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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.

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.

Background: During implantation, apoptosis is critical for the appropriate tissue remodeling of the maternal decidua and invasion of the developing embryo, yet the regulation of apoptosis is also imperative for a successful pregnancy. The quick and effective removal of apoptotic cells by tissue macrophages represents an essential process, which prevents the release of self-antigens, and in the case of pregnancy, paternal alloantigens., Methods of Study: Recent studies have shown that the process of apoptotic cell clearance is not a neutral event, but rather an active one that induces macrophage production of anti-inflammatory cytokines and survival factors. Apoptotic cell clearance is, therefore, necessary for the resolution of inflammatory conditions, which during pregnancy could have lethal consequences., Conclusions: The function of the maternal immune system during implantation and throughout pregnancy is, therefore, an important area of investigation. This review will discuss the role of decidual macrophages in apoptotic cell clearance during pregnancy.

Pregnancy is associated with changes in host susceptibility to infections and inflammatory disease. We hypothesize that metabolic enzyme trafficking affects maternal neutrophil activation. Specifically, immunofluorescence microscopy has shown that glucose-6-phosphate dehydrogenase (G-6-PDase), the rate-controlling step of the hexose monophosphate shunt (HMS), is located near the cell periphery in control neutrophils but is found near the microtubule-organizing centers in cells from pregnant women. Cytochemical studies confirmed that the distribution of the G-6-PDase antigen is coincident with functional G-6-PDase activity. Metabolic oscillations within activated pregnancy neutrophils are higher in amplitude, though lower in frequency, than activated control neutrophils, suggesting limited HMS activity. Analysis of radioisotope-labeled carbon flux from glucose to CO(2) indicates that the HMS is intact in leukocytes from pregnant women, but its level is not enhanced by cell stimulation. Using extracellular fluorescent markers, activated pregnancy neutrophils were found to release reactive oxygen metabolites (ROMs) at a lower rate than activated control neutrophils. However, basal levels of ROM production in polarized pregnancy neutrophils were greater than in control neutrophils. Microtubule-disrupting agents reversed the observed changes in G-6-PDase trafficking, metabolic oscillations, and ROM production by maternal neutrophils. G-6-PDase trafficking appears to be one mechanism regulating ROM production by maternal neutrophils.

Objective: To determine the frequency and type of histopathologic lesions in placentas delivered by women with a normal pregnancy outcome. Methods: This retrospective cohort study included placental samples from 944 women with a singleton gestation who delivered at term without obstetrical complications. Placental lesions were classified into the following four categories as defined by the Society for Pediatric Pathology and by our unit: (1) acute placental inflammation, (2) chronic placental inflammation, (3) maternal vascular malperfusion and (4) fetal vascular malperfusion. Results: (1) Seventy-eight percent of the placentas had lesions consistent with inflammatory or vascular lesions; (2) acute inflammatory lesions were the most prevalent, observed in 42.3% of the placentas, but only 1.0% of the lesions were severe; (3) acute inflammatory lesions were more common in the placentas of women with labor than in those without labor; (4) chronic inflammatory lesions of the placenta were present in 29.9%; and (5) maternal and fetal vascular lesions of malperfusion were detected in 35.7% and 19.7%, respectively. Two or more lesions with maternal or fetal vascular features consistent with malperfusion (high-burden lesions) were present in 7.4% and 0.7%, respectively. Conclusion: Most placentas had lesions consistent with inflammatory or vascular lesions, but severe and/or high-burden lesions were infrequent. Mild placental lesions may be interpreted either as acute changes associated with parturition or as representative of a subclinical pathological process (intra-amniotic infection or sterile intra-amniotic inflammation) that did not affect the clinical course of pregnancy. [ABSTRACT FROM AUTHOR]

Objective: Prostaglandins (PGs) are considered the universal mediators of parturition. Amniotic fluid PGE2and PGF2αconcentrations increase before the onset of spontaneous labor at term, as well as during labor. This study was conducted to determine if the concentrations of umbilical cord PGE2and PGF2α change with advancing gestational age, spontaneous labor at term, and preterm labor (with and without funisitis). Methods: Umbilical cord (UC) tissue samples were obtained from women (N = 158) with singleton pregnancies in the following groups: (1) term deliveries without labor (TNL;n = 20); (2) term deliveries with labor (TIL;n = 20); (3) spontaneous preterm deliveries (sPTD) with (n = 20) and without acute funisitis (n = 20); and (4) preeclampsia without labor (n = 78). The concentrations of PGs were determined in different locations of the UC. PGE2and PGF2αwere measured by specific immunoassays. Non-parametric statistics were used for analysis. Results: (1) In spontaneous preterm deliveries, the median UC PGE2concentration was higher in cases with funisitis than in those without funisitis (233.7 pg/µg versus 87.4 pg/µg of total protein,p = 0.001); (2) the median UC PGE2concentration in sPTD with funisitis was also higher than that obtained from samples who had undergone labor at term (233.7 pg/µg versus 116.1 pg/µg of total protein,p = 0.03); (3) the UC PGE2and PGF2αconcentration increased as a function of advancing gestational age before 36 weeks (PGE2: ρ = 0.59,p < 0.001; PGF2α: ρ = 0.39,p = 0.01), but not after 36 weeks (PGE2: ρ = −0.1,p = 0.5; PGF2α: ρ = −0.2,p = 0.2); (4) the median UC concentrations of PGE2and PGF2αat term was similar in samples obtained from women with and without labor (PGE2: TNL 133.7 pg/µg versus TIL 116.1 pg/µg of total protein,p = 0.9; PGF2α: TNL 8.4 pg/µg versus TIL 8.1 pg/µg of total protein,p = 0.7); and (5) there was no correlation between UC PG concentration and gestational age at term pregnancy (PGE2: ρ = 0.01,p = 0.9; PGF2α: ρ = 0.07,p = 0.7). Conclusions: (1) PGE2concentrations in the UC are higher in the presence of acute funisitis than in the absence of this lesion; (2) spontaneous labor at term was not associated with a change in the UC concentration of PGE2and PGF2α; and (3) the UC concentrations of PGE2and PGF2αincreased as a function of gestational age. We propose that UC PGs act as inflammatory mediators generated in the context of fetal systemic inflammation. [ABSTRACT FROM PUBLISHER]

Objective: Acute atherosis is characterized by subendothelial lipid-filled foam cells, fibrinoid necrosis and perivascular lymphocytic infiltration. This lesion is generally confined to non-transformed spiral arteries and is frequently observed in patients with preeclampsia. However, the frequency of acute atherosis in the great obstetrical syndromes is unknown. The purpose of this study was to determine the frequency and topographic distribution of acute atherosis in placentas and placental bed biopsy samples obtained from women with normal pregnancy and those affected by the "great obstetrical syndromes". We also examined the relationship between acute atherosis and pregnancy outcome in patients with preeclampsia.Material and Methods: A retrospective cohort study of pregnant women who delivered between July 1998 and July 2014 at Hutzel Women's Hospital/Detroit Medical Center was conducted to examine 16, 345 placentas. Patients were classified into the following groups: (1) uncomplicated pregnancy; (2) spontaneous preterm labor (sPTL) and preterm prelabor rupture of membranes (PPROM); (3) preeclampsia; (4) gestational hypertension; (5) small-for-gestational age (SGA); (6) chronic hypertension; (5) fetal death; (6) spontaneous abortion and (7) others. A subset of patients had placental bed biopsy. The incidence of acute atherosis was compared among the different groups.Results: (1) The prevalence of acute atherosis in uncomplicated pregnancies was 0.4% (29/6961) based upon examination of nearly 7000 placentas; (2) the frequency of acute atherosis was 10.2% (181/1779) in preeclampsia, 9% (26/292) in fetal death, 2.5% (3/120) in midtrimester spontaneous abortion, 1.7% (22/1,298) in SGA neonates and 1.2% (23/1,841) in sPTL and PPROM; (3) among patients with preeclampsia, those with acute atherosis than in those without the lesion had significantly more severe disease, earlier onset, and a greater frequency of SGA neonates (p < 0.05 all) and (4) the lesion was more frequently observed in the decidua (parietalis or basalis) than in the decidual segment of the spiral arteries in patients with placental bed biopsies.Conclusions: Acute atherosis is rare in normal pregnancy, and occurs more frequently in patients with pregnancy complications, including preeclampsia, sPTL, preterm PROM, midtrimester spontaneous abortion, fetal death and SGA. [ABSTRACT FROM AUTHOR]

Background: The major challenge for obstetrics is the prediction and prevention of the great obstetrical syndromes. We propose that defining obstetrical diseases by the combination of clinical presentation and disease mechanisms as inferred by placental pathology will aid in the discovery of biomarkers and add specificity to those already known.Objective: To describe the longitudinal profile of placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PlGF/sFlt-1 ratio throughout gestation, and to determine whether the association between abnormal biomarker profiles and obstetrical syndromes is strengthened by information derived from placental examination, eg, the presence or absence of placental lesions of maternal vascular malperfusion.Study Design: This retrospective case cohort study was based on a parent cohort of 4006 pregnant women enrolled prospectively. The case cohort of 1499 pregnant women included 1000 randomly selected patients from the parent cohort and all additional patients with obstetrical syndromes from the parent cohort. Pregnant women were classified into six groups: 1) term delivery without pregnancy complications (n=540; control); 2) preterm labor and delivery (n=203); 3) preterm premature rupture of the membranes (n=112); 4) preeclampsia (n=230); 5) small-for-gestational-age neonate (n=334); and 6) other pregnancy complications (n=182). Maternal plasma concentrations of PlGF and sFlt-1 were determined by enzyme-linked immunosorbent assays in 7560 longitudinal samples. Placental pathologists, masked to clinical outcomes, diagnosed the presence or absence of placental lesions of maternal vascular malperfusion. Comparisons between mean biomarker concentrations in cases and controls were performed by utilizing longitudinal generalized additive models. Comparisons were made between controls and each obstetrical syndrome with and without subclassifying cases according to the presence or absence of placental lesions of maternal vascular malperfusion.Results: 1) When obstetrical syndromes are classified based on the presence or absence of placental lesions of maternal vascular malperfusion, significant differences in the mean plasma concentrations of PlGF, sFlt-1, and the PlGF/sFlt-1 ratio between cases and controls emerge earlier in gestation; 2) the strength of association between an abnormal PlGF/sFlt-1 ratio and the occurrence of obstetrical syndromes increases when placental lesions of maternal vascular malperfusion are present (adjusted odds ratio [aOR], 13.6 vs 6.7 for preeclampsia; aOR, 8.1 vs 4.4 for small-for-gestational-age neonates; aOR, 5.5 vs 2.1 for preterm premature rupture of the membranes; and aOR, 3.3 vs 2.1 for preterm labor (all P<0.05); and 3) the PlGF/sFlt-1 ratio at 28 to 32 weeks of gestation is abnormal in patients who subsequently delivered due to preterm labor with intact membranes and in those with preterm premature rupture of the membranes if both groups have placental lesions of maternal vascular malperfusion. Such association is not significant in patients with these obstetrical syndromes who do not have placental lesions.Conclusion: Classification of obstetrical syndromes according to the presence or absence of placental lesions of maternal vascular malperfusion allows biomarkers to be informative earlier in gestation and enhances the strength of association between biomarkers and clinical outcomes. We propose that a new taxonomy of obstetrical disorders informed by placental pathology will facilitate the discovery and implementation of biomarkers as well as the prediction and prevention of such disorders. [ABSTRACT FROM AUTHOR]

Objective: Acute atherosis is a lesion of the spiral arteries characterized by fibrinoid necrosis of the vessel wall, an accumulation of fat-containing macrophages, and a mononuclear perivascular infiltrate, which can be found in patients with preeclampsia, fetal death, small-for-gestational age, spontaneous preterm labor/premature prelabor rupture of membrane, and spontaneous mid-trimester abortion. This lesion is thought to decrease blood flow to the intervillous space which may lead to other vascular lesions of the placenta. The objective of this study was to test whether there is an association between acute atherosis and placental lesions that are consistent with maternal vascular underperfusion (MVU), amniotic fluid infection (AFI), fetal vascular thrombo-occlusive disease (FVTOD) or chronic inflammation. Material and methods: A retrospective cohort study of pregnant women who delivered between July 1998 and July 2014 at Hutzel Women’s Hospital/Detroit Medical Center was conducted examine 16 457 placentas. The frequency of placenta lesions (diagnosed using the criteria of the Perinatal Section of the Society for Pediatric Pathology) was compared between pregnancies with and without acute atherosis. Results: Among 16 457 women who were enrolled, 10.2% (1671/16 457) were excluded, leaving 14 786 women who contributed data for analysis. Among them, the prevalence of acute atherosis was 2.2% (326/14 786). Women with acute atherosis were more than six times as likely as those without to have placental lesions consistent with maternal underperfusion (adjusted odds ratio – aOR: 6.7; 95% CI 5.2–8.6). To a lesser degree, acute atherosis was also associated with greater risks of having either lesions consistent with FVTOD (aOR 1.7; 95% CI 1.2–2.3) or chronic chorioamnionitis (aOR 1.9; 95% CI 1.3–3), but not with other chronic inflammatory lesions, after adjusting for gestational age at delivery. In contrast, women with acute atherosis were 60% less likely to have lesions consistent with AFI, adjusting for gestational age at delivery (aOR 0.4; 95% CI 0.3–0.5). Conclusions: Acute atherosis is associated with increased risks of having placental lesions consistent with MVU, and to a lesser extent, chronic chorioamnionitis and those consistent with FVTOD. [ABSTRACT FROM AUTHOR]

Objective: The objectives of this study were to: (1) determine the amniotic fluid (AF) microbiology of patients with preterm prelabor rupture of membranes (PROM); and (2) examine the relationship between intra-amniotic inflammation with and without microorganisms (sterile inflammation) and adverse pregnancy outcomes in patients with preterm PROM. Methods: AF samples obtained from 59 women with preterm PROM were analyzed using cultivation techniques (for aerobic and anaerobic bacteria as well as genital mycoplasmas) and with broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS). AF concentration of interleukin-6 (IL-6) was determined using ELISA. Results of both tests were correlated with AF IL-6 concentrations and the occurrence of adverse obstetrical/perinatal outcomes. Results: (1) PCR/ESI-MS, AF culture, and the combination of these two tests each identified microorganisms in 36% (21/59), 24% (14/59) and 41% (24/59) of women with preterm PROM, respectively; (2) the most frequent microorganisms found in the amniotic cavity wereSneathiaspecies andUreaplasma urealyticum; (3) the frequency of microbial-associated and sterile intra-amniotic inflammation was overall similar [ 29% (17/59)]: however, the prevalence of each differed according to the gestational age when PROM occurred; (4) the earlier the gestational age at preterm PROM, the higher the frequency of both microbial-associated and sterile intra-amniotic inflammation; (5) the intensity of the intra-amniotic inflammatory response against microorganisms is stronger when preterm PROM occurs early in pregnancy; and (6) the frequency of acute placental inflammation (histologic chorioamnionitis and/or funisitis) was significantly higher in patients with microbial-associated intra-amniotic inflammation than in those without intra-amniotic inflammation [93.3% (14/15) versus 38% (6/16);p = 0.001]. Conclusions: (1) The frequency of microorganisms in preterm PROM is 40% using both cultivation techniques and PCR/ESI-MS; (2) PCR/ESI-MS identified microorganisms in the AF of 50% more women with preterm PROM than AF culture; and (3) sterile intra-amniotic inflammation was present in 29% of these patients, and it was as or more common than microbial-associated intra-amniotic inflammation among those presenting after, but not before, 24 weeks of gestation. [ABSTRACT FROM AUTHOR]

Objective: To determine the frequency and clinical significance of sterile and microbial-associated intra-amniotic inflammation in asymptomatic patients with a sonographic short cervix.Methods: Amniotic fluid (AF) samples obtained by transabdominal amniocentesis from 231 asymptomatic women with a sonographic short cervix [cervical length (CL) ≤25 mm] were analyzed using cultivation techniques (for aerobic and anaerobic as well as genital mycoplasmas) and broad-range polymerase chain reaction (PCR) coupled with electrospray ionization mass spectrometry (PCR/ESI-MS). The frequency and magnitude of intra-amniotic inflammation [defined as an AF interleukin (IL)-6 concentration ≥2.6 ng/mL], acute histologic placental inflammation, spontaneous preterm delivery (sPTD), and the amniocentesis-to-delivery interval were examined according to the results of AF cultures, PCR/ESI-MS and AF IL-6 concentrations.Results: Ten percent (24/231) of patients with a sonographic short cervix had sterile intra-amniotic inflammation (an elevated AF IL-6 concentration without evidence of microorganisms using cultivation and molecular methods). Sterile intra-amniotic inflammation was significantly more frequent than microbial-associated intra-amniotic inflammation [10.4% (24/231) versus 2.2% (5/231); p < 0.001]. Patients with sterile intra-amniotic inflammation had a significantly higher rate of sPTD <34 weeks of gestation [70.8% (17/24) versus 31.6% (55/174); p < 0.001] and a significantly shorter amniocentesis-to-delivery interval than patients without intra-amniotic inflammation [median 35, (IQR: 10-70) versus median 71, (IQR: 47-98) days, (p < 0.0001)].Conclusion: Sterile intra-amniotic inflammation is more common than microbial-associated intra-amniotic inflammation in asymptomatic women with a sonographic short cervix, and is associated with increased risk of sPTD (<34 weeks). Further investigation is required to determine the causes of sterile intra-amniotic inflammation and the mechanisms whereby this condition is associated with a short cervix and sPTD. [ABSTRACT FROM AUTHOR]

Introduction: The objectives of this study were: 1) to determine the amniotic fluid (AF) microbiology of patients with the diagnosis of clinical chorioamnionitis at term using both cultivation and molecular techniques; and 2) to examine the relationship between intra-amniotic inflammation with and without microorganisms and placental lesions consistent with acute AF infection. Methods: The AF samples obtained by transabdominal amniocentesis from 46 women with clinical signs of chorioamnionitis at term were analyzed using cultivation techniques (for aerobic and anerobic bacteria as well as genital mycoplasmas) and broad-range polymerase chain reaction (PCR) coupled with electrospray ionization mass spectrometry (PCR/ESI-MS). The frequency of microbial invasion of the amniotic cavity (MIAC), intra-amniotic inflammation [defined as an AF interleukin 6 (IL-6) concentration ≥2.6 ng/mL], and placental lesions consistent with acute AF infection (acute histologic chorioamnionitis and/or acute funisitis) were examined according to the results of AF cultivation and PCR/ESI-MS as well as AF IL-6 concentrations. Results: 1) Culture identified bacteria in AF from 46% (21/46) of the participants, whereas PCR/ESI-MS was positive for microorganisms in 59% (27/46) - combining these two tests, microorganisms were detected in 61% (28/46) of patients with clinical chorioamnionitis at term. Eight patients had discordant test results; one had a positive culture and negative PCR/ESI-MS result, whereas seven patients had positive PCR/ESI-MS results and negative cultures. 2) Ureaplasma urealyticum (n=8) and Gardnerella vaginalis (n=10) were the microorganisms most frequently identified by cultivation and PCR/ESI-MS, respectively. 3) When combining the results of AF culture, PCR/ESI-MS and AF IL-6 concentrations, 15% (7/46) of patients did not have intra-amniotic inflammation or infection, 6.5% (3/46) had only MIAC, 54% (25/46) had microbial-associated intra-amniotic inflammation, and 24% (11/46) had intra-amniotic inflammation without detectable microorganisms. 4) Placental lesions consistent with acute AF infection were significantly more frequent in patients with microbial-associated intra-amniotic inflammation than in those without intra-amniotic inflammation [70.8% (17/24) vs. 28.6% (2/7); P=0.04]. Conclusion: Microorganisms in the AF were identified in 61% of patients with clinical chorioamnionitis at term; 54% had microbial-associated intra-amniotic inflammation, whereas 24% had intra-amniotic inflammation without detectable microorganisms. [ABSTRACT FROM AUTHOR]

Objective. The activation of the complement system results in the generation of split products with pro-inflammatory properties. The objective of this study was to determine whether preeclampsia and small-for-gestational age (SGA) are associated with changes in the maternal plasma concentrations of anaphylatoxins C3a, C4a and C5a. Methods. A cross-sectional study was conducted in the following groups: (a) normal pregnant women ( n = 134); (b) women who delivered an SGA neonate ( n = 53); (c) preeclampsia with ( n = 52) and without SGA ( n = 54). Maternal plasma anaphylatoxin concentrations were determined by enzyme-linked immunoassay. Results. (1) Women with preeclampsia with or without SGA had a significantly higher median plasma C5a concentration than that of normal pregnant women and those with SGA alone (all P < 0.01); (2) women with SGA alone did not have an increase in plasma C5a concentration; (3) in contrast, the median maternal plasma concentration of C4a was lower in women with preeclampsia and SGA than that of those with a normal pregnancy ( P = 0.001); (4) no changes in C3a were observed among the study groups. Conclusion. Preeclampsia is associated with increased plasma concentration of C5a, regardless of the presence or absence of an SGA fetus. In contrast, there was no difference in the plasma C3a, C4a and C5a concentration in patients with SGA. [ABSTRACT FROM AUTHOR]

Objective. Preeclampsia and pregnancies complicated by small-for-gestational age (SGA) neonates share several underlying mechanisms of disease. However, while an exaggerated systemic maternal inflammatory response is regarded as one of the hallmarks of the pathogenesis of preeclampsia, the presence of a similar systemic intra-vascular inflammation in mothers of SGA neonates without hypertension is controversial. The aim of this study was to determine phenotypic and metabolic changes in granulocytes and monocytes of women who develop preeclampsia and those who deliver an SGA neonate, compared to normal pregnant women. Methods. This cross-sectional study included patients with a normal pregnancy ( n = 33), preeclampsia ( n = 33), and an SGA without preeclampsia ( n = 33), matched for gestational age at blood sample collection. Granulocyte and monocyte phenotypes were determined by flow cytometry, using monoclonal antibodies against selective cluster of differentiation (CD) antigens. The panel of antibodies included the following: CD11b, CD14, CD16, CD18, CD49d, CD62L, CD64, CD66b, and HLA-DR. Intracellular reactive oxygen species (iROS) were assessed at the basal state and after stimulation (oxidative burst). Results were reported as mean channel brightness (MCB) or intensity of detected fluorescence. Analysis was conducted with non-parametric statistics. A p-value < 0.01 was considered statistically significant. Results. (1) Women who delivered an SGA neonate had a higher MCB of CD11b in granulocytes and monocytes than those with a normal pregnancy ( p < 0.001 for both); (2) patients with preeclampsia had a lower median MCB of CD62L in granulocytes ( p = 0.006) and a higher median basal iROS and oxidative burst in monocytes than women with an SGA neonate ( p = 0.003 and p = 0.002, respectively). Conclusion. Pregnancies complicated by the delivery of an SGA neonate are characterized by a higher activation of maternal peripheral leukocytes than in normal pregnancies, but lower than in pregnancies complicated by preeclampsia. [ABSTRACT FROM AUTHOR]

Objectives. Preeclampsia is considered an anti-angiogenic state. A role for the anti-angiogenic factors soluble vascular endothelial growth factor receptor-1 (sVEGFR-1) and soluble endoglin in preeclampsia has been proposed. Soluble vascular endothelial growth factor receptor-2 (sVEGFR-2) has been detected in human plasma, and the recombinant form of this protein has anti-angiogenic activity. There is a paucity of information about maternal plasma sVEGFR-2 concentrations in patients with preeclampsia and those without preeclampsia with small for gestational age (SGA) fetuses. This study was conducted to determine whether: (1) plasma sVEGFR-2 concentration changes throughout pregnancy; and (2) preeclampsia and SGA are associated with abnormalities in the maternal plasma concentration of sVEGFR-2. Study design. This cross-sectional study included non-pregnant women (n = 40), women with normal pregnancies (n = 135), women with an SGA fetus (n = 53), and women with preeclampsia (n = 112). SGA was defined as an ultrasound-estimated fetal weight below the 10th percentile for gestational age that was confirmed by neonatal birth weight. Plasma concentrations of sVEGFR-2 were determined by ELISA. Results. (1) There was no significant difference in the mean plasma concentration of sVEGFR-2 between non-pregnant women and those with normal pregnancies (p = 0.8); (2) patients with preeclampsia and those without preeclampsia with SGA fetuses had a lower mean plasma concentration of sVEGFR-2 than that of women with normal pregnancies (p < 0.001 for both); and (3) there was no significant difference in the mean plasma concentration of sVEGFR-2 between patients with preeclampsia and those without preeclampsia with SGA (p = 0.9). Conclusions. Preeclampsia and SGA are associated with low plasma concentrations of sVEGFR-2. One interpretation of the findings is that plasma sVEGFR-2 concentration could reflect endothelial cell function. [ABSTRACT FROM AUTHOR]

Objectives. The soluble form of vascular endothelial growth factor receptor-1 (sVEGFR-1), an antagonist to vascular endothelial growth factor and placental growth factor, has been implicated in the pathophysiology of preeclampsia. Preeclampsia and pregnancy complicated with small for gestational age (SGA) fetuses share some pathophysiologic derangements, such as failure of physiologic transformation of the spiral arteries, endothelial cell dysfunction, and leukocyte activation. The objectives of this study were to: (1) determine whether plasma concentrations of sVEGFR-1 in mothers with SGA fetuses without preeclampsia at the time of diagnosis are different from those in patients with preeclampsia or normal pregnant women, and (2) examine the relationship between plasma concentrations of sVEGFR-1 and Doppler velocimetry in uterine and umbilical arteries in patients with preeclampsia and those with SGA... [ABSTRACT FROM AUTHOR]

Background: Pregnancy creates a unique situation in which both vasculogenesis and extensive angiogenesis are required for successful fetal and placental development. Recently, the soluble form of vascular endothelial growth factor (VEGF) receptor-1 (sVEGFR-1), an antagonist to VEGF and placental growth factor (PlGF) (two important angiogenic factors), has been implicated in the pathophysiology of preeclampsia and small for gestational age (SGA) without preeclampsia. There is, however, a paucity of information concerning plasma sVEGFR-1 concentrations in other obstetrical disorders. The purpose of this study was to determine plasma sVEGFR-1 concentrations in normal pregnancy, term gestation in labor, and in patients with pregnancy complications including spontaneous preterm labor, preterm premature rupture of the membranes (PROM), fetal death, and acute pyelonephritis.Methods: A cross-sectional study was conducted to determine the concentrations of sVEGFR-1 in plasma obtained from 499 women in the following groups: (1) non-pregnant women (n = 40); (2) pregnant women (n = 135); (3) normal pregnant women at term in labor (n = 60); (4) fetal death (n = 60); (5) spontaneous preterm labor with intact membranes (n = 102); (6) preterm PROM (n = 64); and (7) pregnancy with acute pyelonephritis (n = 38). Since plasma sVEGFR-1 concentration changes with gestational age, the difference between the actual and the expected plasma sVEGFR-1 concentration (derived from regression equation of normal pregnancy) for each patient (delta value) was calculated and used to examine the differences of plasma sVEGFR-1 concentrations among various groups. Plasma concentrations of sVEGFR-1 were determined by enzyme-linked immunoassay. Regression analysis and non-parametric statistics were used for analysis.Results: (1) Normal pregnant women before term had a median plasma sVEGFR-1 concentration significantly higher than non-pregnant women (p < 0.001); (2) plasma sVEGFR-1 concentration increased with advancing gestational age in normal pregnancy (r = 0.5; p < 0.001); (3) there was no significant difference in the median delta plasma concentration of sVEGFR-1 between normal pregnant women at term with and without labor (p = 0.09); (4) patients with fetal death had a median delta plasma concentration of sVEGFR-1 significantly higher than normal pregnant women (p = 0.001). Among patients with fetal death, those with unexplained causes (p = 0.04) and those with preeclampsia (p < 0.001) had a significantly higher delta plasma sVEGFR-1 concentration than normal pregnant women; and (5) there was no significant difference in the median delta plasma sVEGFR-1 concentration between normal pregnancy and preterm labor with intact membranes, preterm PROM (regardless of the presence or absence of microbial invasion of the amniotic cavity), or acute pyelonephritis (all p > 0.05).Conclusions: Plasma sVEGFR-1 concentration is increased in a subset of patients with fetal death, but does not change in term and preterm parturition, rupture of fetal membranes, or acute pyelonephritis. [ABSTRACT FROM AUTHOR]

Summary: The human placenta is a transient organ, the villous surface of which is in direct contact with the maternal circulation during pregnancy. Thus, the syncytiotrophoblast and the basal plate–lining cells are considered continuous with the endothelial layer of the maternal vasculature. Two types of cells are found on the surface of the basal plate: trophoblasts (of fetal origin) and endothelial cells of putative maternal origin. Histologic abnormalities have been described in the basal plate of the placenta obtained from patients with preeclampsia and intrauterine growth restriction. Moreover, endothelial cell dysfunction and intravascular inflammation are key features of preeclampsia. The objectives of this study were to: (1) determine the origin of the endothelial cells located in the basal plate surface of the placenta (from male fetuses); and (2) analyze the relative proportion of the intervillous surface of the basal plate occupied by trophoblasts and endothelial cells. Immunohistochemistry and morphometry were performed in placentas from women in the following clinical groups: (1) normal-term pregnancies (n = 15); (2) severe preeclampsia at term (n = 15); (3) small-for-gestational-age (SGA) neonates delivered at term (n = 15); (4) preterm deliveries (<37 weeks) without inflammation (n = 5); and (5) preterm preeclampsia (n = 5). Laser capture microdissection and polymerase chain reaction were used to determine the allelic pattern of the amelogenin gene of the endothelial cells on the intervillous surface of the basal plate. Our results showed that: (1) the endothelial cells lining the basal plate in placentas of male fetuses were uniformly of maternal origin; and (2) in placentas from uncomplicated pregnancies, the median proportion of trophoblasts and endothelial cells covering the surface of the basal plate were 27.7% and 46.5%, respectively. The remaining area of the intervillous surface of the basal plate was composed of fibrin and anchoring villi. Of interest, placentas from women who delivered an SGA neonate had a higher proportion of trophoblasts and a lower proportion of endothelial cells lining the basal plate than those from normal pregnancies (P < .05). The same tendency was observed in placentas from patients with preeclampsia. This study demonstrates that endothelial cells of maternal origin cover the intervillous surface of the basal plate of the placenta, along with trophoblasts of fetal origin. The proportion of this surface lined by trophoblasts is greater in placentas from SGA and preeclampsia than in normal pregnancy. We propose that this change reflects a compensatory mechanism whereby the basal plate surface covered by injured endothelial cells is replaced by trophoblasts or results from a failure of trophoblastic involution in abnormal pregnancies. Our observations also suggest that the lining of the basal plate can provide information about the pathology of endothelial cells in complications of pregnancy. [Copyright &y& Elsevier]

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&ThickSpace;pg/ml vs. antecubital vein: mean 10,234 ± 4,700&ThickSpace;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&ThickSpace;pg/ml vs. antecubital vein: mean 1,750 ± 475&ThickSpace;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&ThickSpace;pg/ml vs. antecubital vein, mean ± SD: 82 ± 43&ThickSpace;pg/ml; paired t- tests, p = 0.2) and normal pregnancy groups (uterine vein, mean ± SD: 331 ± 254&ThickSpace;pg/ml vs. antecubital vein, mean ± SD: 319 ± 259&ThickSpace;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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to identify differential expression of microRNAs (miRNAs) in chorioamniotic membranes with advancing gestation, labor, and inflammation. Study Design: Expression profiles of 157 miRNAs in the chorioamniotic membranes were obtained from patients in the following groups: 1) term not in labor (n = 10); 2) term in labor (n = 10); 3) preterm labor with histologic chorioamionitis (n = 9); and 4) without histologic chorioamnionitis (n = 10). Results: More than 95% of the miRNAs screened were expressed. Gestational age-dependent changes in expression were observed for 13 miRNAs. No differences in miRNA expression were observed between women without labor and women in labor. Membranes with chorioamnionitis displayed increased expression of miR-223 and miR-338. Gene Ontology analysis of genes targeted by differentially expressed miRNAs revealed enrichment for specific biological process categories. Conclusion: Chorioamniotic membranes with advancing gestational age and chorioamnionitis are associated with the differential expression of a subset of miRNAs. [Copyright &y& Elsevier]