A synthetic analog of lipoxin A4 partially alleviates dexamethasone-induced fetal growth restriction in rats

Fetal growth restriction (FGR) is a major cause of neonatal morbidity and mortality. There is evidence to show that FGR is associated with oxidative stress. Lipoxin A₄ (LXA₄) is an anti-inflammatory mediator and is considered to be a potent endogenous “stop signal” in inflammation. LXA₄ has been extensively studied preclinically in many diseases related to inflammation. Recently, the antioxidant effect of LXA₄ on a variety of cell types has been reported. In the current study, we tested the effect of LXA₄ on rats with experimental FGR. Dexamethasone (DEX) was administered to pregnant rats in order to induce FGR and BML-111, a synthetic analog of LXA₄, was administrated as antioxidant therapy. DEX caused increased oxidative stress and trophoblast cell apoptosis in the placenta, leading to decreased placental weight and fetal weight at term. These effects were partially alleviated by BML-111. As a possible mechanism for this improvement in weight, BML-111 was found to promote nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), up-regulate the expression of antioxidant enzyme genes, superoxide dismutase (SOD) and glutathione peroxidase (GPx), and consequently inhibited trophoblast cells apoptosis. This study demonstrates for the first time that LXA₄ could potentially alleviate FGR in DEX-exposed pregnant rats.     

Ischemia-modified albumin as an oxidative stress biomarker in early pregnancy loss

Background/aims: This study aimed to determine the association between early pregnancy loss and serum ischemia-modified albumin (IMA) concentrations.

Methods: Serum samples of 180 women that included healthy pregnant women, women admitted for termination of pregnancy due to the absence of fetal cardiac activity or absence of fetal pole on ultrasonographic examination, and healthy non-pregnant women attending for gynecological examination. Each group included 60 patients. Serum concentrations of IMA were compared among the groups, and the correlations with patients’ age, gravidity, BMI, gestational age and total serum albumin concentrations were calculated.

Results: When the groups were compared with respect to IMA concentrations, the group with early pregnancy loss was found to have significantly higher IMA concentrations (p?<?0.001). An IMA threshold of >163?ng/mL had a sensitivity of 75%, specificity of 55% to discriminate between healthy pregnant patients and patients with early pregnancy loss in first trimester.

Conclusion: Our findings support the theory that possible oxidative stress, a more hypoxic environment and defective placentation lead to increased serum IMA concentrations. These findings may help to shed light on the complicated pathogenesis of early pregnancy loss.     

Maternal serum and fetal cord-blood ischemia-modified albumin concentrations in normal pregnancy and preeclampsia: a systematic review and meta-analysis

Background/aims: A meta-analysis of maternal serum ischemia-modified albumin (IMA) and fetal cord-blood IMA concentrations in normal pregnancy (NP) compared to non-pregnant healthy controls (HC) and in preeclampsia (PE) compared with normal pregnant controls were studied.

Methods: All major databases were searched for eligible studies. We included eight studies comparing serum IMA between NP and HC, 14 studies comparing serum IMA between PE and NP and five studies comparing cord-blood IMA between PE and NP groups. Meta-analyses on these included studies were performed using Review Manager 5.3. Pooled-overall effect size as standardized mean difference (SMD), publication bias, subgroup, and sensitivity analysis data were generated.

Results: Random-effects meta-analysis indicated a significant increase in serum IMA in the NP group (SMD?=?0.98, p?=?.01) and the PE group (SMD?=?0.94, p?p?Conclusions: This meta-analysis, the first of its kind showed that the increased serum IMA concentrations were indicative of increased oxidative stress in NP and PE. Measurement of maternal serum IMA and fetal cord-blood IMA concentrations were useful as simple, novel, and inexpensive markers of oxidative stress (OS) status in PE patients. Future large-scale studies are needed to explore IMA in relationship to the disease severity in PE.     

Assessment of ischemia-modified albumin level in patients with recurrent pregnancy loss during the first trimester

Objective

The finding that ischemia-modified albumin (IMA) is increased in pre-eclamptic pregnancy suggests a role for IMA as a potential biomarker for abnormal placental development related to miscarriage. This study was undertaken to evaluate IMA levels in women with recurrent pregnancy loss (RPL).

Study design

This case-control study was performed between March 2008 and September 2009, at the Department of Obstetrics and Gynecology of Meram School of Medicine. Serum IMA and albumin concentrations were assessed in 43 women with a history of two or more unexplained first trimester miscarriages (group 1), and 42 healthy pregnant women (group 2) in the first trimester. IMA, adjusted IMA and albumin concentrations were compared between the groups. Statistical analysis was performed using Student's t-test and Mann-Whitney U test.

Results

IMA and adjusted IMA levels were significantly higher in women with RPL (1.11 + 0.08 and 1.09 + 0.09, respectively) compared to women in group 2 (0.88 + 0.10 and 0.88 + 0.11, respectively). Albumin levels in group 1 were significantly lower compared with group 2. There was a negative correlation between IMAand albumin levels in each group.

Conclusion

Maternal IMA levels appear to be elevated in women with early RPL. This finding may suggest that an abnormally high hypoxic intrauterine environment may be associated with abnormal placental development that contributes to early miscarriage.     

Oxidized low-density lipoproteins in cord blood from neonates with intra-uterine growth restriction

Objective

We verified whether oxidative stress indices (oxidized low-density lipoproteins and malondialdehyde) and inflammatory biomarkers (circulating C-reactive protein, interleukin-6, tumour necrosis factor-α, serum amyloid A and soluble intercellular vascular cell adhesion molecule) are increased in the umbilical vein of placental insufficiency induced intra-uterine growth restricted neonates.

Study design

The prospective cohort study, involving 3 tertiary care centers, consists of 200 consecutively recruited pregnant women carrying twins. We chose the twin pregnancy model because both fetuses share the same maternal environment, thereby avoiding potential confounding factors when comparing oxidative stress and inflammation biomarkers. We analysed only twin pairs with one with intra-uterine growth restriction (N = 38) defined as fetal growth < 10th percentile with abnormal Doppler of the umbilical artery. Blood samples were taken at birth from the umbilical vein. Intra-pair comparisons on the biomarkers were performed using the Student paired t-test.

Results

We observed increased cord blood levels of oxidized low-density lipoproteins, (2.394 ± .412 vs 1.296 ± .204, p = .003) but not of malondialdehyde in growth restricted neonates when compared to their normal counterparts. Although indices of inflammation tended to be increased in cord blood from growth restricted newborns, the difference did not reach statistical significance.

Conclusion

In the twin model, intra-uterine growth restriction is associated with low-density lipoprotein oxidation without apparent dysregulation of inflammation biomarkers.

Condensation

Increased oxidized low-density lipoproteins are observed in growth restricted twins compared to their co-twins with normal growth at birth.     

Ischemia-modified albumin as an oxidative stress marker in preeclampsia

Objective.?We examined serum ischaemia-modified albumin (IMA) levels in normal pregnant and preeclamptic women. The primary aim of our study was to assess IMA in women with mild and severe preeclampsia.

Methods.?Serum ischaemia-modified albumin levels were measured in 18 normotensive and 36 preeclamptic pregnant women by enzyme linked immuno-sorbent assay. Patients were subdivided as having either mild (n?=?18) or severe preeclampsia (n?=?18). Receiver operating characteristic curve was constructed, and sensitivity and specificity were calculated based on the best cut-off.

Results.?IMA levels were significantly higher in the mild and severe preeclamptic groups than in the control group. IMA with a cut-off point of 0.31 identified women with preeclampsia with sensitivity 80% and specificity 77.8%.

Conclusion.?Our study demonstrates that serum levels of IMA correlate with severity of preeclampsia.     

Elevated levels of the circulatory ischemia-modified albumin in patients with polycystic ovary syndrome: a meta-analysis

Oxidative stress (OS) has been reported to be associated with the pathogenesis of polycystic ovary syndrome (PCOS). Ischemia-modified albumin (IMA) levels in the circulation have been recently studied as a novel marker of OS. The studies in the literature on IMA levels in PCOS are inconsistent. This meta-analysis was conducted to compare circulatory IMA levels between PCOS patients and non-PCOS controls. Relevant studies were retrieved by online database and manual searching. The standardized mean differences (SMDs) with 95% confidence intervals (CIs) were obtained by a random-effects meta-analysis. The funnel plot analysis with Begg’s and Egger’s tests was used for publication bias. A total of nine studies were included in this meta-analysis. The results indicated that the serum IMA levels were significantly elevated in PCOS patients as compared to non-PCOS controls (SMD?=?0.49, 95% CI?=?0.23–0.75, Z?=?3.75, p?=?.0002). A one-study leave-out sensitivity analysis indicated that no single study had a significant influence on the overall outcome, suggesting the good validity and stability of these meta-analytic results. There was no evidence of publication bias as evidenced by the Egger (p?=?.28) and Begg’s tests (p?=?.21). The present meta-analysis suggests that IMA might be considered as a reliable and novel marker reflecting increased OS in PCOS.     

The Expression of Connective Tissue Growth Factor in Pregnancies Complicated by Severe Preeclampsia or Fetal Growth Restriction

We tested the hypothesis that the expression of placental connective tissue growth factor (CTGF) is enhanced in pregnancies complicated by severe preeclampsia (PE) or fetal growth restriction (FGR). CTGF expression was analyzed using immunostaining, western blot and real-time quantitative PCR in placental samples obtained after third trimester cesarean deliveries without labor from women with severe PE (n = 11), idiopathic FGR (n = 14), or healthy controls (n = 14). Serum CTGF concentrations were analyzed using ELISA. We found that CTGF was stably expressed in villous trophoblasts throughout pregnancy. The expression of CTGF mRNA in placentas from severe PE or FGR was higher than placentas from controls. Whereas the levels of placental CTGF protein were similar between normal and severe PE, maternal and fetal serum CTGF levels were elevated in severe PE. Maternal CTGF levels were also distinctively elevated in women with PE or FGR with histological evidence of placental injury. The enhancement of CTGF expression as well as serum CTGF levels in clinical conditions attributed to placental dysfunction suggests a role for this secretary protein in the pathophysiology of placental injury or its sequelae.     

Serum ischemia-modified albumin as a novel marker of ovarian torsion: An experimental study

Objective

To evaluate the effect of ovarian torsion on serum levels of ischemia-modified albumin (IMA) in an experimental model.

Study design

Sixteen female adult Sprague–Dawley rats were involved in the study. Rats were allocated randomly to group I or group II on the day of the experiment. Group I (eight rats) comprised the control (sham operated) group. In group II (eight rats), a torsion model was created by using atraumatic vascular clips just above and below the right ovary. At the end of a 3-h period of ischemia, the ovaries were removed. Blood was sampled before and after operation to assess serum IMA levels. Serum IMA levels (absorbance units) and histopathologic damage scores were evaluated.

Results

Initial serum IMA levels were similar in both groups. After the operation, significant elevation was observed in group II in contrast to group I (0.191 ± 0.034 and 0.277 ± 0.089 ABSU, p = 0.05). Histologic specimens of the ovaries in group II had higher scores of follicular cell degeneration, vascular congestion, hemorrhage and inflammatory cell infiltration than those in group I (p < 0.001).

Conclusions

The elevated serum IMA levels observed in the ovarian torsion model seem to have a potential role as a serum marker in the early diagnosis of ovarian torsion.     

A diagnostic test accuracy meta-analysis of maternal serum ischemia-modified albumin for detection of preeclampsia

Background/aims: Ischemia-modified albumin (IMA) has been widely accepted as a serological biomarker. IMA has been proposed as a simple and novel marker of oxidative stress in preeclampsia (PE). This systematic review and diagnostic test accuracy meta-analysis aims to evaluate the diagnostic accuracy of this novel serological biomarker, IMA to detect PE.

Methods: A systematic search of major databases was performed to identify all published diagnostic accuracy studies on IMA. Risk of bias and applicability concerns were assessed for included studies. Summary estimates; the pooled sensitivity, specificity, and the diagnostic odds ratio (DOR) of IMA for the diagnosis of PE were computed using random-effects models. The overall test performance was summarized using summary receiver operating characteristic (SROC) curve analysis.

Results: Six articles were included in this meta-analysis. The overall estimates of IMA in detecting PE were pooled sensitivity; 0.80 (95%CI 0.73–0.86), pooled specificity; 0.76 (95%CI 0.70–0.81), DOR; 14.32 (95%CI 5.06–40.57), and area under curve (AUC); 0.860. There was no between-study heterogeneity due to threshold effect.

Conclusions: This meta-analysis showed IMA could be useful as a biomarker for PE with good accuracy (AUC?=?0.860). However, further research is needed for re-evaluation and clinical validation of fairly promising results of this meta-analysis.     

Primary pneumococcal peritonitis in pregnancy

Objective: To compare cord blood oxidative stress markers (OSM) between intrauterine small fetuses with high umbilical artery (UA) Doppler indices and normal indices. Methods: Forty women who had oligohydramnios and intrauterine growth-restricted fetuses with abnormal (n = 20, group I) or normal Doppler indices (n = 20, group II) were included. All patients underwent fetal Doppler ultrasound studies. Cord blood was collected at birth and six OSMs (ischemia-modified albumin (IMA), hepatocyte growth factor (HGF), malondialdehyde (MDA)) levels, total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI) were studied. Results: The mean cord blood IMA, MDA, TOS, and OSI values for group I were significantly increased when compared to the group II (p < 0.001 for IMA, MDA, TOS, and OSI). However the mean cord blood HGF and TAS values were statistically significantly decreased in group I, compared with group II (p < 0.001 for HGF, and TAS). A significant positive (for IMA, MDA,TOS levels, and OSI ratio) and negative (for HGF and TAS levels) correlations between UA pulsatility index (PI) and cord blood OSM were found. Conclusion: The correlation between cord blood OSM and Doppler blood flow changes shown in this study may contribute to understanding the underlying oxidative stress-related mechanisms.     

Idiopathic urinary findings and fetal growth restriction in low risk pregnancy

Objective

To determine whether maternal urinary findings in the first trimester of pregnancy are associated with fetal growth restriction.

Study design

The prevalence of urinary findings in singleton pregnancies complicated by fetal growth restriction were compared with a low-risk control group of pregnancies who gave birth to normal weight babies, in the same condition.

Results

There were significant statistical differences in the mean gestational age (p < 0.001), isolated asymptomatic bacteriuria (p < 0.001), hematuria (p = 0.002, OR = 6.6, CI = 1.8–24.2) and proteinuria (p = 0.016, OR = 4.1, CI = 1.2–13.3). There was no recognizable relation between ketonuria and fetal growth restriction.

Conclusion

Our data showed a relation between the increase of adverse pregnancy outcomes, including fetal growth restriction, and hematuria, proteinuria and asymptomatic bacteriuria. Appropriate monitoring of pregnant women using these findings may be helpful in the identification of more complications.     

子痫前期并发胎儿生长受限的临床特征及妊娠结局分析

目的 探讨子痫前期并发胎儿生长受限(fetal growth restriction,FGR)的临床特征及母儿结局.方法 回顾性分析2009年1月1日至2019年12月31日在广州医科大学附属第三医院产科就诊并分娩的单胎子痫前期患者的病例资料,根据是否合并FGR,分为FGR组和对照组,分析两组的临床特征及母儿结局.结果...     

Oxidative conditions prevail in severe IUGR with vascular disease and Doppler anomalies

Objective: Intrauterine growth restriction (IUGR) and prenatal exposure to oxidative stress are thought to lead to increased risks of cardiovascular disease later in life. The objective of the present study was to document whether cord blood oxidative stress biomarkers vary with the severity of IUGR and of vascular disease in the twin pregnancy model in which both fetuses share the same maternal environment.

Methods: This prospective cohort study involved dichorionic twin pairs, with one co-twin with IUGR. Oxidative stress biomarkers were measured in venous cord blood samples from each neonate of 32 twin pairs, and compared, according to severity of IUGR (IUGR <5th percentile), Doppler anomalies of the umbilical artery and early onset IUGR (in the second trimester) of the growth restricted twin.

Results: Oxidized Low-Density Lipoproteins (oxLDL) and Malondialdehyde (MDA) concentrations were increased proportionally in cases of severe IUGR. OxLDL concentrations were also increased in cases of IUGR with Doppler anomaly.

Conclusion: Our data indicate that severe IUGR, is related to a derangement in redox balance, illustrated by increased venous cord blood oxidative stress biomarkers concentrations. Severe IUGR and IUGR with abnormal Doppler can be translated into conditions with intense oxidative stress.     

Evaluation of serum ischemia-modified albumin levels in pregnant women with and without gestational diabetes mellitus

Objective. To investigate serum ischemia-modified albumin (IMA) levels in gestational diabetes mellitus and the effect of treatment with continuous subcutaneous insulin infusion on the biomarker. Methods. The gestational diabetes mellitus women in the second trimester were evaluated before and after the two kinds of treatments with continuous subcutaneous insulin infusion and medical nutrition therapy for 6 weeks. Maternal serum ischemia-modified albumin and metabolic parameters were measured at baseline and at the 6th week. Results.Serum ischemia-modified albumin levels and metabolic parameters were higher in patients with gestational diabetes mellitus at baseline than in controls. Ischemia-modified albumin levels were correlated with plasma glucose (p < 0.05). Variables of glycemic control and ischemia-modified albumin levels were significantly reduced at the 6th week. The effect of insulin treatment was generally better than diet therapy. Linear regression analysis showed that fasting plasma glucose was an independent determinant for IMA levels (β = 0.611, p = 0.035).Fetal outcome was similar except for macrosomia and Apgar score at 5 min. Conclusion.Serum ischemia-modified albumin levels were higher in gestational diabetes mellitus compared to normal pregnancy. Continuous subcutaneous insulin infusion consistently improved metabolic disorder control. Gestational diabetes mellitus women were associated to a higher risk of oxidative stress and pregnancy complications.     

子痫前期合并胎儿生长受限的母儿妊娠结局分析

目的:探讨子痫前期(PE)合并胎儿宫内生长受限(FGR)的母儿结局。方法:选取591例PE孕妇,按新生儿出生体重分为小于胎龄儿组(SGA组,95例)和适于胎龄儿组(AGA组,496)。随访母体妊娠结局和新生儿结局。结果:与AGA组孕妇相比,SGA组孕妇的胎盘早剥发生率增加,因胎儿窘迫行剖宫产的比率增加(P0.05),新生儿病房收治率增加,住院时间延长,差异均有统计学意义(P0.05);其他孕妇严重并发症包括重度高血压、肺水肿、肾功能异常和HELLP综合征发生率,以及孕期和产后降压药和硫酸镁使用比率均无显著变化,差异无统计学意义。结论:PE合并FGR未导致除胎盘早剥之外母体严重不良妊娠结局的增加,但新生儿不良预后增加。     

Evaluation of cord blood ischemia modified albumin in normal pregnancies and pre-eclampsia

Objective: Pre-eclampsia is associated with ischemia and increased oxidative stress, which may lead to modification of plasma albumin to ischemia modified albumin (IMA). Methods: IMA levels were estimated in cord blood of 30 newborns born to pre-eclamptic mothers and compared with 30 normal newborns. IMA was estimated colorimetrically and the results were compared statistically. Results: The levels of IMA were found to be significantly higher (p?<?0.001) in newborns born to pre-eclamptic mothers (0.835?±?0.02 ABSU) as compared to those born to normal mothers (0.325?±?0.01 ABSU). Conclusion: IMA may act as a marker of ischemia and oxidative stress in newborns delivered to pre-eclamptic mothers.     

Role of ischemia-modified albumin in the evaluation of oxidative stress in intrahepatic cholestasis of pregnancy

Objective: The objective of this study is to investigate the ischemia-modified albumin (IMA) level, and the IMA/albumin ratio (IMAR) in healthy pregnant women, and pregnant women with intrahepatic cholestasis of pregnancy (ICP).

Material and method: This cross-sectional study included 53 women with ICP and 52 healthy pregnant women. Their serum IMA and albumin levels were analyzed, and the women were followed up to delivery.

Results: No significant intergroup differences were identified in maternal age, body mass index, and gestational age at the time that the blood samples were taken. The gestational age at delivery and the serum albumin level was significantly lower (p?=?.002 and p?p?=?.004).

Conclusion: Serum IMA levels did not differ between pregnant women with ICP and healthy pregnant women, while the IMAR was significantly higher in the ICP group versus the healthy pregnant women.     

妊娠肝内胆汁淤积症胎盘超微结构及其表皮生长因子受体表达的研究

目的　观察妊娠肝内胆汁淤积症 (intrahepaticcholestasisofpregnancy ,ICP)胎盘超微结构病理改变和表皮生长因子受体 (EGFR)的表达 ,研究胆汁酸对滋养细胞的毒性作用及其对胎儿生长发育的影响。　方法　透射电镜观察 2 2例ICP患者胎盘组织 ,其中ICP合并胎儿生长受限 (fetalgrowthrestriction ,FGR) 7例、ICP未合并FGR 15例 ,应用免疫组化方法和逆转录 聚合酶链反应 (RT PCR)技术测定胎盘滋养细胞表皮生长因子受体 (EGFR)的表达 ,并和 15例正常晚期胎盘比较。　结果　电镜显示 ,ICP胎盘合体滋养细胞较对照组微绒毛减少、内质网扩张、线粒体肿胀或髓鞘样改变 ,核染色质异常分布。ICP合并FGR组上述病理改变更为明显 ,绒毛间质毛细血管减少 ,并出现大量胶原原纤维。ICP合并FGR组胎盘EGFR免疫组化的平均A值 (0 .2 39± 0 .0 17)和ICP未合并FGR组EGFR免疫组化的平均A值 (0 .2 5 3± 0 .0 15 )均比对照组 (0 .384± 0 .0 16 )低 ,差异具非常显著性 (P<0 .0 1)。ICP合并FGR组胎盘EGFRmRNA指数 (0 .2 30± 0 .0 4 8)和ICP未合并FGR组EGFRmRNA指数 (0 .2 31± 0 .0 4 2 )表达均比对照组 (0 .4 6 0± 0 .0 5 1)低 ,差异具非常显著性 (P <0 .0 1) ,ICP合并FGR组与ICP未合并FGR组之间胎盘EGFR的表达无显著性差异 (P     

Neurodevelopmental and Cognitive Assessment of Children Born Growth Restricted to Mothers with and Without Preeclampsia

We examined neurological and intellectual outcome of growth‐restricted newborns of pregnancies complicated with preeclampsia and without preeclampsia. Seventy‐five consecutive growth restricted newborns (<5th percentile) were prospectively followed up at 6 months' intervals. Newborns with major congenital malformations and newborns with evident intrauterine viral infection were excluded. At 3 years of age all children had detailed neurological examination and intellectual examination using the Mean developmental index (Stanford Binnet‐IQ). Eleven children were born to mother with preeclampsia (ACOG criteria), and 64 were born to mothers without a definite diagnosis of preeclampsia. Gestational age was 34.7 weeks in the preeclamptic group and 37 weeks in the non‐preeclamptic group. After adjustment for gestational age, there was no significant difference in the neurological exam score between groups, but the IQ was 85.5 in the preeclamptic group and 96.9 in the non‐preeclamptic group (p<0.03). We conclude that newborns born growth restricted after pregnancies complicated by preeclampsia have a lower IQ at the age of 3 years compared to growth‐restricted babies without preeclampsia.