Tai-Ho Hung

Risk factors for pre-eclampsia in an Asian population.

Objective: To identify the risk factors for pre‐eclampsia in an Asian population. Method: We conducted a retrospective cohort study involving 29 375 Taiwanese women who delivered between July 1990 and September 1998, excluding pregnancies complicated by chronic hypertension or fetal malformations. Result: Four hundred and fifteen women had pre‐eclampsia (1.4%). Women who had a history of pre‐eclampsia (OR 6.3, 95% CI 4.4, 9.2), multiple gestation (OR 3.6, 95% CI 2.4, 5.5), a prepregnancy BMI>24.2 kg/m2 (OR 2.4, 95% CI 1.8, 3.1), were>34 years of age (OR 1.8, 95% CI 1.4, 2.4), nulliparous (OR 1.3, 95% CI 1.2, 1.5), had urinary tract infection (OR 4.8, 95% CI 1.5, 15.8), or worked during pregnancy (OR 1.9, 95% CI 1.4, 2.4) were at increased risk of pre‐eclampsia. Conclusion: Some of the risk factors for pre‐eclampsia among Asian women are the same as those of other ethnic groups, whereas some of the risk factors are different.

A Longitudinal Study of Oxidative Stress and Antioxidant Status in Women With Uncomplicated Pregnancies Throughout Gestation

Pregnancy is associated with increased oxidative stress, and exaggeration of oxidative damage is considered important in pregnancy complications such as preeclampsia. There is, however, only scattered information regarding the longitudinal change of oxidative stress during pregnancy. We surmised that the placenta is the cause of the increased oxidative stress during pregnancy and hypothesized that the amount of placenta-derived cell-free fetal DNA in maternal plasma is correlated with maternal oxidative stress status. Blood and urine samples were collected at different stages of gestation and 6 to 8 weeks postpartum from 105 women with uncomplicated pregnancies. Additionally, 40 healthy women of reproductive age, but not pregnant, were recruited as controls. All oxidative stress markers, including urinary 8-hydroxydeoxyguanosine (8-OHdG), plasma 8-isoprostane, total antioxidant capacity (TAC), and erythrocyte glutathione peroxidase (GPX) and superoxide dismutase (SOD) activities, were increased in the third trimester, and most of them returned to nonpregnant levels postpartum. Furthermore, the DYS14 gene of the Y chromosome was quantified from plasma samples obtained at 26 to 30 weeks’ gestation in 54 women who later delivered a male infant. Significant associations were noted between plasma concentrations of the DYS14 gene and the levels of urinary 8-OHdG and plasma 8-isoprostane, suggesting an association between the breakdown of syncytiotrophoblast and maternal oxidative stress during pregnancy.

Advanced maternal age and adverse perinatal outcomes in an Asian population

OBJECTIVE To investigate (1) whether there is an increasing trend in the mean maternal age at the birth of the first child and in the group of women giving birth at age 35 or older, and (2) the association between advanced maternal age and adverse perinatal outcomes in an Asian population. STUDY DESIGN We conducted a retrospective cohort study involving 39,763 Taiwanese women who delivered after 24 weeks of gestation between July 1990 and December 2003. Multivariable logistic regression was used to adjust for potential confounding variables. RESULTS During the study period, the mean maternal age at the birth of the first child increased from 28.0 to 29.7 years, and the proportion of women giving birth at age 35 or older increased from 11.4% to 19.1%. Compared to women aged 20-34 years, women giving birth at age 35 or older carried a nearly 1.5-fold increased risk for pregnancy complications and a 1.6-2.6-fold increased risk for adverse perinatal outcomes. After adjusting for the confounding effects of maternal characteristics and coexisting pregnancy complications, women aged 35-39 years were at increased risk for operative vaginal delivery (adjusted odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2-1.7) and cesarean delivery (adjusted OR 1.6, 95% CI 1.5-1.7), while women aged 40 years and older were at increased risk for preterm delivery (before 37 weeks of gestation) (adjusted OR 1.7, 95% CI 1.3-2.2), operative vaginal delivery (adjusted OR 3.1, 95% CI 2.0-4.6), and cesarean delivery (adjusted OR 2.6, 95% CI 2.2-3.1). In those women who had a completely uncomplicated pregnancy and a normal vaginal delivery, advanced maternal age was still significantly associated with early preterm delivery (before 34 weeks of gestation), a birth weight <1500 g, low Apgar scores, fetal demise, and neonatal death. CONCLUSION In this population of Taiwanese women, there is an increasing trend in the mean maternal age at the birth of the first child. Furthermore, advanced maternal age is independently associated with specific adverse perinatal outcomes.

Increased Autophagy in Placentas of Intrauterine Growth-Restricted Pregnancies

Background Unexplained intrauterine growth restriction (IUGR) may be a consequence of placental insufficiency; however, its etiology is not fully understood. We surmised that defective placentation in IUGR dysregulates cellular bioenergic homeostasis, leading to increased autophagy in the villous trophoblast. The aims of this work were (1) to compare the differences in autophagy, p53 expression, and apoptosis between placentas of women with normal or IUGR pregnancies; (2) to study the effects of hypoxia and the role of p53 in regulating trophoblast autophagy; and (3) to investigate the relationship between autophagy and apoptosis in hypoxic trophoblasts. Methodology/Principal Findings Compared with normal pregnant women, women with IUGR had higher placental levels of autophagy-related proteins LC3B-II, beclin-1, and damage-regulated autophagy modulator (DRAM), with increased p53 and caspase-cleaved cytokeratin 18 (M30). Furthermore, cytotrophoblasts cultured under hypoxia (2% oxygen) in the presence or absence of nutlin-3 (a p53 activity stimulator) had higher levels of LC3B-II, DRAM, and M30 proteins and increased Bax mRNA expression compared with controls cultured under standard conditions. In contrast, administration of pifithrin-α (a p53 activity inhibitor) during hypoxia resulted in protein levels that were similar to those of the control groups. Moreover, cytotrophoblasts transfected with LC3B, beclin-1, or DRAM siRNA had higher levels of M30 compared with the controls under hypoxia. However, transfection with Bcl-2 or Bax siRNA did not cause any significant change in the levels of LC3B-II in hypoxic cytotrophoblasts. Conclusions/Significance Together, these results suggest that there is a crosstalk between autophagy and apoptosis in IUGR and that p53 plays a pivotal and complex role in regulating trophoblast cell turnover in response to hypoxic stress.

Autophagy in the Human Placenta throughout Gestation

Background Autophagy has been reported to be essential for pre-implantation development and embryo survival. However, its role in placental development and regulation of autophagy during pregnancy remain unclear. The aims of this study were to (1) study autophagy by characterizing changes in levels of beclin-1, DRAM, and LC3B in human placenta throughout gestation; (2) determine whether autophagy is involved in regulation of trophoblast invasion in JEG-3 cells (a choriocarcinoma cell line); (3) examine the effects of reduced oxygen and glucose on the autophagic changes; and (4) investigate the effect of reoxygenation and supplementation of glucose after oxygen-glucose deprivation (OGD) on the autophagic changes in primary cytotrophoblasts obtained from normal term pregnancy. Methodology/Principal Findings An analysis of 40 placental samples representing different gestational stages showed (1) no significant differences in beclin-1, DRAM, and LC3B-II levels in placentas between early and mid-gestation, and late gestation with vaginal delivery; (2) placentas from late gestation with cesarean section had lower levels of LC3B-II compared to early and mid-gestation, and late gestation with vaginal delivery; levels of DRAM were also lower compared to placentas from early and mid-gestation; and (3) using explant cultures, villous tissues from early and late gestation had similar rates of autophagic flux under physiological oxygen concentrations. Knockdown of BECN1, DRAM, and LC3B had no effects on viability and invasion activity of JEG-3 cells. On the other hand, OGD caused a significant increase in the levels of LC3B-II in primary cytotrophoblasts, while re-supplementation of oxygen and glucose reduced these changes. Furthermore, there were differential changes in levels of beclin-1, DRAM, and LC3B-II in response to changes in oxygen and glucose levels. Conclusions/Significance Our results indicate that autophagy is involved in development of the human placenta and that changes in oxygen and glucose levels participate in regulation of autophagic changes in cytotrophoblast cells.

The Association Between Maternal Oxidative Stress at Mid-Gestation and Subsequent Pregnancy Complications

Objective: To investigate the association between maternal oxidative stress at mid-gestation and subsequent development of pregnancy complications. Study design: A total of 503 healthy pregnant women provided their blood and urine samples at 24 to 26 weeks of gestation and were prospectively followed through postpartum. These samples were used to assess a variety of oxidative stress markers, including plasma total antioxidant capacity, 8-isoprostane, erythrocyte glutathione peroxidase and superoxide dismutase activity, and urinary 8-hydroxydeoxyguanosine (8-OHdG). Results: Compared with women with uncomplicated pregnancies, significantly higher plasma 8-isoprostane levels were noted in women who developed preeclampsia (P = .008) and small-for-gestational age infants (P = .002), while higher urinary 8-OHdG concentrations were noted in women who subsequently had low-birth-weight neonates (<2500 g, P = .043). Conclusion: Increased maternal oxidative stress at mid-gestation was associated with subsequent pregnancy complications.

Risk Factors for Placental Abruption in an Asian Population

The objective of this study was to identify risk factors for placental abruption in an Asian population. The authors conducted a retrospective review of 37 245 Taiwanese women who delivered between July 1990 and December 2003. Pregnancies complicated by placenta previa, multiple gestation, and fetal anomalies were excluded. Multivariable logistic regression was used to adjust for potentially confounding variables and to identify independent risk factors for placental abruption. Three hundred thirty-two women had placental abruption (9 per 1000 singleton deliveries). Women who smoked during pregnancy (adjusted odds ratio [OR] = 8.4; 95% confidence interval [CI] = 3.0-23.9), had gestational hypertensive diseases (adjusted OR = 4.9; 95% CI = 3.3-7.3), pregnancies complicated by oligohydramnios (adjusted OR = 4.2; 95% CI = 2.7-6.7), polyhydramnios (adjusted OR = 3.3; 95% CI = 1.4-7.7), preterm premature rupture of membranes (adjusted OR = 1.9; 95% CI = 1.1-3.1), entanglement of umbilical cord (adjusted OR = 1.6; 95% CI = 1.2-2.1), were of or more than 35 years of age (adjusted OR = 1.5; 95% CI = 1.1-2.0), and had a low prepregnancy body mass index (adjusted OR = 1.3; 95% CI = 1.0-1.6) were at increased risk for placental abruption. Some risk factors for placental abruption among Taiwanese women are the same as those of other ethnic groups, whereas some of the risk factors are different.

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

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.

The impact of interpregnancy interval and previous preterm birth on the subsequent risk of preterm birth

Objective: To examine the impact of the interpregnancy interval and a previous preterm birth on the subsequent risk of a preterm birth. Methods: A retrospective analysis was conducted on a group of 4072 women who had at least two consecutive births, excluding multiple gestation, fetal anomalies, cervical incompetence, and stillbirth. Multivariate logistic regression was used to investigate the association between interpregnancy interval, preterm birth of the first child in the pair (index pregnancy), and the risk of a preterm birth of the second child in the pair (outcome pregnancy). Results: Women with interpregnancy intervals of less than 12 months (odds ratio [OR] 1.3; 95% confidence interval [CI] 1.01. 1.7) were at increased risks of preterm birth with the outcome pregnancy. Furthermore, there was an increased risk for a subsequent preterm birth in women who had a preterm birth in the index pregnancy (OR 4.2; 95% CI 3.0-6.0). The risk decreased as the interpregnancy interval increased, with a relatively low risk at 18 to 48 months; subsequently, it increased sharply. In contrast, women who had delivered their previous infants at term carried an increased risk of preterm birth with the outcome pregnancy only if the interval was less than 6 months. Conclusion: A difference was found in the impact of the interpregnancy interval on the subsequent risk of preterm birth between women with a prior preterm birth and those who previously delivered an infant at term.

Differential effects of concomitant use of vitamins C and E on trophoblast apoptosis and autophagy between normoxia and hypoxia-reoxygenation.

Background Concomitant supplementation of vitamins C and E during pregnancy has been reportedly associated with low birth weight, the premature rupture of membranes and fetal loss or perinatal death in women at risk for preeclampsia; however, the cause is unknown. We surmise that hypoxia-reoxygenation (HR) within the intervillous space due to abnormal placentation is the mechanism and hypothesize that concomitant administration of aforementioned vitamin antioxidants detrimentally affects trophoblast cells during HR. Methodology/Principal Findings Using villous explants, concomitant administration of 50 µM of vitamins C and E was observed to reduce apoptotic and autophagic changes in the trophoblast layer at normoxia (8% oxygen) but to cause more prominent apoptosis and autophagy during HR. Furthermore, increased levels of Bcl-2 and Bcl-xL in association with a decrease in the autophagy-related protein LC3-II were noted in cytotrophoblastic cells treated with vitamins C and E under standard culture conditions. In contrast, vitamin treatment decreased Bcl-2 and Bcl-xL as well as increased mitochondrial Bak and cytosolic LC3-II in cytotrophoblasts subjected to HR. Conclusions/Significance Our results indicate that concomitant administration of vitamins C and E has differential effects on the changes of apoptosis, autophagy and the expression of Bcl-2 family of proteins in the trophoblasts between normoxia and HR. These changes may probably lead to the impairment of placental function and suboptimal growth of the fetus.