Physiology International 107 (2020) 4, 479–490

DOI: 10.1556/2060.2020.00041

Evaluation of oxidative/nitrative stress and uterine

artery pulsatility index in early pregnancy
p

PENYIGE1†z, Z. MEZEI1, B. SARAI-SZAB
D. GERSZI1,2 z , A.

1, R. BENKO
O } 1,


B. BANYAI 1 2
, S. VARB
, C. DEMENDI , E. UJVARI 2

IRO
and
2

E.M. HORVATH 1

1
Department of Physiology, Semmelweis University, Budapest, Hungary
2
Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary

Received: January 14, 2020 • Accepted: October 05, 2020

Published online: January 06, 2021
© 2020 The Author(s)

ABSTRACT
Introduction: Increased oxidative/nitrative stress is characteristic not only in pathologic, but also in
healthy pregnancy. High uterine artery pulsatility index (UtAPI) at the end of the first trimester is
associated with altered placentation and elevated risk for adverse pregnancy outcomes. We aimed to
examine the relationship of systemic oxidative/nitrative stress and uterine artery pulsatility index in the
first trimester and their correlation to pregnancy outcomes. Material and methods: Healthy pregnant
women were recruited at 12–13th gestational week ultrasound examination; UtAPI was determined by
color Doppler ultrasound. Patients were divided into high (UtAPI ≥ 2.3) (n 5 30) and low (n 5 31)
resistance groups, and pregnancies were followed until labor. Systemic oxidative/nitrative stress was
estimated by measuring total peroxide level, total antioxidant capacity and nitrotyrosine level. Results:
Plasma total peroxide level was significantly lower (2,510 ± 39 mM vs. 2,285 ± 59 mM), total antioxidant
capacity was higher (781 ± 16 mM CRE vs. 822 ± 13 mM CRE) in the high UtAPI group, which were
accompanied by lower birth weight (3,317 ± 64 vs. 3,517 ± 77 g, P < 0.05). Plasma total peroxide level
showed a negative correlation (by Pearson) to UtAPI (P < 0.01) and positive correlation to birth weight
(P < 0.05). Conclusions: According to our results, lower systemic oxidative stress showed correlation
with high UtAPI measured between the 12–13th weeks of gestation. We also found significant

p
Corresponding author: Department of Obstetrics and Gynecology, Semmelweis University, 78/A Ull}€ oi u

t, H-
1082 Budapest, Hungary. Tel.: þ36 1 459 1500; fax: þ 36 1 333 4934. E-mail: dora.gerszi@gmail.com
z

D
ora Gerszi and Aron Penyige contributed equally to this work.
y
Present address: Department of Obstetrics and Gynecology, Saint Margaret Hospital, 132. B
ecsi Str., H-1032
Budapest, Hungary.

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480 Physiology International 107 (2020) 4, 479–490

differences in the birth weight of healthy newborns; therefore it is worth examining this relationship in
pathological pregnancies.

KEYWORDS
uterine artery pulsatility index (UtAPI), pregnancy, birth weight, oxidative stress, nitrative stress

INTRODUCTION
The decrease in uterine artery pulsatility index (UtAPI) on the border of the first and second
trimester is a well-established clinical marker of physiological placentation. This decline is due to
the development of the specialized uteroplacental vasculature: expanded, high-flow, low-resis-
tance vessels to satisfy the growing nutritional and oxygen requirements of the fetus [1].
However, delay in this process might contribute to altered placentation and can be a warning
sign of later placental dysfunction.
Examination of the uterine artery’s blood flow by ultrasound Doppler method at the end of
the first trimester with the determination of pulsatility index and resistance is widely accepted in
obstetrical practice. Its predictive value was proposed in intrauterine growth restriction (IUGR)
and preeclampsia. Over 95 percentile might be pathognostic to preeclampsia [2–5]. The
simultaneous measurement of other early markers, like maternal plasma pregnancy related
plasma protein A (PAPP-A), placental growth factor (PlGF), soluble fms-like tyrosine kinase-1
(sFlt-1), etc. may increase the sensitivity and specificity of the prognosis [6–8].
In healthy pregnancy and placentation, in the first trimester, during the period of trophoblast
invasion, concentrations of reactive oxygen species (ROS) rise. At this time, placental oxygen
tension is relatively low, ca. 20 mmHg. This low oxygen tension is necessary for producing the
required level of angiogenic factors such as VEGF, PlGF and HIF resulting in placental
angiogenesis and normal cell and tissue proliferation. When the maternal side of placental
circulation has developed, both oxygen tension and ROS level get tripled. The placenta adapts to
elevated oxygen tension and free radical concentration by modulating HIF-1a and increasing
cellular levels of antioxidants. In physiological adaptation this process is advantageous in respect
of fetal development and leads to a decrease in vascular resistance. In the high resistance group
this process is partially flawed and results in damaged maternal vascular network of the placenta,
which may be the consequence of lower oxygen tension and the elevation of ROS concentration.
Oxygen- and nitrogen-derived reactive species are involved in biological pathways, where they
act as mediators; however, their overproduction leads to oxidative/nitrative stress that takes part
in the pathogenesis of numerous diseases [9, 10]. Oxidative stress increases during the course of
physiological pregnancy; however, in pathological complications, like gestational diabetes
mellitus (GDM), preeclampsia and IUGR this elevation is more pronounced both in the placenta
and in the blood plasma [11, 12]. Nitrative stress rises by the third trimester in physiological
pregnancy. In pathological conditions mentioned above, this elevation might appear earlier and
can reach higher levels [13, 14].
Our aim was to examine the relationship between systemic oxidative/nitrative stress and the
uterine artery pulsatility index (UtAPI) on the 12–13th week of healthy pregnancy, and their
correlation to pregnancy outcome and neonatal characteristics.

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MATERIALS AND METHODS

Patients
A prospective observational study was performed at the Department of Obstetrics and Gyne-
cology and the Department of Physiology, Faculty of Medicine, Semmelweis University,
Budapest, Hungary between 27 May 2016 and 12 December 2017. The study was approved by
the Scientific and Research Ethics Committee of the Hungarian Medical Research Council
(43102-2/2014/EKU (425/2014) 49768-1/2015/EKU (392/2015). Written informed consent was
obtained from all subjects.
Healthy pregnant women were invited randomly during the 12th week ultrasound
screening (transabdominal sonography) to participate in the study (12þ0–12þ6 week of
gestation). Method: A transducer should be positioned longitudinally and placed medially.
The vessel can be identified with colored Doppler. The best place for measuring uterine artery
PI and RI is 1 cm after the branching from the iliac artery. Exclusion criteria were age below
18 and over 40 years, malignant tumors, hypertension, diabetes mellitus, obesity (BMI over
30), twin pregnancy and chronic inflammatory diseases. During transabdominal ultraso-
nography examination by GE Volusion E8 (Boston, MA, USA), flowmetric measurement by
color Doppler method was performed on the uterine artery 1 cm from the branching of the
iliac artery; the pulsatility index was determined according to the equation below. Pregnant
women were divided into two groups based on the mean of the right and left artery pulsatility
indices; normal UtAPIgroup (termed in the text as low UtAPI < 2.3), (n 5 31) and high
UtAPIgroup (n 5 30).
PI ¼ ðpeak systolic velocityðPSVÞ
 end diastolic velocityðEDVÞÞ=time averaged velocityðTAVÞ
Inclusion/admission method was: when recruiting a high UtAPI patient, we also recruited an
age- and BMI-fitted low UtAPI patient. Cut off point was set to 90% percentile of the average of
the European population [15]. The study size was estimated according to earlier measurements
of plasma total peroxide level in healthy women. With a pooled standard deviation of 269 mM, a
200-mM difference by unpaired Student’s t-test may be detected with a 5 0.05 and a power of
0.8 by a sample size of 29 per group [16].

Study protocol
At the 12th week, following the ultrasound examination, participants filled in a questionnaire
about their family, internal medicines and obstetric anamnesis, and blood samples were taken.
From these samples routine laboratory tests (total blood cell count, CRP, hepatic and renal
function) were performed; furthermore serum, plasma and mononuclear leukocyte fractions
were isolated for measuring oxidative/nitrative stress laboratory parameters. Circulating
mononuclear cells were isolated from blood samples by gradient centrifugation using Histo-
paque-1077 according to the users’ manual (Sigma-Aldrich, St. Louis, MO, USA). Methanol-
fixed smears were made from the cell suspension and stored at 4 8C until further processing.
Pregnancies were followed until birth in order to note pregnancy complications, labor cir-
cumstances, and neonates’ anthropometric data. We were not able to register labor circum-
stances in six cases (low UtAPIgroup: 4, high UtAPIgroup: 2).

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Determination of oxidative/nitrative stress related parameters

Total plasma peroxide (PRX) concentration, reflecting systemic oxidative stress, was deter-
mined from plasma samples by colorimetric method using OxyStat assay (Biomedica, Wien,
Austria). Plasma total antioxidant capacity was measured from plasma samples by a
commercially available assay kit (OxiSelectÔ Total Antioxidant Capacity (TAC) Assay Kit,
Cell Biolabs Inc., San Diego, CA, USA). Nitrative stress was characterized by measuring serum
levels of 3-nitrotyrosine (NT) using competitive ELISA based on HRP-conjugated anti-3NT
antibody (OxiSelectÔ Nitrotyrosine Elisa Kit, Cell Biolabs Inc., San Diego, CA, USA). To
examine intracellular nitrative stress, immunohistochemistry was performed on methanol-
fixed leukocyte smears with anti-nitrotyrosine rabbit polyclonal antibody (Abcam, Cambridge,
UK) (1:80, 4 8C, overnight). Aspecific labeling was avoided by incubating the smears in 15%
normal horse serum for 1 h at room temperature. Secondary labeling was achieved by
horseradish peroxidase-conjugated horse anti-rabbit immunoglobulin (Vector Laboratories,
Burlingame, CA, USA) (30 min, room temperature). Brown colored diaminobenzidine (6 min,
room temperature, brown color) was used for visualizing the labeling (Vector Laboratories).
Smears were counter-stained with blue colored hematoxylin (Vector Laboratories). Images of
five representative microscopic fields of each smear were taken with 200x magnification
(Zeiss-Imager.A1 light microscope, 20x/0.45 objective, AxioCam MRc5 camera, AxioVision –
Rel. 4.8 software; Carl Zeiss Microscopy GmbH, Jena, Germany). The ratio of the positively
stained cellular area compared to the total cellular area was determined by a blinded exper-
imenter using ImageJ software (MBFImageJ, NIH, Bethesda, MA, USA); at least 300 cells were
evaluated on each smear. Lower number of data in measured parameters was due to samples
inadequate for analysis (hemolyzed plasma, serum or low cell count on leukocyte smears).
In order to examine the possible additive value of PRX in the correlation between UtAPI and
birth weight, a new parameter was calculated, namely the quotient of UtAPI and plasma
PRX:PIPX 5 UtAPI/PRXp 100.

Statistical analysis
Normal distribution data are presented as mean ± SEM. In the case of non-Gaussian distri-
bution, logarithmic transformation was implemented (TAC) and data are presented as median
[IQR]. Statistical significance between the two study groups was determined by the two-tailed
unpaired Student’s t-test. Nominal variables were tested by Chi-square test. Correlations be-
tween variables were estimated using Pearson’s correlation. Missing data were treated as
missing. Probability values of P < 0.05 were considered significant. For the statistical analysis
SPSS 22.0 and Graphpad Prism 6.0 softwares were used.

RESULTS
Correlation between uterine artery PI and demographic and historical parameters
Pulsatility index of the uterine artery as our grouping variable was significantly higher in the
high resistance group (Fig. 1A).
Age and BMI did not differ in the study groups. On the other hand, gravidity, parity, and the
number of miscarriages were significantly lower among women with higher UtAPI (Table 1).

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Fig. 1. Pulsatility index and oxidative stress markers. Panel A. Mean pulsatility index of the uterine artery.
(N 5 31; 30) Panel B. Plasma total peroxide levels were significantly lower in the high UtAPI group. (N 5
22; 22) Panel C. Plasma TAClevels were significantly higher in the high UtAPI group. (N 5 29; 27) Panel
D. PIPX calculated from UtAPI and PRX was significantly higher in the high PI group. (N 5 22; 22). Data
are presented as mean ± SEM, or Median [IQR]in case of TAC. p : P < 0.05, pp : P < 0.01, ppp : P < 0.001

Clinical laboratory parameters including plasma creatinine, liver enzymes, hemoglobin, CRP
and glucose levels were similar in our study groups; only LDH was significantly lower in women
with higher UtAPI (Table 1).

Correlation between uterine artery pulsatility index and pregnancy outcome

The rate of Cesarean section was also similar in the two groups. All newborns were in the
normal body parameter range; however, newborns of the high UtAPI group had significantly
lower birth weight and chest circumference than those of the low UtAPI group. There was no
difference in gestational weeks at labor; therefore these differences were not due to earlier de-
livery (Table 1).

Correlation between uterine artery PI and oxidative/nitrative stress

Plasma total peroxide level, which refers to systemic oxidative stress, was significantly lower in
the high UtAPI group than in the low UtAPIgroup (Fig. 1B), whereas total antioxidant capacity
was significantly higher in the high UtAPI group (Fig. 1C). PIPX calculated from UtAPI and
PRX (PIPX: UtAPI/PRXp 100) was significantly higher in the high UtAPIgroup (Fig. 1D). On the
other hand, serum and mononuclear cell NT levels were similar in the low and high UtAPI
groups (Fig. 2A and B).

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Table 1. Clinical and anthropometric data of women and their offspring. The two study groups were
matched according to their age and BMI. On the other hand, gravidity, parity and the number of previous
miscarriages were lower in the high UtAPI group. There were no significant difference between the two
groups in their major clinical laboratory parameters, however LDH level was significantly lower in the high
UtAPI group. Development of preeclampsia was not observed among the study subjects. The occurrence of
GDM and Cesarean section was similar in the two groups. The newborns of the high UtAPI group had
smaller birth weight and chest circumference despite the gestational age of the mothers at labor being
similar. Data are presented as mean ± SEM, where not indicated otherwise
Variable low UtAPI (n 5 31) high UtAPI (n 5 30) Significance
Anamnestic data
Age (years) 32.00 ± 0.66 31.00 ± 0.73 ns
(min–max) (26–39) (22–38)
BMI (kg/m2) 21.60 ± 0.71 22.60 ± 0.39 ns
Gravidity 1.60 ± 0.27 0.80 ± 0.19 P < 0.05
(min–max) (0–6) (0–4)
Parity 1.00 ± 0.19 0.40 ± 0.15 P < 0.05
(min–max) (0–4) (0–4)
Miscarriages 0.50 ± 0.15 0.10 ± 0.07 P < 0.05
Clinical parameters
LDH (U/L) 152.66 ± 2.75 144.70 ± 2.47 P < 0.05
Hemoglobin (g/L) 128.73 ± 1.53 126.92 ± 1.56 ns
Hematocrite (L/L) 0.38 ± 0.00 0.37 ± 0.00 ns
Glucose (mmol/L) 4.60 ± 0.12 4.63 ± 0.14 ns
Triglycerides (mmol/L) 1.40 ± 0.10 1.45 ± 0.73 ns
HDL (mmol/L) 1.87 ± 0.05 1.77 ± 0.05 ns
LDL (mmol/L) 3.31 ± 0.13 3.30 ± 0.10 ns
Bilirubin (mmol/L) 8.34 ± 0.79 7.80 ± 0.42 ns
Creatinine (mmol/L) 47.77 ± 1.55 47.43 ± 1.25 ns
AST (U/L) 18.45 ± 0.53 18.70 ± 0.83 ns
ALT (U/L) 14.58 ± 0.88 15.77 ± 1.62 ns
gGT (U/L) 13.32 ± 0.78 13.17 ± 0.96 ns
CRP (U/L) 6.27 ± 0.70 5.99 ± 0.60 ns
ALP (U/L) 56.81 ± 2.89 53.60 ± 2.25 ns
Pregnancies’ outcome
Cesarean section (N) 13 11 ns
out of emergent fetal/maternal 1/1/2 3/2/5 ns
indication/total (N)
GDM (N) 3 3 ns
PE (N) 0 0 ns
IUGR (N) 0 0 ns
Newborns’ anthropometry
Bodyweight (g) 3,517.41 ± 77.02 3,316.79 ± 63.76 P < 0.05
Gestational week 39.80 ± 0.19 39.30 ± 0.20 ns
Chest circumference (cm) 34.41 ± 0.29 33.57 ± 0.26 P < 0.05
Head circumference (cm) 35.00 ± 0.26 34.39 ± 0.30 ns
Apgar 19 9.44 ± 0.11 9.61 ± 0.09 ns
Apgar 59 10.00 ± 0.00 10.00 ± 0.00 ns

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Fig. 2. Pulsatility index and nitrative stress markers. Panel A and B. Serum and mononuclear cell 3-
nitrotyrosine levels were similar in the study groups. (N 5 21; 28 and N 5 16; 14). Data are presented as
mean ± SEM, or Median [IQR]in case of TAC. p : P < 0.05, pp : P < 0.01, ppp : P < 0.001

Correlations between oxidative/nitrative stress, UtAPI and clinical data in the total
study cohort
In the total study cohort, plasma total peroxide level showed negative correlation to UtAPI and
positive correlation to the birth weight of the newborns (Table 2). On the other hand, TAC
showed negative correlation to the number of previous pregnancies and positive correlation to
serum bilirubin and creatinine levels (Table 2). Intracellular NT immunohistochemical staining
intensity showed positive correlation to gGT levels. It also positively correlated to the occur-
rence of Cesarean section.
We also found that the negative correlation of UtAPI to birth weight in our cohort can be
improved by combining UtAPI measurements with plasma PRX level by calculating their ratio
(PIPX) (Table 3).

Table 2. Clinical parameters correlating to systemic oxidative/nitrative stress markers measured on the 12–
13th weeks of gestation. Plasma total peroxide level positively correlated to birth weight. Plasma total
antioxidant capacity negatively correlated to the number of previous healthy pregnancies and positively to
serum bilirubin and creatinine levels. Intracellular tyrosine nitration of circulating mononuclear cells
positively correlated to gGT levels and the occurrence of Cesarean section
Dependent variable R P N
Independent variable: Plasma Total Peroxide
Birth weight 0.342 0.031 40
UtAPI 0.428 0.004 44
Independent variable: Log (Plasma TAC)
Gravidity 0.323 0.015 56
Bilirubin 0.268 0.045 56
Creatinine 0.357 0.007 56
Independent variable: Leukocyte NT
gGT 0.407 0.026 30
Cesarean section 0.391 0.048 26

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Table 3. Correlation of birth weight of the newborns to UtAPI, plasma total peroxide level and their
combined variable PIPX (UtAPI/PRXp 100). All analyzed parameters showed correlation to birth weight;
however, the strongest correlation could be found in case of PIPX
Dependent variable R P N
Independent variable: UtAPI
Birth weight 0.347 0.009 55
Independent variable: PIPX
Birth weight 0.450 0.004 40

Results only for primiparas

All statistical analysis was also repeated with primiparas only, and the results were similar to
those of the entire study group.

DISCUSSION
Several research groups have examined the relationship between the first and second trimesters’
elevated UtAPI or resistance index and lower birth weight, mainly because of the risk for in-
trauterine growth restriction (IUGR) [17–20]. In our healthy study cohort, the newborns of
high-UtAPI mothers were born with significantly smaller weight and chest circumference than
the newborns of the low-UtAPI group, although there was no difference in the gestational week
at birth. In the total study cohort, UtAPI negatively correlated to the birth weight of the neonates
that were within the normal range. These results may suggest that UtAPI measured in this
period may indicate later placental function and fetal development also in physiological preg-
nancy.
Plasma PRX indicating oxidative stress was significantly lower in the high UtAPI group,
whereas total antioxidant capacity was significantly higher compared to the low UtAPI group.
Low oxygen tension in the first trimester having an important role in the initial normal
placentation triples by the end of the first trimester, along with the levels of reactive oxygen
species, a change that significantly contributes to further placental development. The placenta
adapts to the elevated oxidative stress by modulating the levels of cellular antioxidants [21]. The
low level of oxidative stress in the high UtAPI group may reflect the impairment or delay of this
oxidative burst. This hypothesis may be supported by the negative correlation of oxidative stress
to UtAPI and its positive correlation to birth weight of the neonates in the total study cohort
even in physiological pregnancies – therefore further examination of oxidative stress markers
might be also useful in pathological pregnancies. That is the reason why we try to develop more
sensitive diagnostic indicators, like PIPX, involving classical and oxidative stress parameters.
As both UtAPI and plasma PRX showed a correlation to lower birth weight, we generated a
variable that reflects their simultaneous change defined as PIPX:UtAPI/PRXp 100. PIPX showed
a stronger correlation to birth weight than UtAPI alone, suggesting that measuring oxidative
stress may improve the predictive value of UtAPI on fetal development.
At this time, together with the oxidative burst, the secondary invasion of the trophoblast cells
occurs in the placenta [22] that is associated with cellular degradation. Tissue degradation
usually leads to the elevation of serum LDH concentration. In our study, serum LDH

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concentration was lower in the high UtAPI group at the end of the first trimester. We hy-
pothesize that this lower LDH reflects the decreased trophoblast invasion.
Additionally, it has been previously shown by our research group that even after a healthy
pregnancy, the degree of oxidative stress is elevated after three years [16]. It is also conceivable
that low-resistance pregnant women had higher oxidative stress levels because of their higher
number of previous pregnancies. Our observation that plasma total antioxidant capacity
negatively correlates to the number of previous pregnancies may also support this hypothesis.
Gravidity and parity were significantly higher in our low UtAPIgroup. This observation
may be related to findings showing that multiparity protects against the development of high
uterine artery pulsatility index. The significantly higher parity and gravidity in our low UtAPI
group may reflect that multiparous women’s body had previously practiced the steps of
placentation, leading to a higher chance of success in trophoblast invasion and circulatory
adaptation [23].
Despite the decreased oxidative stress in the high UtAPI group, we found no difference in
nitrative stress between the two study groups. Nitrotyrosine is mainly produced by the reaction
of protein tyrosine residues and peroxynitrite, whereas peroxynitrite is produced by the reaction
of nitric oxide and superoxide anion [24]. According to this reaction pathway, the change in
nitrotyrosine levels might be expected to follow the changes in PRX concentration. On the other
hand, previous studies also failed to confirm to this relationship, especially in chronic disease
and healthy conditions [16, 25].
Intracellular nitrative stress showed a positive correlation to serum gGT value. Several prior
studies suggested that gGT could be used as a clinical marker of inflammation and oxidative
stress. Simona Bo et al. studied the relationship between serum NT and serum gGT. Based on
their results, these two markers showed a positive correlation [26]. An interesting finding of our
study is that the level of intracellular NT also correlated to Cesarean section outcome, however
further investigations are required to clarify its mechanism and importance.
The limitations of the study were the relatively small number of cases and the high variability
of oxidative/nitrative stress markers among pregnant women. Due to these, we were not able to
define distinct cutoff values of oxidative/nitrative stress markers for pregnancy outcomes.
Combined parameters, like the variable calculated from UtAPI and PRX, could be expected to
improve the predictive value of oxidative/nitrative stress parameters. On the other hand, additional
studies are required to identify a more clinically relevant oxidative/nitrative stress parameter.

CONCLUSION
In conclusion, according to our results high UtAPI without other risk factors results in smaller
newborns in the normal range. On the other hand, plasma oxidative stress and LDH were
decreased in the high UtAPI group of our cohort that may be in connection with the disturbance
of placentation. This hypothesis is further supported by our finding that combining UtAPI with
an oxidative stress parameter (PRX) strengthens its correlation to birth weight. Measurement of
oxidative stress markers together with UtAPI at the 12–13th weeks of gestation may provide
additional information about placentation. We found significant differences also in the birth
weight of healthy newborns; therefore it is worth examining this relationship in pathological
pregnancies.

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Data availability: According to the ethical approval, the detailed datasets of the present study
cannot be shared with a third party without permission. Permission may be asked upon indi-
vidual request.

Conflict of interest: The authors declare that no competing financial interests exist.

ACKNOWLEDGMENTS
The study was supported by the Hungarian National Research, Development and Innovation
Office (OTKA-PD 113022). The funding sources had no involvement in the study design; in the
collection, analysis and interpretation of data; in the writing of the report; or in the decision to
submit the article for publication.

ABBREVIATIONS
gGT Gamma-glutamyl transferase
GDM Gestational diabetes mellitus
HRP Horse raddish peroxidase
IUGR Intrauterine growth restriction
LDH Lactate dehydrogenase
NT Serum nitrotyrosine
PlGF Placental growth factor
PAPP-A Plasma pregnancy related plasma protein A
PE Praeclampsia
PIPX The quotient of UtAPI and plasma PRX, UtAPI/PRXp 100
PRX Plasma total peroxide
sFlt-1 Soluble fms-like tyrosine kinase-1
TAC Plasma total antioxidant capacity
UtAPI Uterine artery pulsatility index

REFERENCES

1. Gomez O, Figueras F, Fernandez S, Bennasar M, Mart
ınez JM, Puerto B, et al. Reference ranges for uterine
artery mean pulsatility index at 11-41 weeks of gestation. Ultrasound Obstet Gynecol 2008; 32(2): 128–32.
https://doi.org/10.1002/uog.5315.
2. Pijnenborg R, Bland JM, Robertson WB, Brosens I. Uteroplacental arterial changes related to interstitial
trophoblast migration in early human pregnancy. Placenta 1983; 4(4): 397–413.
3. Jauniaux E, Greenwold N, Hempstock J, Burton GJ. Comparison of ultrasonographic and Doppler mapping
of the intervillous circulation in normal and abnormal early pregnancies. Fertil Steril 2003; 79(1): 100–6.
4. McLeod L. How useful is uterine artery Doppler ultrasonography in predicting pre-eclampsia and intrauterine
growth restriction? CMAJ 2008; 178(6): 727–9. https://doi.org/10.1503/cmaj.080242.

Unauthenticated | Downloaded 11/05/24 04:10 PM UTC

Physiology International 107 (2020) 4, 479–490 489

5. Gonzalez-Gonzalez NL, Gonzalez-Davila E, Gonzalez Marrero L, Padron E, Conde JR, Plasencia W. Value of
placental volume and vascular flow indices as predictors of intrauterine growth retardation. Eur J Obstet
Gynecol Reprod Biol 2017; 212: 13–9. https://doi.org/10.1016/j.ejogrb.2017.03.005.
6. Mosimann B, Amylidi-Mohr S, Holand K, Surbek D, Risch L, Raio L. Importance of Timing First-Trimester
Placental Growth Factor and Use of Serial First-Trimester Placental Growth Factor Measurements in
Screening for Preeclampsia. Fetal Diagn Ther 2017; 42(2): 111–6. https://doi.org/10.1159/000455946.
7. Kalousova M, Muravska A, Zima T. Pregnancy-associated plasma protein A (PAPP-A) and preeclampsia.
Adv Clin Chem 2014; 63: 169–209.
8. Karampas GA, Eleftheriades MI, Panoulis KC, Rizou MD, Haliassos AD, Metallinou DK, et al. Prediction of
pre-eclampsia combining NGAL and other biochemical markers with Doppler in the first and/or second
trimester of pregnancy. A pilot study. Eur J Obstet Gynecol Reprod Biol 2016; 205: 153–7. https://doi.org/10.
1016/j.ejogrb.2016.08.034.
9. Auten RL, Davis JM. Oxygen toxicity and reactive oxygen species: the devil is in the details. Pediatr Res 2009;
66(2): 121–7. https://doi.org/10.1203/PDR.0b013e3181a9eafb.
10. Pham-Huy LA, He H, Pham-Huy C. Free radicals, antioxidants in disease and health. Int J Biomed Sci 2008;
4(2): 89–96.
11. Sanchez-Aranguren LC, Prada CE, Riano-Medina CE, Lopez M. Endothelial dysfunction and preeclampsia:
role of oxidative stress. Front Physiol 2014; 5: 372. https://doi.org/10.3389/fphys.2014.00372.
12. Cuffe JS, Xu ZC, Perkins AV. Biomarkers of oxidative stress in pregnancy complications. Biomark Med 2017;
11(3): 295–306. https://doi.org/10.2217/bmm-2016-0250.
13. Horvath EM, Magenheim R, Kugler E, Vacz G, Szigethy A, Levardi F, et al. Nitrative stress and poly(ADP-
ribose) polymerase activation in healthy and gestational diabetic pregnancies. Diabetologia 2009; 52: 1935–43.
14. Ramirez-Emiliano J, Fajardo-Araujo ME, Zuniga-Trujillo I, Perez-Vazquez V, Sandoval-Salazar C, Ornelas-
Vazquez JK. Mitochondrial content, oxidative, and nitrosative stress in human full-term placentas with
gestational diabetes mellitus. Reprod Biol Endocrinol 2017; 15(1): 26. https://doi.org/10.1186/s12958-017-
0244-7.
15. Valent S, Nemeth J, Sara L, Gidai J, T
oth P, Schaff Z, et al. High early uterine vascular resistance values
increase the risk of adverse pregnancy outcome independently from placental VEGF and VEGFR1 reactivities.
Eur J Obstet Gynecol Reprod Biol 2011; 156(2): 165–70. https://doi.org/10.1016/j.ejogrb.2011.01.029.
16. Horvath EM, Magenheim R, Beres NJ, Benk}
et al. Oxidative/nitrative stress and poly
o R, P
ek T, Tab
ak AG,
(ADP-Ribose) polymerase activation 3 years after pregnancy. Oxid Med Cell Longev 2018; 2018: 1743253.
https://doi.org/10.1155/2018/1743253.
17. Sarmiento A, Casasbuenas A, Rodriguez N, Angarita AM, Sarmiento P, Sepulveda W. First-trimester uterine
artery Doppler velocimetry in the prediction of birth weight in a low-risk population. Prenat Diagn 2013;
33(1): 21–4. https://doi.org/10.1002/pd.3997.
18. Martin AM, Bindra R, Curcio P, Cicero S, Nicolaides KH. Screening for pre-eclampsia and fetal growth
restriction by uterine artery Doppler at 11-14 weeks of gestation. Ultrasound Obstet Gynecol 2001; 18(6):
583–6. https://doi.org/10.1046/j.0960-7692.2001.00594.x.
19. Sharma N, Srinivasan S, Jayashree K, Nadhamuni K, Subbiah M, Rajagopalan V. Prediction of intrauterine
growth restriction in highpulsatility index of uterine artery. Br J Med Med Res 2017; 22(2): 1–6. https://doi.
org/10.9734/BJMMR/2017/34137.
20. Melchiorre K., Leslie K., Prefumo F., Bhide A., Thilaga B. First-trimester uterine artery Doppler indices in the
prediction of -for-gestational age pregnancy and intrauterine growth restriction. Ultrasound Obstet Gynecol
2009; 33(5): 524–9. https://doi.org/10.1002/uog.6368.

Unauthenticated | Downloaded 11/05/24 04:10 PM UTC

490 Physiology International 107 (2020) 4, 479–490

21. Pereira AC, Martel F. Oxidative stress in pregnancy and fertility pathologies. Cell Biol Toxicol 2014; 30(5):
301–12. https://doi.org/10.1007/s10565-014-9285-2.
22. Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen T, et al. Vascular endothelial growth factor
ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia
and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol 2002; 160(4): 1405–23.
https://doi.org/10.1016/S0002-9440(10)62567-9.
23. Lin JH, Liang AJ, Lin QD, Liu XH, Sun LZ, Zhang WY, et al. A multi-center study to evaluate the dynamic
changes of uterine artery and umbilical artery flow in a normal pregnancy and hypertensive disorders in
pregnancy. Zhonghua Fu Chan Ke Za Zhi 2010; 45(8): 583–7.
24. Dijkstra G, Moshage H, van Dullemen HM, de Jager-Krikken A, Tiebosch AT, Kleibeuker JH, et al.
Expression of nitric oxide synthases and formation of nitrotyrosine and reactive oxygen species in inflam-
matory bowel disease. J Pathol 1998; 186(4): 416–21. 10.1002/(SICI)1096-9896(199812)186:4<416::AID-
PATH201>3.0.CO;2-U.


25. Molnar A, Toth A, Bagi Z, Papp Z, Edes I, Vaszily M, et al. Activation of the poly(ADP-ribose) polymerase
pathway in human heart failure. Mol Med 2006; 12(7–8): 143–52. https://doi.org/10.2119/2006-00043.
26. Bo S, Gambino R, Durazzo M, Guidi M, Tiozzo E, Ghione F, et al. Associations between gamma-glutamyl
transferase, metabolic abnormalities and inflammation in healthy subjects from a population-based cohort: a
possible implication for oxidative stress. World J Gastroenterol 2005; 11(45): 7109–17.

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