Academic Editor: John C. Morrison
Copyright © 2009 Naomi Schneid-Kofman et al. This is an open
access article distributed under the Creative Commons
Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the
original work is properly cited.
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 ( mM
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.
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,
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 (a
tripeptide consisting of glutamic acid-cysteine-glycine).
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
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 .
Red blood cells ()
are prone to lipid peroxidation by virtue of their function
as oxygen carriers and their lipid composition. Measurement
of Malondialdehyde ()
content using thiobarbituric reagent is widely used to
quantify lipid peroxidation and is indicative of the amount
of oxygen radicals in the
environment. An alternative method of evaluating lipid
is by measuring uptake of phenol red .
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 .
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 ,
and Oxytocin augmentation did not increase perinatal risk .
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
In this study, we compared the oxidative stress induced
by normal vaginal delivery with that following Oxytocin
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 2040 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
Blood samples were drawn from the umbilical cord artery
immediately after fetal delivery, before delivery of the
placenta and stored at
up to 8 hours. Whole blood samples were analyzed within five
minutes of collection by a blood gas analyzer for pH, carbon
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
Plasma and red blood cell ()
levels of Malondialdehyde ()
were measured for lipid peroxidation;
uptake of phenol red was measured for cell penetrability .
Measurements of penetrability are displayed as arbitrary
units of absorption.
Statistical analysis was performed with an
software package (,
Chicago, IL). Statistical significance was determined using
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
Multivariate analysis was preformed.
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.
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,
Demographic characteristics were comparable between the
Table 1: Demographic characteristics.
In the Oxytocin group, the dose of administered Oxytocin
ranged 216 mIU/min, (mean 9.3 mIU/min). Duration of
treatment was between 111 hours (mean 3.7 hours). The sole
indication for treatment was augmentation of labor.
was significantly lower in the Oxytocin group ( mM
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 for
(Beta = (),
Uptake of phenol red was similar between the groups (0.08
No differences were found between the groups in levels of
in plasma ( M
Cord blood gas characteristics are summarized in Table
Table 2: Cord blood characteristics.
Comparing the groups, significant differences were noted
regarding length of delivery. First stage was significantly
longer among the Oxytocin group ( minutes.
as was second stage of labor ( minutes.
Epidural anesthesia was more prevalent in the Oxytocin group
(15% versus 4%,
No difference was noted in meconium stained amniotic fluid
(15% versus 12%,
between the groups.
levels among first deliveries between the groups
demonstrated a lower level of
following Oxytocin treatment ( mM
The length of second stage of labor was similar in first
deliveries in both groups ( minutes.
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,
No correlation was found between iron treatment and
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,
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,
No hypertensive disorders were detected. None had G6PD
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 (
previous early abortion (
or previous cesarean section (
No difference was found regarding prenatal care between the
groups, the Oxytocin group
(in a scale of 13, 1 = lack of care, 3 = complete prenatal
for the control group,
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. The
antioxidant systems suffice to prevent cell damage of lipid
peroxidation or increased permeability of the
membrane. Higher levels of
that are noted in the newborn according to previous
may contribute to an enhanced defensive mechanism against
oxidative stress in the neonate .
pH levels were similar between the groups, in accordance
with previous publications .
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,
In the Oxytocin group, primiparity was more prevalent.
Length of second stage of labor among primiparas was not
significantly different between the groups ( minutes.
These parameters support the observation that
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
levels might become substantial in compromised fetuses [15,
The correlation between Oxytocin level and lower
is not supported by lower
levels found during elective cesarean deliveries compared to
vaginal deliveries ;
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
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 .
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.
- N. Yaacobi, G. Ohel, and A. Hochman, Reactive
oxygen species in the process of labor, Archives
of Gynecology and Obstetrics, vol. 263, no. 1-2, pp.
- I. Fogel, I. Pinchuk, M. J. Kupferminc, D.
Lichtenberg, and O. Fainaru, Oxidative
stress in the fetal circulation does not depend on mode
of delivery, American Journal of Obstetrics and
Gynecology, vol. 193, no. 1, pp. 241246, 2005.
- A. MacLennan, A
template for defining a causal relationship between
acute intrapartum events and cerebral palsy:
international consensus statement. International
Cerebral Palsy Task Force, Australian and New
Zealand Journal of Obstetrics and Gynaecology, vol.
40, no. 1, pp. 1321, 2000.
- B. H. Yoon and S. W. Kim, The
effect of labor on the normal values of umbilical blood
acid-base status, Acta Obstetricia et
Gynecologica Scandinavica, vol. 73, no. 7, pp.
- D. P. Jones, R. J. Coates, E. W. Flagg, et
al., Glutathione in foods listed in the National Cancer
Institute's Health Habits and History Food Frequency
Questionnaire, Nutrition and Cancer, vol. 17,
no. 1, pp. 5775, 1992.
- A. H. Sawas and S. N. Pentyala, Evaluation
of lipid peroxidation in red blood cells by monitoring
the uptake of sucrose and phenol red, Journal of
Applied Toxicology, vol. 24, no. 3, pp. 223229,
- J. G. Smith and D. C. Merrill, Oxytocin
for induction of labor, Clinical Obstetrics and
Gynecology, vol. 49, no. 3, pp. 594608, 2006.
- J. A. Thorp, P. C. Boylan, V. M. Parisi, and
E. P. Heslin, Effects of high-dose oxytocin
augmentation on umbilical cord blood gas values in
primigravid women, American Journal of Obstetrics
and Gynecology, vol. 159, no. 3, pp. 670675, 1988.
- D. J. Cahill, P. C. Boylan, and C.
O'Herlihy, Does oxytocin augmentation increase
perinatal risk in primigravid labor?, American
Journal of Obstetrics and Gynecology, vol. 166, no.
3, pp. 847850, 1992.
- E. Beutler, O. Duron, and B. M. Kelly,
Improved method for the determination of blood
glutathione, The Journal of Laboratory and Clinical
Medicine, vol. 61, pp. 882888, 1963.
- I. A. Buhimschi, C. S. Buhimschi, M.
Pupkin, and C. P. Weiner, Beneficial
impact of term labor: nonenzymatic antioxidant reserve
in the human fetus, American Journal of
Obstetrics and Gynecology, vol. 189, no. 1, pp.
- T. Silberstein, D. Mankuta, A. I. Shames,
et al., Neonatal
blood is more resistant to oxidative stress induced by
stable nitroxide radicals than adult blood,
Archives of Gynecology and Obstetrics, vol. 277, no.
3, pp. 233237, 2008.
- E. M.-J. Xenakis, O. Langer, J. M. Piper,
D. Conway, and M. D. Berkus, Low-dose
versus high-dose oxytocin augmentation of labora
randomized trial, American Journal of Obstetrics
and Gynecology, vol. 173, no. 6, pp. 18741878,
- D. C. Merrill and F. J. Zlatnik, Randomized,
double-masked comparison of oxytocin dosage in induction
and augmentation of labor, Obstetrics and
Gynecology, vol. 94, no. 3, pp. 455463, 1999.
- R. Robles, N. Palomino, and A. Robles, Oxidative
stress in the neonate, Early Human Development,
vol. 65, pp. S75S81, 2001.
- Z. Hracsko, H. Orvos, Z. Novak, A. Pal, and
I. S. Varga, Evaluation
of oxidative stress markers in neonates with
intra-uterine growth retardation, Redox Report,
vol. 13, no. 1, pp. 1116, 2008.
- O. Paamoni-Keren, T. Silberstein, A. Burg,
I. Raz, M. Mazor, and O. Saphier, Oxidative
stress as determined by glutathione (GSH) concentrations
in venous cord blood in elective cesarean delivery
versus uncomplicated vaginal delivery, Archives
of Gynecology and Obstetrics, vol. 276, no. 1, pp.
- S. Lurie, Z. Matas, M. Boaz, A. Fux, A.
Golan, and O. Sadan, Different
degrees of fetal oxidative stress in elective and
emergent cesarean section, Neonatology, vol.
92, no. 2, pp. 111115, 2007.