Chiharu Kimura

The severity of hypoxic changes and oxidative DNA damage in the placenta of early-onset preeclamptic women and fetal growth restriction.

Objective: To investigate the relation between the severity of hypoxic changes and oxidative DNA damage in the placenta of early and late-onset preeclampic women and fetal growth restriction (FGR), serum parameters of oxidative stress, placental hypoxic change, and oxidative DNA damage were determined. Methods: We examined 10 participants with uncomplicated pregnancies, 13 with early-onset and 12 with late-onset preeclampsia. Maternal and umbilical plasma derivatives of reactive oxygen metabolites (d-ROMs) were measured as markers of oxygen free radicals. Immunohistochemical analysis was performed to measure the proportion of placental trophoblast cell nuclei staining positive for 8-hydroxy-2’-deoxyguanosine (8-OHdG), redox factor-1 (ref-1), and hypoxia-induced factor-1α (HIF-1α), which are markers of oxidative DNA damage, repair functions, and hypoxia status, respectively. Results: 8-OHdG was higher in both preeclamptic groups, but significantly higher in the early-onset preeclamptic group. Ref-1 was higher in the late-onset preeclamptic group. HIF-1α was higher in both preeclamptic groups, with a tendency towards a higher in the early-onset preeclamptic group. Conclusions: Our findings indicate that the severity of hypoxic changes and oxidative DNA damage are greater in the placenta of women with early-onset preeclampsia, and that the prolonged preeclamptic conditions may reduce placental blood flow, ultimately leading to FGR.

Increased oxygen free radical production during pregnancy may impair vascular reactivity in preeclamptic women.

To determine whether enhanced oxidative stress during pregnancy impairs vascular endothelial function and improves after delivery in preeclamptic women, we measured serum parameters of oxidative stress and endothelial function during pregnancy and 1 month after delivery in women with or without preeclampsia. We evaluated 18 participants with uncomplicated pregnancies, 11 with mild preeclampsia and 13 with severe preeclampsia. The plasma concentrations of reactive oxygen metabolite derivatives (d-ROMs) were measured, and the biological antioxidant potential (BAP) was determined to evaluate the oxygen free radicals and antioxidants, respectively. Flow-mediated vasodilation (FMD) was also assessed as a marker of endothelial function. FMD was decreased significantly in both preeclamptic groups compared with control during pregnancy. FMD did not change after delivery in the control group, but it significantly increased after delivery in both the mildly and severely preeclamptic groups, nearing control levels 1 month after delivery (mild, 6.5±3.6–9.0±3.5%; severe, 4.3±3.3–9.7±2.6%). No changes in d-ROM concentrations were observed in the control group; however, the concentrations in both the mildly and severely preeclamptic groups significantly decreased to normal levels 1 month after delivery (mild, 562.0±106.5–430.5±90.5 CARR U (Carratelli units); severe, 681.0±239.0–411.8±69.7 CARR U). The plasma BAP levels did not change significantly in all three groups. A negative correlation between FMD and d-ROM concentrations was observed in the preeclamptic group, but not in the control group (r=−0.497; P<0.05). Our findings indicated that enhanced oxidative stress during pregnancy may impair endothelial function and improve after delivery in preeclamptic women.

Differences in vascular reactivity between pregnant women with chronic hypertension and preeclampsia.

The purpose of this study was to evaluate the distinct pathogenic mechanisms underlying chronic hypertension in pregnancy and preeclampsia in terms of oxidative stress and vascular reactivity. A total of 17 women with uncomplicated pregnancies, 30 women with preeclampsia and 17 women with chronic hypertension were evaluated. We measured serum derivatives of reactive oxygen metabolites (d-ROMs; marker of oxygen free radicals), flow-mediated vasodilation (FMD; marker of endothelial function) and intima-media thickness in the carotid artery (IMT; marker of atherogenesis) during pregnancy and 1 month after delivery. Serum d-ROM concentrations were significantly higher in women with chronic hypertension and severe preeclampsia than in the control group during pregnancy. d-ROM concentrations in all groups significantly decreased to similar levels 1 month after delivery. FMD was significantly lower during pregnancy in preeclamptic and chronic hypertension groups compared with the control group. FMD in preeclamptic groups significantly increased and normalized to control levels after delivery. Similarly, FMD in the chronic hypertension group significantly increased after delivery but was still lower. IMT in the chronic hypertension group was significantly higher than that in control and preeclamptic groups. These findings suggest that endothelial dysfunction induced by enhanced oxidative stress is reversible in women with preeclampsia, whereas impaired vascular reactivity may be associated with atherosclerotic changes in women with chronic hypertension.

Increased oxidant generation in the metabolism of hypoxanthine to uric acid and endothelial dysfunction in early-onset and late-onset preeclamptic women

Objective: The purpose of this study was to evaluate the association of vascular endothelial dysfunction with increased oxidant generation in the metabolism of hypoxanthine to uric acid in early-onset compared to late-onset preeclampsia. Methods: We investigated 12 women with early-onset preeclampsia, 14 women with late-onset preeclampsia, and 20 women with uncomplicated pregnancies. We measured serum derivatives of reactive oxygen metabolites (d-ROMs) as a marker of oxygen free radicals, serum biological antioxidant potential (BAP), hypoxanthine, uric acid, uric acid clearance (CUA), and flow-mediated vasodilation (FMD) as a marker of endothelial function in preeclamptic women. Results: Concentration of d-ROMs was significantly higher in both preeclamptic groups compared to the control group. Plasma levels of uric acid were significantly elevated in both preeclamptic groups compared to the control group. Plasma levels of hypoxanthine were significantly higher in early-onset preeclamptic women compared to controls, but not in late-onset preeclamptic women. CUA was significantly lower in late-onset preeclamptic women compared to controls, but not in early-onset preeclamptic women. The concentrations of hypoxanthine and uric acid correlated positively with the concentration of d-ROMs in all pregnant women. FMD was significantly lower in both preeclamptic groups compared with controls, but FMD in the early-onset preeclamptic group was significantly lower than in the late-onset preeclamptic group. Conclusions: We found that increased oxidant generation during metabolism of hypoxanthine to uric acid may impair endothelial function in early-onset preeclampsia.

Pregnancy-induced hypertension is associated with an increase in the prevalence of cardiovascular disease risk factors in Japanese women.

ObjectiveThis study assessed whether pregnancy-induced hypertension (PIH) affects the prevalence of cardiovascular disease (CVD) risk factors in later life among Japanese women. MethodsStudy participants were 1,185 women (mean [SD] age, 46.5 [5.6] y; range, 38-73 y) aged 40 years or older who underwent a health checkup at a periodic health examination facility between January 2012 and December 2013 and had experienced giving birth. Questionnaires were sent to potential participants, and they were encouraged to provide their Maternal and Child Health Handbook (handbook). We recruited 101 women with a history of PIH (PIH group) and 1,084 women with uncomplicated pregnancy at delivery (control group). Groupings were based on information from the handbook. We assessed the association between PIH and CVD in later life among Japanese women by focusing on hypertension, diabetes mellitus, and dyslipidemia as risk factors for CVD. Odds ratios (ORs) for the use of antihypertensive, diabetes mellitus, and dyslipidemic medications in the PIH group were determined. ResultsWomen with PIH had increased risk of antihypertensive medication use compared with women without PIH (2.9% vs 13.9%; OR, 4.28; 95% CI, 2.14-8.57). Triglycerides were significantly higher and high-density lipoprotein cholesterol was significantly lower in the PIH group than in the control group. The OR for dyslipidemic medication use in the PIH group relative to the control group was 3.20 (95% CI, 1.42-7.22). ConclusionsOur findings suggest that a history of PIH may be associated with an increased risk of hypertension (a risk factor for CVD) in later life among Japanese women.

Differences in levels of oxidative stress in mothers and neonate: the impact of mode of delivery

Abstract Objective: To determine there are differences in the production levels of oxygen free radical between mothers and neonates by the mode of delivery, we measured oxygen free radical concentrations in maternal vein and umbilical artery. Methods: Forty-four women with singleton term pregnancies were prospectively recruited and classified into two groups: those who had a spontaneous uncomplicated vaginal delivery (VD group; n = 21), and those who had an elective cesarean delivery (CD group; n = 23). We determined maternal and fetal oxidative stress levels by measuring concentrations of derivatives of reactive oxygen metabolites (d-ROMs) in maternal vein before delivery and on postnatal day 5, and in umbilical artery at delivery. We also measured the pH, partial pressure of oxygen (PaO2), partial pressure of carbon dioxide (PaCO2) and base excess (BE) in umbilical artery blood collected at delivery. Results: The concentrations of d-ROMs in maternal vein on postnatal day 5 were significantly decreased in the VD group, but were significantly increased in the CD group, compared to before delivery. The concentrations of d-ROMs in umbilical artery were significantly higher in the VD group than the CD group. Compared to the CD group, umbilical artery pH tended to be lower (p = 0.07), and BE significantly lower (p < 0.005), in the VD group. There were no significant differences in umbilical artery PaO2 and PaCO2 between the two groups. Conclusion: Our findings indicate that those production levels of oxygen free radical in mothers are greater by CD than by VD, while those in neonates are greater by VD than by CD.

Placental oxidative stress and maternal endothelial function in pregnant women with normotensive fetal growth restriction

Abstract Objective: The purpose of this study was to investigate the relationship between placental oxidative stress and maternal endothelial function in pregnant women with normotensive fetal growth restriction (FGR). Methods: We examined serum concentrations of oxygen free radicals (d-ROMs), maternal angiogenic factor (PlGF), and sFlt-1, placental oxidative DNA damage, and maternal endothelial function in 17 women with early-onset preeclampsia (PE), 18 with late-onset PE, 14 with normotensive FGR, and 21 controls. Flow-mediated vasodilation (FMD) was assessed as a marker of maternal endothelial function. Immunohistochemical analysis was performed to measure the proportion of placental trophoblast cell nuclei staining positive for 8-hydroxy-2’-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage. Results: Maternal serum d-ROM, sFlt-1 concentrations, and FMD did not significantly differ between the control and normotensive FGR groups. The proportion of nuclei staining positive for 8-OHdG was significantly higher in the normotensive FGR group relative to the control group. Conclusions: Our findings demonstrate that, despite the presence of placental oxidative DNA damage as observed in PE patients, pregnant women with normotensive FGR show no increase in the concentrations of sFlt-1 and d-ROMs, or a decrease in FMD.

PP043. Oxidative stress in the maternal body also affects the fetus in preeclamptic women with fetal growth restriction

The purpose of the present study was to determine whether oxidative stress occurring in the maternal body also affects the fetus in preeclamptic women with FGR. We ∥@consecutively recruited 17 preeclamptic women with FGR, 16 preeclamptic women without FGR, and 16 healthy pregnant women with uncomplicated pregnancy. We measured concentrations of derivatives of reactive oxygen metabolites (d-ROMs) as a marker of oxygen free radicals in a maternal vein, umbilical artery, and umbilical vein. ∥@Maternal d-ROM levels were higher in preeclamptic groups compared to the control group. Umbilical artery and vein d-ROM levels were elevated in preeclamptic women with FGR compared to the control group. Umbilical artery d-ROM levels were significantly higher than in the vein in preeclamptic women with FGR, but not in those without FGR. Umbilical arterial blood pH was significantly lower in preeclamptic women with FGR. The partial pressure of oxygen (PaO2) in umbilical arterial blood tended to be lower in preeclamptic women with FGR (p=0.08). The partial pressure of carbon dioxide (PaCO2) in umbilical arterial blood was significantly higher in preeclamptic women with FGR. These results indicate that oxidative stress occurring in the maternal body also affects the fetus in preeclamptic women with FGR.

PP075. Endothelial dysfunction may be impaired by increased oxidative stress in preeclamptic women.

INTRODUCTION The essential pathogenesis in preeclampsia is vasospasm induced by endothelial cell injury. The vascular endothelium regulates vascular smooth muscle tone by producing vasoconstrictors and vasodilators, such as nitric oxide (NO). Recently, it has been reported that the levels of oxidative stress are increased and they may impair endothelial NO production and induce endothelial dysfunction in preeclampsia. OBJECTIVES To determine whether maternal release of oxygen free radical and antioxidants are associated with maternal vascular endothelial cell injury, we measured serum parameters of oxidative stress and endothelial function during pregnancy in women with or without preeclampsia. METHODS We evaluated 20 participants with uncomplicated pregnancies, 15 with mild preeclampsia, and 18 with severe preeclampsia. Plasma concentrations were measured for derivatives of reactive oxygen metabolites (d-ROMs) and biological antioxidant potential (BAP) as markers of oxygen free radicals and antioxidants, respectively. Flow-mediated vasodilation (FMD) was also assessed as a marker of endothelial function. RESULTS D-ROMs were increased in the maternal blood of the severe preeclamptic group compared with the control group (681.0±239.0 vs 478.6±101.4 CARR U, P<0.001), but not in the mild preeclamptic group (562.0±106.5 CARR U). Plasma BAP levels did not change significant in all three groups. The proportion of d-ROMs to BAP was higher in the severe preeclamptic group than in controls (0.28±0.11 vs 0.21±0.05, P<0.01), but not in the mild preeclamptic group (0.24±0.08). FMD was significantly decreased in both preeclamptic groups (severe, 4.3±3.3%, P<0.001; mild, 6.5±3.6%, P<0.001) compared with controls (10.5±2.3%), but FMD in the severe preeclamptic group was significantly greater than in the mild preeclamptic group. A negative correlation between FMD and d-ROM concentrations was observed in all participants (r=-0.376, P<0.05), and the ratio of serum d-ROMsto BAP correlated negatively with FMD (r=-0.413, P<0.05) in all participants. CONCLUSION We found that the production of oxygen free radicals increased, but not the production of antioxidants which decreased, as a result, an imbalance between reactive oxygen species formation and antioxidant defence mechanisms may have impaired endothelial function in preeclamptic women.