The associations between labor and delivery mode and maternal and placental oxidative stress

doi:10.1016/j.reprotox.2010.11.009

Reproductive Toxicology

Volume 31, Issue 2, February 2011, Pages 144-150

https://doi.org/10.1016/j.reprotox.2010.11.009 Get rights and content

Abstract

To study oxidative stress differences between women with normal vaginal deliveries (VD) and those with elective cesarean sections without labor (CS), total antioxidant capacity (TAC), erythrocyte glutathione peroxidase (GPX) and superoxide dismutase (SOD) activity, 8-isoprostane, nitrotyrosine and 8-hydroxydeoxyguanosine (8-OHdG) in blood, urine, and placental samples were assessed. The VD group had significantly higher placental 8-isoprostane and 8-OHdG levels as well as greater plasma TAC and 8-OHdG levels and lower erythrocyte SOD activity in umbilical venous blood. Women with VD exhibited differential changes in maternal oxidative stress before and after delivery compared with women with CS. Furthermore, we found that repetitive hypoxia-reoxygenation increased the 8-isoprostane and 8-OHdG levels in villous explants compared with the normoxic controls. Together, these results indicate that labor is associated with increased placental oxidative stress and has an influence on maternal oxidative stress. Therefore, women with VD exhibit different oxidative stress indicators than do those with CS.

Introduction

Many studies have shown that oxidative stress increases during pregnancy, and oxidative damage is exaggerated by pregnancy complications such as preeclampsia [1], [2], [3]. However, the association between labor and delivery mode and oxidative stress remains controversial. Some investigators have observed that vaginal delivery is associated with increased oxidative stress in the mother [4], [5], [6], the fetus [7], [8] and the placenta [9], while others have failed to detect similar relationships [10], [11], [12], [13], [14]. Most prior studies included small samples and evaluated few markers of oxidative stress. Moreover, those studies did not use a paired antepartum–postpartum design to control for inter-individual variations. These factors may contribute to the inconsistent results between studies.

On the other hand, the placenta's contribution to oxidative stress during labor is unclear. The human placenta is hemochorial, and maternal blood directly bathes the syncytiotrophoblast of the fetal villous tree. Several lines of evidence suggest it is plausible that blood flow in the intervillous space is intermittent in normal pregnancies [3], [15], [16]. This intermittency culminates with labor, when uterine contractions are the most frequent and vigorous [17], creating the possibility of an ischemia-reperfusion type injury to the placenta. One of the many harmful effects of reperfusion injury is the production of reactive oxygen species that can peroxidize membrane lipids, oxidize DNA or denature enzyme proteins, leading to oxidative cell damage. We surmise that intermittent perfusion of the intervillous space, e.g., repetitive hypoxia-reoxygenation (HR), causes oxidative stress in the human placenta during labor; further, we hypothesize that labor is associated with increased oxidative stress in maternal and placental–fetal circulation.

The objectives of this study were therefore (1) to study oxidative stress levels in the placenta and in maternal and placental–fetal circulation in women who had normal vaginal deliveries and those who had elective cesarean sections without labor and (2) to test the hypothesis that repetitive HR increases placental oxidative stress levels, and administration of the antioxidant N-acetyl-cysteine (NAC) reduces these levels.

Section snippets

Materials and methods

This study was approved by the Institutional Review Board of Chang Gung Memorial Hospital, Taiwan (No. 94-498 and No. 95-1392B). All blood, urine and placental samples were collected after the subjects provided written informed consent. The materials and chemicals used in this study were purchased from Sigma Chemical Co., St. Louis, MO, except where otherwise indicated.

Women with vaginal deliveries exhibited increased placental oxidative stress compared to those with elective cesarean sections

Table 1 shows the characteristics of our study population. There were no differences in maternal age, parity, prepregnancy body mass index, gestational age at delivery, birth weight, placental weight or 1- and 5-min Apgar scores. There were no differences in the prevalence of male fetuses, primiparity, transfusion, epidural anesthesia, group B streptococcal colonization at the rectogenital tract, meconium-stained amniotic fluid, nuchal cord or use of uterotonic agents. However, women having

Discussion

Our study shows evidence of increased placental oxidative stress, including greater amounts of 8-isoprostane and 8-OHdG in the villous tissues and higher levels of plasma 8-OHdG, but lower erythrocyte SOD activity in the umbilical venous blood, in women with normal vaginal deliveries compared with those with elective cesarean sections. Consistent with our in vivo findings, we further demonstrated that repetitive HR is a possible cause of placental oxidative stress during labor. Because of the

Conclusions

Labor is associated with increased placental oxidative stress, and women with normal vaginal deliveries exhibit different oxidative stress indicators than do those with elective cesarean sections.

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgements

This work was supported by the National Science Council, Taiwan (NSC 96–2314-B182A-061-MY3) and Chang Gung Memorial Hospital (NMRPG166021). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References (40)

R.E. Little et al.
Levels of lipid peroxides in uncomplicated pregnancy: a review of the literature
Reprod Toxicol
(1999)
O. Fainaru et al.
Active labour is associated with increased oxidisibility of serum lipids ex vivo
BJOG
(2002)
M.G. Sridhar et al.
Oxidative stress varies with the mode of delivery in intrauterine growth retardation: association with Apgar score
Clin Biochem
(2007)
T. Cindrova-Davies et al.
Oxidative stress, gene expression, and protein changes induced in the human placenta during labor
Am J Pathol
(2007)
I.A. Buhimschi et al.
Beneficial impact of term labor: nonenzymatic antioxidant reserve in the human fetus
Am J Obstet Gynecol
(2003)
I. Fogel et al.
Oxidative stress in the fetal circulation does not depend on mode of delivery
Am J Obstet Gynecol
(2005)
V.H. Roberts et al.
Effect of increasing maternal body mass index on oxidative and nitrative stress in the human placenta
Placenta
(2009)
T.H. Hung et al.
Hypoxia and reoxygenation: a possible mechanism for placental oxidative stress in preeclampsia
Taiwan J Obstet Gynecol
(2006)
H.S. Brar et al.
Qualitative assessment of maternal uterine and fetal umbilical artery blood flow and resistance in laboring patients by Doppler velocimetry
Am J Obstet Gynecol
(1988)
T.H. Hung et al.
Tumour necrosis factor-alpha converting enzyme in human gestational tissues from pregnancies complicated by chorioamnionitis
Placenta
(2006)

T.H. Hung et al.

Bax, Bak and mitochondrial oxidants are involved in hypoxia-reoxygenation-induced apoptosis in human placenta

Placenta

(2008)

I.F. Benzie et al.

The ferric reducing ability of plasma (FRAP) as a measure of “antioxidant power”: the FRAP assay

Anal Biochem

(1996)

C. Sun et al.

A common mutation of the MYH gene is associated with increased DNA oxidation and age-related diseases

Free Radic Biol Med

(2010)

C.C. Chiou et al.

Urinary 8-hydroxydeoxyguanosine and its analogs as DNA marker of oxidative stress: development of an ELISA and measurement in both bladder and prostate cancers

Clin Chim Acta

(2003)

A. Many et al.

Xanthine oxidase/dehydrogenase is present in human placenta

Placenta

(1996)

A. Many et al.

Increased xanthine oxidase during labour—implications for oxidative stress

Placenta

(1997)

N.Z. Dordevic et al.

Oxidative stress and changes in antioxidative defense system in erythrocytes of preeclampsia in women

Reprod Toxicol

(2008)

K.S. Khaw et al.

Effects of high inspired oxygen fraction during elective caesarean section under spinal anaesthesia on maternal and fetal oxygenation and lipid peroxidation

Br J Anaesth

(2002)

T.H. Hung et al.

Secretion of tumor necrosis factor-{alpha} from human placental tissues induced by hypoxia-reoxygenation causes endothelial cell activation in vitro: a potential mediator of the inflammatory response in preeclampsia

Am J Pathol

(2004)

T. Cindrova-Davies et al.

Nuclear factor-kappa B, p38, and stress-activated protein kinase mitogen-activated protein kinase signaling pathways regulate proinflammatory cytokines and apoptosis in human placental explants in response to oxidative stress: effects of antioxidant vitamins

Am J Pathol

(2007)

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The associations between labor and delivery mode and maternal and placental oxidative stress

Abstract

Introduction

Section snippets

Materials and methods

Women with vaginal deliveries exhibited increased placental oxidative stress compared to those with elective cesarean sections

Discussion

Conclusions

Conflict of interest statement

Acknowledgements

Reprod Toxicol

BJOG

Clin Biochem

Am J Pathol

Am J Obstet Gynecol

Am J Obstet Gynecol

Placenta

Taiwan J Obstet Gynecol

Am J Obstet Gynecol

Placenta

Placenta

Anal Biochem

Free Radic Biol Med

Clin Chim Acta

Placenta

Placenta

Reprod Toxicol

Br J Anaesth

Am J Pathol

Am J Pathol