# Labor Augmentation with Oxytocin Decreases Glutathione Level

Authors: Naomi Schneid-Kofman; Tali Silberstein; Oshra Saphier; Iris Shai; Dorith Tavor; Ariela Burg
Journal: Obstetrics and Gynecology International
 (2009)

---

## Abstract

Objective. To compare oxidative stress following spontaneous vaginal delivery with that induced by Oxytocin augmented delivery. Methods. 98 women recruited prior to labor. 57 delivered spontaneously, while 41 received Oxytocin for augmentation of labor. Complicated deliveries and high-risk pregnancies were excluded. Informed consent was documented. Arterial cord blood gases, levels of Hematocrit, Hemoglobin, and Bilirubin were studied. Glutathione (GSH) concentration was measured by a spectroscopic method. Plasma and red blood cell (RBC) levels of Malondialdehyde indicated lipid peroxidation. RBC uptake of phenol red denoted cell penetrability. SPSS data analysis was used.
Results. Cord blood GSH was significantly lower in the Oxytocin group (2.3±0.55 mM versus 2.55±0.55 mM, P=.01). No differences were found in plasma or RBC levels of MDA or in uptake of Phenol red between the groups. Conclusion. Lower GSH levels following Oxytocin augmentation indicate an oxidative stress, though selected measures of oxidative stress demonstrate no cell damage.


---

## Body

## 1. Introduction

Labor is a state of stress, though the oxidative burden upon the fetus is of controversy in literature [1, 2]. Neonatal adverse outcome may result from
oxidative stress, thus cord blood pH is currently the most used method for assessing
fetal oxidative metabolic stress with some correlation to neonatal outcome [3, 4].Reactive
oxygen free radicals are produced by aerobic cell metabolic activity. The
accumulation of these radicals can produce toxic changes within the cells by an uncontrolled self-enhancing process of lipid
peroxidation of membranes and inner cell components resulting
in a disruption of membrane lipids and other cell components. The cell
defensive system consists of antioxidative free-radical scavenging molecules such
as glutathione (GSH—a tripeptide consisting of glutamic acid-cysteine-glycine). GSH acts as the substrate for the
enzyme glutathione peroxidase. As such it is an important component of
intracellular antioxidant defense, protecting cytosolic organelles, in
particular, from the damaging effects of hydroperoxides. In addition, GSH also
acts synergistically with ascorbic acid and alphatocopherol to recycle these
nutrient antioxidant vitamins to their reduced state after their interaction
with reducing chemical species inside the cell [5].Red blood cells (RBCs) are prone to lipid peroxidation by virtue
of their function as oxygen carriers and their lipid composition. Measurement
of Malondialdehyde (MDA) content using thiobarbituric reagent is widely used to
quantify lipid peroxidation and is indicative of the amount of oxygen radicals
in the RBC environment. An alternative method of evaluating lipid peroxidation
in RBC is by measuring uptake of phenol red [6].Initiation
and progress of labor are generated by endogenous Oxytocin hormone levels. Low
contraction frequency and protracted labor are treated with administration of
exogenous Oxytocin for augmenting labor [7].Uterine
blood flow is reduced during contractions and further reduced during intensive
uterine activity, resulting in compromised placental blood flow. Therefore,
administration of Oxytocin during labor may induce fetal oxidative stress.
Previous studies have found no adverse effect of Oxytocin treatment on pH
levels [8], and Oxytocin augmentation did not increase perinatal risk [9].
Measuring the level of antioxidation enzymes in cord blood following Oxytocin
treatment provides useful information regarding the extent of fetal oxidative
stress and the information regarding the safe use of this treatment in labor.In
this study, we compared the oxidative stress induced by normal vaginal delivery
with that following Oxytocin augmented delivery.


## 2. Materials and Methods

Prior to delivery, 98 women were recruited
from labor and delivery department in Soroka medical center during November
2006 and February 2007. Of these, 57 delivered uncomplicated spontaneous vaginal
deliveries; 41 received Oxytocin treatment (Oxytocin Injection, BP 10
Units/ampule, produced by Rotexmedica GmbH, Germany) for augmentation of labor
resulting in vaginal delivery.  Four
women of the control group and one of the Oxytocin group were excluded during
data analysis, all for incomprehensive lab analysis (hemolytic sample, coagulated
sample). The protocol of treatment in our institution for Oxytocin
administration was followed. Oxytocin was diluted at 5 mIU in 500 mL NaCl 0.9%,
administered at an initial rate of 2 mIU/min and increased by 2 mIU every
20–40 minutes, until effective regular contractions were achieved. The maximum
dose administered was 16 mIU/min. Dose and duration of therapy were
documented. The final appropriate dose administered was determined by observed
frequency of resulting uterine contractions and by progress of labor.Excluded
from the study were multifetal deliveries, surgical or mechanical deliveries,
Postdate deliveries (42 completed weeks of pregnancy), or suspected
intrauterine growth restricted fetuses.Data
were collected by personal interviews, validated through medical records. We
collected data regarding demographics, past medical and obstetric history, the
indication for augmentation of labor, duration of labor (first and second
stages), neonatal data, and use of epidural anesthesia.Blood samples were drawn from
the umbilical cord artery immediately after fetal delivery, before delivery of
the placenta and stored at4°C, up to 8 hours. Whole blood samples were
analyzed within five minutes of collection by a blood gas analyzer for pH,
carbon dioxide (pCO2), oxygen (pO2), oxygen saturation,
and base excess (BE). Levels of Hematocrit, Hemoglobin, and Bilirubin were
analyzed within an hour of delivery. Measurements of oxidative stress
indicators were concluded within eight hours. Glutathione concentration was
determined by a spectroscopic method, measuring the production of the yellow
anion produced by redox reaction between sulphahydryl (–SH) groups and the
reagent 5,5'-Dithiobis-2-nitrobenzoic acid (DTNB) [10]. Plasma and red blood
cell (RBC) levels of Malondialdehyde (MDA) were measured for lipid
peroxidation; RBC uptake of phenol red was measured for cell penetrability [6].
Measurements of penetrability are displayed as arbitrary units of absorption.Statistical analysis was performed with anSPSS software
package (SPSS, Chicago, IL). Statistical significance was determined
using the χ2 test, the Fisher exact test for differences
between qualitative variables, and the t-test for differences between
continuous variables. Odds ratios (OR) and their 95% confidence intervals (CI) were
calculated. Pearson correlation coefficient was used to calculate the
correlation of GSH on pO2. Multivariate analysis was
preformed. P<.05 was considered statistically
significant. This study is preliminary in the field of Oxytocin in
vaginal delivery and oxidative stress. Due to lack of previous data, power
analysis was not done.The study was approved by the Institutional Review Board; informed consent was documented.


## 3. Results

Excluded
from the data analysis were four of the control group and one of the Oxytocin
group, all for failure to attain comprehensive lab results (hemolytic sample,
coagulated sample).Demographic
characteristics were comparable between the groups (Table1).Table 1
Demographic characteristics.
With
Oxytocin (mean±Standard deviation) n = 40Without
Oxytocin (mean±Standard deviation) n = 53PMaternal
age (years)26.9±5.628.5±5.7P=.18Pregnancy
order2.9±24.1±2P=.01Delivery
number1.6±22.6±2P=.03Gestational
age (weeks)39.0±1.439.5±1.3P=.09Birth
weight (g)3207±3503308±405P=.202In the
Oxytocin group, the dose of administered Oxytocin ranged 2–16 mIU/min, (mean 9.3 mIU/min).
Duration of treatment was between 1–11 hours (mean 3.7 hours). The sole
indication for treatment was augmentation of labor.Cord
bloodGSH was significantly lower in the Oxytocin group (2.0±0.55 mM versus 2.3±0.55 mM, P=.01) (Figure 1).Figure 1
GSH level by Oxytocin treatment.In a
multivariate analysis, adjusted for numbers of deliveries, fetal gender and
fetal weight, Oxytocin remained the main predictor forGSH (Beta = (−1.859),
P=.066).Uptake
of phenol red was similar between the groups (0.08 versus 0.076,P=.11).  No differences were found between the groups
in levels of MDA in plasma (0.9±0.03 μM versus 0.97±0.05 μM, P=.1) or MDA levels in
RBC (2.05±0.16 μM versus 1.93±0.10 μM, P=.23).Cord
blood gas characteristics are summarized in Table2.Table 2
Cord blood characteristics.
With
Oxytocin (mean±Standard deviation) n = 53Without
Oxytocin (mean±Standard deviation) n = 40PpH7.31±0.067.33±0.06P=.15pO2 mmHg36±1735±21P=.83pCO2 mmHg40±1040±9P=.94Base
excess(−5.2)±2.2(−4.6)±2.1P=.16Comparing
the groups, significant differences were noted regarding length of delivery.
First stage was significantly longer among the Oxytocin group (361±267 minutes.
versus 172±130 minutes. P<.001) as was second stage of labor (25±28 minutes. versus 13±12 minutes. P=.01). Epidural anesthesia was more prevalent in the Oxytocin group
(15% versus 4%, P=.05). No difference was noted in meconium stained amniotic
fluid (15% versus 12%, P=.61) between the groups.Comparison
ofGSH levels among first deliveries between the groups demonstrated a lower
level of GSH following Oxytocin treatment (2.18±0.40 mM versus 2.79±0.17 mM,
P=.002). The length of second stage of labor was similar in first deliveries
in both groups (41±38 minutes. versus 44±25 minutes, P=.85).As
many as 63% of women from Oxytocin group were treated by iron supplements
during pregnancy, while 72% received iron supplementation in the control group,P=.35.  No correlation was found between
iron treatment and GSH levels (correlation significance 0.73).None
received vitamin formulas during the last week before delivery. Two women from
the Oxytocin group smoked during the pregnancy while none smoked in the control
group,P=.1. The participants were questioned regarding disease prevalence.
Gestational diabetes treated by diet alone was noted in two women from the
Oxytocin group and in none from the control group, P=.1. No hypertensive
disorders were detected.  None had G6PD
deficiency.Obstetric
history was examined for detection of high-risk pregnancies. No significant
differences were noted between the Oxytocin and the control group regarding previous
preterm labor (0.07±0.2 versus 0.1±0.5, P=.47), previous early abortion (0.2±0.5
versus 0.3±0.7, P=.6), or previous cesarean section (0±0 versus 0.07±0.2, P=.07). No
difference was found regarding prenatal care between the groups, the Oxytocin
group 2.7±0.5 (in a scale of 1–3, 1 = lack of care, 3 = complete prenatal care)
and 2.5±0.6 for the control group, P=.2.


## 4. Discussion

Oxytocin
augmentation of labor is an acceptably safe modality of treatment. Lower Glutathione levels compared to normal vaginal
delivery indicate oxidative stress, yet no fetal red blood cell damage is
instituted. TheRBC antioxidant systems suffice to prevent cell damage of lipid
peroxidation or increased permeability of the RBC membrane.  Higher levels of GSH that are noted in the
newborn according to previous publications [11] may contribute to an enhanced
defensive mechanism against oxidative stress in the neonate [12]. pH levels
were similar between the groups, in accordance with previous publications [8].Oxytocin
dose tapering is determined by frequency of contractions and labor progression,
thus, the same drug dose might induce a different frequency of contractions in
different patients as well as dissimilar rates of oxidative stress. Consistent
with the local protocol of treatment by Oxytocin, frequency of contractions was
maintained at less than five contractions in ten minutes. Dose of oxytocin was
adjusted as needed to attain this goal. Quantification of Oxytocin treatment
for the purpose of precise comparison between the groups was of concern due to
the short half life of this hormone and the debate whether the total dose
administered during labor or the last dosage of treatment is the most accurate
indicator of the Oxytocin impact. Provided that a drug with short term effect
administered hours prior to a measured oxidative reaction which is quick and changing
in nature has questionable effect upon the outcome, the last dose administered was
chosen as the index of treatment.Direct
measurements of Oxytocin in maternal blood might have improved the precision of
our results though others have failed to demonstrate a correlation between
measured blood Oxytocin concentration and fetal pH [8, 13, 14].In
the Oxytocin group, primiparity was more prevalent. Length of second stage of
labor among primiparas was not significantly different between the groups (41±38 minutes. versus 44±25 minutes, P=.85).
These parameters support the observation that GSH was lower in the study group
due to Oxytocin treatment and not due to longer first deliveries. There is some
evidence that the detected impact of Oxytocin upon GSH levels might become
substantial in compromised fetuses [15, 16].The correlation between Oxytocin level and
lowerGSH is not supported by lower GSH levels found during elective cesarean
deliveries compared to vaginal deliveries [17]; this inconsistency may evolve
from higher oxidative stress caused by the operative delivery and anesthesia
process and not attributed to the labor-induced Oxytocin level.  A study comparing fetal oxidative stress
following elective and emergent cesarean sections demonstrated higher oxidative
stress in emergent cesarean deliveries (increased MDA levels); the author implied
in this case that the mode of delivery was not the main attributor to oxidative
stress but rather previous fetal condition [18]. This remains to be further
explored.In
conclusion, Oxytocin treatment for augmentation of low-risk vaginal deliveries
contributes to oxidative stress; however, no fetal cell damage is induced. Higher-power studies are required to further establish these findings.



---

*Source: 807659-2009-04-16.xml*