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Biomedical subjects

Roberto Romero

Publications and source records attributed to Roberto Romero.

At least 73 records · Page 4Linked to original sources
PubMed2005

Progesterone receptor isoform (A/B) ratio of human fetal membranes increases during term parturition.

OBJECTIVE: The role of progesterone in the control of human parturition remains unsettled. Because there is no systemic progesterone withdrawal before the onset of labor, a 'functional progesterone withdrawal' has been proposed to be operative before human parturition. This may be accomplished by a change in the density of the progesterone receptor (PR) isoforms in myometrium and fetal membranes. The purpose of our study was to determine if spontaneous term labor is associated with changes of PR isoforms (PR-A and PR-B) in the fetal membranes. STUDY DESIGN: Fetal membranes were obtained from women undergoing elective cesarean delivery at term (not in labor group), and from women with a vaginal delivery (labor group). The expression of PR isoforms was assessed by Western blot analysis of amnion and chorio-decidua. Densitometric analysis of PR-A/PR-B ratio was performed. Immunohistochemistry with specific antibodies to PR-A and PR-B was done. Nonparametric statistics were used for analysis. RESULTS: 1) The predominant isoform of PR in women not in labor was PR-B, and PR-A in patients in labor. The ratio of PR-A/PR-B in fetal membranes was significantly higher in women in labor than in those not in labor (for amnion, median 4.3, range [0.9-8.4] vs median 0.4, range [0.3-2.6], P < .001; for chorio-decidua, median 2.0, range [1.1-19.2] vs median 1.2, range [0.1-2.0], P < .05). 2) Fetal membranes expressed both types of PR. 3) Immunohistochemistry showed the presence of PR-A and PR-B in the cytoplasm of amnion epithelial cells, chorion trophoblast, and decidual cells. CONCLUSION: Human parturition at term is associated with changes in PR isoforms in the fetal membranes and, thus, a local 'functional progesterone withdrawal' may operate in human parturition through this mechanism.

Blotting, Western↗
PubMed2005

Expression of bone morphogenetic protein 2 in normal spontaneous labor at term, preterm labor, and preterm premature rupture of membranes.

OBJECTIVE: Genome-wide screening studies of the chorioamniotic membranes unexpectedly identified an increase in the expression of bone morphogenetic protein 2 in spontaneous labor at term. The objective of this study was to determine whether bone morphogenetic protein 2 messenger RNA and protein expression are altered in the chorioamniotic membranes of patients with term labor, preterm labor, and preterm premature rupture of membranes. STUDY DESIGN: Chorioamniotic membranes were obtained from patients at term (with and without labor), with preterm labor (with and without histologic chorioamnionitis), and with preterm premature rupture of membranes (with and without histologic chorioamnionitis). The expression of bone morphogenetic protein 2 was studied by real-time quantitative reverse transcriptase-polymerase chain reaction (n = 88) and immunohistochemistry (n = 124). Nonparametric statistics were used for analysis. Primary amnion cells obtained from women at term not in labor were treated with bone morphogenetic protein 2 to examine whether there was increased prostaglandin E2 expression. RESULTS: The median bone morphogenetic protein 2 messenger RNA and protein expression were significantly higher in the membranes of patients with spontaneous labor at term than in those of patients not in labor at term (P < .001 for both). Bone morphogenetic protein 2 messenger RNA and protein expression were increased in patients with preterm labor with histologic chorioamnionitis than in those without histologic chorioamnionitis (P < .05 and P < .001, respectively). There was no difference in bone morphogenetic protein 2 messenger RNA and protein expression in patients with preterm premature rupture of membranes, regardless of chorioamnionitis (P = .13 and P = .08, respectively). There was a correlation between bone morphogenetic protein 2 and cyclooxygenase 2 protein expression in chorioamniotic membranes (R = .34; P < .001). CONCLUSION: Bone morphogenetic protein 2 messenger RNA and protein expression are increased in the chorioamniotic membranes of patients with spontaneous labor at term and patients with preterm labor associated with histologic chorioamnionitis. Its expression pattern and biologic effects strongly suggest that bone morphogenetic protein 2 is involved in human parturition.

Amnion↗
PubMed2005

An elevated maternal plasma, but not amniotic fluid, soluble fms-like tyrosine kinase-1 (sFlt-1) at the time of mid-trimester genetic amniocentesis is a risk factor for preeclampsia.

OBJECTIVE: The purpose of this study was to determine if an elevated concentration of soluble fms-like tyrosine kinase-1(sFlt-1) in maternal plasma and amniotic fluid is a risk factor for the subsequent development of preeclampsia. STUDY DESIGN: A case-control study was conducted to compare mid-trimester concentrations of maternal plasma and amniotic fluid sFlt-1 in patients who developed preeclampsia with those who did not. The study included 32 cases with preeclampsia (18 cases: severe preeclampsia) and 128 matched controls with normal outcomes. Patients with an abnormal fetal karyotype or major anomaly, multiple pregnancies, chronic hypertension, diabetes, and renal disease were excluded. Soluble Flt-1 concentration was measured by specific immunoassay. Nonparametric techniques were used for statistical analysis. RESULTS: 1) The median maternal plasma, but not amniotic fluid, sFlt-1 concentration in patients who developed preeclampsia was significantly higher than in the control cases (maternal plasma: median 730 pg/mL, range 60-3375 pg/mL vs median 441 pg/mL, range 58-1959 pg/mL, P < .05; amniotic fluid: median 10,504 pg/mL, range 5253-38,023 pg/mL vs median 10,236 pg/mL, range 4326-87,684 pg/mL, P = .65). 2) The median plasma concentration of sFlt-1 was higher in cases of severe preeclampsia than in those with mild preeclampsia without reaching statistical significance (median 762 pg/mL, range 261-3309 pg/mL vs median 334 pg/mL, range 60-3375 pg/mL; P = .07). However, there was no significant difference in the median amniotic fluid sFlt-1 concentrations between patients with severe preeclampsia and those with mild preeclampsia (P = .45). 3) An elevated maternal plasma sFlt-1 concentration (higher than 700 pg/mL) is a risk factor for the development of preeclampsia (OR 3.9, 95% CI 1.7-8.6) and severe preeclampsia (OR 7.4, 95% CI 2.5-22.1) after genetic amniocentesis. 4) The median interval from amniocentesis to the diagnosis of preeclampsia in patients with maternal plasma sFlt-1 concentrations higher than 700 pg/mL was 117 days (range 19-154 days). CONCLUSION: An elevated concentration of sFlt-1 in maternal plasma at the time of mid-trimester amniocentesis is a risk factor for the subsequent development of preeclampsia.

Adult↗
PubMed2005

Maternal plasma osteoprotegerin concentration in normal pregnancy.

OBJECTIVE: Pregnancy is associated with major changes in calcium metabolism because the neonatal skeleton contains approximately 30 g of calcium, which are largely deposited in the third trimester. Osteoprotegerin (OPG) acts as a decoy receptor for the "Receptor Activator of Nuclear Factor-kappaB Ligand" (RANKL), which is an essential factor for bone remodeling. This study was conducted to determine whether there were changes in maternal plasma OPG concentration during normal pregnancy. STUDY DESIGN: A cross-sectional study was performed in 433 patients of reproductive age (40 nonpregnant and 393 pregnant). Pregnant patients were classified into 4 groups according to gestational age: group 1: 11 to 14 weeks (n = 100); group 2: 15 to 18 weeks (n = 99); group 3: 27 to 30 weeks (n = 100); and group 4: 37 to 42 weeks (n = 94). Plasma OPG concentrations were measured with the use of a sensitive and specific immunoassay. Nonparametric statistics were used for analysis. RESULTS: OPG was detected in the plasma of all women tested. The median OPG concentration was significantly higher in term patients than in those in early pregnancy (median: 6.63 pmol/L [range: 1.57-25.57] vs median: 3.98 pmol/L [range: 0.41-13.71], P < .001). There was no significant difference in plasma OPG concentrations between nonpregnant women and those in groups 1 or 2 (nonpregnant women median: 3.86 pmol/L [range: 1.64-15.29] vs group 1 median: 3.98 pmol/L [range: 0.41-13.71] vs group 2 median: 3.87 pmol/L [range: 1.14-69.83], P = .75). CONCLUSION: The median maternal plasma OPG concentration is higher in the third trimester than in the first trimester of pregnancy. OPG may be involved in the regulation of bone turnover during pregnancy.

Adult↗
PubMed2005

Toll-like receptor 4: a potential link between "danger signals," the innate immune system, and preeclampsia?

OBJECTIVE: Toll-like receptors (TLRs) recognize microbial ligands and host products that are released during tissue damage, the so-called "danger signals." This study was conducted to determine whether changes in TLR-4 and TLR-2 expressions can be detected in the trophoblasts at the placental bed of women with and without preeclampsia. STUDY DESIGN: Placental bed biopsy specimens were obtained from women with: (1) normal term pregnancies with and without labor (each n = 20); (2) preeclampsia who delivered preterm (n = 15); and (3) preterm labor and intact membranes with and without chorioamnionitis (each n = 15). The expression pattern of TLR-4 and TLR-2 in the trophoblasts was analyzed by double immunohistochemistry. RESULTS: (1) The median percentage of TLR-4 positive interstitial trophoblasts was significantly higher in patients with preeclampsia than in patients with preterm labor without or with histologic chorioamnionitis (P = .0002 and P = .02, respectively). (2) The median percentage of TLR-2 positive interstitial trophoblasts was not different among the study groups (P>.05). (3) TLR-4 positive trophoblasts were also frequently immunoreactive to activated nuclear factor-kappaB, tumor necrosis factor-alpha, and M30 (a specific apoptosis antigen for trophoblast). (4) Lipopolysaccharide treatment inhibited the migration of trophoblast cell lines in vitro. CONCLUSION: TLR-4 protein expression is increased in interstitial trophoblasts of patients with preeclampsia. We propose that "danger signals" at the feto-maternal interface, which are recognized by trophoblasts through TLR-4, may play a key role in the creation of a local abnormal cytokine milieu. This suggests a novel mechanism that links the activation of the innate immune system through TLR-4 and preeclampsia.

Cell Movement↗
PubMed2005

Transaldolase is part of a supramolecular complex containing glucose-6-phosphate dehydrogenase in human neutrophils that undergoes retrograde trafficking during pregnancy.

Previous studies have shown that glucose-6-phosphate dehydrogenase (G6PDase) and 6-phosphogluconate dehydrogenase form a supramolecular complex in human neutrophils that undergoes retrograde trafficking in cells from pregnant women, but anterograde trafficking in cells from nonpregnant individuals. Using fluorescence resonance energy transfer techniques, we now demonstrate that transaldolase (TALase), a key regulatory enzyme in the nonoxidative branch of the hexose monophosphate shunt, is in close physical proximity with G6PDase, but not with lactate dehydrogenase, thus suggesting the formation of a TALase-G6PDase complex. Moreover, immunofluorescence microscopy demonstrated that TALase undergoes anterograde trafficking in neutrophils from nonpregnant individuals, whereas retrograde trafficking is found during pregnancy. However, pregnancy did not affect lactate dehydrogenase distribution. Colchicine treatment blocked the retrograde distribution of TALase, suggesting that microtubules are involved in TALase trafficking. We suggest that TALase is part of a supramolecular hexose monophosphate shunt complex, which likely increases the efficiency of the shunt via substrate channeling. We further suggest that TALase's retrograde motion contributes to uncoupling the shunt from its source of glucose-6-phosphate at the plasma membrane, thereby blunting nicotinamide adenine dinucleotide phosphate (reduced form) production and downstream oxidant production by neutrophils.

Cell Membrane↗
PubMed2005

Is there a seasonal variation in the diagnosis of oligohydramnios?

OBJECTIVE: We hypothesized that oligohydramnios would be diagnosed more frequently in the warm summer months when dehydration might be more common. METHODS: The clinical diagnosis of oligohydramnios was extracted from the databases of four completed National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network protocols. These data were stratified by quarter of delivery and compared using Fisher's Exact Test. RESULTS: The clinical diagnosis of oligohydramnios was made more frequently in deliveries occurring in the summer months of June, July and August as compared with the remainder of the calendar year (7.2% vs 5.9%, p=0.0178). CONCLUSIONS: In these studies the diagnosis of oligohydramnios is made more frequently in those pregnancies delivered during the summer months. Although not proven by this association, maternal dehydration may contribute to this finding.

Adolescent↗
PubMed2005

Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of pre-eclampsia.

OBJECTIVE: Accumulating evidence suggests that the balance between vascular endothelial growth factor (VEGF), placental growth factor (PIGF), and their receptors is important for effective vasculogenesis, angiogenesis, and placental development. Recently, the soluble form of VEGFR-1 (sVEGFR-1), an antagonist to VEGF and PIGF, has been implicated in the pathophysiology of pre-eclampsia. Plasma sVEGFR-1 concentration is elevated in pre-eclampsia at the time of clinical diagnosis and correlates with the severity of the disease. The purpose of this study was to determine whether the concentrations of sVEGFR-1 in plasma of pre-eclamptic patients change prior to the clinical manifestations of the disease. METHODS: A longitudinal case-control study was conducted in normal pregnant women (n = 44) and patients with pre-eclampsia (n = 44). Blood sampling was performed at six intervals: (1) 7-16 weeks; (2) 16-24 weeks; (3) 24-28 weeks; (4)28-32 weeks; (5) 32-36 weeks; and (6) more than 37 weeks of gestation. To examine the relationship between plasmasVEGFR-1 concentration and interval to clinical diagnosis of pre-eclampsia, plasma samples of pre-eclamptic patients at different gestational ages were stratified according to the interval from blood sampling to clinical development of the disease into five groups: (1) at clinical manifestation; (2) 2-5 weeks; (3) 6-10 weeks; (4) 11-16 weeks; and (5) 17-25 weeks before clinical manifestations. Plasma concentrations of sVEGFR-1 were determined by enzyme-linked immunoassay. Parametric statistics and repeated measure procedures were used for the analysis. RESULTS: The mean plasma sVEGFR-1 concentration in pre-eclamptic patients before the clinical manifestation of the disease was significantly higher than in normal pregnant women at 24-28, 28-32, and 32-37 weeks of gestation (p = 0.02,p < 0.001, and p < 0.001, respectively). In contrast, no significant differences in the mean plasma sVEGFR-1 concentration between patients with pre-eclampsia and normal pregnant women were observed both at 7-16 weeks and 16-24 weeks of gestation (p= 0.1 and p= 0.9). Similarly, the mean plasma sVEGFR-1 concentration was significantly higher in pre-eclamptic patients than in normal pregnant women at clinical manifestation, at 2-5 weeks (mean 3.8 weeks), and at 6-10 weeks (mean 8.2 weeks) prior to the development of clinical pre-eclampsia (p < 0.001, p < 0.001, and p = 0.002,respectively). Among patients with early-onset pre-eclampsia (defined as gestational age of 34 weeks or less), the mean plasma sVEGFR-1 concentration was significantly higher in pre-eclampsia (before clinical diagnosis) than in normal pregnant women at 24-28 (mean 26.4) weeks of gestation (p = 0.008). In contrast, among patients with the late-onset disease(defined as gestational age of more than 34 weeks), plasma sVEGFR-1 concentration in pre-clinical pre-eclampsia was significantly higher than in normal pregnant women at 28-32 (mean 30.2) weeks of gestation (p < 0.001). CONCLUSIONS: Plasma sVEGFR-1 concentration is elevated in pre-eclampsia prior to the clinical diagnosis of the disease. This elevation began 6-10 weeks prior to the clinical manifestations, and the increase was more pronounced at 2-5 weeks before the diagnosis, as well as at clinical presentation. Furthermore, in early-onset pre-eclampsia, plasma concentration ofsVEGFR-1 is elevated earlier than the late-onset disease.

Adult↗
PubMed2005

Normal pregnancy is characterized by systemic activation of the complement system.

BACKGROUND: The complement system, a major component of innate immunity, has recently been implicated in the mechanisms of fetal loss and placental inflammation in the anti-phospholipid antibody syndrome. Inhibition of complement has been proposed as an absolute requirement for normal pregnancy. Yet, pregnancy is characterized by a generalized activation of the innate immune system. This study was conducted to determine whether or not normal pregnancy is associated with complement activation in the maternal circulation. METHODS: Anaphylatoxins (C3a, C4a and C5a) were determined in the plasma of normal pregnant (20-42 wks; n=134) and non-pregnant women (n=40). These complement split products (C3a, C4a and C5a) were measured using specific immunoassays. Non-parametric statistics were used for analysis. RESULTS: 1) The median plasma concentrations of C3a, C4a and C5a were significantly higher in normal pregnant women than in non-pregnant women (all p<0.001); 2) the concentration of C3a, C4a and C5a did not change with gestational age (p>0.05); and 3) the median plasma concentration of C3a had a positive correlation with the plasma C4a and C5a concentrations (r=0.36, p<0.001 and r=0.35, p<0.001, respectively). CONCLUSION: 1) Normal human pregnancy is associated with evidence of complement activation, as determined by higher concentrations of the anaphylatoxins C3a, C4a and C5a in the maternal circulation; and 2) we propose that physiologic activation of the complement system during pregnancy is a compensatory mechanism aimed at protecting the host against infection.

Adolescent↗
PubMed2005

Increased concentration of the complement split product C5a in acute pyelonephritis during pregnancy.

OBJECTIVE: Pregnant women with acute pyelonephritis develop acute respiratory distress syndrome (ARDS) more frequently than non-pregnant women. The reasons for this remain unknown. The complement system is a complex set of self-assembling proteins that have been implicated in the pathophysiology of ARDS and sepsis. The purpose of this study was to determine if activation of the complement system occurs in pregnant women with acute pyelonephritis. METHODS: A cross-sectional study was conducted to determine the plasma concentrations of C3a, C4a and C5a (i.e., complement split products) in pregnant patients with acute pyelonephritis (n=38) and normal pregnant women (n=38). The complement split products C3a, C4a and C5a were measured using ELISA. Data were analyzed using non-parametric statistics. RESULTS: 1) The median plasma concentration of C5a in pregnant patients with acute pyelonephritis was significantly higher than that in normal pregnant women (p<0.001); 2) there was no statistical difference in the median plasma concentration of C3a and C4a between the two groups (p>0.05); and 3) concentrations of C3a, C4a and C5a were not different among patients with acute pyelonephritis with and without bacteremia. CONCLUSIONS: 1) Pyelonephritis in pregnant women is associated with an increased plasma concentration of C5a, but not C3a and C4a; and 2) an excess of C5a can predispose pregnant women to develop ARDS and multi-organ failure in pyelonephritis. This finding may have clinical implications since blocking C5a improves ARDS in experimental sepsis.

Acute Disease↗
PubMed2005

Four-dimensional fetal echocardiography with spatiotemporal image correlation (STIC): a systematic study of standard cardiac views assessed by different observers.

OBJECTIVE: To test the agreement between observers and reproducibility of a technique to display standard cardiac views of the left and right ventricular outflow tracts from four-dimensional volume datasets acquired with Spatiotemporal Image Correlation (STIC). METHODS: A technique was developed to obtain dynamic multiplanar images of the left ventricular outflow tract (LVOT) and right ventricular outflow tract (RVOT) from volume datasets acquired with STIC. Volume datasets were acquired from fetuses with normal cardiac anatomy. Twenty volume datasets of satisfactory quality were pre-selected by one investigator. The data was randomly assigned for a blinded review by two independent observers with previous experience in fetal echocardiography. Only one volume dataset was used for each fetus. After a training session, the observers obtained standardized cardiac views of the LVOT and RVOT, which were scored on a scale of 1 to 5, based on diagnostic value and image quality (1=unacceptable, 2=marginal, 3=acceptable, 4=good, and 5=excellent). Median scores and interquartile range, as well as inter- and intraobserver agreement were calculated for each view. RESULTS: The mean menstrual age at the time of volume acquisition was 25.5+/-4.5 weeks. Median scores (interquartile range) for LVOT images, obtained by the first and second observers, were 3.5 (2.25-5.00) and 4 (3.00-5.00), respectively. The median scores (interquartile range) for RVOT images obtained by the first and second observers were 3 (3.00-5.00) and 3 (2.00-4.00), respectively. The interobserver intraclass correlation coefficient for the LVOT was 0.693 (95% CI 0.380-0.822), and 0.696 (95% CI 0.382-0.866) for the RVOT. For the intraobserver agreement analysis, observer 1 gave higher scores to the LVOT the second time the volumes were analyzed [LVOT: 3.50 (2.25-5.00) vs. 5.00 (4.00-5.00, p=0.008)]. CONCLUSION: STIC can be reproducibly used to evaluate fetal cardiac outflow tracts by independent examiners. Slightly better image quality rating scores during the intraobserver variability trial suggests the presence of a learning curve for the manipulation and analysis of volume data obtained by STIC.

Double-Blind Method↗
PubMed2005

Monocyte chemotactic protein-1 is increased in the amniotic fluid of women who deliver preterm in the presence or absence of intra-amniotic infection.

OBJECTIVE: Pro-inflammatory chemokines have been associated with preterm parturition. Monocyte chemotactic protein-1 (MCP-1) is a chemokine capable of recruiting monocytes/macrophages into sites of inflammation, as well as stimulating the respiratory burst required for macrophage activation. MCP-1 transcripts and immuno-reactivity are expressed by uterine tissues (i.e., decidual cells and myometrium) and, thus, may participate in the process of labor. This study was conducted to determine if preterm labor leading to preterm delivery and intra-amniotic infection (IAI) are associated with changes in the amniotic fluid concentrations of MCP-1. STUDY DESIGN: A cross-sectional study was designed to examine the amniotic fluid concentrations of MCP-1 in women in two groups: 1) those presenting with preterm labor with intact membranes; and 2) those with preterm prelabor rupture of membranes (PROM). Amniotic fluid was obtained by transabdominal amniocentesis from 131 women in preterm labor with intact membranes and 105 women with preterm PROM. IAI was defined by a positive amniotic fluid culture for microorganisms. Group 1 included women with preterm labor and intact membranes (n=131), and was subdivided into the following groups: a) delivery at term in the absence of IAI (n=42); b) preterm delivery (< 37 weeks) in the absence of IAI (n=58); and c) preterm delivery in the presence of IAI (n=31). Group 2 consisted of women with PROM (n=105), and was subdivided into women with (n=51) and without (n=54) IAI. Non-parametric statistics were used for data analysis. RESULTS: 1) Immuno-reactive MCP-1 was detected in all amniotic fluid samples; 2) IAI, regardless of the membrane status, was associated with a significantly higher median amniotic fluid concentration of immuno-reactive MCP-1 than those without IAI (p<0.001 for both comparisons); 3) women in preterm labor who delivered preterm without IAI had a significantly higher median amniotic fluid concentration of immuno-reactive MCP-1 than those who delivered at term (p<0.001); 4) histological chorioamnionitis was associated with increased amniotic fluid concentrations of immuno-reactive MCP-1; and 5) a significant relationship existed between the amniotic fluid concentrations of immuno-reactive MCP-1 and the interval from amniocentesis to delivery. CONCLUSIONS: Amniotic fluid concentrations of immuno-reactive MCP-1 were increased in women in preterm labor with IAI, those without IAI who delivered preterm, and those who displayed acute inflammatory lesions in the extra-placental membranes. These findings suggest that MCP-1 may play a role in preterm labor regardless of the presence of IAI.

Adolescent↗
PubMed2005

Evidence supporting that the excess of the sVEGFR-1 concentration in maternal plasma in preeclampsia has a uterine origin.

BACKGROUND: Preeclampsia has been considered an anti-angiogenic state. Two factors have been implicated in the genesis of this state: soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and placental growth factor (PlGF). Indeed, the concentrations of PlGF, an angiogenic factor, are lower in preeclampsia than in normal pregnancy, while the opposite is the case for the anti-angiogenic factor, sVEGFR-1. The source of the excess sVEGFR-1 has not yet been determined. Since the placenta could be a source of sVEGFR-1, we conducted a study to determine whether there is a gradient in the plasma concentration of sVEGFR-1 and PlGF between the uterine vein and the antecubital vein in both patients with preeclampsia and normal pregnant women. METHODS: A cross-sectional study was performed to determine the plasma concentrations of sVEGFR-1 and PlGF in the uterine and antecubital vein of patients with preeclampsia (n = 9) and normal pregnant women at term (n = 9). Plasma samples were collected from antecubital and uterine veins at the time of cesarean section. The concentrations of sVEGFR-1 and PlGF were determined using specific enzyme-linked immunoassays. The differences of plasma concentrations of sVEGFR-1 and PlGF between uterine and antecubital veins in both groups were compared by paired t-tests. RESULTS: Patients with preeclampsia had a significantly higher mean plasma concentration of sVEGFR-1 in the uterine vein than in the antecubital vein (uterine vein: mean 13,675 +/- 5,684 pg/ml vs. antecubital vein: mean 10,234 +/- 4,700 pg/ml; paired t-tests, p = 0.04). In contrast, among normal pregnant women at term, there was no significant difference in plasma concentrations of sVEGFR-1 between the uterine and antecubital veins (uterine vein: mean 1,918 +/- 665 pg/ml vs. antecubital vein: mean 1,750 +/- 475 pg/ml; paired t-tests, p = 0.1). The mean plasma concentration of sVEGFR-1, either in the antecubital or uterine vein, was significantly higher in preeclampsia than in normal pregnancy (unpaired t-tests; both p < 0.001). There was no significant difference in the mean plasma concentration of PlGF between the uterine and the antecubital veins in both the preeclamptic (uterine vein, mean +/- SD: 129 +/- 106 pg/ml vs. antecubital vein, mean +/- SD: 82 +/- 43 pg/ml; paired t-tests, p = 0.2) and normal pregnancy groups (uterine vein, mean +/- SD: 331 +/- 254 pg/ml vs. antecubital vein, mean +/- SD: 319 +/- 259 pg/ml; paired t-tests, p = 0.4). The mean plasma concentration of PlGF, either in the uterine or antecubital vein, was lower in preeclampsia than in normal pregnancy (unpaired t-tests; p = 0.008 and 0.02 respectively). CONCLUSIONS: Plasma concentration of sVEGFR-1 was higher in the uterine vein than in the antecubital vein in women with preeclampsia. This provides evidence supporting the concept that the uterus is a potential source of the excess circulating sVEGFR-1 concentration in preeclamptic women.

Adult↗
PubMed2005

Idiopathic vaginal bleeding during pregnancy as the only clinical manifestation of intrauterine infection.

OBJECTIVE: To determine the frequency and clinical significance of microbial invasion of the amniotic cavity (MIAC) in patients with vaginal bleeding in the absence of placenta previa, preterm labor or preterm premature rupture of membranes (PROM). STUDY DESIGN: This retrospective cohort study included patients who presented with vaginal bleeding between 18 and 35 weeks, and underwent an amniocentesis shortly after admission for the assessment of the microbiologic status of the amniotic cavity and/or fetal lung maturity. Amniotic fluid was cultured for aerobic and anaerobic bacteria, as well as genital mycoplasmas. Patients presenting with preterm labor, preterm PROM, placenta previa, overt placental abruption, and an intrauterine device in situ were excluded, as well as those with local cervical bleeding. MIAC was defined as a positive amniotic fluid culture. Analysis was conducted with non-parametric statistics. RESULTS: One hundred and fourteen patients met the entry criteria. MIAC was detected in 14% of cases (16/114). Patients with vaginal bleeding and a gestational age < 28 weeks at the time of amniocentesis had a significantly higher frequency of MIAC than those with a gestational age 28 weeks [25% (13/52) vs. 4.8% (3/62), respectively; p < 0.01]. Ureaplasma urealyticum was the microorganism most frequently isolated from the amniotic fluid. Except for one case admitted at 33 weeks, all patients with MIAC had an early preterm delivery 32 weeks. Patients with vaginal bleeding and MIAC had a shorter procedure-to-delivery interval than those without MIAC [MIAC, median survival 19 days (95% CI 10-27 days) vs. no MIAC, median survival 50 days (95% CI 37-62 days); p < 0.0001]. Patients with vaginal bleeding and MIAC had a significantly lower gestational age at delivery and lower birth weight than those with vaginal bleeding and negative amniotic fluid cultures (for gestational age, median 25 weeks, range 21-33 weeks vs. median 37 weeks, range 19-42 weeks, respectively; p < 0.01, and for birth weight, median 750 grams, range 520-1820 grams vs. 2800 grams, range 520-4880 grams, respectively; p < 0.01), as well as a higher frequency of subsequent preterm PROM [81.3% (13/16) vs. 9.2% (9/98); p < 0.01]. CONCLUSIONS: MIAC was detected in 14% of patients with 'idiopathic' vaginal bleeding and was associated with subsequent preterm PROM and early preterm delivery. Vaginal bleeding may be the only clinical manifestation of MIAC, and it predisposes to adverse outcome.

Adult↗
PubMed2005

Oxidant release is dramatically increased by elevated glucose concentrations in neutrophils from pregnant women.

OBJECTIVE: To evaluate the mechanism of oxidative stress at glucose levels accompanying diabetic pregnancy. Specifically, we hypothesize that elevated glucose overwhelms hexose monophosphate shunt (HMS) down-regulation observed during pregnancy. METHODS: Peripheral blood cells from normal healthy pregnant women were exposed to heightened glucose levels to provide an in vitro model of the effects of diabetic pregnancy. Changes in NAD(P)H, reactive oxygen species (ROS) and nitric oxide (NO) production were evaluated in single cells. RESULTS: Altered metabolic dynamics, as judged by NAD(P)H autofluorescence of neutrophils from both pregnant and non-pregnant women, were observed during incubation with 14 mM glucose, a pathophysiologic level. In parallel, increased production of ROS and NO was observed. The ROS and NO levels attained in cells from pregnant women were greater than those observed in cells from non-pregnant women. Inhibitors of the HMS and NAD(P)H oxidase blocked these effects. These metabolic and oxidant changes required approximately one minute, suggesting that transient glucose spikes during pregnancy could trigger this response. CONCLUSIONS: Elevated glucose levels enhance HMS activity and oxidant production in cells from pregnant women. This mechanism may be generally applicable in understanding the role of diabetes in materno-fetal health.

Blood Glucose↗
PubMed2005

Macrophage migration inhibitory factor in patients with preterm parturition and microbial invasion of the amniotic cavity.

OBJECTIVE: Macrophage migration inhibitory factor (MIF) has emerged as an important mediator of septic shock. The administration of MIF increases lethality during endotoxemia, whereas neutralization of this cytokine prevents endotoxic shock and death associated with bacterial infection. The objective of this study was to determine whether there is a change in the amniotic fluid concentration of MIF in intra-amniotic infection and human parturition. STUDY DESIGN: A cross-sectional study was conducted in women in the following categories: (1) mid-trimester (n = 84); (2) preterm labor and intact membranes who delivered at term (n = 33), who delivered preterm (n = 53) and preterm labor with intra-amniotic infection (n = 23); (3) preterm premature rupture of membranes (PROM) with (n = 25) and without intra-amniotic infection (n = 26); and (4) term with intact membranes, in labor (n = 52) and not in labor (n = 31). MIF concentrations in amniotic fluid were determined using a sensitive and specific immunoassay. MIF concentrations in maternal plasma were also determined in patients with preterm labor and intact membranes. Immunohistochemistry was conducted in chorioamniotic membranes obtained from a different set of patients presenting with preterm labor with (n = 18) and without (n = 20) histologic chorioamnionitis. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to measure MIF mRNA expression in chorioamniotic membranes of patients with preterm labor with (n = 13) and without (n = 13) histologic chorioamnionitis. Parametric and non-parametric, receiver-operating characteristic (ROC) curve, survival analysis, and Cox regression model were used for analysis. RESULTS: Immunoreactive MIF was detectable in 96% (313/327) of amniotic fluid samples. The concentration of amniotic fluid MIF at term was higher than that in the mid-trimester (p = 0.004). Intra-amniotic infection in women with preterm labor and preterm PROM was associated with a significant increase in median amniotic fluid MIF concentration (p < 0.001 and 0.004, respectively). Patients with preterm labor with sterile amniotic fluid who delivered preterm had a significantly higher median amniotic fluid MIF concentration than those who delivered at term (p = 0.007). Among patients with preterm labor with intact membranes, survival analysis indicated that the median amniocentesis-to-delivery interval was significantly shorter in patients whose amniotic fluid concentrations of MIF were above 302 ng/ml than those below this cutoff value (p < 0.001). Human parturition at term was not associated with changes in the amniotic fluid MIF concentrations (p > 0.05). There was no significant difference in median maternal plasma MIF concentrations among patients with preterm labor and intact membranes who delivered at term, those who delivered preterm, and those who had intra-amniotic infection (p > 0.05 for all comparisons). Immunohistochemistry demonstrated that MIF protein was present in amniotic epithelial cells, and the mean percentage of immunoreactive MIF-staining cells was higher in patients with histologic chorioamnionitis than in those without this lesion (p = 0.03). Similarly, the mean MIF mRNA expression was higher in chorioamniotic membranes obtained from patients with histologic chorioamnionitis than in those without this lesion (p = 0.03). CONCLUSIONS: Intra-amniotic infection and preterm parturition, but not term parturition, are associated with a significant increase in amniotic fluid MIF concentrations. Among patients with preterm labor with intact membranes, elevated amniotic fluid concentrations of MIF are associated with intra-amniotic inflammation, histologic chorioamnionitis, and shorter amniocentesis-to-delivery interval. These changes in amniotic fluid were not reflected in maternal plasma. An increased expression of MIF protein and mRNA in chorioamniotic membranes was observed in patients with histologic choricamnionitis.

Amniocentesis↗
PubMed2005

C-reactive protein concentration in vaginal fluid as a marker for intra-amniotic inflammation/infection in preterm premature rupture of membranes.

OBJECTIVE: The purpose of this study was to determine whether C-reactive protein (CRP) concentrations in vaginal fluid can identify patients with intra-amniotic inflammation/infection (IAI) and predict adverse outcome in preterm premature rupture of membranes (PROM). METHODS: The study population consisted of 121 singleton pregnant women with preterm PROM (36 weeks of gestation) who had an amniocentesis and vaginal fluid collection. A Dacron polyester-tipped applicator was soaked with vaginal fluid for 10 seconds and diluted with 1 mL buffer solution. Amniotic fluid was cultured for aerobic and anaerobic bacteria, as well as mycoplasmas. Vaginal fluid CRP and amniotic fluid matrix metalloproteinase-8 (MMP-8) were determined by specific immunoassays. IAI was defined as an amniotic fluid MMP-8 concentration >23 ng/mL and/or a positive amniotic fluid culture. Nonparametric tests and survival techniques were used for statistical analysis. RESULTS: Patients with IAI had a significantly higher median vaginal fluid CRP concentration than those without IAI (median (range), 7.8 (0.1-1310.1) ng/mL vs. 1.0 (0.1-319.4) ng/mL, p < 0.005). The median amniotic fluid white blood cell (WBC) count was significantly higher in patients with a vaginal fluid CRP concentration of >10 ng/mL than in those with a lower concentration (median (range), 82.5 (0-8640) cells/mm3 vs. 2 (0->1000) cells/mm3, p < 0.001). Patients with vaginal fluid CRP concentration of >10 ng/mL had a significantly shorter sampling-to-delivery interval and higher rates of preterm delivery within five days, funisitis, and histologic chorioamnionitis than did those with a vaginal fluid CRP concentration below this cut-off. A vaginal fluid CRP cut-off of 10 ng/mL had a specificity of 89% and a sensitivity of 45% in the identification of IAI. CONCLUSION: An elevated CRP concentration in vaginal fluid collected by polyester-tipped applicator is a risk factor for intra-amniotic inflammation/infection and impending preterm delivery in preterm PROM.

Amniocentesis↗