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doi:10.1111/jog.13263 J. Obstet. Gynaecol. Res. Vol. 43, No.

5: 860–865, May 2017

Assessment of oxidative stress markers in cord blood of


newborns to patients with oxytocin-induced labor

Talip Karaçor1, Sibel Sak2, Serdar Başaranoğlu3, Nurullah Peker1, Elif Ağaçayak1,
Muhammet Erdal Sak1, Abdulkadir Turgut1, Mehmet Sıddık Evsen1, Osman Evliyaoğlu4 and
Talip Gül1
Departments of 1Obstetrics and Gynecology, 4Biochemistry, Dicle University School of Medicine, Diyarbakır, 2Department of Obstetrics
and Gynecology, Harran University School of Medicine, and 3Department of Obstetrics and Gynecology, Bilge Hospital, Istanbul, Turkey

Abstract
Aim: We aimed to measure the extent of oxidative stress experienced during labor by the neonates of pregnant
women undergoing induced or spontaneous birth and to compare the effects of induced labor on fetal well-being.
Methods: Sixty-four healthy pregnant women referring to the Department of Gynecology and Obstetrics, Dicle
University Medical Faculty between October 2010 and May 2011 were included in this comparative study.
Pregnant women undergoing induced labor by oxytocin were group 1 and those without labor induction were
group 2. Post-partum Apgar score was calculated at 1 and 5 min and measurements of weight and height of
the neonates were carried out. After the fetal cord was clamped, 5 cm3 blood was drawn into a plain tube without
anticoagulant. The samples were centrifuged at 5000 r.p.m. for 5 min. Separated sera were transferred to
Eppendorf tubes and were stored at 80 C° until the analysis time.
Results: The complete blood counts and biochemistry results indicated that there were no statistically significant
differences in regards to diseases between the two groups. Nitric oxide and asymmetrical dimethylarginine
values of the two groups were not significantly different; however, there were statistically significant differences
in the malondialdehyde, paraoxonase, total antioxidative status, and total oxidative status values of the two
groups (respectively, P = 0.005, P = 0.006, P = 0.008, and P = 0.007).
Conclusion: We observed that oxytocin-induced labor increases stress markers but does not affect Apgar scores.
Oxidative stress in pregnant women may trigger antioxidative mechanisms. Prospective studies in larger cohorts
are needed to better understand the impact of oxytocin-induced labor on pregnant women and neonates.
Key words: Apgar scores, delivery, newborn, oxidative stress, oxytocin induction.

Introduction contractility is regulated and irregular contractions be-


fore labor and effective contractions during labor take
In line with improvements in medicine and technology, place. Labor is a physiological event and starts spontane-
one of the main targets of obstetrics has become to main- ously at term or near term in pregnant women. Induction
tain healthy development of the fetus during intrauterine of labor is employment of mechanical or pharmacologi-
life and to accomplish birth with minimal maternal–fetal cal methods in order to start regular uterine contractions
trauma. A series of cellular, molecular, and hormonal to establish cervical dilatation or effacement when labor
events is involved in the birth process.1 As a consequence does not start spontaneously. In nearly 20–30% of all
of the coordinated work of these factors, myometrial births, induction to start labor is needed.2

Received: July 2 2016.


Accepted: November 7 2016.
Correspondence: Dr Serdar Başaranoğlu, Department of Obstetrics and Gynecology, Bilge Hospital, Şemsipaşa Mahallesi 56. Sokak No: 2
Küçükköy –G.O. Paşa / Istanbul 34240, Turkey. Email: drsbasaran@gmail.com.tr

860 © 2017 Japan Society of Obstetrics and Gynecology


Oxidative stress in induced labor

Oxidants are reactive oxygen radicals produced dur- by ultrasound exam done in the first trimester. Subjects
ing metabolic and physiological processes. Their detoxi- with abnormal complete blood count /blood biochemis-
fication in the body is accomplished by antioxidants try test results and/or complete urine analysis were ex-
formed in the body or taken from outside. Oxidative cluded from the study. In addition, subjects with a
stress is the imbalance between the antioxidant defense history of gestational hypertension, intrauterine growth
mechanism of the body and formation of free oxygen retardation, gestational or pre-gestational diabetes, or
radicals leading to peroxidation of the lipid layer of cells. cardiac disease were excluded from the study; further-
It was reported that intrauterine oxidative stress devel- more, pregnancies that had occurred as a result of
oped in women who gave birth or who underwent in- assisted reproductive techniques were also excluded.
duction of labor.3 In order to determine oxidative stress Umbilical cord blood gas is routinely taken from new-
status, cord or scalp blood sampling may be done and borns in our clinic.
Apgar score is also widely used as it is a simple and re-
peatable method even though it is not a reliable marker.4 Start of induction
There are studies in the literature regarding oxidative An infusion solution was prepared by adding an am-
status determined by using cord blood. However, nitric poule of synthetic oxytocin liquid (5 IU/mL; Synpitan
oxide (NO), asymmetrical dimethylarginine (ADMA), Forte ampoule, Deva Pharmaceuticals) into 500 cm3
paraoxonase (PANX), total oxidative status (TOS), and 0.9% sodium chloride (NaCl). Initial dose was 2
total antioxidative status (TAS) have not yet been men- mIU/min intravenous infusion as per oxytocin infusion
tioned as markers in the literature. dose protocol recommended by the American College
In our study, we aimed to measure the extent of oxida- of Obstetricians and Gynecologists.5 Until effective con-
tive stress experienced by the neonates of pregnant tractions were achieved (in 10-min 200 Montevideo for-
women giving induced or spontaneous birth during la- mation) infusion dose was increased by 2 mIU/min
bor and to compare the effects of induced labor on fetal every 20 min. Maximum dose average was 20
well-being relative to spontaneous birth. mIU/min. Dose of the induction agent and formed con-
tractions during labor were documented.

Methods Obtaining the samples and their storage


After the fetal cord was clamped, 5 cm3 blood was
Our prospective randomized controlled study was ap- drawn into a plain tube without anticoagulant. Cord
proved by the local ethics committee of Dicle University. blood samples were obtained from the umbilical artery.
Sixty-four healthy pregnant women referring to the ob- The samples were centrifuged at 5000 r.p.m. for 5 min.
stetrics unit of the Department of Gynecology and Ob- Separated sera were transferred to Eppendorf tubes
stetrics, Dicle University Medical Faculty between and were stored at 80 C° until the analysis time. The
October 2010 and May 2011 were included in this com- samples obtained from groups 1 and 2 were analyzed
parative study. Pregnant women undergoing induced la- in the Biochemistry lab when they reached an adequate
bor by oxytocin were group 1 and those without labor number. To assess postnatal morbidity, the Apgar score
induction were group 2. The subjects in groups 1 and 2 was calculated at the 1- and 5-min systemic physical
were informed in writing or orally about the information exams. Measurements of the weight and height of the
included in the consent form before the study. We ob- neonate were performed by a pediatrician.
tained signed informed consent of all patients. The study
period was planned as 6 months and subjects who did Operating standards of kits used in the study
not want to participate in the study during this period Human ADMA immunoassay was done by the enzyme-
or who withdrew their participation were excluded from linked immunosorbent assay method using Catalog No-
the study. Group 1 consisted of 32 pregnant women who CSB-E0929h kits. NO testing was carried out with color-
underwent post-term oxytocin-induced labor or elective imetric assay kit (780 001 03.30.2011, Cayman Chemical
oxytocin-induced labor (family preferences) and group 2 Company). We used the fully automated PANX activity
consisted of 32 pregnant women without history of ce- measurement kit (RL0031, Mega Medical Industry and
sarean section or uterus operation and carrying a living Trade, Ltd). TAS was tested with the fully automated
single fetus with head presentation at term. Gestational third-generation TAS assay kit (RL0017, Mega Medical
age of the expectant mothers was determined by last Industry and Trade, Ltd). We used the fully automated
menstrual period and in equivocal cases it was approved TOS assay kit (RL0024, Mega Medical Industry and

© 2017 Japan Society of Obstetrics and Gynecology 861


T. Karaçor et al.

Trade, Ltd). MDA was tested with a fully automated were assessed, NO and ADMA values of the two groups
MDA assay kit. were not significantly different; however, there were sta-
tistically significant differences in the MDA, PANX, TAS,
Statistical analysis and TOS values of the two groups (respectively, P =
For the statistical analysis, all data were entered into SPSS 0.005, P = 0.006, P = 0.008, P = 0.007). The results of the
for Windows 16.0. Mean and frequency values of the blood gas data are shown in Table 4. Nine women in
variables were calculated. The Kolmogorov–Smirnov group 1 and 12 in group 2 were primiparous (28.1% vs
test was used to detect normal distribution of numeric 37.5%).
values. The Student’s t-test was used for normally dis-
tributed NO, PANX, and asymmetrical arginine and
the Mann–Whitney U-test was used for non-normal dis-
Discussion
tributed TOS, TAS, and MDA. P < 0.05 was considered
Pregnancy is a physiological state in which the metabolic
statistically significant.
and oxygen requirements of the tissues increase.6 In-
creased need for oxygen in the body triggers free radical
Results formation and increases oxidative stress and lipid perox-
idation in pregnant women compared to non-pregnant
Table 1 lists the demographic data of the pregnant women.7 Placenta is the source of free oxygen radicals.
women in groups 1 and 2, including age, gestational Additionally, in the coming weeks of pregnancy, antioxi-
age, height, weight, and 1- and 5-min Apgar scores of ne- dants, such as NO, PANX, catalase, Glutathione peroxi-
onates. Table 2 presents the initial routine complete dase (GPx) and glutathione, also increase and thus
blood count and blood biochemistry test results, such provide containment of the maternal and fetal effects of
as hematocrit, hemoglobin, platelet, white blood cells, al- free oxygen radicals.8,9 Induction of labor is an inevitable
anine aminotransferase, and aspartate amino transfer- practice in obstetrics. Induction methods may vary de-
ase. NO, ADMA, MDA, PANX, TAS, and TOS values pending on gestational age.10 Currently, intravenous
obtained from the separated sera of the women in oxytocin is the most widely employed and accepted
groups 1 and 2 are listed in Table 3. When the results method in the induction of labor in third-trimester

Table 1 Demographic data and newborn results of groups 1 and 2


Group 1† Group 2‡
(n = 32) Mean  SD (n = 32) Mean  SD P
Age 25.4  4.3 27.1  4.1 0.103
Gestational week 38.3  0.6 38.5  0.7 0.113
Birthweight (g) 3263.6  341.1 3393.5  370.5 0.147
Birth size (cm) 50.4  1.4 50.9  1.6 0.173
1-min Apgar 7.6  0.6 7.8  0.5 0.315
5-min Apgar 9.6  0.6 9.4  0.6 0.227
P-value < 0.05 was significant. †Pregnant women undergoing oxytocin-induced labor. ‡Control group (pregnant women without labor induc-
tion). SD, standard deviation.

Table 2 Complete blood and biochemical parameters


Group 1† Group 2‡
(n = 32) Mean  SD (n = 32) Mean  SD P
Hemoglobin 11.9  1.2 11.7  1.2 0.300
Hematocrit 35.3  3.0 35.1  2.8 0.774
Platelet 252.3  58.8 234.1  65.3 0.241
White blood cells 10.9  2.3 10.7  2.9 0.702
ALT 14.1  4.9 12.1  6.1 0.170
AST 19.6  4.9 18.4  5.6 0.350
P-value < 0.05 was significant. †Pregnant women undergoing oxytocin-induced labor. ‡Control group (pregnant women without labor induc-
tion). ALT, alanine aminotransferase; AST, aspartate aminotransferase; SD, standard deviation.

862 © 2017 Japan Society of Obstetrics and Gynecology


Oxidative stress in induced labor

Table 3 Values of NO, ADMA, MDA, PANX, TAS, and TOS in groups 1 and 2
Group 1† Group 2‡
(n = 32) Mean  SD (n = 32) Mean  SD P
NO (nmol/mL) 59.4  31.1 66.6  37.8 0.406
ADMA (μmol/L) 31.1  38.7 52.4  87.5 0.206
MDA (nmol/mL) 32.7  14.1 22.7  13.7 0.005
PANX (mmol/L) 3.3  3.4 1.5  1.1 0.006
TAS (mmol Trolox equivalent/L) 0.5  0.2 0.4  0.2 0.008
TOS (μmol H2O equivalent/L) 4.9  2.2 3.4  1.7 0.007
P-value < 0.05 was significant. Bold font indicates statistical significance. †Pregnant women undergoing oxytocin-induced labor. ‡Control group
(pregnant women without labor induction). ADMA, asymmetrical dimethylarginine; MDA, malondialdehyde; NO, nitric oxide; PANX, paraox-
onase; SD, standard deviation; TAS, total antioxidative status; TOS, total oxidative status.

Table 4 Umbilical cord blood gas results


Group 1† Group 2‡
(n = 32) Mean  SD (n = 32) Mean  SD P
pH 7.26  0.08 7.28  0.05 0.114
PO2 (mmHg) 17.9  9.5 16.3  8.7 0.103
PCO2 (mmHg) 47.7  8.9 49.1  7.3 0.218
Base deficit (mmol/L) –5.3  2.5 -5.5  2.7 0.271
P-value < 0.05 was significant. †Pregnant women undergoing oxytocin-induced labor. ‡Control group (pregnant women without labor induc-
tion). SD, standard deviation.

pregnancies.11 Although fetal asphyxia is not a precise NO levels were not statistically different in our two
marker for assessment of perinatal morbidity, the Apgar groups (P = 0.406). These results imply that antioxidant
score is widely used for this aim because it is simple and mechanisms were sufficiently functioning in both
repeatable.4 groups and that stress status is not enough to cause an al-
Whether or not the induction of birth with oxytocin in- teration in NO level. We identified that the oxytocin in-
creases oxidative stress remains controversial. Oxidative duction had no adverse affect on the labor. In pre-
stress markers TOS, MDA, and ADMA and antioxidants eclampsia, development of placental infarct due to
TAS, NO, and PANX assessed in our study have also atherosis and thrombosis is eminent.15 Low paraoxonase
been studied by other investigators in numerous studies. level increases high-density lipoprotein and low-density
These markers have not been studied in women deliver- lipoprotein oxidation and is thus involved in numerous
ing their babies via oxytocin-induced or spontaneous la- cardiac vascular conditions, including atherosclerosis.16
bor. Ours is the first study in the literature assessing the For a healthy pregnancy, both vascular structure of the
effect of oxytocin induction on oxidative stress. mother and vessel functions within the placental bed
In our study, TAS and TOS values were statistically should be normal.17 At this point, the effect of PANX
significantly higher in the induction group (group 1) as an antioxidant gains importance. In a study by
compared to the control group (group 2; respectively, Babacan et al., PANX activity was reported to be lower
P = 0.008, P = 0.007). These results imply that initiating in pre-eclamptic patients compared to healthy pregnant
induction by oxytocin during labor increases oxidative women.18 Aksoy et al. reported that PANX values were
stress and thus antioxidative mechanisms occur as a re- lower in mild and severe pre-eclampsia cases compared
sponse to this. A study by Vural et al. reports that oxida- to healthy pregnant women in their study.19 In our study,
tive stress increased in habitual abortus but antioxidant PANX values were higher in the oxytocin-induced
mechanisms were not sufficient enough to compensate group compared to the control group (P = 0.006). PANX
for it. They have suggested that increased oxidative has an antioxidant function; thus, high levels of PANX
stress may be involved in the etiology of abortus.12 In a imply presence of a defense mechanism against the
study assessing the role of NO in hypertensive pregnant stress occurring in the mother. ADMA leads to endothe-
women, Seligman et al. found that NO levels were lower lial dysfunction and vasospasm by inhibition of endogen
in pre-eclamptic patients compared to healthy pregnant NO synthase activity.
women.13 Similarly, in a study by Conrad et al., levels Oxidative stress may lead to alterations in the activity
of NO and its secondary harbinger, cGMP, were found of enzymes involved in ADMA formation and degrada-
to be lower in pre-eclamptic patients.14 In our study, tion.20 Pettersson et al. reported that ADMA levels were

© 2017 Japan Society of Obstetrics and Gynecology 863


T. Karaçor et al.

significantly higher in pre-eclamptic patients compared Disclosure


to healthy pregnant women and this increase was ob-
served before manifestation of clinical findings of pre- The authors declare that there are no conflicts of interest
eclampsia and accompanied abnormal uterine artery or financial disclosures for this article.
Doppler waves.21,22 In another study by Alaçam et al.,
ADMA values in the cord blood of pre-eclamptic preg- References
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© 2017 Japan Society of Obstetrics and Gynecology 865

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