Insight into the Key Points of Preeclampsia Pathophysiology: Uterine Artery Remodeling and the Role of MicroRNAs.

Preeclampsia affects about 3-8% of all pregnancies. It represents a complex and multifaceted syndrome with at least several potential pathways leading to the development of disease. The main dogma in preeclampsia is the two-stage model of disease. Stage 1 (placental stage) takes place in early pregnancy and is thought to be impaired placentation due to inadequate trophoblastic invasion of the maternal spiral arteries that leads to reduced placental perfusion and release of numerous biological factors causing endothelial damage and development of acute maternal syndrome with systemic multiorgan failure (stage 2-the onset of maternal clinical symptoms, maternal stage). Recently, in the light of the vast body of evidence, two-stage model of preeclampsia has been updated with a few novel pathways leading to clinical manifestation in the second part of pregnancy. This paper reviews current state of knowledge about pathophysiology of preeclampsia and places particular focus on the recent advances in understanding of uterine artery remodeling alterations, as well as the role of microRNAs in preeclampsia.

Current progress in the inflammatory background of angiogenesis in gynecological cancers.

A tumor growth depends on the potency of the tumor to support itself with nutrients and oxygen. The development of a vascular network within the tumor is key to its survival. The permanent contest between the tumor and its host involves tumor cells on one side and an immunological system and tissue stroma on the other. The angiogenesis is not only a specialty of the tumor, but it also depends on this complex multidirectional interaction. The most common gynecological cancers, cervical, endometrial and ovarian carcinoma are good examples for studying this problem. In this review, we aim to show that an inflammatory response against a tumor can be reverted into an undesirable process leading to the development of a vascular network within the tumor and, subsequently, further growth of the tumor and progression of a disease. Therefore, a key for tumor management should be searched within the immunological system, rather than focused on cell cycle and anti-angiogenic treatment only.

Diagnostic Imaging of Pregnant Women - The Role of Magnetic Resonance Imaging.

BACKGROUND: Presentation of magnetic resonance imaging (MRI) findings in pregnant women in the Department of Diagnostic Imaging, Institute of Mother and Child, Warsaw, Poland. MATERIAL/METHODS: Forty-three symptomatic pregnant women underwent MRI between 9 and 33 weeks of gestation (mean of 23 weeks). Moreover, we included 2 pregnant women who underwent fetal MRI and had incidental abnormalities. RESULTS: In 9 cases, we excluded the suspected brain abnormalities. In 4 cases, we found unremarkable changes in the brain without clinical significance. One patient was diagnosed with multiple sclerosis, one with cortical dysplasia, one with pineal hemorrhage and one with a brain tumor. On abdominal MRI, 2 patients had normal findings, one patient had colon cancer with a hepatic metastasis, one patient had a hepatic angioma, one patient had an extraadrenal pheochromocytoma, one patient had an abscess in the iliopsoas muscle, 9 patients had myomas, two patients had ovarian simple cysts, two endometrial cysts, three dermoid cysts, one patient had sacrococcygeal teratoma, one patient had a cystadenofibroma (partial borderline tumor), one patient had an androgenic ovarian tumor and two patients had hyperreactio luteinalis. One patient was diagnosed with transient osteoporosis of the hip and one with a stress fracture of the sacral bone. CONCLUSIONS: Magnetic resonance imaging is the best imaging modality for pregnant women. Although ultrasonography is the method of choice, doubtful cases as well as structures that cannot be examined with ultrasonography can be non-invasively evaluated with MRI.

The role of magnetic resonance imaging in the prenatal diagnosis of cleft lip and palate.

INTRODUCTION: Cleft lip and/or palate is the most common congenital craniofacial anomaly. Ultrasonography plays a key role in the early diagnosis of this anomaly and is completed by MRI. The purpose of this paper is to present and summarize the experience in diagnosis of cleft lip/palate by means of MRI. MATERIAL AND METHODS: The material consists of 62 fetuses that required more detailed evaluation which was conducted with the use of a 1.5 T scanner in SSFSE/T2 sequence in the sagittal, transverse and coronal plane. RESULTS: The cleft was diagnosed in 15 fetuses: an isolated cleft lip in one case (6.7%), a cleft lip and alveolar process in 2 (13.3%), a cleft lip and palate in 12 (80%). In eight fetuses (53.3%) the defect was unilateral, in 6 (40%) on both sides, in one case (6.7%) - a bilateral cleft lip and unilateral cleft palate was diagnosed. In three cases (20%), the cleft lip and/or palate defect was isolated, in 12 (80%) - it coexisted with other fetal abnormalities. MRI was less useful than ultrasound in 1 case (6.7%), in 4 cases (26.7%) it did not add any significant new information, in the remaining 10 cases (66.6%) important additional information was obtained on MRI. MRI revealed more details of the cleft in 5 cases (33.3%). In 10 fetuses (66.7%), cleft diagnosis was based on ultrasound and MRI only confirmed it. In 47 cases MRI allowed to show normal fetal faces, while there were difficulties of visualisation on ultrasound. CONCLUSIONS: Prenatal MRI is a method supporting fetal ultrasound and is used to confirm/expand sonographic diagnosis, but can also change it. In the case of cleft lip and palate fetal MRI produces a better picture of the connections between the cavities, the degree of involvement of the secondary palate and cleft extent, and also helps to detect/assess other associated fetal abnormalities.

Effect of tobacco smoking on the maternal and fetal adipokine axis in relation to newborn birth weight and length.

We examined the effect of tobacco smoking on the concentrations of leptin, soluble leptin receptor (sOB-R), total adiponectin, and free leptin index (FLI) in the serum of maternal-cord pairs. We also investigated the correlations between these biochemical parameters and newborn birth weight and length. The study included eighty-five healthy pregnant women, who were divided into smoking and tobacco- abstinent groups according to serum cotinine concentrations. We found that maternal and fetal leptin, sOB-R concentrations, and free leptin index were similar in smoking and tobacco abstinent groups. We observed significant negative relationship between the reported number of cigarettes smoked daily during pregnancy and cord blood leptin (r=-0.37; p<0.05). In the group of smoking women, total serum adiponectin concentrations were significantly lower than in the tobacco abstinent group in mothers as well as in cord blood (p<0.05). A significant negative association between the number of cigarettes smoked per day and total adiponectin concentration in maternal as well as newborn serum was observed (r=-0.38; p<0.05). Umbilical serum leptin, sOB-R, and FLI levels were significantly lower and adiponectin higher compared with maternal concentrations at birth (p<0.05). Mean birth weight and body length of the smoking mothers' infants were significantly lower (p<0.001; p=0.015, respectively) compared with the abstinent group, and negatively correlated with the daily number of cigarettes consumed (birth weight r=-0.39; p<0.05; birth length r=-0.37; p<0.05). Cord blood values of leptin, FLI and adiponectin were significantly correlated with newborn birth weight. We also observed a positive relationship between cord blood adiponectin levels and the birth body length in the two studied groups (r=0.49; p<0.002). Tobacco smoking during pregnancy decreases maternal and fetal serum adiponectin levels but does not have a significant effect on blood leptin concentrations. The direct association between the cord blood values of these adipokines and birth weight and length suggest that rather fetal (not maternal) adiponectin and leptin concentrations may be involved in fetal development during pregnancy.

[The effect of tobacco smoking on serum concentration of selected angiogenic factors and somatomedin C in pregnant women and umbilical cord blood]. / Wplyw palenia tytoniu na stezenia wybranych czynników angiogennych oraz somatomedyny C w surowicy krwi kobiet ciezarnych i krwi pepowinowej.

The objective of this study was to evaluate the effect of cigarette smoking on concentration of selected angiogenic factors (vascular endothelial growth factor VEGF, placenta growth factor PIGF) and somatomedin C (insulin-like growth factor-I) in blood of mothers and umbilical cord blood. The correlations between studied biochemical parameters and markers of estimated intensity of cigarette smoking as well as birth weight were also determined. Fifty healthy pregnant women were divided into two groups: smoking and tobacco abstinent group according to serum cotinine concentration. The current smokers were defined as those who had smoked 5 cigarettes per day for 2 years before conception and continued smoking during pregnancy. In the group of smoking mothers the mean serum concentration of cotinine was 91.6 microg/L and correlated positively with number of cigarettes daily consumed (r = 0.58, p < 0.01) as well as with time of smoking before conception (r = 0.40, p < 0.05). The mean serum concentration of PIGF in III trimester of pregnancy was significantly higher in the group of smokers than in non-smoking ones (p < 0.0001) and correlated with serum cotinine concentration (r = 0.41, p < 0.05) and number of cigarettes daily consumed (r = 0.58, p < 0.01). The concentration of serum VEGF was similar in both studied group. The mean serum level of IGF-I was significantly lower in group of smokers than in non-smokers in the I and III trimester of gestation (p < 0.01). Also in umbilical cord blood of smoking newborn the concentration of IGF-I was lower by 20% than in nonsmoking group (p < 0.05). We observed negative correlation between number of cigarettes daily consumed and serum level of IGF-I in blood of mothers as well as in blood of their children (I trimester: r = -0.43, p < 0.05; III trimester: r = -0.70, p < 0.001; umbilical cord blood: r = -0.45, p < 0.05). In both studied groups there were a positive correlation between birth weight and concentrations of IGF-I in blood of mothers and umbilical cord blood (group of smokers: mothers r = 0.43, p < 0.05, cord blood r = 0.50, p < 0.01; group of tobacco abstinent: mothers r = 0.51, p < 0.01, cord blood r = 0.41, p < 0.05). The birth weight of the smoking mothers' infants was lower by about 400 g (p < 0.01) and their birth body length by 1.5 cm (p < 0.05) and negatively correlated with number of cigarettes smoked per day (r = -0.55; p < 0.005). Our results indicate, that tobacco smoking during pregnancy increased serum PIGF levels in the final stages of gestation and has no effect on the concentration of VEGF, which may lead to an increase of trophoblast proliferation and uteroplacental dysfunction. Lower than in tobacco abstinent levels of IGF-I in serum of smoking mothers and in umbilical cord blood and their close relationship with birth weight, may suggests a direct effect of this factor on birth anthropometric parameters.

Influence of Oxidative Stress Generated by Smoking during Pregnancy on Glutathione Status in Mother-Newborn Pairs.

Glutathione plays a key role in maintaining a physiological balance between prooxidants and antioxidants in the human body. Therefore, we examined the influence of maternal smoking as a source of oxidative stress measured by total oxidant capacity (TOC) on reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione peroxidase (GPx-3), and reductase (GR) amount in maternal and umbilical cord blood in 110 (45 smoking and 65 non-smoking) mother-newborn pairs. Concentrations of glutathione status markers and TOC were evaluated by competitive inhibition enzyme immunoassay technique. Plasma TOC levels were significantly higher and the GSH/GSSG ratio, which is considered an index of the cell's redox status, were significantly lower in smoking women and their offspring than in non-smoking pairs. Decreased GR levels were found in smoking mothers and their newborns compared with similar non-smoking groups. Although plasma GPx-3 concentrations were similar in both maternal groups, in the cord blood of newborns exposed to tobacco smoke in utero they were reduced compared with the levels observed in children of tobacco abstinent mothers. Oxidative stress generated by tobacco smoke impairs glutathione homeostasis in both the mother and the newborn. The severity of oxidative processes in the mother co-existing with the reduced potential of antioxidant systems may have a negative effect on the oxidative-antioxidant balance in the newborn.

Associations between Maternal and Fetal Levels of Total Adiponectin, High Molecular Weight Adiponectin, Selected Somatomedins, and Birth Weight of Infants of Smoking and Non-Smoking Mothers.

The aim of the study was to determine the relationships between maternal smoking, total adiponectin, high molecular weight adiponectin (HMW adiponectin), selected somatomedins, and the birth weight of newborns. A total of 78 women with a healthy, singleton pregnancy, 41 active smokers and 37 non-smokers, and their offspring were studied. Total and HMW adiponectin, insulin-like growth factor I (IGF-I), and insulin-like growth factor binding protein-1 (IGFBP-1) and 2 (IGFBP-2) were determined in maternal and cord blood by enzyme-link immunosorbent assay. Serum levels of total and HMW adiponectin were lower in smokers compared to the tobacco abstinent in both the mothers (p = 0.013; p = 0.006) and the infants (p = 0.001; p = 0.047). In smoking women and their children, serum concentrations of IGF-I were significantly lower (p = 0.014; p = 0.042), IGFBP-1 significantly higher (p = 0.009; p = 0.039), and IGFBP-2 did not differ from that observed in the non-smoking group. In multivariate analysis performed on the whole group of mothers, the highest impact of serum cotinine and IGFBP-2 levels were indicated for adiponectin and cotinine and the number of cigarettes/day for HMW adiponectin concentration. In correlation analysis estimated separately for smokers and non-smokers, neonatal birth weight was positively associated with total and HMW adiponectin concentrations in umbilical cord blood. Birth weight was also inversely associated with IGFBP-1 and positively correlated with IGF-I levels in maternal serum as well as in cord blood (r = -0.317, p = 0.005; r = -0.294, p = 0.004; r = 0.245, p = 0.031; r = 0.271, p = 0.009, respectively). The present study showed the levels of total and HMW adiponectin in umbilical cord blood may have a significant effect on fetal development. Both IGF-I and IGFBP-1 concentrations also play an essential role in fetal growth, which is an important predictor of birth weight. Cigarette smoking during pregnancy negatively affected adiponectin and the insulin growth factor profile in the serum of women and the cord blood and may be the reason for the lower birth weight of the smokers newborns compared with the nonsmokers offspring.

Active Tobacco Smoke Exposure in Utero and Concentrations of Hepcidin and Selected Iron Parameters in Newborns.

The aim of this study was to assess the influence of active tobacco smoke exposure in utero on the concentration of hepcidin and selected iron markers in umbilical cord blood and to evaluate the relationships between these parameters. Newborns of smoking mothers had significantly lower concentrations of serum hepcidin (p < 0.001), iron, and ferritin (p = 0.043; p = 0.042, respectively), but higher levels of erythropoietin (EPO, p < 0.001) and soluble transferrin receptor (sTfR, p = 0.011) compared with newborns of non-smoking women. Negative correlations between cotinine and the number of cigarettes smoked per day with hepcidin serum level (r = -0.33, p = 0.033, r = -0.32, p = 0.041, respectively) and EPO (r = 0.47, p = 0.002; r = 0.46, p = 0.003, respectively) were found. Univariate analysis defined for the whole group of children revealed significant associations between the concentration of hepcidin and other iron status parameters. In the models estimated separately for smokers and non-smokers, we found relations between the level of hepcidin and erythropoietin (B = -0.23, p = 0.004; B = -0.46, p = 0.01, respectively). In the multivariate regression model, a negative association between hepcidin and EPO concentrations in the whole group of newborns (ß = -0.53; p = 0.001) and in the group of smokers (ß = -0.57; p = 0.011) was confirmed. The present study shows significant relations between smoking during pregnancy and hepcidin levels in children born at term. Decreased cord serum concentrations of hepcidin associated with high erythropoietin levels suggest induced fetal erythropoiesis, probably due to the hypoxic effects imposed by maternal smoking.

Influence of Active Exposure to Tobacco Smoke on Nitric Oxide Status of Pregnant Women.

Smoking tobacco can impair proper vascular endothelial functioning. This is exhibited through reduced nitric oxide synthesis as well as activity due to accompanying oxidative stress. We examined the relationship between nitric oxide and markers of oxidative stress/antioxidant defense in serum of smoking and non-smoking pregnant women. Subjects included 99 healthy pregnant women, who were tested for nitric oxide (NO), endothelial (eNOS) and inducible (iNOS) nitric oxide synthase, total oxidant capacity (TOC), and total antioxidant capacity (TAC). NO, eNOS, and TAC serum concentrations were significantly lower (p < 0.005), but iNOS (p < 0.05) and TOC (p < 0.001) were higher in smokers than in non-smokers. Multivariate regression analysis showed associations between NO concentration and eNOS, TAC, and smoking status in the whole group of patients. In the model estimated separately for smokers, the highest impact of eNOS (ß = 0.375; p = 0.021) and cotinine (ß = -0.323; p = 0.037) was indicated for NO concentration. In the model of non-smokers, eNOS (ß = 0.291, p = 0.030) and TAC (ß = 0.350; p = 0.015) were important for NO level. Smoking during pregnancy could exacerbate oxidative stress, impair the action of nitric oxide synthases, and adversely affect the balance of oxygen and nitrogen metabolism. Relationships between NO concentrations and TAC in the studied women's blood can confirm the antioxidant nature of nitric oxide.

Serum pregnancy-associated plasma protein A levels in the first, second and third trimester of pregnancy: relation to newborn anthropometric parameters and maternal tobacco smoking.

INTRODUCTION: The purpose of this study was to evaluate the associations of the first, second and third trimester serum pregnancy-associated plasma protein A (PAPP-A) concentrations with neonatal anthropometric parameters. The effect of tobacco smoking during pregnancy on PAPP-A level was also studied. MATERIAL AND METHODS: One hundred and fifty healthy pregnant women were divided into smoking and tobacco-abstinent groups. Serum PAPP-A level was measured with the KRYPTOR rapid random-access immunoassay analyzer. The relationship between PAPP-A and newborn related outcome as well as markers of estimated intensity of cigarette smoking was evaluated by univariate and multivariate linear regression. RESULTS: Pregnancy-associated plasma protein A concentration was positively correlated with birth weight in the first (ß = 31.6; p < 0.001), second (ß = 10.6; p < 0.05), and third (ß = 4.6; p < 0.001) trimester of gestation. A significant association between PAPP-A and birth body length and head circumference in the second (ß = 0.02; p < 0.05) and third trimester (ß = 0.01; p < 0.01) was also found. The serum PAPP-A levels were significantly lower in the smoking than in the tobacco-abstinent group in each trimester of pregnancy (p < 0.001). The largest impact of the number of cigarettes smoked per day on PAPP-A level was found in the second (ß = -1.2; p = 0.004) and third trimester (ß = -2.6; p = 0.001). CONCLUSIONS: Maternal serum PAPP-A levels during gestation might be significant predictors for birth weight. Increased PAPP-A concentrations in the second and third trimester appeared to also be predictive for newborn body length and head circumference. Smoking alters maternal PAPP-A levels in all trimesters, with the greatest impact related to the number of cigarettes smoked per day.

Hepcidin and Iron Metabolism in Pregnancy: Correlation with Smoking and Birth Weight and Length.

To estimate the effect of tobacco smoking on iron homeostasis and the possible association between hepcidin and the neonatal birth weight and length, concentrations of serum hepcidin and selected iron markers were measured in 81 healthy pregnant women (41 smokers and 40 nonsmokers). The smoking mothers had significantly lower concentrations of serum hepcidin (p < 0.001), iron (p < 0.001), and hemoglobin (p < 0.05), but higher erythropoietin (p < 0.05) levels compared with non-smoking pregnant women. Logistic regression analysis showed the highest negative impact of the number of cigarettes smoked per day (ß = -0.46; p < 0.01) and positive impact of ferritin level (ß = 0.47; p < 0.001) on serum hepcidin concentration. The birth weight and the body length of smoking mothers' infants were significantly lower than in tobacco abstinent group (p < 0.001). In multiple regression analysis, birth body weight (ß = 0.56; p < 0.001) and length (ß = 0.50; p < 0.001) were significantly related to maternal hepcidin values. Tobacco smoking affected hepcidin level in serum of pregnant women in a dose-dependent manner. Low concentrations of iron and hemoglobin in maternal serum coexisting with high level of erythropoietin suggest that smoking could lead to subclinical iron deficiency and chronic hypoxia not only in mothers but also in fetus. Low serum hepcidin concentration in smoking pregnant women might be associated with lower fetal birth weight and length.

Cord Blood Adiponectin and Visfatin Concentrations in relation to Oxidative Stress Markers in Neonates Exposed and Nonexposed In Utero to Tobacco Smoke.

Aims. Maternal smoking is considered as a source of oxidative stress, which has been implicated to disrupted adipokines expression in adipose tissue. We examined the relationship between selected adipokines and markers of oxidative stress/antioxidant defence in the umbilical cord of neonates exposed and nonexposed in utero to tobacco smoke. Methods. Subjects including 85 healthy neonates (born to 41 smokers and 44 nonsmokers) were tested for adiponectin, visfatin, oxidized low density lipoprotein (ox-LDL), total oxidant capacity (TOC), and total antioxidant capacity (TAC). Results. Cord serum visfatin, ox-LDL, and TOC were significantly higher (p < 0.001) but adiponectin and TAC were lower (p < 0.001 and p < 0.05, resp.) in smoking group than in tobacco abstinents. In whole group of children (adjusted for smoking status, gender, and birth weight) adiponectin showed negative and visfatin positive correlations with ox-LDL. In the model estimated separately for smokers ox-LDL explained 36% of adiponectin and 35.5% of visfatin variance, while in the model of nonsmokers it explained 36.8% and 69.4%, respectively. Conclusion. Maternal smoking enhances oxidative status and depletes antioxidant potential in newborns. Lower level of adiponectin and higher visfatin concentration seem to be related with a less beneficial oxidative stress profile and higher level of lipid peroxidation in neonates exposed and nonexposed in utero to tobacco smoke.

Tobacco smoke exposure during pregnancy increases maternal blood lead levels affecting neonate birth weight.

To assess the effect of lead exposure from cigarette smoke on fetal growth, blood lead concentrations were measured using inductively coupled plasma mass spectrometry in 150 healthy pregnant women. Mean lead concentrations in plasma and whole blood were significantly higher in the smoking group compared with the nonsmoking group in each trimester of pregnancy (p < 0.001). Logistic regression analysis showed the highest impact of the number of cigarettes smoked per day for serum lead concentration (ß = 0.238; p < 0.05), while in whole blood, it was duration of smoking before conception (ß = 0.297; p < 0.001). Birth weight of the smoking mothers' infants was significantly lower (mean ± SEM, 3,192 ± 50.8 and 3,569 ± 49.6 g, respectively; p < 0.001) and negatively correlated with lead levels in plasma (r = -0.38; p < 0.001) and in whole blood (r = -0.27; p < 0.001). Therefore, it is suggested that smoking during pregnancy increases lead concentrations in maternal blood. Fetal exposure to low doses of lead in utero may be a serious risk factor causing lower birth weight.