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Title: A prospective study of Willis-Ekbom disease/restless legs syndrome
during and after pregnancy
Author: Abdurrahman Neyal, Gulcin Benbir, Rahime Aslan, Mecbure
Nalbantoglu, Serdar Acikgoz, Nevin Yilmaz, Feray Bolukbasi Tumay, Munife
Neyal, Derya Karadeniz
PII: S1389-9457(15)00737-6
DOI: http://dx.doi.org/doi:10.1016/j.sleep.2015.01.026
Reference: SLEEP 2752
To appear in: Sleep Medicine
Received date: 15-10-2014
Revised date: 22-1-2015
Accepted date: 24-1-2015
Please cite this article as: Abdurrahman Neyal, Gulcin Benbir, Rahime Aslan, Mecbure
Nalbantoglu, Serdar Acikgoz, Nevin Yilmaz, Feray Bolukbasi Tumay, Munife Neyal, Derya
Karadeniz, A prospective study of Willis-Ekbom disease/restless legs syndrome during and after
pregnancy, Sleep Medicine (2015), http://dx.doi.org/doi:10.1016/j.sleep.2015.01.026.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service
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A prospective study of Willis-Ekbom
disease/restless legs syndrome during
and after pregnancy
Abdurrahman Neyala, Gulcin Benbirb,*, Rahime Aslana, Mecbure Nalbantoglub, Serdar
Acikgozc, Nevin Yilmazc, Feray Bolukbasi Tumayb, Munife Neyala, Derya Karadenizb
aGaziantep Dr Ersin Arslan State Hospital, Gaziantep, Turkey
b Department of Neurology, Istanbul University Cerrahpasa, Istanbul, Turkey
cDepartment of Obstetrics and Gynecology, Istanbul University Cerrahpasa, Istanbul,
Turkey
*Corresponding author. Department of Neurology, Faculty of Medicine, Istanbul University
Cerrahpasa, Istanbul, 34098, Turkey. Tel: ±905332263797; fax: ±902126329696.
E-mail address: drgulcinbenbir@yahoo.com (Gulcin Benbir MD)
Comment [A1]: Please ensure that each
affliation has a department, institution, cit y and
country, in that order as i have done for b and c.
Please provide the department for a.
Page 1 of 22
Highlights
1. Willis-Ekbom’s disease/restless legs syndrome was more commonly reported in
the second and third trimesters of pregnancy.
2. Early emergence of Willis-Ekbom’s disease/restless legs syndrome was related to
residual symptoms after delivery.
3. Pregnant women with Willis-Ekbom’s disease/restless legs syndrome had lower
ferritin and transferrin saturation.
Abstract
Objectives: Willis-Ekbom disease (restless legs syndrome, WED/RLS) is the most common sleep-
related movement disorder in pregnancy. We designed a prospective longitudinal study to
investigate the correlates of WED/RLS during and after pregnancy.
Design: A total of 138 pregnant women with WED/RLS and a control group of 251 age-matched
pregnant women were enrolled prospectively. A questionnaire was administered during face-to-face
interview at first evaluation during pregnancy and three months after delivery.
Results: Among all women in the 1st trimester, 15.6% were diagnosed with WED/RLS, whereas 32.8%
of those in the 2nd trimester and 38.8% of those in the 3rd trimester were diagnosed with WED/RLS
(p=0.032). In regression analysis, later gestational age (p<0.001; odds ratio (OR) 1.054) and previous
history of WED/RLS (p=0.001; OR 2.795) were positively correlated with the presence of WED/RLS,
while ferritin levels (p=0.001; OR 0.956) were negatively correlated with the presence of WED/RLS.
Ferritin levels were also negatively correlated with the International RLS Study Group severity index
(p=0.041). Forty-eight patients (34.8%) experienced WED/RLS symptomatology after delivery. The
ferritin levels were lower, and the mean number of pregnancies was higher, in women with residual
WED/RLS (p=0.008).
Conclusion: Our survey showed that WED/RLS was more common in the 2nd and 3rd trimesters.
Emergence of WED/RLS during the 2nd trimester was strongly associated with residual WED/RLS.
Lower ferritin levels were associated with both WED/RLS in pregnancy and residual WED/RLS after
delivery. A higher number of pregnancies was also associated with a greater likelihood of having
residual WED/RLS after delivery.
Keywords:
Willis-Ekbom disease
Pregnancy
Ferritin levels
Page 2 of 22
Delivery
Introduction
Willis-Ekbom disease/restless legs syndrome (WED/RLS) is a common sleep-related
movement disorder with a prevalence of up to 10% in the general population [1]. In most
epidemiological studies based on International Restless Legs Syndrome Study Group
Page 3 of 22
(IRLSSG) criteria, the prevalence of WED/RLS has been demonstrated to be about one and a
half to two times greater in women [2]. It has been suggested that this gender difference may
be related to differences in either iron deficiency or hormone status [3]. The increased
prevalence of WED/RLS in pregnant women has prompted investigations into the relevance
of female hormones, particularly the increased levels of estrogen found during late pregnancy
[4-5]. Indeed, appearance or exacerbation of pre-existing WED/RLS symptoms during
pregnancy has been reported by IRLSSG criteria-based surveys. The prevalence of WED/RLS
during pregnancy is around three times greater than in the general population, and is reported
to vary between 15-35% [5-8]. It also shows a tendency to be more severe during this period
[5,8].
However, factors related to the occurrence of WED/RLS in pregnant women are not
well known. It has been suggested that the increased prevalence of WED/RLS associated with
pregnancy may be related to iron deficiency and hormonal changes during this period [8-10].
On the other hand, well-designed studies have failed to find evidence that female hormones,
or iron, and/or folate deficiencies, play a major role in the occurrence of WED/RLS during
pregnancy, or have shown inconsistent results [4,5,10,11]. On this basis, a prospective
longitudinal study was designed with the aim of investigating the correlates of WED/RLS
during and after pregnancy.
Page 4 of 22
Methods
Population and setting
A total of 138 pregnant women who had been diagnosed as having WED/RLS at any
stage of their pregnancies, and were aged 18 years or older were enrolled prospectively into
the study. The study population was formed from the pregnant women attending routine
prenatal office visits at the Gaziantep Cengiz Gökçek Obstetrics and Gynecology Hospital in
Gaziantep city and at the Istanbul University Cerrahpasa Medical Faculty in Istanbul city,
Turkey. Both of these clinics provide public services and have separate facilities for high-risk
pregnancies. Study participants were only recruited from among those who attended these
facilities for women and had no potential maternal or fetal risk. Women with eclampsia,
preeclampsia, or other gestational complications that might favor or trigger WED/RLS
symptoms were excluded, while women with other known causes of symptomatic WED/RLS
were not. A control group of 251 age-matched pregnant women was also prospectively
enrolled. The participants were not recruited consecutively, but women attending these clinics
were evaluated for 1 year, on 2 days per week, and those who met the inclusion criteria and
agreed to participate in the study were prospectively recruited. The study was approved by
Gaziantep Clinical Research Ethical Committee. All participants were informed about the
nature of the research, and informed consent was obtained from every participant.
Study procedure
Questionnaires were administered during face-to-face interviews conducted by three
clinicians with training in the diagnosis of WED/RLS (MN, RA and FB). Participants were
interviewed regardless of the period of pregnancy, with a cross-sectional approach. Each
interview lasted for about 30 min. All problems regarding the diagnosis were then discussed
Page 5 of 22
with the senior authors (AN and DK). The clinical-diagnostic interview was conducted in
accordance with the criteria defined by the International RLS Study Group (IRLSSG), and the
severity of WED/RLS was assessed using IRLSSG criteria [3,12].
The questionnaire consisted of 50 questions, which included: (1) demographic
characteristics such as age, height, body weight, education, income, number of previous
pregnancies, gestational age for the current pregnancy; (2) habitual behaviors such as current
or past history of smoking, alcohol intake, use of iron or other vitamin supplements; (3) past
medical history, including the past medical records of the participants; and (4) detailed
characteristics of WED/RLS, if present, such as disease duration, triggering factors, family
history or use of WED/RLS treatment.
Blood samples were collected from all participants, and were investigated to obtain the
complete blood count, fasting glucose, blood urea nitrogen, creatine, ferritin, transferrin
saturation, total iron binding capacity, urine analysis for albuminuria, and the level of
estradiol.
All pregnant women with WED/RLS underwent a follow-up face-to-face interview 3
months after parturition, which was conducted by the same clinicians. Women who reported
the presence of WED/RLS at the third postpartum month were questioned again at 6 months.
Statistical analysis
Statistical Package for the Social Sciences (SPSS) version 15.0 for Windows was used
for the statistical analysis. Descriptive variables were expressed as percentages for categorical
variables, and as mean±SD for continuous variables. The Chi-squared test was used in the
comparisons of independent categorical variables. Student’s t-test was used to compare the
means of continuous variables with normal distribution; and the Mann-Whitney U test was
used in the comparisons of continuous variables without normal distribution. Pearson’s
Page 6 of 22
correlation, logistic regression or ANOVA (analysis of variance analysis) were used to
analyze risk factors and interactions between non-parametric and parametric variables. The
Bonferonni correction test was applied for multiple comparisons. The measure of association
that was used was OR with 95% CI. All calculated p-values were two-tailed, and considered
to be statistically significant if equal to or lower than 0.05.
Comment [A2]: Please check this as you use
<0.05 in your tables. Please corect whichever is not
correct, thanks.
Page 7 of 22
Results
A total of 138 pregnant women diagnosed with WED/RLS had a mean score on the
IRLSSG scale of 18.5±6.0 points. According to the gestational age, seven pregnant women
(5.2%) were in the first trimester, 40 women (28.9%) were in the second trimester, and 91
women (65.9%) were in the third trimester. Among all women in the first trimester, 15.6%
were diagnosed with WED/RLS, whereas 32.8% of those in the second trimester and 38.8%
of those in the third trimester were diagnosed with WED/RLS (p=0.032). Symptoms of
WED/RLS had emerged for the first time during the current pregnancy in 106 women (76.8%,
106/138); 29 of these pregnant women (27.4%, 29/106) were experiencing their first
pregnancies. The number of pregnancies did not show a statistically significant relationship
with the presence of WED/RLS (p=0.749, Mann-Whitney U test). Twenty-three women
(16.6%, 23/138) stated that they had had similar symptoms of WED/RLS during their
previous pregnancies, but they were all free of symptoms between pregnancies. Only nine
women (6.5%, 9/138) had symptoms of WED/RLS before pregnancy; all of whom had a
previous diagnosis of WED/RLS. About 33.6% of pregnant women with WED/RLS reported
that tiredness exacerbated their WED/RLS symptoms, and 10.5% reported stress as a
triggering factor. Other than walking and/or leg movements relieving the symptoms of
WED/RLS, which was the case in all women, leg massage (44.3%) and washing the legs with
hot (14.8%) or cold water (12.0%) were also stated as relieving maneuvers.
The comparison of the pregnant women with and without WED/RLS is shown in
Table 1. The mean age of the pregnant women in both groups was similar, although the mean
gestational age was higher in women with WED/RLS (28.3±8.7 vs 25.9±9.7 weeks, p=0.022).
All other demographic variables were similar between the two groups.
Page 8 of 22
Among the pregnant women with WED/RLS, 79.0% had nocturnal leg cramps, while
31.1% of the pregnant women without WED/RLS had nocturnal leg cramps (p<0.001).
Varicose veins were present in 26.8% of the women with WED/RLS, versus 17.9% of those
without (p=0.040). Rheumatoid complaints were reported in 6.5% of the pregnant women
with WED/RLS and 2.8% of those without WED/RLS (p=0.076). Only one pregnant woman
with WED/RLS had peripheral neuropathy (0.7%), and none of women without WED/RLS
reported peripheral neuropathy. A family history of WED/RLS was present for 8.7% of the
women with WED/RLS, but for 2.5% of those without (p=0.006).
Most of the study population had between 6-8 hours of sleep per night: 46.4% among
women with WED/RLS and 47.8% among women without WED/RLS. Having less than 6
hours of sleep per night was reported by 28.9% of women with WED/RLS and 22.3% of
women without WED/RLS (p=0.470). Mean subjective sleep latency was also longer in
pregnant women with WED/RLS: 47.1% of women with WED/RLS (compared with 31.1%
of those without WED/RLS) reported that it took them more than 30 minutes to fall asleep
(p=0.005).
The laboratory investigations are summarized in Table 2. Mean blood urea nitrogen
(p=0.040), ferritin (p=0.010) and mean transferrin saturation levels (p=0.004) were
significantly lower in women with WED/RLS (Fig. 1). Other measures were similar between
the two groups.
All the demographic and laboratory variables were evaluated in the regression
analysis. Among them, later gestational age (p<0.001, OR 1.054 [1.024-1.084 95% CI OR])
and previous history of WED/RLS (p=0.001, OR 2.795 [1.560–5.005 95% CI OR]) were
positively correlated with the presence of WED/RLS, whereas ferritin levels (p=0.001, OR
0.956 [0.932–0.980 95% CI OR]) were negatively correlated with the presence of WED/RLS.
Ferritin levels were also negatively correlated with the IRLSSG severity index (p=0.041,
Page 9 of 22
linear regression analysis and ANOVA). Comparison of women with WED/RLS that recurred
during their pregnancies (n=23) and those who experienced WED/RLS symptoms
continuously (n=9) showed that ferritin levels were lower in those with continous WED/RLS,
although not significantly (24.4±16.1 ng/mL versus 21.6±15.8 ng/mL, p=0.167).
Follow-up examinations 3 months after parturition, with face-to-face interviews
conducted by the same clinicians revealed that 48 women (34.8%) still experienced
WED/RLS symptoms. Of these, nine women had WED/RLS continuously (18.7%, 9/48), four
women had had WED/RLS temporarily during their previous pregnancies (8.3%, 4/48), and
35 women (70%) were experiencing WED/RLS symptoms for the first time in their lives.
Twenty-seven out of the latter 35 women had symptoms that started during the second
trimester (77.1%). Among these 35 women, 19 were primiparous (54.2%, 19/35), while 16
had had more than one pregnancy (45.8%, 16/35). The mean number of pregnancies was
higher in women with residual WED/RLS symptoms (4.0±1.4 between three and six
pregnancies) when compared with those with no symptoms following delivery (2.2±1.1
between one and four pregnancies, p=0.050). The mean gestational age for women with
residual WED/RLS was also higher than in those with no residual symptoms (32.0±9.2 vs
29.4±7.5 years), but this difference was not significant (p=0.434). Ferritin levels were
significantly lower in women with residual WED/RLS symptoms when compared with those
with no residual symptoms (13.7±7.0 ng/mL vs 28.6±10.4 ng/mL, p=0.008) (Fig. 1). All other
demographic and laboratory data, including estradiol levels, failed to show statistically
significant differences between the two groups.
Page 10 of 22
Discussion
Willis-Ekbom disease/restless legs syndrome is the most common movement disorder
of pregnancy. The appearance of symptoms is most commonly reported in the last trimester of
gestation [2,8], and has been reported to generally disappear in the month following delivery
[4,7]. In a Brazilian study [8], 94.4% of pregnant women with WED/RLS were in the second
or third trimester. An earlier onset of WED/RLS during pregnancy, around the 20th week, has
also been reported [13]. The present survey replicated the finding that WED/RLS usually
started by the second trimester of pregnancy and was more common in second and third
trimesters. In addition, it was observed that the emergence of WED/RLS symptoms during the
second trimester was associated with residual WED/RLS after delivery.
A follow-up study performed about 6.5 years after delivery showed that women who
had transient WED/RLS during their pregnancy had a four-fold increased risk of developing
chronic WED/RLS [14]. Another recent study reported that 38.5% of pregnant women who
experienced symptoms for the first time during the index pregnancy developed chronic
WED/RLS [6,14]. In the present study, 34.8% of pregnant women still experienced
WED/RLS symptoms after parturition; 70% of these were experiencing WED/RLS symptoms
for the first time in their lives, and half of them were multiparious. Studies have reported
conflicting results as to whether the number of pregnancies is a risk factor for WED/RLS
[6,7,15]. Berger et al. reported data from a large epidemiological study showing that parous
women had a significantly greater prevalence of WED/RLS than nulliparous women, and that
nulliparous women had the same incidence of WED/RLS as men [15]. The present study
found that the number of pregnancies did not show a statistically significant relationship with
the presence of WED/RLS; on the other hand, the mean number of pregnancies was higher for
women with residual WED/RLS symptoms after delivery.
Page 11 of 22
Among other demographic factors, no difference between pregnant women with and
without WED/RLS was reported in previous studies for age, ethnicity or education [7,13]. In
the present study, mean gestational age was significantly higher in women with WED/RLS; it
was also higher in those with residual WED/RLS than in those with remission, although not
significantly.
A positive family history has been reported as one of the predictors of WED/RLS in
pregnancy, as has the occurrence of WED/RLS in a previous pregnancy [13,15]. In the
present study, a family history of the condition was also significantly more common in
pregnant women with WED/RLS. However, a family history of WED/RLS was not
significantly associated with the presence of residual WED/RLS symptoms after delivery.
There are different hypotheses for the higher prevalance of WED/RLS in pregnancy.
Among them, associations with hormone levels, such as estrogen alterations, and metabolic
changes, such as iron deficiency, have been investigated in many studies. In the third trimester
of gestation, elevated levels of estradiol, which counteracts the action of dopamine, occur at
the core time for development of the pathophysiology of transient WED/RLS in pregnancy
[10]. However, many analyses have failed to show significant differences in estrogen levels
between pregnant women with and those without WED/RLS, challenging the hypothesis that
estrogen levels may play an important role in the pathophysiology of WED/RLS in this
context [13]. In the present study, estradiol levels were also similar between pregnant women
with and those without WED/RLS. They were also similar in postpartum women with or
without residual symptoms.
Although there is convincing evidence for a major role of iron (which is required for
the function of tyrosine hydroxylase in dopamine synthesis) in the pathophysiology of
WED/RLS in non-pregnant individuals, this relationship is not well established in pregnant
women. Disturbances in iron transport, metabolism and storage in pregnancy might play a
Page 12 of 22
role in aggravating WED/RLS symptoms in pregnant women [4,16]. However, the rapid
improvement in symptoms in the postpartum period is difficult to account for by changes in
total iron stores, which typically remain low postpartum [5,10]. In addition, many studies
have failed to show a difference in hemoglobin and ferritin levels between pregnant women
with and without WED/RLS [5,13]. In the present survey, however, it was possible to
demonstrate that pregnant women with WED/RLS had significantly lower ferritin levels,
transferrin saturation, and blood urea nitrogen levels. Moreover, pregnant women with
WED/RLS had a slightly, but significant, higher mean gestational age than those without, and
ferritin levels showed a progressive decrease during pregnancy. Low ferritin levels during
pregnancy were also significantly associated with residual WED/RLS symptoms after
delivery, supporting the ferritin hypothesis.
Another hypothesis related to the development of WED/RLS in pregnancy involves
water retention in the lower extremities secondary to increased peripheral venous distension
and decreased peripheral vascular resistance, which in turn increase the pressure in the tissues
surrounding peripheral somatosensory system receptors and thus enhance their stimulation
[17]. This hypothesis has not been supported by other studies [13], although in the present
study, the presence of varicose veins was found to be significantly more common in pregnant
women with WED/RLS. A recent study indicating a possible association between the
occurrence of WED/RLS in pregnancy and preeclampsia may provide indirect evidence to
support this hypothesis [18].
The present study had some limitations: (1) the limited number of women included
during their first trimester did not allow for speculation about this period of pregnancy; (2) the
apparently high numbers of pregnant women with WED/RLS – this probably occurred
because the participants were not consecutively recruited and no randomization was used; (3)
although estimation of the prevalence of WED/RLS was beyond the scope of this study, this
Page 13 of 22
finding may attract attention to a social issue related to differences among geographical areas
in iron status and the response to iron loss.
The present survey showed that WED/RLS was more common in the second and third
trimesters, and the emergence of WED/RLS symptoms during the second trimester was
strongly associated with residual WED/RLS after delivery. The data also confirmed that later
gestational age, previous history of WED/RLS and positive family history were significantly
correlated with the presence of WED/RLS in pregnancy. In addition, lower ferritin levels,
transferrin saturation and blood urea nitrogen levels were shown to be associated with
WED/RLS in pregnant women. Lower ferritin levels were also associated with residual
WED/RLS symptoms after delivery. Finally, a higher number of pregnancies were associated
with a greater likelihood of having residual WED/RLS symptoms after delivery.
Page 14 of 22
Acknowledgements
This study was supported by Istanbul University BAP Project number 47610.
Disclosure: There was no financial support, off-label or investigational use.
Conflict of interest: None declared.
Page 15 of 22
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Comment [A3]: Please list the first SIX authors,
then use et al. Please supply all authors names up to
and including six, then use et al. Thanks.
Comment [A4]: As previous comment
Comment [A5]: As previosu comment
Comment [A6]: As previous comments
Page 16 of 22
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Fig. 1. Ferritin (a) and transferring saturation levels (b) in pregnant women with and without
WED/RLS; ferritin (c) and transferring saturation levels (d) in postpartum women with and
without residual Willis-Ekbom’s disease/restless legs syndrome.
Comment [A7]: As previous comments
Comment [A8]: As previous comments
Comment [A9]: Please ensure that each figüre
has a label to Show a, b, c or d.
Page 17 of 22
WED/RLS, Willis-Ekbom’s disease/restless legs syndrome
Comment [A10]: Please maket he following
amendments to these figures:
Ml should be mL
P= should be p= (with p in italics)
Please Show in footnotes what the + and – mean
Chnage the minus sign from – to – (hyphen to en-
dash)
Page 18 of 22
Table 1. Comparison of descriptive variables between women with and without Willis-
Ekbom’s disease/restless legs syndrome.
Demographic variables
Women with Willis-
Ekbom’s disease/restless
legs syndrome
(n=138)
Women without Willis-
Ekbom’s disease/restless
legs syndrome
(n=251)
p
Age (years, mean±SD)
27.8±5.8
27.9±6.0
0.854
Age groups, years,
n (%)
15-19
14 (10.4)
20 (8.1)
0.442
20-29
62 (45.9)
130 (52.4)
30-39
59 (43.7)
98 (39.5)
Education, years, n
(%)
None
10 (7.2)
11 (4.4)
0.630
<8 years
74 (53.6)
137 (54.6)
8-12
47 (34.1)
83 (33.0)
>12
7 (5.1)
20 (8.0)
Current or previous smoking
history, n (%)
14 (10.1)
18 (7.2)
0.307
Use of iron or other vitamin
supplements, n (%)
104 (75.3)
175 (69.7)
0.073
Current BMI, kg/m2
(mean±SD)
27.6±4.4
27.4±4.3
0.803
Gestational history
Gestational week (mean±SD)
28.3±8.7
25.9±9.7
0.022*
Current pregnancy number,
median (min-max)
3 (1-13)
2 (1-8)
0.065
Number of previous
1 (0-6)
1 (0-6)
0.970
Page 19 of 22
children, median (min-max)
Number of abortions, n (%)
28 (20.4)
40 (15.9)
0.265
*p-value <0.05 indicates statistical significance
Comment [A11]: As per my comment in the text
Page 20 of 22
Table 2. Comparison of laboratory variables between women with and without Willis-
Ekbom’s disease/restless legs syndrome.
Laboratory variables
Women with Willis-Ekbom’s
disease/restless legs
syndrome
(n=138)
Women without Willis-
Ekbom’s disease/restless legs
syndrome
(n=251)
p
Fasting glucose
(mg/dL), mean±SD
82.7±16.8
80.9±18.9
0.265
Blood urea nitrogen
(mmol/L), mean±SD
10.5±5.2
12.0±6.1
0.040*
Creatinine (mg/dL),
mean±SD
0.5±0.09
0.5±0.1
0.468
Ferritin (ng/mL),
mean±SD
17.5±33.4
23.0±19.0
0.010*
Transferrin saturation
(%), mean±SD
23.3±15.2
52.9±29.2
0.004*
Total iron binding
capacity (μg/dL),
mean±SD
438.1±64.6
421.9±66.7
0.161
Hemoglobin (g/dL),
mean±SD
11.8±1.2
12.4±8.5
0.590
Hematocrit (%),
mean±SD
35.5±3.3
35.9±3.7
0.242
Presence of albuminuria,
n (%)
25 (18.1)
36 (14.5)
0.344
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Estradiol levels (pg/mL),
mean±SD
4446.7±5728.6
4532.4±6185.9
0.154
*p-value <0.05 indicates statistical significance.
Comment [A12]: As previous comment
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