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Cyclic endometrial neoangiogenesis contributes to changes in local vascular patterns and is amenable to non-invasive assessment with Doppler sonography. We hypothesize that the uterine artery (UtA) impedance, measured by its pulsatility index (PI), exhibits a regular pattern during the normal menstrual cycle. Therefore, the main study objective was to derive normative new day-cycle-based reference ranges for the UtA-PI during the entire cycle from days 1 to 34 according to the isolated time effect and potential confounders such as age and parity. From January 2009 to December 2012, a cross-sectional study of 1,821 healthy women undergoing routine gynaecological ultrasound was performed. The Doppler flow of the right and left UtA-PI was studied transvaginally by colour and pulsed Doppler imaging. The mean right and left values and the presence or absence of a bilateral protodiastolic notch were recorded. Reference intervals for the PI according to the cycle day were generated by classical linear regression. The majority of patients (97.5%) presented unilateral or bilateral UtA notches. The crude 5th, 50th, and 95th reference percentile curves of the UtA-PI at 1-34 days of the normal menstrual cycle were derived. In all curves, a progressive significant decrease occurred during the first 13 days, followed by an increase and recovery in the UtA-PI. The adjusted 5th, 50th, and 95th reference percentile curves for the effects of age and parity were also obtained. These two conditions generated an approximately identical UtA-PI pattern during the cycle, except with small but significant reductions at the temporal extremes. The median, 5th, and the 95th percentiles of the UtA-PI decrease during the first third of the menstrual cycle and recover to their initial values during the last two thirds of the cycle. The rates of decrease and recovery depend significantly on age and parity.
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RESEARCH ARTICLE
Reference Ranges for Uterine Artery
Pulsatility Index during the Menstrual Cycle:
A Cross-Sectional Study
Luís Guedes-Martins
1,2,3
*, Rita Gaio
4,5
, Joaquim Saraiva
1,3,6
, Sofia Cerdeira
7,8
,
Liliana Matos
1,2,9
, Elisabete Silva
1,2
, Filipe Macedo
10
, Henrique Almeida
1,2,11
1Department of Experimental Biology, Faculty of Medicine, University of Porto, 4200319 Porto, Portugal,
2IBMC-Instituto de Biologia Molecular e Celular, 4150180 Porto, Portugal, 3Centro Hospitalar do Porto
EPE, Departamento da Mulher e da Medicina Reprodutiva, Largo Prof. Abel Salazar,4099001 Porto,
Portugal, 4Department of Mathematics, Faculty of Sciences, University of Porto, Rua do Campo Alegre,
4169007 Porto, Portugal, 5CMUP-Centre of Mathematics, University of Porto, Rua do Campo Alegre,
4169007 Porto, Portugal, 6Obstetrics-Gynecology, Private Hospital Trofa, 4785409 Trofa, Portugal,
7Gulbenkian Program for Advanced Medical Education, 1067001 Lisbon, Portugal, 8Department of
Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United
States of America, 9Faculty of Nutrition and Food Sciences, University of Porto, Rua Dr. Roberto Frias,
4200465 Porto, Portugal, 10 Department of Cardiology, Faculty of Medicine, University of Porto, 4200319
Porto, Portugal, 11 Obstetrics-Gynecology, Hospital-CUF Porto, 4100180 Porto, Portugal
*luis.guedes.martins@gmail.com
Abstract
Background
Cyclic endometrial neoangiogenesis contributes to changes in local vascular patterns and
is amenable to non-invasive assessment with Doppler sonography. We hypothesize that
the uterine artery (UtA) impedance, measured by its pulsatility index (PI), exhibits a regular
pattern during the normal menstrual cycle. Therefore, the main study objective was to derive
normative new day-cycle-based reference ranges for the UtA-PI during the entire cycle from
days 1 to 34 according to the isolated time effect and potential confounders such as age
and parity.
Methods
From January 2009 to December 2012, a cross-sectional study of 1,821 healthy women un-
dergoing routine gynaecological ultrasound was performed. The Doppler flow of the right
and left UtA-PI was studied transvaginally by colour and pulsed Doppler imaging. The mean
right and left values and the presence or absence of a bilateral protodiastolic notch were re-
corded. Reference intervals for the PI according to the cycle day were generated by classi-
cal linear regression.
Results
The majority of patients (97.5%) presented unilateral or bilateral UtA notches. The crude
5th, 50th, and 95th reference percentile curves of the UtA-PI at 134 days of the normal
PLOS ONE | DOI:10.1371/journal.pone.0119103 March 5, 2015 1/18
OPEN ACCESS
Citation: Guedes-Martins L, Gaio R, Saraiva J,
Cerdeira S, Matos L, Silva E, et al. (2015) Reference
Ranges for Uterine Artery Pulsatility Index during the
Menstrual Cycle: A Cross-Sectional Study. PLoS
ONE 10(3): e0119103. doi:10.1371/journal.
pone.0119103
Academic Editor: Fatima Crispi-Brillas, University of
Barcelona, SPAIN
Received: September 26, 2014
Accepted: January 28, 2015
Published: March 5, 2015
Copyright: © 2015 Guedes-Martins et al. This is an
open access article distributed under the terms of the
Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any
medium, provided the original author and source are
credited.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information file.
Funding: The authors have no support or funding to
report.
Competing Interests: The authors have declared
that no competing interests exist.
menstrual cycle were derived. In all curves, a progressive significant decrease occurred
during the first 13 days, followed by an increase and recovery in the UtA-PI. The adjusted
5th, 50th, and 95th reference percentile curves for the effects of age and parity were also
obtained. These two conditions generated an approximately identical UtA-PI pattern during
the cycle, except with small but significant reductions at the temporal extremes.
Conclusions
The median, 5th, and the 95th percentiles of the UtA-PI decrease during the first third of the
menstrual cycle and recover to their initial values during the last two thirds of the cycle. The
rates of decrease and recovery depend significantly on age and parity.
Introduction
The uterus requires an adequate blood supply to fulfil its essential role in human reproduction.
As the uterine artery (UtA) provides most of the perfusion, assessment of its vascular proper-
ties is expected to provide important information on the uterine ability to allow the fertilized
ovum to implant and pregnancy to progress. Doppler ultrasound has become a mainstay in the
assessment of such properties because of the development of adequate, non-invasive proce-
dures and easy-to-use equipment. Using Doppler ultrasound, a variety of circulatory data can
be estimated and integrated into a quantitative determination of different impedance parame-
ters. Of these, major importance has been attributed to the pulsatility index (PI) because it ap-
pears to more appropriately describe the blood velocity waveform [1].
Pregnancy is the most impressive change that occurs in the uterus. The nutritionally de-
manding growing foetus necessitates a large and progressive adaptation in the pelvic circula-
tion, which includes the UtA and the internal iliac artery, from where it is derived [2]. In the
non-pregnant condition, the UtA Doppler waveform velocity shows a systolic flow rapid rise
and sudden fall that is immediately followed by a notch during early diastole [3]; however, this
high impedance feature progressively disappears during pregnancy and is present in only 5%
of women from 25 weeks onwards [1]. In this context, the most important change in the UtA-
PI is its progressive decrement [1,4]. This change is related to major changes at the placental
bed and in the uterine artery itself, which shifts from a resistance vessel to a capacitance vessel
to cope with the foetal demands. Such change is so important that, during the second trimester,
the uterine artery PI increases rather than decreases, and combined with the notch presence, is
considered a good predictor of preeclampsia and severe intra-uterine growth restriction [5].
The monthly cyclic changes in the non-pregnant genital tract also suggest that regulated
changes occur in the uterine blood supply to endow the endometrium with the ability to receive
the ovum, should fertilization occur. Indeed, such cyclic changes were the subject of a number
of studies measuring circulatory data in the UtA and its distal branches such as the radial and
spiral arteries. The reports, however, evidenced complex temporal relationships and sometimes
conflicting results.
Both a lack of significant UtA impedance changes during the cycle [6] and higher UtA-PI
early and late in the cycle, with a comparatively lower level during the mid-cycle period or lute-
al phase, were reported [7,8]. In addition, other reports have found small peaks at mid-cycle
just before ovulation [9] that appeared to interrupt the seeming regularity of UtA-PI trends. In-
terestingly, studies of the UtA distal branches indicated low impedance to flow during the late
follicular and midluteal phases [8,10], times when the endometrial thickness and vascularity
UtA-PI during the Menstrual Cycle
PLOS ONE | DOI:10.1371/journal.pone.0119103 March 5, 2015 2/18
increased [11]. The decreased UtA-PI, particularly during the luteal phase, together with the
increased blood velocity in the UtA and its vascular network, indicated increased uterine perfu-
sion in preparation for implantation [8,9]. In fact, low PI of the uterine artery [12] and endo-
metrial flow [13] were associated with improved implantation rates, further supporting the
view that increased local perfusion favours successful establishment of pregnancy.
It should be emphasized that, in contrast to the UtA distal branches, the data for the UtA it-
self have been less consistent. While some studies failed to evidence any association [1315],
others reported an association between the lower UtA-PI at mid-cycle, higher pregnancy rates
[12,16,17], and fewer miscarriage events [18]. These findings indicate that a more in-depth
knowledge of the uterine circulation during the normal menstrual cycle (NMC) will provide
relevant insights on reproductive physiological changes and allow the recognition of abnormal
patterns; in turn, these data would prove useful in the management of reproductive disorders
such as polycystic ovary syndrome, miscarriage, and repeated abortion.
Notwithstanding the gains afforded by previous investigations in unveiling UtA impedance
variations during the menstrual cycle, these studies were limited by the number of women en-
rolled and the duration that each cycle was evaluated. In addition, day-cycle-based reference
ranges for the mean UtA-PI have not been established using well-established methodological
guidelines [1921], which would prove helpful in the management of fertility disorders such as
those mentioned above.
These shortcomings led us to determine normative new reference ranges for the UtA-PI
based on the day-cycle from days 1 to 34 of the NMC, while also isolating the time effect and
adjusting the findings for potential confounders such as age and parity.
Materials and Methods
Subjects
The research protocol was approved by the ethics committee (IRB protocol number: 15013
[096-DEFI/122-CES]) of Centro Hospitalar do Porto, Unidade Maternidade Júlio Dinis (CHP-
MJD), and all subjects provided written informed consent.
A cross-sectional study of 1821 healthy women undergoing routine gynaecological ultra-
sound examination was performed from January 2009 to December 2012. During the first ap-
pointment that coincided with the ultrasound evaluation, subjects were examined by a senior
specialist who reviewed the patients history, and verified the absence of previous hypertension,
structural heart disease, diabetes and other endocrine disorders, immune disease, renal and
haematological conditions, and chronic infections. A detailed gynaecological examination
ruled out the presence of any pelvic or gynaecological abnormality. Inclusion criteria were:
identification of the first day of the most recent menstrual period (day 1); regular menstrual cy-
cles; absence of gynaecological disorders, menorrhagia, and established pelvic pathology on
transvaginal ultrasound examination (including fibroids, abnormal sizes or clusters of ovarian
cysts, and tubal disease); no chronic medication, including hormonal contraception, for the
preceding 4 months; and absence of pregnancy as confirmed by ultrasound.
On the day of ultrasound examination, a menstrual calendar was handed to the patient, and
a subsequent clinical appointment was scheduled 6090 days later. The date and duration of
the most recent menstruation and the date of the ultrasound evaluation were recorded on the
menstrual calendar. Additionally, patients were instructed to write the dates of subsequent
menstruation. Patients failing to complete the menstrual calendar or those becoming pregnant
during follow-up were excluded.
UtA-PI during the Menstrual Cycle
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Doppler flow assessment
The ultrasound examination was performed with the woman in the lithotomy position and at
any time of day. Uterine artery Doppler evaluation was performed using a Voluson 730 Pro
(GE Healthcare Technologies, Milwaukee, WI, USA) ultrasound unit containing multifrequen-
cy transvaginal and transabdominal transducers. Assessments were performed by a single op-
erator with vast experience in Doppler ultrasound to avoid inter-observer variability using a
transvaginal transducer. A sagittal image of the uterus that included the cervical canal and in-
ternal cervical os was obtained. The transducer was then gently tilted from side to side, and col-
our flow mapping was used to identify each uterine artery at the level of the internal os. Pulsed
wave Doppler was used with a sampling gate set at 2 mm to image the entire vessel and ensure
that the angle of insonation was less than 30°. UtA-PIs were measured automatically as follows:
PI ¼systolic peak velocity end diastolic velocity
mean velocity during cardiac cycle
Three similar consecutive waveforms were obtained, and the mean PI of the left and right
arteries was calculated. The presence or absence of a bilateral early protodiastolic notch in UtA
was evaluated. A positive notch was defined as a persistent decrease in the blood flow velocity
during early diastole that was less than the diastolic peak velocity in at least one UtA Doppler
ultrasound spectrum. Absence of the notch was defined by its bilateral absence.
Intraobserver reliability was obtained from two readings performed at the beginning and
end of the examination during the first 100 recordings of pulsatility indices in the
uterine arteries.
Statistical analysis
The Chi-squared test assessed the homogeneity of proportions for categorical variables. The
population reference intervals for PI were derived by regression modelling of the PI values over
time during the menstrual cycle. The response was log-transformed because of the positive
skewness observed in the empirical distribution (Fig. 1). Age group, Body Mass Index (BMI),
parity status (primiparous vs multiparous), and smoking were considered potential time-effect
confounders. However, adequate adjustment for these variables identified age and parity as the
only statistically significant confounders. The crude and adjusted (for age group and parity)
trends of the PI during the menstrual cycle were identified.
To study the crude effect of the menstrual cycle progression on the UtA-PI, a cubic polyno-
mial fit the data significantly better than did a quadratic. No polynomial of a degree higher
than three was considered, as those curves may exhibit unrealistic features such as waviness or
sharp deviation at extreme values of the days [19]. Each day of the menstrual cycle was denoted
as d, and a fitted model was generated as follows:
Eðlog PIðÞjdÞ¼b0þb1
d
10 þb2
d
10

2
þb3
d
10

3
ð1Þ
with constants β
0
β
1
β
2
β
3
and a rescaling in the variable dto avoid very small regression coef-
cients. This equation was rewritten using multiplicative effects as follows:
EðPI jdÞ¼Ceg1dþg2d2þg3d3
with C¼eb0;g1¼b1
10 ;g2¼b2
102and g3¼b3
103. The letter Ein both equations denoted
the conditional expected value.
UtA-PI during the Menstrual Cycle
PLOS ONE | DOI:10.1371/journal.pone.0119103 March 5, 2015 4/18
Every centile curve for PI was then estimated by the following equation:
centileðdÞ¼exp½d
logðPIÞðdÞþKb
sdÞ:
Here, d
logðPIÞðdÞis the predicted response at day dof model (1), K is the corresponding centile
of the standard Gaussian distribution, and b
sd is the standard deviation of the unscaled residuals
of model (1).
To obtain centile curves stratified by age group (group 1, 1826 years; group 2, 2735 years;
group 3, 3650 years) and parity (nulliparous vs parous), the above regression procedure was
refined. For age group aand parity status p, the best fitted model was as follows:
Elog PIðÞjd;a;pðÞðÞ¼b0a;pðÞþb1aðÞd
10 þb2aðÞ d
10

2
þb3
d
10

3
ð2Þ
with β
0
depending on the two considered factors, β
1
and β
2
depending only on the age group,
and β
3
designated as a constant. The reference categories corresponded to the youngest and the
nulliparous classes.
Intraclass correlation coefficients (ICC) and 95% confidence intervals were calculated using
a two-way mixed-effects model with absolute agreement. The reliability coefficient, which is
the difference value exceeded by only 5% of pairs of measurements in a single subject, was cal-
culated as 1.96 times the standard deviation of the difference between pairs of repeated mea-
surements [22].
All statistical analyses were carried out using the R language and software environment for
statistical computation, version 2.12.1 [23]. The significance level was fixed at 0.05.
Fig 1. Plot of PI (left panel) and the log(PI) (right panel) measured in the uterine artery during the menstrual cycle. PI, pulsatility index.
doi:10.1371/journal.pone.0119103.g001
UtA-PI during the Menstrual Cycle
PLOS ONE | DOI:10.1371/journal.pone.0119103 March 5, 2015 5/18
The study adhered to the STROBE (Strengthening the Reporting of Observational studies in
Epidemiology) guidelines for observational studies, and all recommendations were included in
the study [S1 Table].
Results
A total of 1821 healthy women were considered eligible for this study. Of these, 153 were ex-
cluded (8.4%); 128 women did not have clinical records in the menstrual calendar according to
the study protocol; 11 women were pregnant at the time of ultrasound assessment; in 10 cases,
the pulsatility index in the uterine arteries could not be measured because of technical difficul-
ties; and four women refused to participate in the study.
The demographic characteristics of the 1668 women included in the study are summarized
in Table 1. Their ages ranged from 18 to 50 years old, and 41.4% were older than 35 years. Ad-
ditionally, 39.1% were nulliparous, and the majority of the patients (97.5%) exhibited a notch
in the uterine arteries (unilaterally or bilaterally).
UtA-PI during the normal menstrual cycle
The reliability coefficient for the UtA-PI was 0.434. The ICC for the intraobserver reliability of
the UtA-PI measurements was 0.984, with a 95% confidence interval ranging from 0.976 to
0.989.
Table 1. Demographic characteristics of the 1668 women included in the study.
n(%)
Age (intervals in years) Group 1. 1826 251 (15.0)
Group 2. 2735 727 (43.6)
Group 3. 3650 690 (41.4)
Body Mass Index
a
(Kg/m
2
)1624 1032 (61.9)
2529 480 (28.8)
3039 156 (9.3)
Parity 0 653 (39.1)
1 1015 (60.9)
Age at menarche, years (mean±SD) 12.1 (1.17) -
Age at rst sexual intercourse (years±SD) 17.9 (2.33) -
History of miscarriage No 1479 (88.7)
Yes 188 (11.3)
History of preeclampsia No 1644 (98.6)
Yes 24 (1.4)
Smoking No 1380 (82.7)
Yes 288 (17.3)
Presence of bilateral notching No 100 (6.0)
Yes 1568 (94.0)
Presence of unilateral notching No 42(2.5)
Yes 1626 (97.5)
Menstrual cycle length, days (mean±SD) 28.8(4.2) -
Menstrual period length, days (mean±SD) 5.0(1.7) -
SD, standard deviation
a
Body Mass Index (BMI) was measured immediately before Doppler assessment.
doi:10.1371/journal.pone.0119103.t001
UtA-PI during the Menstrual Cycle
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The days evaluated in the menstrual cycle varied from 1 to 34, and the collected data
were slightly unbalanced. The least frequently assessed point was day 34 (39 patients), and
the most frequently assessed were days 22 and 26 (54 patients each) (Table 2). However,
the empirical distribution for the day number was essentially uniform, with a sample
mean ± standard deviation of 17.3 ± 9.7 compared with 17.0 ± 9.8 expected in a
uniform distribution.
Concerning the fitting of model (1), visual inspection of the normality and homosce-
dasticity of the residuals was performed (Fig. 2, Panel A). There were no serious depar-
tures from normality except at a few extreme points, mostly located on the left tail. Data
with an absolute value of the standardized residuals greater than three were removed. A
total of 11 data points were removed (eight on the left tail), corresponding to less than 1%
of the total sample size. The highest and lowest cutoff values for PI in these women were
7.26 and 1.03, respectively.
All parameter estimates of the final fitted model were statistically significant (Table 3). Stan-
dard errors of the estimates were up to 3% smaller than the errors in the model using the total
data. Residual plots exhibited reasonable properties for normality adherence (Fig. 2, Panel B):
89% of the standardized residuals lay between-1.645 and 1.645; the boxplot revealed an approx-
imately symmetric distribution with the median line at approximately the centre of the
box and symmetric whiskers; and the quantile-quantile (Q-Q) plot of the studentized residuals
showed little departure from the confidence band for the correspondent tdistribution. In addi-
tion, the Lilliefors-corrected Kolmogorov-Smirnov normality test provided a p-value of 0.002;
this statistical significance was overlooked because of the large sample size (n = 1657). The out-
liers were again removed, but the results were no better.
The plot of the logarithmized UtA-PI values against the days of the cycle did not show any
substantive changes in the standard deviations of the values along the menstrual cycle (Fig. 1);
however, a formal statistical model for this relationship was applied. The linear regression of
the scaled absolute residuals (SARs), defined as the product of ffiffiffiffiffiffiffi
p=2
pby the absolute residuals,
on a polynomial of degree 1 in the variable Day was statistically significant (p <0.001), and no
higher-order terms were identified. As this regression only explained approximately 1% of the
SARstotal variability, it was considered redundant, and therefore the residual homoscedastici-
ty of model (1) did not appear violated.
The predicted 5
th
,50
th
, and 95
th
percentile regression curves are presented in Table 2 and
plotted in Fig. 3. The expected ovulation date (EOD) was calculated in each patient assuming
that the luteal phase lasted approximately 2 weeks (i.e., E0D = menstrual cycle length14). Ac-
cordingly, the 50
th
centile curve for PI, which under the normality assumption coincides with
the mean curve, began at day 1 at its maximum value (3.40) and decreased until reaching its
minimum value at day 1213. From this day onwards, the curve increased until reaching 3.20
(50
th
centile) at the end of the menstrual cycle (day 34). If the curve failed to stop at day 34, it
continued to decrease afterwards. Day 34 corresponded to the local maximum of the
defined function.
As the 5
th
and the 95
th
centile curves were simply the product of the 50
th
percentile and a
constant value, they showed the same monotonicity behaviour as the 50
th
centile curve, with
maximum and minimum values attained on the same days (Table 2). The 5
th
centile curve
began at 2.08, ended at a similar PI value of 1.96, and had a minimum PI value of 1.60. The
95
th
centile curve began at 5.55, ended at 5.23, and had a minimum PI value of 4.27. The stee-
pest decrease in the PI during the first 1213 days of the menstrual cycle occurred in the 95
th
centile curve, and the smallest decrease occurred in the 5
th
centile curve (Fig. 3).
UtA-PI during the Menstrual Cycle
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Effect of maternal age and parity on UtA-PI during normal menstrual
cycle
To obtain centile curves stratified by age group and parity status, the regression procedure was
refined taking these factors into consideration, while also excluding the same 11 data points as
previously. The best fitted model is described in model (2), and the estimated regression coeffi-
cients and corresponding 95% confidence intervals are summarized in Table 4. All estimates
Table 2. Observed and predicted percentiles of the uterine artery pulsatility index on each cycle day.
Observed Predicted
Cycle (days) n EOD
a
(n) 5
th
centile 50
th
centile 95
th
centile 5
th
centile 50
th
centile 95
th
centile
1 50 0 1.74 3.37 5.55 2.08 3.40 5.55
2 50 0 2.00 3.04 4.59 1.99 3.24 5.29
3 49 0 1.88 3.02 4.90 1.90 3.11 5.07
4 48 0 1.83 3.17 4.60 1.83 2.99 4.89
5 51 0 1.94 3.25 5.00 1.78 2.90 4.73
6 52 1 1.88 3.15 5.77 1.73 2.82 4.60
7 46 20 1.80 3.12 5.37 1.69 2.76 4.50
8 52 46 1.59 2.41 4.03 1.66 2.71 4.42
9 50 107 1.83 2.48 4.64 1.63 2.67 4.36
10 52 110 1.09 2.21 3.93 1.62 2.64 4.31
11 49 136 1.24 2.40 4.48 1.61 2.62 4.28
12 48 131 1.05 2.60 4.10 1.60 2.61 4.27
13 49 103 1.52 2.62 4.18 1.60 2.61 4.26
14 53 209 1.81 2.33 4.09 1.60 2.62 4.27
15 46 160 1.42 2.56 3.66 1.61 2.63 4.29
16 50 71 1.43 2.60 4.87 1.62 2.65 4.32
17 52 104 1.36 2.33 3.93 1.63 2.67 4.36
18 52 103 1.93 2.99 4.66 1.65 2.70 4.40
19 49 67 1.62 2.88 3.96 1.67 2.73 4.45
20 49 99 1.89 2.74 4.78 1.69 2.76 4.51
21 50 96 1.85 2.72 4.31 1.72 2.80 4.57
22 54 61 2.14 3.01 4.18 1.74 2.84 4.64
23 48 19 2.30 2.86 5.03 1.77 2.88 4.70
24 45 21 1.56 2.91 4.81 1.79 2.92 4.77
25 51 4 1.81 3.07 4.73 1.82 2.97 4.84
26 54 0 1.87 2.96 4.30 1.84 3.01 4.91
27 46 0 2.08 2.86 4.71 1.87 3.05 4.98
28 47 0 1.67 2.94 4.52 1.89 3.09 5.04
29 47 0 2.16 2.90 4.58 1.91 3.12 5.09
30 50 0 1.97 3.00 4.61 1.93 3.15 5.14
31 43 0 2.19 2.94 4.90 1.94 3.17 5.18
32 49 0 2.16 3.25 4.95 1.95 3.19 5.21
33 48 0 2.41 3.14 4.29 1.96 3.20 5.23
34 39 0 2.11 3.21 5.42 1.96 3.20 5.23
a
For each patient, the expected ovulation date (EOD) was calculated assuming that the luteal phase exhibited a consistent duration of approximately 2
weeks, i.e., E0D =menstrual cycle length14.
doi:10.1371/journal.pone.0119103.t002
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Fig 2. Residual plots for the fitted models; from top to bottom and from left to right: boxplot of the standardized residuals, histogram of the
standardized residuals, plot of the standardized residuals against the predicted values, and QQ-plot of the studentized residuals. Panel A employs
the entire dataset; Panel B eliminates data from 11 outliers.
doi:10.1371/journal.pone.0119103.g002
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but one (a quadratic term on days of the menstrual cycle for women aged 2735 years, p =
0.089) were statistically significant.
No significant interaction effects involving parity were identified. No serious outliers or evi-
dence of violations in normality and homoscedasticity assumptions were detected within each
age-parity sub-model (Figs. 4and 5). The residual regression on the explanatory variables, with
a linear dependence on the cycle days, presented a value for the coefficient of determination
(R
2
) of approximately 1% and did not identify the effect of age group as statistically significant.
As before, the residual homoscedasticity of the model did not appear compromised. The resid-
ual normality could only be rejected for nulliparous women aged 2735 years (Fig. 4).
The standard deviation of the residuals of model (2) did not significantly change during the
menstrual cycle; therefore, the coefficient significance in Table 4 remained true for all
centile curves.
For any fixed age group and centile curve, a significant difference between the intercepts of
the curves for nulliparous and parous women was identified, with the menstrual cycle in nullip-
arous women beginning at higher UtA-PI values. Similarly, for any fixed parity status and cen-
tile curve, there were significant differences between the intercept of the age group 2 (or 3)
curve and that of age group 1 (Fig. 5).
Overall, the PI values exhibited a soft wave-like trend during the menstrual cycle within
each maternal age and parity group. The values decreased until approximately the first third of
the menstrual cycle and then increased to approximately the original value over the remainder
of the cycle. This trend was independent from the parity status but was significantly dependent
on the maternal age at the linear and quadratic levels. As the age increased, the minimum UtA-
PI was reached more quickly, the range of the PI values decreased, and the curves became flat-
ter (Fig. 5).
Discussion
Transvaginal assessment of UtA perfusion employing Doppler ultrasound offers several advan-
tages over the transabdominal route [24]. The vessel is easily identified and located at close
proximity, thus yielding clearer waveforms, and the insonation angle is near 0°, which results
in high reproducibility [24,25]. Despite the diversity of features that may be determined
through arterial resistance, it is impedance, the combination of forward and reflected blood
flow, that is measured [26]. This is accomplished by indirectly measuring the UtA-PI, a tech-
nique that has gained popularity in recent studies compared with other Doppler indices such
as resistance index [1,27] and other scoring systems [28,29].
These principles were applied in the current study to generate Doppler colour-based refer-
ence ranges for the mean UtA-PI between days 1 and 34 of the NMC in an appropriately large
Table 3. Estimates of the regression coefcients and corresponding 95% condence intervals (CI)
of model (1) tted without the 11 identied outliers.
Variables Regression Coefcients 95% CI
Intercept 1.279 (1.214, 1.344)*
Day/10 -0.573 (-0.730, -0.416)*
(Day/10)
2
0.310 (0.206, 0.414)*
(Day/10)
2
-0.044 (-0.064, -0.024)*
*Signicant at the 0.05 level.
doi:10.1371/journal.pone.0119103.t003
UtA-PI during the Menstrual Cycle
PLOS ONE | DOI:10.1371/journal.pone.0119103 March 5, 2015 10 / 18
Fig 3. (A) Observed (circles) and predicted 5
th
,50
th
, and 95
th
percentile regression curves for the pulsatility index during the menstrual cycle.
Histogram (B) and boxplot (C) of the expected ovulation date (EOD). For each patient, the EOD was calculated assuming that the luteal phase exhibited a
consistent duration of approximately 2 weeks, i.e., E0D = menstrual cycle length14.
doi:10.1371/journal.pone.0119103.g003
UtA-PI during the Menstrual Cycle
PLOS ONE | DOI:10.1371/journal.pone.0119103 March 5, 2015 11 / 18
sample of healthy women. In addition, the effects of age and parity were assessed for each day
during the NMC.
Statistics
The reliability evaluation demonstrated that UtA-PI measurement was highly repeatable as in-
dicated by the ICC. There is sufficient scientific consensus that an ICC >0.7 reflects very low
measurement error [22,30].
Stringer and validated methodological guidelines were used to construct the reference
curves from the collected data [1921,31]; a cross-sectional design was used as such studies are
easier to perform and combine with clinical practice; and finally, the good intraobserver repro-
ducibility in our study suggests that the mean UtA-PI is a reliable parameter in a clinical set-
ting. The overarching principle is that a reference interval is the range of values encompassed
by a pair of symmetrically placed extreme centiles, such as the 2.5
th
and 97.5
th
centiles for a
95% interval [19]. Values lying outside the reference limits are considered unusual or extreme.
Several statistical methods have been used to generate reference intervals: linear regression
(if necessary with modelling of the residual standard deviation), the LMS method [32], the
non-parametric method of Healy, Rabash, and Young (HRY), and non-parametric quantile re-
gression [21]. Each method has its advantages and limitations; however, the method that is
most desired is the one allowing identification of the population centile of a given observation.
Linear regression has that property and is simple and easily implemented by basic statistical
software packages.
Perfusion changes during the normal menstrual cycle
The current study revealed a cyclic variation in the UtA impedance during the NMC; the UtA-
PI was high during the temporal extremes and showed a mid-cycle depression, with the mini-
mal values occurring between days 13 and 17. Independent assessment of the effects of age and
parity also revealed that both conditions were associated with a significant decrease in the UtA
impedance at the extremes of the cycle, but not during the mid-cycle, when the uterus under-
goes impressive structural changes. These circulatory variations include the median, 5
th
, and
95
th
percentiles of the UtA-PI regression curves from the initial through to the final third of
Table 4. Estimates of the regression coefcients and corresponding 95% condence intervals (CI)
for the model stratied by age and parity.
Variables Regression Coefcients 95% CI
Intercept 1.546 (1.438, 1.654)*
Age Group 2 -0.236 (-0.361, -0.110)*
Age Group 3 -0.335 (-0.463, -0.206)*
Parous -0.066 (-0.098, -0.034)*
Day/10 -0.792 (-0.992, -0.592)*
(Day/10)
2
0.353 (0.244, 0.461)*
(Day/10)
3
-0.042 (-0.062, -0.023)*
(Age Group 2):(Day/10) 0.216 (0.041, 0.391)*
(Age Group 3):(Day/10) 0.365 (0.188, 0.543)*
(Age Group 2):(Day/10)
2
-0.044 (-0.044, 0.026)
(Age Group 3):(Day/10)
2
-0.091 (-0.142, -0.039)*
*Signicant at the 0.05 level.
doi:10.1371/journal.pone.0119103.t004
UtA-PI during the Menstrual Cycle
PLOS ONE | DOI:10.1371/journal.pone.0119103 March 5, 2015 12 / 18
the menstrual cycle. The mechanism underlying such impedance variation is unknown, but it
likely reflects regulatory factors affecting the local vasculature and myometrium function.
Early during the cycle, increased myometrial tone is required to expel the remains of the
sloughing endometrium; for this purpose, the smooth muscle cells contract, which has a nega-
tive effect on uterine perfusion and generates high impedance to UtA blood flow. We suspect
that a similar muscular change underlies the UtA-PI rise near the end of the cycle.
There is evidence that variations in muscular tone reflect circulating levels of female steroid
hormones, particularly oestrogen, which is low early in the cycle but increases later during the
follicular phase. Oestrogen promotes vascular smooth muscle relaxation and reduces sensitivity
to adrenergic stimulation [33]; moreover, in experimental conditions, it was found to depress
uterine contractility both in vivo [34] and in freshly isolated rat uterine specimens [35]. This
decrease in myometrial tone and increasingly thickened endometrium during the proliferative
phase, together with the development of an extensive small vessel network, is the likely cause
for the downward trend in impedance that reaches a minimum near day 13. After ovulation,
progesterone concentration rises through the mid-secretory phase, promoting endometrium
decidualization. Oestrogen decrement [36] and the ability of progesterone to overcome the
Fig 4. Quantile-quantile (Q-Q) plots of the standardized residuals of model (2) for each combination of age and parity groups. Nulliparous women
are presented in the first row, and parous women are presented in the second row. The age group increases from the left to right columns. From left to right
and from top to bottom, the Lilliefors-corrected Kolmogorov-Smirnov normality test calculated p-values of 0.738,<0.001, 0.111, 0.954, 0.082, and
0.373, respectively.
doi:10.1371/journal.pone.0119103.g004
UtA-PI during the Menstrual Cycle
PLOS ONE | DOI:10.1371/journal.pone.0119103 March 5, 2015 13 / 18
inhibitory action of 17β-oestradiol on smooth muscle contractility [34,35] favour the rise in
UtA-PI.
Other important molecules, acting independently or under the effect of sex steroids, may
contribute to the circulatory changes. Prostanoids such as prostaglandin F
2α
and latanoprost
promote murine [35,36] and human [35] myometrial contractility, but their blood concentra-
tion variation during the cycle is uncertain. In addition, vasopressin and oxytocin stimulate
uterine contraction via myometrial vasopressin V
1a
and oxytocin receptors [37]. Near the end
of the cycle, although circulating at a lower concentration [38], vasopressin exerts a stronger ef-
fect than oxytocin [37]. Therefore, although the known actions of these compounds on the
myometrium and its perfusion are appealing, their role during the cycle remains to
be established.
Effect of parity and age on uterine flow impedance
In the current study, in non-pregnant women, the UtA-PI early and late in the cycle was signif-
icantly lower in parous women than in nulliparous women. This point has not been examined
in any known reports previously.
Fig 5. Observed (points) and estimated 5
th
,50
th
, and 95
th
percentile regression curves of the pulsatility index during the menstrual cycle for each
combination of age and parity groups. Nulliparous and parous women are presented in the first and second rows, respectively. The age group increases
from the left to right columns.
doi:10.1371/journal.pone.0119103.g005
UtA-PI during the Menstrual Cycle
PLOS ONE | DOI:10.1371/journal.pone.0119103 March 5, 2015 14 / 18
UtA-PI reduction is important because it is accompanied by improved myometrium perfu-
sion, which provides local benefits. Indeed, it has been suggested that impaired uterine perfu-
sion is a cause for unexplained infertility [39] and is reportedly a predictive indicator for the
implantation and pregnancy outcomes [4042]. Moreover, upon pregnancy establishment,
parous women appear to have improved perfusion. In fact, as early as the first trimester, parous
women exhibited lower UtA-PI and total peripheral resistance compared with those in nullipa-
rous women [43], a finding that was also described in twin pregnancies compared between par-
ous and nulliparous women [44]. Furthermore, all reports indicate that parous women have a
lower prevalence of protodiastolic notching [45,46], a feature whose persistence is associated
with a poor prognosis [5].
The enhanced perfusion in parous women likely results from vascular structural features
that persist after the first pregnancy. Shortly after implantation, the spiral arteries undergo re-
markable structural remodelling, which is necessary to accommodate the increased uteropla-
cental perfusion [47]. At the end of pregnancy, these largely regress, but not entirely; in
contrast to nulliparous women, spiral artery internal elastic lamina duplication or fragmenta-
tion has been observed at the endometrial/myometrial junction of parous women [48]. Such
permanent structural changes endow spiral arteries with reduced impedance that supports the
parity-related UtA-PI reduction here reported.
Similar to parous women, the UtA-PI decreased at the extremes of the cycle in older women
when compared with younger women. Interestingly, uterine stripes from aged non-pregnant
women exhibited reduced contractility either spontaneously or upon exposure to oxytocin
[49], suggesting that reduced uterine muscular tone underlies the lessened UtA impedance.
The cause for this sluggish response in unknown but may be consequent to an age-related
change in local regulation. For example, in the pregnant uterus, the UtA-PI shows a general de-
creasing trend starting at the first trimester [1,2,4]; yet, when the UtA is measured at specific
pregnancy time-points, a slight age-related increase may be observed [50,51]. Degenerative
changes in the UtA wall, present even before menopause [52], or other local factors are the like-
ly contributors to this particular observation.
Therefore, both age and parity similarly affect the UtA-PI of non-pregnant women during
the NMC. Interestingly, the downward trend favours perfusion, which appears to bear repro-
ductive benefits. Infants born to parous women tend to have increased birth weight [43], while
older pregnant women tend to have increased placental weights [53], but the significance of
these trends remains undefined.
Study limitations and future research
(1) The study was conducted in a sample of healthy women. (2) Further studies are necessary
to assess abnormal uterine artery PI as a diagnostic or prognostic tool of reproductive disorders
as the ovulation day was not identified, and the endometrial structure was not examined. (3)
Our data were collected by a single, experienced operator, which could compromise the exter-
nal validity of his results. Because the usefulness of a screening test depends not only on its pre-
dictive ability but also on its reproducibility, future studies are needed to demonstrate the
usefulness of these reference ranges, as well as their applicability.
Conclusions
This cross-sectional study employing a large set of women evidences a clear decrement in the
UtA impedance during the middle of the menstrual cycle compared with its extremities. For
unknown reasons, age and parity do not change this trend; they instead flatten the extremes
UtA-PI during the Menstrual Cycle
PLOS ONE | DOI:10.1371/journal.pone.0119103 March 5, 2015 15 / 18
while leaving the mid-cycle unchanged, suggesting that local mechanisms regulate an adequate
uterine perfusion in preparation for implantation.
To the well-known cyclic structural features occurring in the uterus, the current study adds
another cyclic circulatory event. The elucidation of the mechanisms underlying these changes,
apart from providing new insights into the fascinating implantation process, may improve pre-
diction of reproductive and pregnancy disorders, thus enhancing the importance of
UtA assessment.
Supporting Information
S1 Table. STROBE Statementchecklist of items that should be included in reports of ob-
servational studies.
(DOCX)
Acknowledgments
We thank the staff at the Department of Gynaecology of Centro Hospitalar do Porto for their
kind contribution to this work.
Author Contributions
Conceived and designed the experiments: LG-M FM. Performed the experiments: LG-M HA.
Analyzed the data: LG-M RG SC LM ES HA. Contributed reagents/materials/analysis tools:
LG-M JS. Wrote the paper: LG-M HA FM SC. Critical revision of the manuscript: JS SC LM
ES.
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UtA-PI during the Menstrual Cycle
PLOS ONE | DOI:10.1371/journal.pone.0119103 March 5, 2015 18 / 18
... The UAs provide most of the perfusion of the uterus; therefore, assessment of their vascular properties is expected to provide important information on the uterine blood supply and its ability to fulfil its essential role in human reproduction. The non-invasive and easy-to-use Doppler ultrasound equipment has become a mainstay in the assessment of such properties [21][22][23]. Using Doppler ultrasound, different impedance parameters can be estimated. ...
... Of these, PI has been given more importance as it seems to more accurately describe the blood velocity waveform. The reference ranges for the PI values of UAs during menstrual cycles in healthy patients were examined in different studies [21][22][23]. The relationship between menstrual pain and PI values of UAs during different phases of the menstrual cycle in healthy patients and those with PD was also examined in other studies [8,24,25]. ...
... The PI of UAs detected via ultrasound Doppler flowmetry measurement has gained more importance as it seems to more accurately describe the blood velocity waveform [22]. The PI values of the UAs are dependent on age and number of births; there were no significant differences between IG and CG members in these data in the demographic analysis [23]. ...
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Background: Primary dysmenorrhea (PD) is one of the most common diseases in women of reproductive age. Our aim was to examine whether a twice-weekly thirty-minute exercise intervention could result in a difference in the pulsatility index (PI) of the uterine arteries (UAs) and level of menstrual pain in patients with PD. Methods: In our prospective observational trial, the observation period included one spontaneous menstrual cycle and the consecutive time of the next menstruation of all participants, aged 18–44, with no extensive sports experience. In total, 73 volunteers were enrolled: 38 persons in the intervention group (IG) and 35 in the control group (CG). The intervention program was accompanied by music, performed in groups under the supervision of a qualified instructor in Hungary. The primary outcome was the difference between the IG and CG regarding the PI values of UAs at the 1st and the 2nd ultrasound (US) Doppler flowmetry. The secondary outcome was the difference between the IG and CG regarding the PI of UAs and menstrual pain measured by using the Numeric Rating Scale and adherence to the intervention. Statistical tests such as an independent-samples t-test, chi-square test, Mann–Whitney test and analysis of covariance (ANCOVA) were used during the analyses. Results: Examining the mean of the PI of UAs in the IG and the CG at the 1st and the 2nd US measurement, a significant difference was found in the change in the measured value (Z = −2.545; p = 0.011). The IG showed a significantly higher increase in the mean of the PI of UAs (Median = 0.825) than the CG (Median = 0.130). The difference in the PI of the UAs of the IG and the CG is not related to the level of pain in any group (p = 0.336) and not related to the whole sample (p = 0.354); furthermore, the level of pain did not significantly differ between the two groups. Conclusions: Our study is the first to document the significant effects of mild-to-moderate exercise training on the change in the PI of the UAs in individuals with PD. The IG had a reduced blood flow due to circulatory redistribution after exercise. The level of menstrual pain of primary dysmenorrhea patients is independent of the level of blood circulation regarding the PI of the UAs. Randomized controlled studies with more participants and a longer research period are needed to confirm our findings regarding the association between regular exercise and the PI of UAs. The study was registered at clinicaltrials.gov: NCT04618172.
... It is known that during luteal phase, which coincides with the implantation process, the uterine artery's PI gradually decreases. Therefore, it has been suggested that uterine artery PI assessment during the mid-luteal phase of spontaneous cycles be used to identify individuals with recurrent pregnancy loss connected with poor uterine circulation [7] . ...
... PI of uterine arteries is recognized to gradually decline during the crucial luteal phase, which has a crucial role in the implantation process [7] . Ideal uterine receptivity seems to be associated with a mean PI value ranging between 2 and 3. A notable decline in implantation and pregnancy rates is observed when the PI surpasses 3 or 4 or when diastolic flow is absent in Doppler waveform [10] . ...
... Uterine artery provides most of the blood supply of uterus and assessment of its vascular properties are expected to provide information about the ability of uterus to allow implantation of the fertilized ovum and pregnancy progression. 10 For such assessment, Doppler ultrasound is the investigation of choice, and it is noninvasive and easy to use equipment. 10 Moreover, uterine artery blood flow can be expressed by pulsatility index (PI) and resistance index (RI). ...
... 10 For such assessment, Doppler ultrasound is the investigation of choice, and it is noninvasive and easy to use equipment. 10 Moreover, uterine artery blood flow can be expressed by pulsatility index (PI) and resistance index (RI). 11 In a normal cycle, there is a higher early and late uterine artery PI with lower levels during the mid-cycle or luteal phase. ...
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Background and objectives: Infertility is inability to conceive after one year of regular unprotected intercourse. Unexplained infertility is present if the basic fertility investigations are normal. The objective of this study is to investigate the use of uterine artery blood flow as a cause of unexplained infertility (using pulsatility index, resistance index) and compare them to fertile women. Methods: A prospective cohort study was performed on 70 patients (35 fertile and 35 with unexplained infertility patients) in Sulaymaniyah Maternity Teaching Hospital, Kurdistan Region, Iraq, during October 2016 to December 2017. Transvaginal color Doppler ultrasound was done in the mid luteal phase (day 21 - 24) for uterine artery by using pulsatility index and resistance index. Results: The age of the patients ranged from 20 - 39 years. The uterine artery pulsatility index was significantly higher in the unexplained infertile women (mean ± SD = 2.78 ± 0.615) than fertile women (mean ± SD = 2.42 ± 0.325). The uterine artery blood flow resistance index was significantly higher in unexplained infertile group (mean ± SD = 0.899 ± 0.066) than fertile women (mean ± SD = 0.83 ± 0.054). Conclusions: Unexplained infertility is associated with decreased uterine artery blood flow and increase uterine artery resistance (pulsatility index and resistance index) when compared with fertile women.
... Low PI of the UtA and endometrial flow have been demonstrated to be linked with higher frequencies of successful implantation. ~ 106 ~ This finding provides more evidence that enhanced local blood flow promotes the successful establishment of apregnancy [7,8] . The purpose of this work was to assess the role of UtA Doppler indices in the second half of stimulated cycle as predicator of early pregnancy occurrence. ...
... The UAs are mainly responsible for the blood supply of the uterus [47]. The pulsatility index (PI) of UAs detected via ultrasound Doppler flowmetry measurements has become more important, as it seems to more accurately describe the blood velocity waveform [48]. Our previous research was the first in the literature to date to investigate the effect of exercise intervention on UA PI values in PD individuals [22]. ...
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Background and Objective: Primary dysmenorrhea (PD) is one of the most common clinical disorders in women of reproductive age. Our aim was to examine whether a twice-weekly thirty-minute Aviva exercise intervention could result in improvements in pain level and body awareness in patients with PD. Materials and Methods: In our prospective observational trial, the observation period included two consecutive menstrual cycles and the period of the next menstrual bleeding. The first menstrual bleeding period was the first measurement time (T1), the second was the second measurement time (T2), and the third was the third measurement time (T3) in a total of 78 volunteers. The primary endpoint was the change in the level of menstrual pain according to the Numeric Rating Scale (NRS) questionnaire between the intervention group (IG) and the control group (CG) at T1, T2, and T3. In this study, the secondary outcomes were the differences between the IG and CG regarding the different subscales of the Hungarian version of the Body Awareness Questionnaire (BAQ-H) at T1, T2, and T3; the Borg scale results of the IG; and adherence to the intervention. Statistical tests such as independent-sample t-tests, chi-square tests, Pearson’s linear correlation coefficient, and repeated-measure ANCOVA were used for the analyses. Results: In total, 78 volunteers were enrolled: 40 persons in the IG and 38 in the CG. There was a significant change in the level of menstruation pain according to the NRS questionnaire between the IG and CG (p < 0.001). There was no significant difference between the IG and CG regarding the different subscales of the BAQ-H. Only in the case of the “Note responses or changes in body process” subscale of the BAQ-H was there a trend-like effect from the Aviva exercises (p = 0.086). Conclusions: The Aviva exercise could contribute to pain relief from PD. Regarding body awareness, no significant difference was found between the two groups. Due to the short detection period and prospective observational design, our results are preliminary and need to be confirmed in larger clinical trials.
... In addition, the pulsatility index of uterine artery (UtA-PI) is an indicator of vascular resistance and blood flow [38,39]. A cross-sectional study of 1821 women showed significant increases of UtA-PI and reduction of uterine perfusion in nulliparous women, which was related to permanent uterine artery structure changes after women gave their first birth [40,41]. Higher blood impedance and UtA-PI are related to fewer uteroplacental perfusion and blood flow, leading to insufficient nutrients and oxygen supply to fetus, which was the underlying mechanism of intrauterine growth restriction, LBW and SGA [39,42]. ...
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Background: Nulliparity is considered to be a risk factor of preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA). With the new two-child policy launched in 2016, more Chinese women have delivered their 2nd baby. Yet few studies have assessed the impact of parity on adverse birth outcomes in China. This study aimed to examine the association between parity and risks of PTB, LBW and SGA in a Chinese population. The combined effects of maternal age and parity on adverse birth outcomes were also assessed. Methods: This retrospective study included all non-malformed live births born during January 1, 2014 and December 31, 2018 in Chengdu, China. A total of 746,410 eligible live singletons with complete information were included in the analysis. Parity was classified into nulliparity (i.e. has never delivered a newborn before) and multiparity (i.e. has delivered at least one newborn before). Log-binomial regression analyses were applied to evaluate the association between parity and PTB, LBW and SGA. We further divided maternal age into different groups (< 25 years, 25-29 years, 30-34 years and ≥ 35 years) to assess the combined effects of maternal age and parity on adverse birth outcomes. Results: Multiparity was associated with reduced risks of PTB (aRR = 0.91, 95% CI: 0.89-0.93), LBW (aRR = 0.74, 95% CI: 0.72-0.77) and SGA (aRR = 0.67, 95% CI: 0.66-0.69) compared with nulliparity. In each age group, we observed that multiparity was associated with lower risks of adverse birth outcomes. Compared to nulliparous women aged between 25 and 29 years, women aged ≥35 years had greater risks of PTB and LBW, regardless of their parity status. In contrast, multiparous women aged ≥35 years (aRR = 0.73, 95% CI: 0.70-0.77) and those aged < 25 years (aRR = 0.88, 95% CI: 0.84-0.93) were at lower risk of SGA compared with nulliparous women aged between 25 and 29 years. Conclusion: Multiparity was associated with lower risks of all adverse birth outcomes. Special attention should be paid to nulliparous mothers and those with advanced age during antenatal care, in order to reduce the risks of adverse birth outcomes.
... We attributed this delay to many factors such as maternal age, history of dilation and curettage (D&C), previous uterine surgical history and previous CD. [26,27] In the study, 1 limitation is that the data were retrospectively analyzed in which selection bias may be not totally avoided. Doctor choose different hemostasis methods according to the amount of bleeding, the bleeding speed and the specific bleeding location of the patient during the operation. ...
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This retrospective study was designed to explore the recovery of uterine and ovarian function in patients with complete placenta previa (PP) after caesarean delivery (CD). 136 complete placenta previa patients (group completed placenta previa) and 140 patients without complete PP (group non-PP, control group) were included in this study from Jan 2016 to Dec 2018. Subgroup analysis of patients with complete PP was made to determine the impact of different hemostatic methods used during CD on the recovery of uterine function. There were no statistically significant differences between the 2 groups in postpartum menstrual cycle changes, ovarian hormone, and uterine vascular supply as measured by pulsatility index and systolic/diastolic ratio (P > .05). However, the group with complete PP had a reduced endometrial thickness (0.47 ± 0.11 vs 0.50 ± 0.12, P < .001), a lower uterine resistance index at 42nd days (0.84 ± 0.03 vs 0.90 ± 0.03, P < .001), and a delayed resumption menstruation (7.07 ± 2.61 vs 5.31 ± 2.16, P < .001) when compared with control group. Subgroup analysis showed that RI index of all subgroups in completed PP group was lower, endometrial thickness was thinner and the time to menstrual recovery was longer than that of non-PP group. In conclusion, the endometrial thickness and blood supply at 42nd days, not ovarian function, maybe affected after CD in patients with complete PP.
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A unique immunological condition, pregnancy ensures fetus from maternal rejection, allows adequate fetal development, and protects against microorganisms. Infections during pregnancy may lead to devastating consequences for pregnant women and fetuses, resulting in the mother's death, miscarriage, premature childbirth, or neonate with congenital infection and severe diseases and defects. Epigenetic (heritable changes in gene expression) mechanisms like DNA methylation, chromatin modification, and gene expression modulation during gestation are linked with the number of defects in the fetus and adolescents. The feto-maternal crosstalk for fetal survival during the entire gestational stages are tightly regulated by various cellular pathways, including epigenetic mechanisms that respond to both internal as well outer environmental factors, which can influence the fetal development across the gestational stages. Due to the intense physiological, endocrinological, and immunological changes, pregnant women are more susceptible to bacterial, viral, parasitic, and fungal infections than the general population. Microbial infections with viruses (LCMV, SARS-CoV, MERS-CoV, and SARS-CoV-2) and bacteria (Clostridium perfringens, Coxiella burnetii, Listeria monocytogenes, Salmonella enteritidis) further increase the risk to maternal and fetal life and developmental outcome. If the infections remain untreated, the possibility of maternal and fetal death exists. This article focused on the severity and susceptibility to infections caused by Salmonella, Listeria, LCMV, and SARS-CoV-2 during pregnancy and their impact on maternal health and the fetus. How epigenetic regulation during pregnancy plays a vital role in deciding the fetus's developmental outcome under various conditions, including infection and other stress. A better understanding of the host-pathogen interaction, the characterization of the maternal immune system, and the epigenetic regulations during pregnancy may help protect the mother and fetus from infection-mediated outcomes.
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The aim of this study was to evaluate the effect of parity (primipara vs multipara) on the histopathology of the placenta in singleton live births following in vitro fertilization. We conducted a retrospective cohort study evaluating data of all IVF resulted live births from one university affiliated hospital during 2009-2017. All patients had the placenta sent for pathological evaluation. Exclusion criteria were history of miscarriage or elective termination of pregnancy, abnormal uterine cavity findings, previous uterine surgery, in vitro maturation cycles, gestational carrier cycles, oocyte recipient cycles, preimplantation genetic diagnosis cycles, and multiple pregnancies. The outcomes measured included anatomical, inflammation, vascular malperfusion, and villous maturation placental features. A multivariate analysis was conducted to adjust the results for factors potentially associated with placental pathology features. A total of 395 live births were included in the final analysis and were allocated to the study groups according to parity: primipara (n = 273) and multipara (n = 122). After adjustment for potential confounding factors, multiparity was found to be significantly associated with delayed villous maturation (OR 4.9; 95% CI 1.2-19.8) and primiparity was significantly associated with maternal vascular malperfusion (OR 0.6; 95% CI 0.3-0.8). We showed that parity has an impact on placental histopathological changes which in turn may affect perinatal outcome.
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We aimed to compare the ovarian and uterine artery blood flow of anovulatory patients with polycystic ovary syndrome (PCOS) with those of ovulatory women throughout the menstrual cycle using color Doppler ultrasound. Seventy-one women with PCOS, who were admitted to the infertility outpatient clinic of a training and research hospital, were included in the study. The patients were divided into 2 groups as anovulatory (group 1, n = 23) and ovulatory (group 2, n = 37). Each patient was followed up throughout her menstrual cycle and included in either group 1 or group 2. Anovulatory cycles were determined by consecutive ultrasound examinations, and the progesterone value was measured in the luteal period. Eleven patients were excluded from the study because they did not continue their follow-up. The uterine and ovarian artery pulsatility and resistance indices of all patients in both groups were evaluated 3 times throughout a menstrual cycle: 7th to 10th day, 13th to 17th day, and 21st to 25th day. It was observed that the uterine artery resistances of the patients with anovulatory cycles remained relatively high throughout the menstrual cycle compared with ovulatory cycles. Both pulsatility and resistance indices of uterine and ovarian arteries were significantly higher in anovulatory cycles compared with ovulatory cycles at all evaluation times throughout the menstrual cycle (P < 0.05). Ovarian artery resistance in anovulatory patients did not significantly change during the menstrual cycle. Anovulatory patients with PCOS have higher uterine and ovarian artery resistance than ovulatory artery resistance, and the former shows a significant decrease throughout the cycle.
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The objective of this work was to compare Doppler flows pulsatility index (PI) and resistance indexes (RI) of uterine and internal iliac arteries during pregnancy in low risk women and in those with stage-1 essential hypertension. From January 2010 and December 2012, a longitudinal and prospective study was carried out in 103 singleton uneventful pregnancies (72 low-risk pregnancies and 31 with stage 1 essential hypertension)at the 1(st), 2(nd) and 3(rd) trimesters. Multiple linear regression models, fitted using generalized least squares and whose errors were allowed to be correlated and/or have unequal variances, were employed; a model for the relative differences of both arteries impedance was utilized. In both groups, uterine artery PI and RI exhibited a gestational age related decreasing trend whereas internal iliac artery PI and RI increased. The model testing the hemodynamic adaptation in women with and without hypertension showed similar trend. Irrespective of blood pressure conditions, the internal iliac artery resistance pattern contrasts with the capacitance pattern of its immediate pelvic division, suggesting a pregnancy-related regulatory mechanism in the pelvic circulation.
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The uterine artery Doppler has potentials for screening for complications of impaired placentation. This study examines the indices of uterine artery impedance at 22-23 weeks gestation and their relationship with maternal age and parity. Uterine artery colour imaging and pulsed wave Doppler ultrasound was conducted between 22nd and 23rd weeks in 430 pregnancies. The pregnancies were classified into 2 groups: normal and abnormal outcomes. The indices of impedance recorded were pulsatility index, resistance index and the systolic/diastolic ratio. Relevant obstetric information was retrieved from the antenatal records. The student t- test and Pearson's product moment were used for statistical analysis. Fifty eight (13.5%) out of 430 pregnancies had complications of impaired placentation, mainly intrauterine growth restriction and preterm birth (24 or 41.4% each). The indices in normal pregnancies were similar to presently used values. There was no statistically significant difference in the 2 pregnancies groups. The Pulsatility Index (PI) in the right uterine artery was statistically different from the left (t-test 32.8, p < 0.05). Maternal age and parity demonstrate statistically significant positive correlation with PI (r =0.9, p < 0.05; r =0.8, p < 0.05). The indices in normal pregnancies were similar to values from previous studies. The values are however not significantly different in pregnancies with abnormal outcome.
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Objective: To evaluate uterine artery blood flow and subendometrial blood flow in women with unexplained recurrent miscarriage (RM) compared to normal fertile women. Design: Case control study. Settings: Departments of Obstetrics and Gynaecology, Cairo university and, Beni Souif University, Cairo, Egypt. Patients and methods: Women were divided into two groups: those with history of unexplained recurrent miscarriage (study group, no. = 40), and those with no history of miscarriage and at least one child born at term (control group, no. = 40), transvaginal 3D power Doppler ultrasonography was performed to all patients in the second phase of non-pregnant unstimulated cycle to detect uterine artery pulsatility index (UAPI) and subendometrial area to detect subendometrial blood flow presented by the indices vascularisation index (VI), flow index (FI), and vascular flow index (VFI). The indices between the two groups were compared. Results: UAPI was significantly higher in the study group (p = 0.000), on the other hand VI (p = 0.000), FI (p = 0.000), VFI (p = 0.000) were significantly lower in the study group. A significant positive correlation was found between UAPI and recurrent miscarriage in the study group (r = 0.8, p = 0.00), whereas a significant negative correlation was found between VI (r = −0.56, p = 0.00), and FI (r = −0.79, p = 0.00) and recurrent miscarriage in the study group, but no significant correlation was found between endometrial thickness and endometrial volume between the two groups. However the application of binary logistic regression analysis model found that adding variables has not significantly increased the ability to predict the occurrence of miscarriage. Conclusion: The presence of good uterine and endometrial blood flow is an important prerequisite for successful implantation and continuation of pregnancy as shown by higher uterine artery blood flow resistance and lower endometrial blood flow in recurrent miscarriage cases and those patients with unexplained RPL may have abnormalities in the uterine and endometrial blood flow. Despite these findings we could not find any cut off values that could predict the occurrence of miscarriage which may be attributed to small sample size and short period of follow up so larger prospective studies are needed aiming to confirm such results and reaching values that can accurately predict the occurrence of miscarriage.
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A method is developed to calculate the required number of subjects k in a reliability study, where reliability is measured using the intraclass correlation ρ. The method is based on a functional approximation to earlier exact results. The approximation is shown to have excellent agreement with the exact results and one can use it easily without intensive numerical computation. Optimal design configurations are also discussed; for reliability values of about 40 per cent or higher, use of two or three observations per subject will minimize the total number of observations required. © 1998 John Wiley & Sons, Ltd.
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The assessment of the fetal size based on ultrasound biometry is important for proper pregnancy management. The means for evaluations of these measurements represent age-related reference intervals and centile charts which are used to detect the extreme values, possibly indicating pathology. The key features concerning the design of studies used for the construction of these intervals are given. The aim of this paper is to review possible statistical approaches, pointing out the methodology, goodness of fit, advantages and limitations.
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The aim of the study was to construct gestational age based reference ranges for the uterine artery (UtA) mean pulsatility (PI) and resistance indexes (RI) from 6 -10 weeks of pregnancy. A prospective, cross-sectional, observational study was carried out in 312 singleton pregnancies with gestational age ranging from 6 to 10 weeks. UtAs were examined transvaginally by color and pulsed Doppler imaging, and the mean of the right and left values of PI and RI, as well as the presence or absence of a bilateral protodiastolic notch, were recorded. UtA-PI and UtA-RI reference percentiles were derived through time-conditional quantile regression. The authors derived the 10(th) , the 50(th) and the 90(th) reference percentile curves, and correspondent 95% confidence intervals, for the evolution of the uterine artery mean pulsatility and resistance indexes from week 6 to week 10 of gestation. The prevalence of bilateral notching absence was 8.1% (6/74) at 6 weeks and 28.8% (15/52) at 10 weeks. The authors present evidence of progressive reduction of uterine vascular impedance in a very early stage of pregnancy and provide new, averaged, UtA-PI and UtA-RI charts between 6-10 weeks of gestation. This article is protected by copyright. All rights reserved.
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To investigate whether success rates of IVF/ICSI could be predicted by using the Color Doppler technique by measuring the uterine artery and arcuate artery pulsatility (PI), resistance (RI), and velocity (Vs) indices on the day of hCG injection. This was a prospective observational study at the St Lazar Hospital, Skopje; 106 patients with an indication for IVF or ICSI according to departmental protocol underwent controlled ovarian hyperstimulation followed by IVF/ICSI and embryo transfer. Using Color Doppler in the two-dimensional (2D) mode, flow velocity waveforms were obtained from the ascending main branch of the uterine artery on the right and left sides of the cervix in a longitudinal plane and arcuate arteries, before they entered the uterus. The PI, RI and peak systolic velocity (PSV) of the uterine arteries and arcuate arteries were calculated electronically when similar consecutive waveforms of good quality were obtained and results were compared between patients who conceived and those who did not. In total, 106 patients, aged 24-42 years were included in the study. The patients were divided into two groups according to successful outcome, defined as pregnancy and failure of implantation, where no pregnancy was detected. A total of 40 pregnancies resulted; a crude pregnancy rate was 40/106 (37.7%). There were no significant differences between either group in patients' age, type and duration of infertility; basal levels of FSH, LH and E2; number of gonadotropin ampoules used for ovulation induction; number of retrieved oocytes and number of transferred embryos. No cycle was canceled after initiation of gonadotropin stimulation. In our results, there were statistically significant lower mean uterine artery PI and RI in the pregnant group than in the non-pregnant group (P < 0.05). Arcuate artery PI value was lower in the pregnant group than in the non-pregnant group, but this did not reach statistical significance. Peak systolic velocity (Vs) values in both the mean uterine artery and arcuate artery were higher in the pregnant group than in the non-pregnant group; however, the difference was not statistically significant. Vascular impedance was calculated with PI, RI, and Vs values, among which PI was found to be the most important. Optimal uterine receptivity can be accomplished by reduced vascular resistance and increased blood flow, which will improve pregnancy success. We suggest the use of transvaginal color Doppler ultrasonography to measure the blood flow in uterine arteries and arcuate arteries before hCG in IVF cycles.
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We investigated the effect of uterine artery blood flow on recurrent pregnancy loss. One hundred and twelve patients admitted to our clinic were included in the prospective study. The study group consisted of 28 cases with a history of three miscarriages before the 20th gestational week, and the control group consisted of cases with at least one prior live birth without any history of miscarriage or poor obstetric outcome. The mean pulsatility index (PI) , resistance index (RI) and systolic/diastolic ratio (S/D ratio) values of the uterine artery were measured between the 18th and 23rd days of the menstrual cycle via transvaginal Doppler ultrasonography. No statistically significant difference could be detected regarding uterine artery PI (p=0.703), RI (p=0.333), and S/D (p=0.403) values between the study group and the control group (p>0.05). In order to clearly determine etiologic causes of recurrent pregnancy loss, new randomized and controlled clinical trials with large patient populations are needed.
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The uterine artery Doppler waveform has been extensively investigated, though its widespread clinical use as a predictor of adverse pregnancy outcome remains under debate. The determinants of the waveform have classically been ascribed to transformation of the spiral arteries and the development of a low resistance uteroplacental circulation, failure of which predisposes to pre-eclampsia, fetal growth restriction and other adverse outcomes. It has become increasingly evident that although spiral artery transformation determines in some part the characteristics of the Doppler waveform, factors pertaining to maternal vascular and endothelial function are also important.
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Objective To study in nonpregnant women myometrial actions of vasopressin and oxytocin and the involvement in these effects of specific uterine receptors. Subjects Twenty-eight women undergoing hysterectomy for benign gynaecological disorders. Interventions Intrauterine pressure recordings. Intravenous bolus injections of 10 pmol/kg body weight of vasopressin and oxytocin. Repeated blood sampling for measurement of vasopressin and oxytocin concentrations in plasma. Recording of effects of vasopressin and oxytocin on isolated myometrium. Estimation of myometrial concentrations of vasopressin V1a and oxytocin receptors. Measurement of plasma oestradiol and progesterone. Main outcome measures Vasopressin- and oxytocin-induced increases of the area under the in vivo recording curve over 10 minutes and EC50 concentrations of dose-responses in vitro. Concentrations of vasopressin V1a and oxytocin receptors. Results Vasopressin was on average four times more potent than oxytocin in vivo. The effect of vasopressin premenstrually was more pronounced than in women under oestrogen influence only (proliferative phase-hyperproliferation; P= 0.02), and tended to be more marked than in those in the luteal phase (P = 0.07). No significant variation in oxytocin response with the hormonal state was observed. EC50 concentrations of vasopressin were more than 20 times lower than those of oxytocin. The median concentration of the vasopressin V1a receptor was 208 (range 139–343) fmol/mg protein and that of the oxytocin receptor 49 (38–87) fmol/mg protein. Vasopressin receptor concentrations and in vivo effects of this peptide did not correlate, whereas for those of oxytocin a significant correlation was observed (P= 0.02). Conclusion The high potency of vasopressin in nonpregnant women, particularly premenstrually, firmly supports an aetiological importance of this peptide in the uterine hyperactivity of primary dysmenorrhoea. Oxytocin seems to be less important in this condition in view of its much smaller potency and the absence of increase in effect premenstrually. Vasopressin appears to influence both the oxytocin and the vasopressin Vla receptor sites in the uterus, whereas oxytocin acts specifically on its own receptor.