Trimester Of Normal Pregnancy Research Articles

The Expressions of CD200 and CD200R Molecules on Myeloid and Lymphoid Dendritic Cells in Pre‐Eclampsia and Normal Pregnancy

The purpose of our study was to test the hypothesis that the expressions of CD200 and CD200R tolerance molecules are increased on peripheral blood dendritic cells (DCs) in normal pregnancy and decreased on peripheral blood DCs in pre-eclampsia. Thirty-three patients with pre-eclampsia, 38 normal pregnant women, and 10 healthy non-pregnant women were included in the study. Dendritic cells were isolated from peripheral blood, stained with monoclonal antibodies against blood dendritic cell antigens as well as CD200 and CD200R antigens, and estimated using flow cytometry. The expressions of CD200 and CD200R molecules on CD1c(+) myeloid and BDCA-2(+) lymphoid DCs in the first trimester of normal pregnancy were significantly higher when compared to the luteal phase of the ovarian cycle. The expressions of CD200 molecule on CD1c(+) myeloid DCs were significantly lower in the third trimester of normal pregnancy when compared to the second trimester. The expressions of CD200R molecule on CD1c(+) myeloid DCs and BDCA-2(+) lymphoid DCs did not differ in pre-eclampsia and healthy third trimester pregnant women. However, the expressions of CD200 molecule on CD1c(+) myeloid and BDCA-2(+) lymphoid DCs were significantly higher in pre-eclampsia when compared to the healthy third trimester pregnant women. The results suggest increased tolerogenic properties of myeloid and lymphoid DCs in normal human pregnancy. Moreover, they suggest a decrease in tolerogenic properties of DCs before delivery. It seems possible that higher expressions of CD200 molecule on CD1c(+) myeloid and BDCA-2(+) lymphoid DCs in pre-eclampsia may constitute the tolerogenic mechanism secondary to the pro-inflammatory response that is observed in this syndrome.

Serum Concentrations of Soluble Flt-1 Are Decreased among Women with a Viable Fetus and No Symptoms of Miscarriage Destined for Pregnancy Loss

Miscarriage is the most common complication of pregnancy. Pre-clinical miscarriage has an estimated incidence of 30%, whilst clinical miscarriage has an incidence of 12-15%. Two thirds of pregnancies lost to miscarriage are believed to be attributable to defective placentation, thus a number of studies have sought to identify markers of defective placentation that could be used as clinical biomarkers of miscarriage. Decreased soluble FMS-like tyrosine kinase-1 (sFlt1), placental growth factor (PlGF), and soluble endoglin (sEng) in the maternal circulation during the first trimester have recently been proposed as potential markers of pregnancy loss. However, in these studies clinical samples were only obtained once women had presented with symptoms of miscarriage. In this study we prospectively screened serum samples collected from asymptomatic women with a viable fetus. We assessed maternal serum levels of sFlt1, PlGF and sEng across the first trimester of normal pregnancy and compared levels between women who continued to a live birth, to those who subsequently miscarried. Both sFlt1 and PlGF significantly (p≤0.05) increased across gestation in normal pregnancy with serum levels rising from 0.65±0.12 ng/ml at 6 weeks to 1.85±0.24 ng/ml at 12 weeks for sFlt1, and 57.2±19.2 pg/ml to 106±22.7 pg/ml for PlGF. sEng remained unchanged throughout the the first trimester. Importantly we detected a significant (35%, p≤0.05) decrease in sFlt1 levels between our control and miscarriage cohort, however there was significant overlap between cases and controls, suggesting serum sFlt1 is unlikely to be useful as a clinical biomarker in asymptomatic women. Nevertheless, our data suggests a dysregulation of angiogenic factors may be involved in the pathophysiology of miscarriage.

The predominance of Th17 lymphocytes and decreased number and function of Treg cells in preeclampsia

The aim of this study was to estimate the prevalence of CD3(+)CD4(+) T lymphocytes producing IL-17, IL-2, IFN-γ, and IL-4, plus CD4(+)CD25(+)FoxP3(+) T regulatory (Treg) cells, in peripheral blood of patients with preeclampsia and healthy women in the third trimester of normal pregnancy. Another purpose was to assess the immunosuppressive activity of Treg cells from patients with preeclampsia compared with controls. Thirty-four preeclampsia patients and 27 healthy pregnant women were included. The percentages of CD4(+)CD25(+)FoxP3(+) Treg cells and CD3(+)CD4(+) T lymphocytes with intracellular expressions of cytokines were estimated using monoclonal antibodies and flow cytometry. In vitro functional assays were performed using a Treg Cell Isolation Kit and (3)H-thymidine incorporation assays. The percentage of CD3(+)CD4(+) T lymphocytes producing IL-17A was significantly higher in preeclampsia than in healthy, normotensive pregnant women in the third trimester (p<0.001). The population of CD4(+)CD25(+)FoxP3(+) Treg cells was significantly lower in the study group compared with controls (p<0.05). There was no change in the stimulation index of CD3(+)CD4(+)CD25(-) T lymphocytes from preeclampsia patients without Treg cells and after addition of autologous Treg cells. In normal pregnancy, the stimulation index of CD3(+)CD4(+)CD25(-) T lymphocytes was significantly higher without Treg cells compared with the response after addition of autologous Treg cells (p<0.05). The results suggest up-regulation of the Th17 immune response in preeclampsia. The decreased number and function of Treg cells may be responsible for activating the inflammatory response characteristic of this disorder. In preeclampsia, the predominance of Th17 immunity could act through modulating the Th1/Th2 immune balance.

ST2 and IL-33 in Pregnancy and Pre-Eclampsia

Normal pregnancy is associated with a mild systemic inflammatory response and an immune bias towards type 2 cytokine production, whereas pre-eclampsia is characterized by a more intense inflammatory response, associated with endothelial dysfunction and a type 1 cytokine dominance. Interleukin (IL)-33 is a newly described member of the IL-1 family, which binds its receptor ST2L to induce type 2 cytokines. A soluble variant of ST2 (sST2) acts as a decoy receptor to regulate the activity of IL-33. In this study circulating IL-33 and sST2 were measured in each trimester of normal pregnancy and in women with pre-eclampsia. While IL-33 did not change throughout normal pregnancy, or between non-pregnant, normal pregnant or pre-eclamptic women, sST2 was significantly altered. sST2 was increased in the third trimester of normal pregnancy (p<0.001) and was further increased in pre-eclampsia (p<0.001). This increase was seen prior to the onset of disease (p<0.01). Pre-eclampsia is a disease caused by placental derived factors, and we show that IL-33 and ST2 can be detected in lysates from both normal and pre-eclampsia placentas. ST2, but not IL-33, was identified on the syncytiotrophoblast layer, whereas IL-33 was expressed on perivascular tissue. In an in vitro placental perfusion model, sST2 was secreted by the placenta into the ‘maternal’ eluate, and placental explants treated with pro-inflammatory cytokines or subjected to hypoxia/reperfusion injury release more sST2, suggesting the origin of at least some of the increased amounts of circulating sST2 in pre-eclamptic women is the placenta. These results suggest that sST2 may play a significant role in pregnancies complicated by pre-eclampsia and increased sST2 could contribute to the type 1 bias seen in this disorder.

Placental proteome differences in first compared to third trimester normal pregnancy

Placental proteome differences in first compared to third trimester normal pregnancy

Soluble Flt-1 and PlGF: New Markers of Early Pregnancy Loss?

Recent data have indicated a relationship between placental oxygen and angiogenic protein levels in the first trimester of normal pregnancies. Our objective was to investigate if maternal serum levels of angiogenic factors Soluble vascular endothelial growth factor (VEGF) receptor 1 (sFlt-1), soluble Endoglin and placental growth factor (PlGF) are altered in women with symptoms of threatened miscarriage (TM) and if they are predictive of a subsequent miscarriage. Blood samples were collected at 6–10 weeks from women presenting with TM (n = 40), from asymptomatic controls (n = 32) and from non- pregnant women in their luteal phase (n = 14). All samples were assayed for serum level of sFLT-1, PlGF, sEndoglin and HSP70 using commercial ELISAs. Samples were analysed retrospectively on the basis of pregnancy outcome. TM group included 21 women with a normal pregnancy outcome and 19 with subsequent complete miscarriage. The latter subgroup had significantly lower mean maternal serum (MS) sFlt-1 (83%, P<0.001) and PlGF (44%, P<0.001) compared to those with a normal pregnancy outcome. Asymptomatic control pregnant women had similar MS levels of sFlt-1 and PlGF compared to the TM patients with a normal outcome. The mean MS sFlt-1 (>10 fold) and MS PlGF (∼2 fold) levels were significantly (P<0.001) higher in control pregnant women compared to the non-pregnant group in the luteal phase of the menstrual cycle. Soluble Endoglin was not altered in the normal pregnant women compared to non pregnant women, although lower in the TM subgroup with a subsequent miscarriage (∼25%, P<0.001) compared to TM with a live birth. There was no significant difference in the mean MS HSP 70 levels between the different groups. This study shows that sFlt1 and PlGF MS levels are increased by several folds in early pregnancy and that MS sFlt-1 and MS PlGF are markedly decreased in threatened miscarriage patients who subsequently have a miscarriage suggesting these proteins are sensitive predictive markers of subsequent pregnancy loss.

P.72 Are the coagulation factor XI levels low during the 3 rd trimester of normal pregnancy?

P.72 Are the coagulation factor XI levels low during the 3 rd trimester of normal pregnancy?

Clinical significance of serum sRAGE and esRAGE in women with normal pregnancy and preeclampsia

We determined serum endogenous secretory receptor of advanced glycation end products (esRAGE) and soluble RAGE (sRAGE) concentrations and the esRAGE/sRAGE ratio in normal pregnancy and preeclampsia because esRAGE and sRAGE have been negatively linked to components of metabolic syndromes and pathologic pregnancy including preeclampsia. Eighty-seven normal pregnant women and 28 with preeclampsia were recruited. Serum sRAGE and esRAGE levels were measured by enzyme-linked immunosorbent assay. There were significant differences in esRAGE concentration and esRAGE/sRAGE ratio between 1(st) and 3(rd) trimester in normal pregnancy (P=0.007 and P=0.003). Serum esRAGE concentrations and esRAGE/sRAGE ratio in patients with preeclampsia significantly increased compared to controls (P=0.005 and P<0.001). Maternal serum esRAGE concentration and esRAGE/sRAGE ratio (1) gradually decrease with gestational age in normal pregnancy; and (2) are higher in patients with preeclampsia than healthy pregnant controls, significantly. Serum esRAGE and esRAGE/sRAGE ratio might be associated with preeclampsia.

Evaluation of fetal nasofrontal angle in the second trimester in normal pregnancies

The nasal bone is one of the important fetal structures to be radiologically evaluated in the first and second trimesters. In this study, we aimed to evaluate the nasal root and to determine the normal range of the naso-frontal angle, which may potentially be used as a predictive or diagnostic parameter in the diagnosis of the above-mentioned syndromes or other congenital abnormalities with associated nasal features using obstetric ultrasonography in normal fetuses. We evaluated the naso-frontal angle using transabdominal ultrasonography in 195 healthy fetuses between the 18(th) and 21(st) weeks of gestation. The measurements were performed with the fetal neck in mild flexion and three echogenic lines (nasal end, skin on the nasal bone, nasal bone) visualized. The minimum, maximum and mean naso-frontal angle values were 110°, 143° and 128°, respectively, between the 18(th) and 21(st) weeks of gestation. Linear regression analysis showed no association between NFA and gestational week (Beta = 0.020 p = 0.786). The normal range of NFA between the 18(th) and 21(st) weeks of gestation was determined in this study. The association between NFA measurements and various congenital anomalies or fetal outcomes remains to be investigated.

The Concentrations of Markers of Bone Turnover in Normal Pregnancy and Preeclampsia

Background. The purpose of our study was to investigate the concentrations of markers of bone turnover in normal pregnancy and preeclampsia. Material and Methods. Forty-five pregnant patients with preeclampsia, 78 healthy pregnant women (26 in first, 26 in the second, and 26 in third trimester of pregnancy), and 20 nonpregnant women were included in the study. Serum concentrations of osteoprotegrin (OPG), receptor activator of nuclear factor kappa B ligand (sRANKL), and the markers of bone turnover, osteocalcin and CrossLaps—degradation products of type I collagen, were determined using the ELISA method. Statistical analysis was performed using Mann–Whitney U-test. Results. The concentrations of sRANKL and OPG were significantly higher in the second trimester of normal pregnancy when compared to the first and the third trimesters and to nonpregnant controls. The concentrations of osteocalcin were significantly higher in the first trimester of physiological pregnancy in comparison with nonpregnant women and with second and third trimesters of pregnancy. The concentrations of CrossLaps were significantly higher in the second trimester of normal pregnancy when compared to the first and third trimester. In preeclampsia, the sera concentrations of osteocalcin and CrossLaps were significantly higher when compared to the third trimester of normal pregnancy. Conclusion. The results suggest that the bone formation is increased in the first trimester, whereas the bone resorption is increased in the second trimester of normal pregnancy. Furthermore, the results suggest that the bone turnover is increased in patients with preeclampsia when compared to healthy normotensive pregnant women.

A cross-sectional study comparing D-Dimer levels from first trimester to day 2 post partum in low risk pregnancies

D-Dimer measurement is a highly recognised test to exclude venous thromboembolism (VTE). However, during pregnancy D-Dimer levels increase significantly, making diagnosis of VTE using the recommended non-pregnancy cut-off point ineffectual.The...

A cross sectional study to compare D-Dimer levels in the first trimester of pregnancy to the recommended cut off in normal non-pregnant population

Venous thromboembolism (VTE) is a major cause of maternal morbidity and mortality. In the non-pregnant patient D-Dimer testing has a role as a negative predicator of thrombosis. This is not...

Pre-evacuation hCG glycoforms in uneventful complete hydatidiform mole and persistent trophoblastic disease

Objective To investigate whether the glycoform distribution patterns of human chorionic gonadotropin (hCG) obtained by chromatofocusing in pre-evacuation serum are different for patients who will eventually develop into persistent trophoblastic disease in case of complete hydatidiform mole pregnancy as compared to those patients for whom trophoblastic tissue will regress uneventfully. Methods Pre-evacuation blood samples were collected from women with complete hydatidiform mole with uneventful spontaneous regression after molar evacuation ( n = 32), from women with complete hydatidiform mole who developed persistent trophoblastic disease after evacuation of their mole ( n = 28) and, as a control group, from women during the first trimester of normal pregnancy ( n = 22). The serum specimens were subjected to chromatofocusing, and hCG was determined in the fractions collected in the pH range 7.0–3.0. Results Receiver operating characteristics (ROC) analysis revealed that 36% of complete hydatidiform mole patients with post-molar persistent trophoblastic disease development had different hCG glycoform profiles at 97% specificity (pH interval 6.3–5.1, hCG cutoff 9.9%). There was a significant difference between complete hydatidiform mole with and without persistent trophoblastic disease for the cumulative percent amounts of hCG in the pH interval 6.3–5.1 ( p < 0.0003). Conclusion In 36% of the patients with complete hydatidiform mole with subsequent development of persistent trophoblastic disease, typical glycoform profiles for hCG are observed in pre-evacuation serum samples. This result suggests that hCG glycoform profiles are of potential use in the prediction of persistent trophoblastic disease.

Fetal cerebral-umbilical Doppler ratio in prediction of fetal distress in patients with preeclampsia

The use of color Doppler ultrasonography provides noninvasive observation, confirmation and quantification of pathophysiological processes in fetoplacental circulation in pregnant patients. By blood vessel mapping and the obtained waves spectral analysis it is posible to evaluate vascular resistency of the fetus blood vessels. The aim of the study was to evaluate cerebral-umbilical pulsatility index ratio in fetal circulation in prediction of fetal distress in patients with preeclampsia. By measurement of pulsatility indices in medial cerebral and umbilical arteries in 400 patients with uncomplicated pregnancy, normal values were calculated for fetuses from 15-40 weeks. In our study group 70 patients with preeclampsia were included. Cerebral-umbilical (C/U) ratio was calculated after pulsatility indices in medial cerebral artery and umbilical artery determining by the spectral Doppler analysis of flow velocity waveforms in these vessels. Fetal outcome was analyzed by measurement of the Apgar score at the 5th minute and fetal pH at birth. The mean C/U ratio values in the third trimester of normal pregnancy were between 1.8 and 1.9. The mean C/U ratio values in the patients complicated with preeclampsia were significantly lower comparing to normal pregnancies (ANOVA, p < 0.05). The mean 5th minute Apgar score in the study group was 6.35 +/- 1.58, and the mean fetal pH at birth was 7.16 +/- 0.15. Linear regression test showed a highly significant correlation between low C/U ratio and fetal pH at birth in patients with preeclampsia (r = 0.49, p < 0.01). The C/U ratio values obtained from spectral Doppler analysis in fetal vessels showed a highly significant correlation with fetal pH at birth in the patients with preeclampsia. The results of our study confirmed the reliability of C/U ratio in estimation of fetal condition in preeclamptic patients. Very low C/U ratio values in patients with preeclampsia indicate that in these fetuses fetal acidosis and fetal distress may be expected.

Regulatory Mechanisms for Apoptosis in Placental Tissue during Normal Pregnancy and Gestosis-Complicated Pregnancy

The localization of apoptosis and expression of proapoptotic and antiapoptotic factors by the placental tissue were compared during normal pregnancy and gestosis-complicated pregnancy. The degree of apoptosis did not differ in the third trimester of normal pregnancy and gestosis-complicated pregnancy. Increased expression of Fas, caspase-8, and caspase-3 in placental tissue during normal pregnancy was shown to contribute to the suppression of angiogenesis and growth of placental tissue. No differences were found in the expression of FasL (CD95L), caspase-2, caspase-9, and Mcl-1 by placental cells during normal pregnancy and gestosis-complicated pregnancy. Increased expression of TRAIL by trophoblast cells is a protective mechanism from apoptotic signals of maternal cytotoxic lymphocytes and NK cells during gestosis.

Plasma visfatin levels in preeclamptic and normal pregnancies

Increasing evidences support the participation of adipokines in the pathogenesis of preeclampsia (PE). Visfatin is a novel adipokine secreted by fat tissue and macrophages and is involved in the regulation of glucose homeostasis. Our aim is to investigate visfatin levels in women with PE, women with the third trimester of normal pregnancy and healthy non-pregnant women. We included 32 preeclamptic patients who received antenatal and obstetric care at Perinatology Clinic. A total of 32 pregnant women with normal ongoing pregnancies and 32 non-pregnant women were taken as the control groups. Plasma levels of visfatin were quantified by ELISA. Plasma levels of visfatin were 63.8 +/- 4.9 ng/ml in women with PE, 43.6 +/- 7.8 ng/ml in pregnant control and 31.6 +/- 4.2 ng/ml in the non-pregnant control, respectively (P < 0.001). Visfatin level was significantly higher in PE compared with non-pregnant control (P < 0.001) and pregnant control (P < 0.001); also, plasma level of visfatin was significantly higher in severe PE (75.3 +/- 4.6 ng/ml) than mild PE (41.8 +/- 5.2 ng/ml) (P < 0.001). The results of the present study indicate that women with PE had significantly increased visfatin concentrations in the third trimester. Furthermore, visfatin levels were significantly higher in severe PE group.

The expression of fucose isoforms of amniotic and plasma alpha-1-acid glycoprotein derived from 2nd and 3rd trimester normal pregnancies

Objectives To analyse modifications in AGP fucosylation in relation to different stages of human pregnancy. Design and methods The relative amounts of three fucosyl-glycotopes on AGP were analysed by lectin-ELISA using fucose-specific biotinylated lectins in 169 plasma and 178 amniotic fluid samples from normal pregnancies with gestational ages of 14 to 42 weeks. Results The plasma AGPs of all the pregnant women and amniotic AGPs from the 2nd trimester lacked fucoses. In contrast, in the 3rd trimester the amniotic AGPs were highly decorated by the innermost α1,6-fucose as well as α1,2- and α1,3-fucoses of the outer arms, reaching the highest expression around the perinatal period. At delivery the relative amounts of the α1,3- and α1,2-AGP isoforms, but not the α1,6 isoform, significantly decreased. Conclusions The highly fucosylated amniotic AGP isoforms could be implicated in regulatory processes to ensure homeostasis during pregnancy and to protect the fetus. They have the potential of becoming laboratory markers in obstetrics to monitor pregnancy.

Maternal serum ADMA is not associated with proinflammatory cytokines or C-reactive protein during normal pregnancy

Normal pregnancy is associated with changes in the immune system. We studied whether asymmetrical dimethylarginine (ADMA) is associated with this immune system change by assaying high sensitive C-reactive protein (hsCRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). The cytokine and dimethylarginine serum concentrations were determined from women with normal pregnancy ( n = 77) and healthy non-pregnant controls ( n = 61) matched for age and smoking status as a part of a large population-based, prospective cohort study conducted in Finland. The hsCRP levels were significantly elevated in the second ( P = 0.016) and third trimesters ( P = 0.001) of pregnancy compared to the levels of non-pregnant women. IL-6 levels were significantly higher in the third trimester ( P = 0.029) of pregnancy than in non-pregnant state. TNF-α concentrations did not change significantly during pregnancy. ADMA and SDMA concentrations were significantly lower during pregnancy compared to the levels of non-pregnant women ( P < 0.001). There was no significant association between ADMA and inflammation markers regardless of the elevated serum concentrations of hsCRP and IL-6 in the third trimester of normal pregnancy. These results suggest that maternal systemic ADMA and SDMA concentrations are more likely to become decreased due to the hemodilution and increased renal clearance than being directly influenced by the change of cytokines during pregnancy.

Decidual Immune Cell Infiltrate in Hydatidiform Mole

Background: Hydatidiform mole is a gestational trophoblastic disease characterized by proliferation of the pregnancy-associated trophoblastic tissue. Complete hydatidiform mole is an entirely paternally derived lesion, and therefore, represents complete intrauterine allografts that can induce an altered maternal immune response Hypothesis: Here, we hypothesize that “the development of hydatidiform moles is associated with numeric alterations of the decidual immune cell infiltrate.” Materials and methods: A total of 30 specimens (decidual tissue), entailing normal first trimester pregnancy terminations and complete hydatidiform moles (15 cases, each), were evaluated for immune cell infiltrate using immunohistological methods and monoclonal antibodies (CD20, CD68, and CD3 for B cells, histiocytes/dendritic cells, and T cells, respectively). Results: Groups of immune cells were seen in the decidual tissue of first trimester normal pregnancy terminations and hydatidiform moles. Compared to the decidual tissue of first trimester normal pregnancy terminations, the mean counts of the immune cells were statistically significantly higher (p< 0.05) in the decidual tissue of the hydatidiform moles (0.33 ± 0.21 vs. 1.66 ± 0.21 for CD20+B cells; 9.80 ± 1.57 vs. 13.14 ± 1.16 for CD68+ cells; and 12.92 ± 3.46 vs. 23.85 ± 1.22 for CD3+ cells for decidual tissue without and with molar changes, respectively). Conclusions: Hydatidiform moles are associated with numeric alterations of immune cell infiltrate. The numeric dominance of immune cells in the hydatidiform moles may reflect either non-specific or specific immunological processes. The possible pathogenetic and prognostic ramifications of our findings are open for further investigations.

Intervillous and uteroplacental circulation in normal early pregnancy and early pregnancy loss assessed by 3-dimensional power Doppler angiography

To assess intervillous and uteroplacental circulation in early normal pregnancies and miscarriages. One hundred normal pregnancies and 46 delayed miscarriages were evaluated by 3-dimensional vaginal ultrasound and power Doppler angiography. Volumes of the early placenta and the subplacental area were obtained between 5 and 12.6 weeks' gestation. The placental volume, vascularization index, flow index, and vascularization flow index was calculated. Intraclass correlation coefficients ranged from 0.961 for placental volume to 0.885 for intervillous flow index. Intervillous power Doppler signals were not detected before the sixth week. Placental volume (R(2) = 0.68), intervillous vascularization index (R(2) = 0.30), flow index (R(2) = 0.33) and vascularization flow index (R(2) = 0.35), uteroplacental flow index (R(2) = 0.34), and vascularization flow index (R(2) = 0.17) increase significantly (P < .001) throughout the first trimester of normal pregnancies. Uteroplacental vascularization index was not significantly related to gestational age. Intervillous vasculariztion index, flow index, and vascularization flow index were significantly raised in miscarriages, but there were no significant differences for uteroplacental vascularization index, flow index, or vascularization flow index. Intervillous and uteroplacental blood flow increases throughout the first trimester of normal pregnancies. Intervillous circulation is abnormally increased when a miscarriage is diagnosed.