaneous abortion and
stillbirth. Obstet Gynecol 124(1):23–31
39. Yanez P, Vasquez CJ, Rodas L et al (2013) Erythrocyte folate
content and serum folic acid and homocysteine levels in
preeclamptic primigravidae teenagers living at high altitude. Arch
Gynecol Obstet 288(5):1011–1015
40. Zhang H, Tao X, Wu J (2014) Association of homocysteine,
vitamin B12, and folate with bone mineral density in post-
menopausal women: a meta-analysis. Arch Gynecol Obstet
289(5):1003–1009
41. Sen U, Tyagi SC (2010) Homocysteine and hypertension in
diabetes: does PPARgamma have a regulatory role? PPAR Res
2010:806538
123
 Arch Gynecol Obstet

42. Huang T, Chen Y, Yang B, Yang J, Wahlqvist ML, Li D (2012) 43. Debreceni B, Debreceni L (2014) The role of homocysteine-
Meta-analysis of B vitamin supplementation on plasma homo- lowering B-vitamins in the primary prevention of cardiovascular
cysteine, cardiovascular and all-cause mortality. Clin Nutr disease. Cardiovasc Ther 32(3):130–138
31(4):448–454

123