












































Journal of Enam Medical College
Vol 11 No 1 January 2021

10

Original Article

Comparison of Blood Homocysteine Levels between Women with 
Recurrent Pregnancy Loss and Women with Normal Fertility

Mossammat Nigar Sultana1, Shamima Rahman2, Julia Akhtar  Nira3, Parveen Fatima4
Received: 11 January 2020    Accepted: 19 June 2020

doi: https://doi.org/10.3329/jemc.v11i1.63168

1. Assistant Professor, Department of Gynaecology and Obstetrics, Mugda Medical College & Hospital, Dhaka
2. Assistant Professor, Department of Gynaecology and Obstetrics, Col. Malek Medical College, Manikganj
3. Graded Specialist, Reproductive Endocrinology & Infertility, Combined Military Hospital, Dhaka Cantonment, Dhaka
4. Professor of Infertility, Bangabandhu Sheikh Mujib Medical University, Shahbag, Dhaka 
Correspondence Mossammat Nigar Sultana, Email: m.nigar.sultana@hotmail.com

Abstract

Background: Recurrent early pregnancy loss is a common but frequently unexplained obstetric 
problem. As it happens in early weeks of pregnancy, abnormal vasculogenesis and disordered 
cell multiplication are possible causes. Hyperhomocysteinemia is associated with both these 
pathological processes. Objective: To assess the association between hyperhomocysteinemia 
and recurrent pregnancy loss. Materials and Methods: This case-control observational study 
was conducted in the Department of Gynaecology and Obstetrics of Bangabandhu Sheikh Mujib 
Medical University, Dhaka during January to December 2015. Sixty patients were divided into 
two groups: 30 with recurrent pregnancy loss (RPL) as cases and 30 normal healthy mothers 
as controls. Results: All the subjects were matched in terms of age (p = 0.504). All were within 
normal BMI range (19.5 to 25 kg/square meter). Subjects in both groups were comparable in 
height, weight and BMI. 33.3% women of control group were in the low income stratum (monthly 
income 20000 taka or less) compared to50% of the RPL group. Control group had an equal 
mix of educational level from below Secondary School to Post-Graduates whereas there were 
fewer Post Graduate patients (3.3%) in the RPL group compared to control group (23.3%). 
The frequency of hyperhomocysteinemia (>15 micromoles/L) was significantly higher in cases 
compared to controls (46.7 vs.16.7%, p= 0.012). Mean homocysteine level was also significantly 
higher in cases compared to controls (13.67+/-4.80 vs. 9.87+/-4.84 micromole/L; p= 0.003). 
Conclusion: This study shows that blood homocysteine level in recurrent pregnancy loss patients 
is significantly higher compared to normal fertile mothers. There is a strong association between 
hyperhomocysteinemia and RPL.

Key words: Recurrent early pregnancy loss; Hyperhomocysteinemia; Fertility

                    J Enam Med Col 2021; 11(1): 10−17

Introduction

Hyperhomocysteinemia has been identified as an 
emerging risk factor for several diseases of diverse 
systems such as vascular thrombosis, adverse 
pregnancy outcome, congenital malformations, 
vascular dementia; its role in unexplained infertility 

and recurrent early pregnancy loss is currently a focal 
point of research, owing to its association with IVF 
failures.
Homocysteine (Hcy) is a sulfhydryl containing amino 
acid which does not occur in natural proteins, but 



January 2021J Enam Med Col Vol 11 No 1

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rather is a de-methylated derivative of methionine 
and also occurs as an intermediary product in the 
metabolism of other amino acids such as glycine, 
cysteine, cystathionine, serine, glutathione etc. 
However, normally the homocysteine thus formed is 
only a transient product, going to produce cysteine (an 
important amino acid required for protein synthesis) 
or glutathione (an important anti-oxidant in cells) 
or being re-methylated into methionine, effectively 
recycling the homocysteine. Impaired function of 
these metabolic pathways leads to accumulation of 
homocysteine, either by insufficient trans-sulfuration 
or by an impairment of re-methylation.1 Elevation 
in intracellular homocysteine concentration with a 
corresponding increase in blood levels can result from 
either genetic defects in the enzymes involved in its 
metabolism or nutritional deficiency of vitamin co-
factors.2

In atherosclerotic vascular disease models, 
homocysteine has been shown to a)  induce vascular  
inflammation by enhanced expression of pro-
inflammatory cytokines;3  b) reduce endothelium-
dependent vasodilatation by accelerated inactivation 
of NO (nitric oxide)/eNO (endothelial NO) or by 
increased serum di-methyl-arginine formation;4 c) 
increase endothelial oxidative stress by auto-oxidation 
by the highly reactive thiol group, formation of 
intracellular  superoxides and peroxyl radicals, and 
reduced cellular anti-oxidants (superoxide dismutase 
and glutathione peroxidase)3 and d) alter cellular 
redox potential and interfere with disulfide bond 
formation in endoplasmic reticulum (ER), causing 
unfolded or misfolded proteins to accumulate in ER, 
which then activate the so called Unfolded Protein 
Reaction (UPR) leading to subsequent growth arrest 
and apoptosis.5

NO is involved in almost every step of female 
reproduction, i.e., ovulation, early embryonic 
cleavage, implantation, regulation of circulatory 
dynamics, uterine quiescence, etc. Physiological NO 
concentration has a very narrow range and either an 
excess or a lack of NO adversely affects reproductive 
outcomes. Similarly, oxidative stress and apoptosis 
play a role in events such as follicular development 
and cyclical endometrial change.6

Traditionally recurrent early pregnancy loss (RPL) 
has been defined as three or more spontaneous 
pregnancy losses before 20 weeks of gestation (age 
of viability). The practice committee of the American 
Society of Reproductive Medicine (ASRM) defines 
RPL as “ a disease distinct from infertility, defined by 
two or more failed pregnancies.” In young women, 15 
to 20% of clinically recognized and more than 50% 
of all pregnancies undergoes spontaneous loss. These 
figures increase substantially with maternal age to as 
high as 40% and 85% respectively in women 40 years 
and older. The chance of having two consecutive 
losses is 5% with 1% of couples experiencing three 
consecutive miscarriages.7 In efforts to minimize 
otherwise preventable pregnancy loss, most clinicians 
favor diagnosing RPL after two consecutive losses, 
but it is important to note that many of the potential 
etiologies of RPL are not absolute, so occurrence of 
interval live births does not preclude a diagnosis of 
RPL.8 A large amount of scientific work has been done 
to investigate the role of hyperhomocysteinemia in 
malformations and pathogenesis of ongoing pregnancy, 
while data and observations are only emerging now 
regarding a possible involvement of this biochemical 
phenomenon in the early stages of reproduction 
and related diseases. There is a significant negative 
correlation between follicular fluid homocysteine 
concentration and the degree of maturity of retrieved 
oocytes as well as embryo quality on day 3 in patients 
undergoing IVF.9  IVF outcomes in terms of pregnancy 
rate (defined as USG detected fetus at 7 weeks of IVF), 
implantation rate (number of gestational sacs per 100 
embryo-transfers) were reduced and abortion rate 
(between USG detected pregnancy and 20 completed 
weeks of gestational age) were significantly increased 
in women with hyperhomocysteinemia compared 
to those in whom interventions were instituted to 
reduce blood homocysteine levels.10  Studies also 
found that folate, cobalamin and tHcy levels in mono-
follicular fluid are related to embryo quality in women 
undergoing IVF/ICSI.11

Review of the evidence on the effects of 
hyperhomocysteinemia on reproductive outcome 
show that while there are evidence that  maternal 
hyperhomocysteinemia is a risk factor for recurrent 



January 2021J Enam Med Col Vol 11 No 1

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embryo loss and even a first early pregnancy loss, 
evidence also indicate that genetic polymorphism 
due to mutation in MTHFR enzyme causing 
high homocysteine concentration from abnormal 
folate metabolism increased risk of REPL.12 
Possible mechanisms of the deleterious effects of 
hyperhomocysteinemia on female reproduction 
include reduced cell division (e.g., of oogonia or of 
granulose cells), increased oxidative stress, apoptosis, 
reduced extra-embryonic vasculogenesis, etc.13

There has been a growing awareness about 
reproductive failure with the advent of reproductive 
techniques and services in Bangladesh recently. The 
investigation of recurrent pregnancy loss includes 
laboratory, imaging, invasive and genetic analysis. 
Despite all these work-up, the cause of a significant 
portion of cases of reproductive failures such as 
recurrent early pregnancy loss remains unknown. 
Such unexplained cases merit exploration for 
other uncommon causes. There are reports of 2 
to 3-fold higher concentration of homocysteine 
among such patients, both in western as well as sub 
continental countries.14,15 Hyperhomocysteinemia 
merits consideration in such cases. Because 
hyperhomocysteinemia is easily detected and 
is amenable to easy intervention by vitamin 
supplementation in a majority (i.e., two-thirds) of 
cases, exploring its relation to and contribution 
towards recurrent early pregnancy loss are important.

The present study explores the blood levels of 
homocysteine in women with recurrent early 
pregnancy loss without an obvious cause compared to 
women with normal fertility.

Materials and Methods

This was a case-control observational study, 
conducted from January 2015 to December 2015. The 
study population consisted of women of reproductive 
age attending the outdoor and indoor department of 
Obstetrics and Gynecology at Bangabandhu Sheikh 
Mujib Medical University with women having 
normal fertility (as controls), unexplained recurrent 
pregnancy loss (as cases). The approval of the Local 
Ethical Committee was taken. The aims, objectives, 
procedures of collecting 

samples, risks (if any) and benefits were explained 
to study subjects in very easily understandable local 
language. Participation of subjects was strictly on 
voluntary basis, on the basis of informed consent. 
Subjects were assured that all records would be kept 
confidential. It was explained to them that the study 
would help both physicians and patients by finding 
out scientific facts that will help in making rational 
treatment choices regarding the management of 
patients. A purposive sampling method was used. All 
subjects were selected by history, examination as well 
as appropriate diagnostic workup.

Inclusion criteria: 
a. Married women aged 20 to 40 years, and BMI 

between 19 and 25.
b. Control group: Healthy women with one or more 

successful pregnancy without any obstetrical 
complications (e.g., intrauterine growth restriction, 
preeclampsia, abortion and MR) and never 
required assisted reproduction, 

c. Cases: Women who, despite conception, have had 
two or more pregnancy losses before 20 weeks of 
gestation and diagnosed as unexplained after i) 
anatomic evaluation of by TAS, TVS and HSG and/
or hysteroscopy with laparoscopy reveal normal 
uterine cavity and absence of polycystic ovaries, ii) 
endocrine assessment by basal FSH, LH, estradiol, 
TSH, prolactin and fasting blood glucose were 
normal, iii) evaluation of immunological factors 
antinuclear antibody (ANA), anti-DNA antibody, 
antiphospholipid antibody, anticardiolipin 
antibody, iv) karyotyping of both partners were 
normal and v) normal semen analysis of husband.

Exclusion criteria:
a. Women aged <20 or >40 years, BMI <19 or >25 

kg/m2

b. Women with recurrent pregnancy loss due to 
identifiable causes

c. Women having other significant medical disorder 
(chronic cardiac, renal, hepatic or pulmonary 
disorders requiring chronic medications). 

d. Women who have received folate, vitamin B6 and 
B12 supplementation within last three months.



January 2021J Enam Med Col Vol 11 No 1

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Operational definitions for the purpose of this study: 

1. Recurrent Early Pregnancy Loss: two consecutive 
or more involuntary termination of pregnancy 
before twenty weeks of gestation (dated from the 
last menstrual period).

2. Hyperhomocysteinemia: Defined as a fasting 
serum homocysteine concentration of more than 
15 micromole/L.

3. Reproductive age group: 15−49 years

Samples were identified and data were collected on 
a structured data collection sheet and divided into 
controls and cases according to the inclusion and 
exclusion criteria. All data were collected by interview, 
physical and laboratory examination of blood samples 
and recorded in the data collection sheet.

After editing and coding, coded data was entered into 
computer database of the Statistical Package for the 
Social Sciences (SPSS) software (SPSS Inc., Chicago, 
Illinois, USA) Version 22 and data organizing and 
final analysis were performed on the above software. 
Categorical data was presented as frequency and 
percentage, and continuous variables were expressed 
as mean and standard deviation. The Chi-squared test 
was used to analyze and compare discrete variable 
and Students t test where appropriate. The statistical 
significance (p) threshold was set to ≤0.05 (two-
tailed).

Results

Results of comparison of sixty women, 30 in control 
group (women with normal fertility) and 30 in the 

unexplained recurrent early pregnancy loss group are 
presented in the following tables. 

All the subjects matched in terms of age group 
categories. The mean ages of all the groups were 
comparable, with no statistically significant difference. 
The subjects in the groups were well-matched in terms 
of height, weight and BMI. The women included in 
the study were within the normal BMI range (from 
19.5 to 25.0 kg/m2) with no statistical difference 
between group means among the pre-specified groups. 
This excluded any role of height or low body weight 
contributing to the incidence of cases among these 
subjects.

Analysis of the socio-economic status in terms of 
monthly income showed that     there were more patients 
in the lowest stratum of monthly income among 
those with recurrent early pregnancy loss; however, 
overall there was no statistically significant difference 
between the groups in terms of monthly income 
level. Since the study was conducted in a hospital 
setting accessible to patients of even low income 
status, subjects included in the study represented 
mostly low and middle income family background. 
The subjects in the control group had an equal mix 
of educational levels from below secondary school 
certificate to post-graduate levels whereas there were 
very low post-graduate patients in the recurrent early 
pregnancy loss group commensurate with their socio-
economic status in terms of monthly income (Table 
II); however, difference in the frequency of various 
educational achievements between the groups did not 
reach statistical significance.

The distribution of various occupations between the 
study groups did not show any significant difference 

Table I: Comparison of biological variables between controls (women with normal fertility) and cases (women 
with recurrent early pregnancy loss) (N=60)

Variables Controls (n=30) Cases (n=30) p values
Age (years) 28.90±5.09 28.0±5.27 0.504ns

Height (cm) 156.17±6.92 153.20±7.14 0.108ns

Weight (kg) 56.73±6.78 56.37±5.77 0.822 ns

BMI (kg/m2) 23.26±1.55 23.75±1.38 0.204 ns

Data are presented as mean ± SD. Student’s t test was used to compare the variables   between the groups. N=Number of 
study population; n=Number in each group; s= Significant; ns=Not significant; SD=Standard deviation



January 2021J Enam Med Col Vol 11 No 1

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Table II: Comparison of socioeconomic status by monthly income of the subjects between two groups (N=60)

Variables Controls (n=30) Cases (n=30) p values
Monthly income
Taka < 1000 1 (3.3%) 7 (23.3%)

0.072ns
Taka 10000−20000 9 (30.0%) 8 (26.7%)
Taka >20000  20 (66.7%) 15 (50.0%)
Educational status
Below SSC   
SSC
HSC
Graduates
Postgraduates

7 (23.3%)
6 (20.0%)
4 (13.3%)
6 (20.0%)
7 (23.3%)

9 (30.0%)
4 (13.3%)
3 (10.0%)
13 43.3%)
1 (3.3%)

0.096ns

Occupations
Housewives
Students
Services
Doctors
Nurses
Day Labors

14 (46.7%)
0 (0.0%)

12 (40.0%)
1 (3.3%)
2 (6.7%)
1 (3.3%)

14 (46.7%)
4 (13.3%)
10 (33.3%)
1 (3.3%)
1 (3.3%)
0 (0.0%)

0.356ns

Chi-square test was used to compare between two groups. N=Number of study population; n=Number in each group; s= 
Significant; ns=Not significant

Table III: Comparison of marital and obstetric history between two groups (N=60)

Variables Controls (n=30) Cases (n=30) p values
Marital history
Marital period (years) 7.88±3.54 7.94±4.40 0.960ns
Coital frequency per week 3.63±0.76 3.40±0.81 0.257ns
Obstetric history
Abortion 0 (0%) 30 (100.0%) <0.001s
Ectopic pregnancy  0 (0%) 1 (3.3%) 0.313ns
MR 0 (0%) 3 (10.0%) 0.076ns
Parity (mean±SD) 1.50±0.63 0.47±0.73 <0.001s

Continuous variables are presented as mean±SD and categorical variables are presented as number and percentage. 
Student’s t test was used to compare continuous variables and Chi-square test for frequency data. N=Number of study 
population; n=Number in each group; s= Significant; ns=Not significant; SD=Standard deviation

Table IV: Comparison of the frequency of hyperhomocysteinemia between two groups (N=60)

Homocysteine level Controls (n=30) Cases (n=30) p values
< 15 μmol/L
> 15 μmol/L

25 (83.3%)
5 (16.7%)

16 (53.3%)
14 (46.7%)

0.012s

Mean, SD μmol/L 9.87±4.84 13.67±4.80 0.003s

Frequency data are presented as number and percentage while continuous variables were presented as mean and standard 
deviation. Statistical analysis was done by Chi-square test. N=Number of study population; n=Number in each group; s= 
Significant; ns=Not significant; SD=Standard deviation



January 2021J Enam Med Col Vol 11 No 1

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Based on the institutional cut-off value of 15 
micromoles/L for serum fasting homocysteine level, 
the frequency of hyperhomocysteinemia was found in 
significantly higher number of patients in the recurrent 
early pregnancy loss group compared to the control 
group. Comparison of serum fasting homocysteine 
levels among the two study groups showed that 
patients and the recurrent early pregnancy loss group 
had significantly higher levels compared to the control 
group of women. 

Discussion

The results of the present study showed that the 
frequency of hyperhomocysteinemia defined as 
fasting serum homocysteine levels >15micromole/L 
(Table IV) are significantly higher in the REPL 
group (46.7% p = 0.012 for difference from controls) 
compared to control group (16.7%). Furthermore, 
the fasting serum homocysteine levels (Table IV) 
in study women with unexplained recurrent early 
pregnancy loss (mean 13.67 ± SD 4.80 micromoles/L) 
were significantly higher compared to those in study 
control women with normal fertility (mean 9.87 ± 
SD 4.84 micromoles/L). The findings of this study 
are consistent with results from previous studies in 
Europe as well as the subcontinent. The association 
of hyperhomocysteinemia with adverse pregnancy 
outcomes, including recurrent pregnancy loss 
has been in evidence in several previous studies. 
Furthermore, while considerable bodies of evidence 
are available from studies in the assisted reproductive 
background, epidemiological evidence is rare. The 

findings of comparable levels of serum homocysteine 
in the recurrent (early) pregnancy loss groups in 
all these studies – upheld by the findings of the 
present study – also strengthens the association of 
hyperhomocysteinemia with unexplained adverse 
pregnancy outcomes. 

As has been already mentioned, a link between 
hyperhomocysteinemia and adverse pregnancy 
outcomes have been demonstrated in various previous 
studies, most notably the large epidemiological 
Hordaland Homocysteine study.16 Data available 
from 5883 women with hyperhomocysteinemia 
in the age group 40−42 years with over 14,000 
pregnancies showed increased incidence of stillbirths 
and placental abruptions among other adverse 
pregnancy outcomes. In China, a pilot study exploring 
the nutritional background of 30 women with an 
embryonic gestations with absent fetal poles showed 
higher homocysteine levels compared to 30 controls 
with a normal healthy delivery.17 A retrospective case-
control study of 200 women in each group found that 
while MTHF 677 T/T (homozygous genotype) was 
associated with increased chances of recurrent early 
and late pregnancy losses as well as similar elevations 
of serum homocysteine among cases and controls, 
regression analysis did not reveal any association 
between hyperhomocysteinemia (defined as serum 
homocysteine level >15micr-moles/L) and recurrent 
pregnancy loses.18 It may be argued that in both studies 
the presence of other stronger adverse modulators of 
fertility and pregnancy out- comes have predominated 
and confounded the effects of hyperhomocysteinemia. 
For example, it is postulated that the association of 
MTHFR 677 T/T homozygous genotype and Vitamin 
B6 status with recurrent early pregnancy loss, 
independently of hyperhomocysteinemia, was due to 
interference with red blood cell folate metabolism.

In the present study confounding variables were 
avoided by matching the cases for age and BMI. 
However, the study included far smaller sample 
size than the number suggested by the sample size 
calculation. Furthermore, since all women with 
history of recent intake of vitamin folic acid, B6 and 
B12 supplementation were excluded and no attempts 
were made to assess their vitamin status, the effects of 

statistically. Subjects from all social strata were 
included in the study, owing to the fact that the place 
of study is an Institution accessible to a wide section 
of the population of the country.

All the subjects included in both the study groups, had 
similar duration of marriage and had a healthy marital 
life in terms of their coital frequencies. This pattern 
reflects regular marital habits. History of previous 
Menstrual Regulation procedures were seen in 10% 
of the subjects with recurrent early pregnancy loss and 
none in the control group, giving rise to a statistically 
significant difference among the groups in terms of 
obstetric history. 



January 2021J Enam Med Col Vol 11 No 1

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serum homocysteine on pre-eclampsia and eclampsia, 
the healthy control population of 136 women at late 
middle to late pregnancy (gestational age of mean 
30.80 ±SD 4.03 weeks) had a fasting homocysteine 
level of 6.86±2.47 micromoles/L, which is 
considerably low compared to the control group in the 
present study (9.87±4.84 micromoles/L). Likewise, 
the 84 pre-eclampsia patients (with homocysteine 
level of mean 9.54±SD 3.21 micromole/L) and 120 
eclampsia patients (homocysteine level 10.57±3.39 
micromole/L) had considerably lower levels of 
homocysteine compared to the cases in the current 
study (Table IV). 

However, their difference can be explained by the 
fact that serum homocysteine level decreases during 
pregnancy, especially in the later parts.19

Das et al20 found a serum homocysteine level in 
a control group without coronary artery disease 
was mean 9.66±SD 3.54 micromole/L, which was 
comparable to finding in the present study (9.87±4.84 
micro-mole/L). 

In a large population based cohort, Gamble et al21 on 
prevalence of folate and cobalamin deficiency and 
incidence of hyperhomocysteinemia in Bangladesh, 
in 973 women, the plasma homocysteine was found to 
be mean 9.5±4.7 micromole/L, also comparable to the 
level found in controls in the current study, showing 
that the subjects were representatives of the women in 
Bangladesh.

In a limited sample of women with Recurrent Early 
Pregnancy Loss mean serum fasting homocysteine 
levels and hyperhomocysteinemia were increased 
compared to age and BMI matched women with 
normal fertility and healthy pregnancy outcomes. 

However, a larger study with adequately powered 
sample size and assessment of other confounding 
variables are required to further corroborate the effect 
of hyperhomocysteinemia on fertility and pregnancy 
outcomes. 

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