J Gynecol Obstet Hum Reprod 52 (2023) 102533

Contents lists available at ScienceDirect

Journal of Gynecology Obstetrics

and Human Reproduction
journal homepage: www.elsevier.com

Original Article

Homocysteine increases uterine artery blood flow resistance in women

with pregnancy loss
Xin Yanga,1, Xiuli Tiana,1, Haoxin Liub, Juan Wanga, Fang Wanga,*
a
Reproductive Medicine Center, Second Hospital of Lanzhou University, No.82, Cuiying Road, Chengguan District, Lanzhou, Gansu 730030, China
b
College of LSA, University of Michigan, Ann Arbor, MI 48109, United States

A R T I C L E I N F O A B S T R A C T

Article History: Objective: Uterine arterial blood flow is an important factor in embryonic development. Increased uterine
Received 7 June 2022 artery blood flow resistance may be related to vascular damage. Homocysteine (HCY) can induce injury of
Revised 8 September 2022 endothelial through various pathways. Therefore, we investigate the association between serum HCY levels
Accepted 1 January 2023
and uterine artery blood flow in the non-pregnant state in women who have experienced pregnancy loss
Available online 4 January 2023
(PL).
Methods: 364 women eligible for PL were included in the study. The detection of HCY was completed by the
Keywords:
Laboratory of Lanzhou University Second Hospital. We divided the patients into three groups: Low-HCY
Homocysteine
Pregnancy loss
(HCY<10 umol/L, n = 144), Medium-HCY (HCY 10»15 umol/L, n = 174) and High-HCY (HCY>15 umol/L,
Uterine artery blood flow n = 46). The patients were subjected to vaginal color Doppler ultrasonography to measure bilateral uterine
Pulsatility index artery resistance index (RI), pulsatility index (PI) and peak systolic velocity/end diastolic velocity (S/D).
Resistance index Result: Among 364 women, the right uterine artery RI in L-HCY, M-HCY, and H-HCY groups were 0.78§0.08,
0.79§0.07 and 0.81§0.07, respectively (P = 0.04). The left uterine artery RI in L-HCY, M-HCY, and H-HCY
groups were 0.78§0.08, 0.81§0.07 and 0.81§0.07, respectively (P = 0.01). The right uterine artery RI level
and the left uterine artery RI was significantly associated with HCY level (r = 0.103, P = 0.050; r = 0.104,
P = 0.047, respectively). Of these, 177 women experienced their next pregnancy, and 33 patients experienced
PL again. The pregnancy rate in L-HCY, M-HCY, and H HCY groups were 47.92% (69/144), 49.43% (86/174)
and 47.83% (22/46), respectively (P = 0.95). In next pregnancy, the PL rate in L-HCY, M-HCY, and H HCY
groups were 8.70% (6/69), 22.58% (22/86) and 22.73% (5/22), respectively (P = 0.03).
Conclusion: HCY can increase the uterine artery resistance in the non-pregnant state and is associated with
the abortion rate of next pregnancy.
© 2023 Elsevier Masson SAS. All rights reserved.

Introduction
Pregnancy loss (PL) is defined as the spontaneous demise of a
pregnancy before the fetus reaches viability, which is a significant
negative life event and impacts 10% to 15% of clinically recognized
pregnancies [1]. 1% 3% of women of childbearing age will have two
or more consecutive pregnancy loss, known as recurrent pregnancy
loss (RPL). PL can affect a couple’s psychological status, with varying
degrees of anxiety and depression [2]. In addition, women with PL
had a higher risk of long-term cardiovascular disease than women
without PL [3]. All this has a negative effect on women and their fam-
ilies. The causes of pregnancy loss are varied, but about 60% of PL eti-
ology and pathogenesis remain unclear [1].
* Corresponding author.
E-mail address: ery_fwang@lzu.edu.cn (F. Wang).
1
These authors contributed equally to this work.
Evidence shows that uterine perfusion is one of many factors reg-
ulating endometrial receptivity and plays a key role in the regulatory
mechanism of human fertility and pregnancy success. Therefore,
abnormal uterine perfusion is one of the causes of PL [4]. Transvaginal
uterine artery color Doppler flow is a noninvasive method to evaluate
uterine perfusion. Several studies have shown that patients with a
history of PL have increased uterine arterial blood flow resistance in
the middle luteal phase [5]. However, the mechanism of PL induced
by abnormal uterine perfusion is not completely clear so far. Some
researchers believe that this may be due to abnormal uterine blood
vessel function, which is reflected in the increased blood flow imped-
ance of the uterine artery during implantation [6].
Homocysteine (HCY) is the product of methionine demethylation,
which is the only source of homocysteine. People normally have low
levels of homocysteine in their blood. HCY is a significant biomarker
for overall health status, which can damage blood vessels in a variety
of ways. It damages vascular endothelial cells and stimulates the
growth of vascular smooth muscle cells, increases the oxidative stress

https://doi.org/10.1016/j.jogoh.2023.102533
2468-7847/© 2023 Elsevier Masson SAS. All rights reserved.
X. Yang, X. Tian, H. Liu et al. Journal of Gynecology Obstetrics and Human Reproduction 52 (2023) 102533

(OS) and stimulates reactive oxygen species (ROS) production during Table 1
the autoxidation process. High HCY (HHCY) also disrupts the normal Baseline characteristics of the study population.

coagulation mechanism and can significantly increase the risk of cor- L-HCY M-HCY H-HCY P
onary heart disease, peripheral vascular and cerebrovascular dis- (n = 144) (n = 174) (n = 46)
eases. Endothelial cell injury in HHCY leads to decreased protein C
Age (year) 30.40§3.85 29.62§3.96 29.96§3.50 0.21
activation and inhibits thrombomodulin expression, which decrease BMI (kg/m2) 22.19§2.76 22.13§3.01 22.23§3.22 0.97
contributes to local procoagulant [7,8]. Increased HCY in women dur- FT3 (pmol/L) 5.19§0.48 5.28§1.01 5.32§0.41 0.46
ing pregnancy is associated with a variety of complications, such as FT4 (pmol/L) 16.16§11.41 16.32§8.34 15.89§2.11 0.96
TSH (mIU/mL) 2.62§1.27 2.72§1.56 2.81§1.45 0.71
preeclampsia (PE), early PL, placental abruption (PA), intrauterine
FBG (mmol/L) 5.00§0.42 4.97§0.74 4.92§0.59 0.76
growth restriction (IUGR), venous thrombosis, etc. [9]. CHO (mmol/L) 3.77§0.68 3.86§0.74 3.75§0.64 0.53
However, it has not been studied whether HCY increases uterine TG (mmol/L) 1.09§0.52 1.06§0.61 1.19§1.16 0.09
artery blood flow resistance in the non-pregnant state, which in turn HCY (umol/L) 8.36§1.00 11.72§1.45 23.59§11.55 <0.01
increases the rate of abortion in the next pregnancy. Therefore, the P<0.05 was considered statistically significant.
purpose of this study is to explore the relationship between HCY and
uterine artery blood flow resistance and pregnancy outcome in
patients with PL. Comparison of RI, PI and S/D levels among three HCY groups

Materials and methods
364 eligible patients who experienced PL were enrolled between
January 2020 to May 2021 from Second Hospital of Lanzhou Univer-
sity were recruited. Diagnosis of PL according to the ESHRE, which
spontaneous abortions prior to 24 weeks of gestation including bio-
chemical pregnancy. Patients who had taken anticoagulants, immu-
nomodulators and hormones in the previous 3 months and one of
the couples had a chromosomal abnormality were excluded. Take 3
−5 mL of blood from an ordinary tube on an empty stomach and
send it for inspection immediately. HCY, free triiodothyronine (FT3),
free thyroxine (FT4), thyroid stimulating hormone (TSH), fasting
blood glucose (FBG), cholesterol (CHO) and triglyceride (TG) were
completed by the Laboratory of Lanzhou University Second Hospital.
We divided the patients into three groups according to HCY levels: L-
HCY (HCY<10 umol/L, n = 144), M-HCY (HCY 10»15 umol/L, n = 174)
and H-HCY (HCY>15 umol/L, n = 46).
The ultrasound examination was performed using Esaote MyLab
Twice. All transvaginal ultrasounds are performed by the same exam-
ining physician. Measure and record the bilateral uterine artery pul-
satility index (PI), uterine artery resistance index (RI), and time-
averaged maximal velocity (TAMX), calculate the systolic/diastolic (S/
D) ratio with the internal software.
Subsequently, we followed each patient for pregnancy outcomes
in their next pregnancy. Among the 364 patients with PL, 177 were
experienced their next pregnancy, and of those 33 patients experi-
enced PL again. This study was approved by the Ethics Committee of
Lanzhou University Second Hospital (Ethics Approval Number:
2022A-521). All participants signed informed consent forms.
Statistical analysis
Data were analyzed using the Student’s t-test, Mann-Whitney U
test, Chi-square test, Fisher’s exact test and Pearson correlation anal-
ysis where appropriate. In all tests, significance was accepted for P
values < 0.05. All data were analyzed using the Statistical Package for
the Social Sciences for Windows (version 22.0, SPSS Inc.)
Results
Baseline characteristics of the study population
In the present study, 364 women who have experienced PL were
enrolled. The basal characteristics in the present study are shown in
Table 1. The mean HCY level was 8.36§1.00 umol/L for the L-HCY
group, 11.72§1.45 umol/L for the M-HCY group, 23.59§11.55 umol/L
for the H HCY group. No statistically different results were observed
between all three groups with age, BMI, FT3, FT3, TSH, FBG, CHO and
TG.
2
Among 364 women, the right uterine artery RI in L-HCY, M-HCY,
and H HCY groups were 0.78§0.08, 0.79§0.07 and 0.81§0.07,
respectively (P = 0.04). The left uterine artery RI in L-HCY, M-HCY,
and H HCY groups were 0.78§0.08, 0.81§0.07 and 0.81§0.07,
respectively (P = 0.01). However, the bilateral uterine artery PI and S/
D levels did not differ between the three groups (P>0.05). The results
are shown in Fig 1(A−F).
Correlation between RI, PI, S/D levels and HCY level in the study
population
Correlation analyses showed that the right uterine artery RI level
and the left uterine artery RI was significantly associated with HCY
level (r = 0.103, P = 0.050; r = 0.104, P = 0.047, respectively). However,
the bilateral uterine artery PI and S/D levels have no correlation with
HCY level (P>0.05). The results are shown in Table 2.
Comparison of pregnancy outcome among three HCY groups
We tracked the next pregnancy of women with PL, found that the
pregnancy rate in the L-HCY group was 47.92% (69/144), in the M-
HCY group was 49.43% (86/174) and in the H HCY group was
47.83% (22/46), there was no statistical difference in clinical preg-
nancy rate under different HCY levels (P = 0.95). The PL rate in L-HCY
group was 8.70% (6/69), in the M-HCY group was 22.58% (22/86) and
in the H HCY group was 22.73% (5/22), the M-HCY and H HCY
groups had a higher abortion rate (P = 0.03). The results are shown in
Fig. 2 and Table 3.
Discussion
This study explored the relationship between HCY and uterine
artery blood flow, and it was found that in PL women who were non-
pregnant, uterine artery RI increased with the increase of HCY, and
when the HCY >10 umol/L, the PL rate of next pregnancy increased.
Uterine artery blood flow is important for implantation and devel-
opment of embryos, but the mechanism of abnormal uterine artery
blood flow is not fully elucidated. It has been suggested that poor
uterine blood flow may be related to an underlying subclinical vas-
culopathy through increase vascular damage [10]. HCY can induce
injury of endothelial, medial and adventitia of arterial wall through
various pathways [11]. Therefore, we boldly speculated that HCY
may also be an important factor in uterine artery injury.
HCY is a sulfur containing amino acid derived from the essential
amino acid methionine (Met), is generally recognized as an indepen-
dent risk factor for coronary, cerebral, and peripheral atherosclerosis,
which can be either regenerated to methionine or metabolized to
cysteine, a precursor for glutathione synthesis [12]. A meta-analysis
indicated that for every 5 mmol/L increase in HCY, the risk of
X. Yang, X. Tian, H. Liu et al. Journal of Gynecology Obstetrics and Human Reproduction 52 (2023) 102533

Fig. 1. Comparison of RI, PI and S/D levels among three HCY groups. (A-C) Right RI, PI and S/D. (D-F) Left RI, PI and S/D. * P<0.05.

Table 2
Correlation between RI, PI, S/D levels and HCY level in the study Table 3
population. The difference of pregnancy outcome with different HCY groups.

R-RI R-PI R-S/D L-RI L-PI L-S/D L-HCY M-HCY H-HCY P

P 0.050 0.712 0.981 0.047 0.122 0.052 Pregnancy rate 69/144(47.92%) 86/174(49.43%) 22/46(47.83%) 0.95
r 0.103 0.019 0.001 0.104 0.081 0.102 PL rate 6/69 (8.70%) 22/86 (22.58%) 5/22 (22.73%) 0.03
R-: Right, L-: Left. P<0.05 was considered statistically significant. P<0.05 was considered statistically significant.
Pearson correlation coefficient were used to assess the correlation
between HCY level and RI, PI, S/D levels.

all−cause mortality increased by 27%, the risk of cardiovascular mor-

Fig. 2. Comparison of pregnancy outcome among three HCY groups (A) pregnancy and
no-pregnancy numbers between three HCY groups. (B) PL and ongoing pregnancy
numbers between three HCY groups.
tality increased by 32% and the coronary heart disease mortality
increased by 52% [13]. In a long-term study of middle-aged and
elderly subjects, increased HCY levels (≥10.8 umol/L) were signifi-
cantly associated with all-cause mortality [14]. A large study of a Pol-
ish population also found that the relative risk of all-cause and CVD
mortality was significantly higher in the highest (HCY> 10.51 mmol/
L) compared to the lowest (HCY< 8.20 mmol/L) [15]. This suggests
that the threshold of adverse events caused by HCY is varies by dis-
ease state, and we should actively search for the threshold of HCY in
PL patients in the future. Cysteine g -lyase (CSE) plays a key role in
the metabolism of HCY to cysteine through the transsulfuration path-
way [16]. The presence of HHCY can inhibit the synthesis of glutathi-
one and cause the imbalance of glutathione homeostasis. A recent
study found that CSE promotes estrogen-stimulated uterine arterial
blood flow through glutathione homeostasis, so when glutathione
homeostasis is unbalanced, uterine artery blood flow may be reduced
[17].
Few studies found that the underweight was associated with a
higher risk of cardiovascular disease in the general population, but it
is not clear whether HHCY is related to cardiovascular disease in
patients with low body weight [18]. In addition, low BMI also
increases the risk of miscarriage, tubal pregnancy and other adverse
events in women [19]. Osikoya et al. first discovered the effect of
uterine perivascular adipose tissue on uterine artery blood flow
through animal experiments. This suggests that low weight women

3
X. Yang, X. Tian, H. Liu et al.
may be affected by uterine artery blood flow due to the reduction of
peripheral adipose tissue, which may lead to adverse pregnancy
events [20].
HCY can be involved in thrombosis by inducing oxidative stress,
which may be similar in uterine arteries, but has been rarely studied
so far [21]. One study found that uterine arterial blood flow in
patients with recurrent miscarriage decreased during the luteal
phase, which could be improved by giving low-dose aspirin, this indi-
cates that patients with recurrent abortion already had hypercoagu-
lability in the uterine artery before pregnancy. Our study found that
such hypercoagulability may be related to the increased level of HCY,
providing a new treatment strategy for the future [22]. In addition,
the study found that on the day of HCG injection in IVF cycles,
reduced vascular resistance and increased blood flow, which can
improve uterine receptivity, increase pregnancy success [23]. The
same study also found that low molecular weight heparin adminis-
tration in early pregnancy will improve uterine artery flow and preg-
nancy outcomes in women with recurrent pregnancy loss [24]. But a
2013 Spanish cohort study found no association between HHCY and
PL [25]. This is inconsistent with our study, possibly due to differen-
ces in the geographic regions of the country. In addition, a recent
study found that compared to abortion with normal karyotype, abor-
tion with abnormal karyotype showed a positive association with
elevated maternal serum HCY level [26]. Differential effects of HCY
on pregnancy outcomes may also be due to inconsistent rates of
embryonic chromosomal abnormalities in the patients. It is well
known that more than half of the early abortions are embryonic chro-
mosomal abnormalities [27]. Studies have found that high levels of
HCY suggest that the methylation pathway is blocked, resulting in
reduced methylation function. The abnormal DNA methylation of
placenta-specific genes, directly or indirectly, affect embryo implan-
tation, growth, development and uterine immune microenviron-
ment, leading to the occurrence of RPL [28].
This study investigated the effects of HCY in uterine artery flow in
the non-pregnant state of PL and our results revealed that HCY can
increase the uterine artery resistance and is associated with the abor-
tion rate in next pregnancy.
Funding
This study was supported by the real-world study of recurrent
pregnancy loss in China (Grant No: YJS-BD-19).
Disclosure statement
The authors have no conflict of interest to disclose.
Acknowledgments
Xin Yang, Haoxin Liu, Juan Wang and Fang Wang contributed in
conception, design, statistical analysis and drafting of the manuscript.
Xiuli Tian complete all vaginal color Doppler ultrasonography exami-
nations. All authors approved the final version for submission.
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