The change of bone mineral density and bone metabolism after gastrectomy for gastric cancer: a meta-analysis.

Bone mineral density (BMD) is significantly decreased after gastrectomy in patients with gastric cancer. Calcium malabsorption, secondary hyperparathyroidism, and dominant bone resorption appear to contribute to bone loss in these patients. Patients should undergo early surveillance and nutritional or pharmacologic intensive interventions for bone health. PURPOSE: Survivorship care, including bone health, has become an important issue in gastric cancer. We performed a meta-analysis of the available observational studies to determine whether and how osteoporosis risk is increased after gastrectomy in patients with gastric cancer. METHODS: A total of 1204 patients (802 men) from 19 cohort studies were included. We evaluated the prevalence of osteoporosis in postgastrectomy patients, comparing the incidence according to the type of gastrectomy and sex. Additionally, we evaluated changes in bone mineral density (BMD) and bone metabolism-related markers pre- to postoperatively and between patients who underwent gastrectomy and matched controls. Proportion meta-analysis was performed and pooled odds ratios (ORs) were calculated. RESULTS: The pooled incidence estimate was 36% [95% confidence interval (CI), 32-40]. The incidence of osteoporosis was significantly higher in women than in men (OR = 1.90, p < 0.001) but was similar between partial and total gastrectomy groups (OR = 0.983, p = 0.939). BMD was significantly decreased, and calcium, phosphorous, and parathyroid hormone levels were significantly increased in patients after gastrectomy compared to those before gastrectomy. BMD and calcium and 25OH-vitamin D levels were significantly decreased, and parathyroid hormone and 1,25OH-vitamin D levels were significantly increased in the gastrectomy group compared to that in the control group. CONCLUSION: We found that BMD is significantly decreased after gastrectomy in patients with gastric cancer. Vitamin D deficiency and secondary hyperparathyroidism are suggested to be common mechanism underlying BMD impairment. After resection, patients should undergo long-term nutritional and bone health surveillance, in addition to their oncological follow-up.

Incidence of second hip fracture and compliant use of bisphosphonate.

UNLABELLED: We determined the incidence of second hip fracture and evaluated whether compliant users of bisphosphonate had a lower incidence of second hip fracture after prior hip fracture. INTRODUCTION: Bisphosphonate has been used to prevent osteoporotic fracture and is recommended for the secondary prevention after hip fracture. However, little is known regarding secondary prevention after first hip fracture. Our purpose was to determine the incidence of second hip fracture and to evaluate whether compliant use of bisphosphonate can reduce the risk of second hip fracture. METHODS: Eight hundred twenty-six patients who sustained the first hip fracture from May 2003 to October 2011 were retrospectively evaluated. The incidence of second hip fracture was compared between compliant users of bisphosphonate and nonusers. RESULTS: Seventy-one (8.6 %) patients suffered a second hip fracture at mean 30.0 months (SD 24.6, range 1 to 90 months) after the initial hip fracture. The cumulative incidence of second hip fracture was 5.1 % (42/826) at 2 years and 8.6 % (71/826) at 8 years. The incidence of second hip fracture was 4.2 % (12/283) in compliant users and 10.9 % (59/543) in nonusers (p = 0.001). CONCLUSIONS: Compliant use of bisphosphonate is effective in the prevention of second hip fractures.

A gene-specific primer extension and liquid bead array system for killer-cell immunoglobulin-like receptor genotyping.

A simple and accurate method for killer-cell immunoglobulin-like receptor (KIR) genotyping is developed using KIR gene-specific primer extension (GSPE) followed by bead array hybridization (GSPE method). After amplification of exons 4, 5, and 9, KIR GSPE and bead array hybridization were performed to verify the presence or absence of 16 KIR subfamilies. GSPE method was validated with natural killer/KIR reference panel I consisting of 48 cell types provided by 13th International Histocompatibility Working Group (IHWG) and genomic DNA from 17 peripheral blood cells, 8 cell lines, and 8 buccal cells. The results of reference panel from GSPE method were 100% concordant with the IHWG reference typing information. All genomic DNAs except reference panel were typed for KIR genes with sequence-specific primer methods and showed 100% identical typing results using this novel system. In addition, GSPE method can obtain results in 8 h from DNA with 10 ng genomic DNA in a 96-well-based assay format.

A focused update on preventing ceramic fractures in hip arthroplasty: is the 'cup' half full?

Ceramic bearings have several desirable properties, such as resistance to wear, hardness, and biocompatibility, that favour it as an articulating surface in hip arthroplasty. However, ceramic fracture remains a concern. We have reviewed the contemporary literature, addressing the factors that can influence the incidence of ceramic bearing surface fracture. Cite this article: Bone Joint J 2019;101-B:897-901.

Distribution of CD14+ and CD68+ macrophages in the placental bed and basal plate of women with preeclampsia and preterm labor.

OBJECTIVE: Macrophages play a key role in implantation, placentation and parturition. Yet, whether or not the number of macrophages at the fetomaternal interface (basal plate of the placenta and placental bed) is altered in women with preeclampsia is the subject of controversy. The purpose of this study was to compare the immunoreactivity and distribution patterns of CD14 and CD68 positive macrophages in both the basal plate and placental bed from preeclamptic and non-preeclamptic pregnancies. METHODS: A cross-sectional study was conducted. Paraffin embedded sections of placental tissues and placental bed biopsies were obtained from patients with early onset preeclampsia (n=10) and from those with preterm labor/delivery (n=10) without preeclampsia matched for gestational age. Double immunohistochemistry using antibodies to CD14 and CD68 was performed, and the density of double or single positive cells in the basal plate and placental bed was evaluated. Non-parametric statistics were used for analysis. RESULTS: 1) A unique subset of CD14-/CD68+ cells was identified. The cells in question were present at a higher level in the decidua than in the myometrial segment of the placental bed (p<0.01); 2) The density and proportion of CD14+/CD68+ cells (double positive cells) were significantly higher in the myometrial segment than in the basal plate (p=0.0003); and 3) There were no significant differences in the density and patterns of immunopositive macrophages in the basal plate, the decidua, and the myometrium between women with preeclampsia and those with preterm labor/delivery (p>0.05). CONCLUSION: The macrophages at the fetomaternal interface can be dichotomized by CD14 and CD68 immunoreactivity. A gradient of CD14+/CD68+ macrophages was demonstrated between the superficial myometrium and the basal plate regardless of the etiology of preterm birth (preeclampsia or spontaneous preterm labor). The biological function of single positive (CD14-/CD68+) and double positive (CD14+/CD68+) macrophages at the fetomaternal interface remains to be established. The overall findings also suggest that the discrepancies in the literature are due to the varying markers used to detect macrophages and in the anatomical plane of the fetomaternal junction analyzed.

Placental deposition of C-reactive protein is a common feature of human pregnancy.

This study examined the occurrence of placental C-reactive protein (CRP) in normal pregnancy with term delivery, spontaneous preterm delivery (sPTD), preeclampsia, and miscarriage. CRP immunoreactivity was detected in the syncytiotrophoblast. The immunopositive rate was significantly higher in sPTD than preeclampsia. The CRP immunopositive rate was also higher in acute chorioamnionitis than those without and showed a good correlation with the maternal serum CRP concentration. CRP mRNA expression was not detected in human and mouse placentas or choriocarcinoma cells. CRP may play a role in the pathological and physiological states of pregnancy.

Acute funisitis of preterm but not term placentas is associated with severe fetal inflammatory response.

Acute funisitis, whose basic pathologic feature is umbilical vasculitis, constitutes a type of fetal inflammatory response to intrauterine infection. In the present study, a comparative analysis was performed between the clinicopathologic profiles of acute funisitis in term and preterm placentas along with measurement of fetal plasma interleukin 6 (IL-6) levels by specific immunoassay to assess the different biologic implications for the fetus. Acute funisitis in preterm placentas showed a significantly higher incidence of umbilical arteritis (P <.000001), higher fetal plasma IL-6 level (P <.0001), and higher prevalence of major perinatal morbidities (P <.0001). To assess the possible variation in fetal cell response to infectious agents according to gestational age, amnion cells and placental villous tissues obtained at different gestational ages were treated with bacterial lipopolysaccharides, and the IL-6 level of the culture media was assayed. Amnion cells and placental villous tissues from preterm placenta showed a more pronounced cytokine response than those from term placenta. The findings of this study indicate that the clinicopathologic significance of acute funisitis in term placentas is different from that of preterm placentas. Furthermore, they indicate that the robust inflammatory response of the fetus associated with elevated fetal plasma IL-6 level may reflect the biologic needs of the premature fetus to escape from the hostile intrauterine environment.

Isolation of Ureaplasma urealyticum from the amniotic cavity and adverse outcome in preterm labor.

OBJECTIVE: To determine the relationship between the presence of Ureaplasma urealyticum in the amniotic cavity and adverse maternal and perinatal outcome in women with preterm labor. METHODS: Amniocentesis was performed in 181 patients with preterm labor and intact membranes. Amniotic fluid (AF) was cultured for aerobic and anaerobic bacteria and mycoplasmas. Patients were divided into three groups according to the results of AF culture: those with negative AF cultures (n=160), those with positive AF cultures and in whom the only microbial isolate was U urealyticum (n=11), and those with positive cultures for non-ureaplasmas or mixed microorganisms (n=10). Survival techniques were used for analysis. RESULTS: The prevalence of positive AF cultures in which the only microbial isolate was Uurealyticum was 6.1% (11 of 181), and of positive cultures with non-ureaplasmas or mixed microorganisms was 5.5% (10 of 181). The amniocentesis-to-delivery interval was significantly shorter in patients with positive cultures limited to U urealyticum than in those with negative cultures (median 7 [range 0.1-149] hours versus median 264 [0.1-2659] hours, P < .001). Preterm delivery within 48 hours, 72 hours, and 7 days was more frequent in patients with U urealyticum in the AF than in those with sterile AF (48 hour: 91% versus 33%; 72 hour: 91% versus 36%; 7 days: 100% versus 45%, P < .001 for each). Patients with positive AF cultures limited to U urealyticum had a significantly higher rate of adverse perinatal outcome than those with negative culture. Adverse outcomes included low gestational age at birth, low birth weight, histologic chorioamnionitis, significant neonatal morbidity, and perinatal death. CONCLUSION: Microbial invasion of the amniotic cavity with U urealyticum is a risk factor for impending preterm delivery and adverse perinatal outcome.

Serum C-reactive protein, white blood cell count, and amniotic fluid white blood cell count in women with preterm premature rupture of membranes.

OBJECTIVE: To compare the diagnostic performance of maternal blood C-reactive protein, white blood cell count (WBC), and amniotic fluid (AF) WBC in the identification of positive AF culture, histologic and clinical chorioamnionitis, and neonatal morbidity in women with preterm premature rupture of membranes (PROM). METHODS: Maternal blood was collected for the determination of C-reactive protein and WBC at the time of amniocentesis from 90 women with preterm PROM. Amniotic fluid was cultured for aerobic and anaerobic bacteria as well as mycoplasmas. Amniotic fluid WBC was determined for research purposes. Receiver operating characteristic curve and logistic regression were used for statistical analysis. RESULTS: The prevalence of positive AF culture was 28% (25 of 90). Women with positive AF culture and clinical chorioamnionitis had significantly higher median C-reactive protein, WBC, and AF WBC than did women without these conditions (P < .05), whereas women with histologic chorioamnionitis and significant neonatal morbidity had higher median C-reactive protein and AF WBC, but not WBC, than those without the conditions (P < .05). An AF WBC of at least 20 cells per mm3 had a greater sensitivity than C-reactive protein (cutoff, 0.7 mg/dL) and WBC (cutoff, 13,000 cells per mm3) in the detection of positive AF culture and histologic chorioamnionitis. Logistic regression analysis indicated that among AF WBC, C-reactive protein, and WBC, AF WBC was the best predictor of positive AF culture (odds ratio [OR] 24.2, 95% confidence interval [CI] 6.0, 97.5, P < .001), histologic (OR 74.0, 95% CI 7.4, 736.3, P < .001) and clinical chorioamnionitis (OR 8.9, 95% CI 0.9, 85.6, P = .057), and neonatal morbidity (OR 4.3, 95% CI 1.1, 16.6, P < .05). CONCLUSION: Amniotic fluid WBC performs better than C-reactive protein and maternal blood WBC in the diagnosis of positive AF culture, histologic and clinical chorioamnionitis, and neonatal morbidity in women with preterm PROM.

Maternal blood C-reactive protein, white blood cell count, and temperature in preterm labor: a comparison with amniotic fluid white blood cell count.

OBJECTIVE: To compare the diagnostic and prognostic performance of maternal blood C-reactive protein, white blood cell count (WBC), and temperature with that of amniotic fluid (AF) WBC in preterm labor. METHODS: One hundred two women with preterm labor and intact membranes were studied. Maternal blood was collected to measure C-reactive protein concentration and WBC, and maternal temperature was also measured. Amniotic fluid obtained by amniocentesis was cultured and WBC determined. Receiver operating characteristic curve, logistic regression, and survival techniques were used for analysis. RESULTS: Patients with acute histologic chorioamnionitis had significantly higher median C-reactive protein concentration, WBC, temperature, and AF WBC than patients without this lesion (P < .05). Receiver operating characteristic curve and survival analysis demonstrated that an elevated C-reactive protein, WBC, or AF WBC was strongly associated with the likelihood of histologic chorioamnionitis, shorter interval to delivery, clinical chorioamnionitis, and neonatal morbidity (P < .05 for each). Of all the tests, AF WBC was the best independent predictor of a positive AF culture (odds ratio [OR] 16.8), interval to delivery (hazard ratio 5.7), clinical chorioamnionitis (OR 15.2), neonatal sepsis (OR 16.8), and significant neonatal complications (OR 7.4), after other confounding variables were adjusted (P < .05 for each). CONCLUSION: An elevated C-reactive protein, WBC, or AF WBC identified patients with intrauterine infection and adverse perinatal outcomes. Amniotic fluid WBC was a better independent predictor of these outcomes than C-reactive protein, WBC, or temperature.

Treatment with the interleukin-I receptor antagonist and soluble tumor necrosis factor receptor Fc fusion protein does not prevent endotoxin-induced preterm parturition in mice.

OBJECTIVE: To determine whether the administration of anticytokine agents, the interleukin-1 receptor antagonist (IL-1ra) and a soluble tumor necrosis factor receptor Fc fusion protein (sTNFR-Fc), prevents endotoxin-induced preterm delivery in mice. METHODS: C3H/HeN pregnant mice at 15 days of gestation (70% gestation) were randomized to receive phosphate-buffered saline (PBS) or lipopolysaccharide (LPS) (50 micrograms/mouse) intraperitoneally (i.p.). Randomly selected PBS- or LPS-treated mice were additionally treated intravenously (i.v.), i.p., or subcutaneously (s.c.) every 3 hours with IL-1ra (1-50 mg) or every 12 hours with sTNFR-Fc (200-400 micrograms) beginning 1 hour before LPS injection. Animals were observed for vaginal bleeding and preterm delivery. RESULTS: Mice treated i.p. with 50 micrograms LPS (n = 13) had a shorter injection-to-delivery interval than mice treated similarly with PBS (n = 19) (median 13.5 hours, range 10-105 versus median 86.8 hours, range 53-120, respectively; P < .001). Saline-treated mice given 10 mg IL-1ra every 3 hours i.p. (n = 3) or 200 micrograms sTNFR-Fc every 12 hours i.v. (n = 4) had similar injection-to-delivery intervals as PBS-treated control mice (median 70 hours, range 70-76 versus median 58 hours, range 50-120, respectively). Similarly, LPS-treated mice given PBS every 3 hours (n = 20) had injection-to-delivery intervals comparable to LPS-treated mice (n = 13) (median 15.5 hours, range 9.8-92 versus median 13.5 hours, range 10-105, respectively). Lipopolysaccharide-treated mice given i.p. injections of 1 (n = 4), 10 (n = 31), or 50 (n = 15) mg of IL-1ra every 3 hours did not have longer injection-to-delivery intervals compared with LPS-treated mice (n = 13) (medians 11.6, 15, 14.5 and 13.5 hours; ranges 10.8-12, 8-95, 11-92, and 10-105, respectively). Lipopolysaccharide-treated mice given i.v. injections of 200 (n = 4) or 400 (n = 9) micrograms sTNFR-Fc every 12 hours did not have longer injection-to-delivery intervals compared with LPS-treated mice (n = 8) (medians 23.3, 22.5, and 21.9 hours; ranges 14.8-33, 15-95.5, and 15.5-44, respectively). The median injection-to-delivery interval of LPS-treated mice given both IL-1ra (10 mg) every 3 hours i.p. and sTNFR-Fc (200 micrograms) every 12 hours i.v. (n = 5) was not different from that of LPS-treated mice (median 26 hours, range 24.5-72 versus median 13.5 hours, range 10-105, respectively; P > .05). CONCLUSION: The anticytokine agents IL-1ra and sTNFR-Fc did not prevent preterm delivery or prolong pregnancy in endotoxin-induced preterm labor in mice.

Patterns of bcl-2 expression in placenta.

A total of 39 placentas, whose gestational ages ranged from 8 to 41 weeks, were analyzed for bcl-2 expression using immunohistochemistry and immunoblotting. Immunohistochemically, both intracytoplasmic and nuclear expression of bcl-2 was observed in villous and extravillous trophoblasts, villous mesenchymal cells and capillary endothelial cells, villous macrophages, intermediate trophoblasts, amnionic epithelium, and even in decidua and endometrial glandular epithelium in early gestational periods. The degree of expression significantly decreased in the placentas after the gestational period of 32 weeks which coincides with the declining phase of placental increase. On immunoblotting lysates of 10(4) cells from single cell suspensions of fresh placentas, bcl-2 was detected in the placentas of 22 and 33 gestational weeks, but it was negligible or absent in three term placentas. The results of the present study suggest two possible implications on the role of bcl-2 in placenta: 1) it may be a type of proliferation or maturation-related marker, especially of trophoblasts, which show decreased expression along with terminal differentiation and maturation, and 2) because the primary role of bcl-2 is the inhibition of programmed cell death (PCD), the decrease in placental bcl-2 around term may be a parturition-associated biological change.

Elevated interleukin-8 concentrations in amniotic fluid of mothers whose neonates subsequently develop bronchopulmonary dysplasia.

OBJECTIVE: To determine if an intrauterine sub-clinical inflammatory process is a risk factor for the development of bronchopulmonary dysplasia. METHODS: A cohort study was conducted in patients who met the following criteria: (1) Singleton gestation; (2) preterm labor or preterm premature rupture of the membranes; (3) amniocentesis for microbiologic studies of the amniotic fluid and (4) delivery between 24 and 28 weeks of gestation. Bronchopulmonary dysplasia was defined as the need for supplemental oxygen for 28 days or longer after birth, associated with compatible chest radiographic findings. Amniotic fluid interleukin-8, was measured using a specific immunoassay. Logistic regression analysis and bootstrap procedure were used for statistical purposes. RESULTS: Forty-seven patients met the inclusion criteria for this study. Among these patients, the prevalence of bronchopulmonary dysplasia was 23.4% (11/47). Amniotic fluid culture was positive in 21 out of 47 (44.7%) patients. Median (range) amniotic fluid interleukin-8 concentration was higher in patients whose neonates subsequently developed bronchopulmonary dysplasia than in those who did not (17 [9.8-583.7] ng ml(-1) versus 9.6 [0.91-744] ng ml(-1), P=0.057). An amniotic fluid IL-8 level greater than 11.5 ng ml(-1) was far more common in mothers whose fetuses went on to develop bronchopulmonary dysplasia than in those who did not (10/11 [90.9%] versus 17/36 [47%]; P=0.01). This relationship remained significant even after correcting for the effect of gestational age and birthweight (Odds ratio: 11.9; P<0.05). CONCLUSION: Sub-clinical intrauterine inflammation is a risk factor for the subsequent development of bronchopulmonary dysplasia. We propose that in utero aspiration of fluid with high concentration of pro-inflammatory mediators may contribute to the lung injury responsible for the development of bronchopulmonary dysplasia.

Unexplained fetal death is associated with changes in the adaptive limb of the maternal immune response consistent with prior antigenic exposure.

OBJECTIVE: The causes of fetal death are largely unknown. CD4 T cells have been classified according to the expression of the CD45 isoforms into 'naive-like' T cells (CD45RA) and 'memory-like' T cells (CD45RO). An increase in the percentage of the CD45RO has been interpreted as indicating prior antigenic exposure of the host and, in newborns, evidence of infection. The purpose of this study was to determine whether unexplained fetal death was associated with a change in the proportion of 'naive-like' and 'memory-like T cells' in the maternal blood, as determined by the CD45 isoforms on the surface of CD4+ lymphocytes. STUDY DESIGN: A prospective study was conducted to compare the CD45 sub-population of lymphocytes in patients with intrauterine fetal death (n = 26) and normal pregnancy (n = 89). The percentages of CD45RA+, CD45RO+ and CD45RA+/CD45RO+ on CD4+ T lymphocytes were determined in maternal blood using flow cytometry and monoclonal antibodies. Results were reported as a percentage of CD4+ lymphocytes. Non-parametric statistics were used for analysis. A p value of < 0.05 was considered significant. RESULTS: Patients with intrauterine fetal death had a higher percentage of CD45RO+ CD4+ T lymphocytes than normal pregnant women (fetal death: median 57.7%, range 35.4-78.6 vs. normal pregnancy: median 49.9%, range 19.1-86.8; p = 0.004). Fetal death was associated with a lower median percentage of CD45RA+ CD4+ lymphocytes than in normal pregnant women (fetal death: median 32.3%, range 15.3-58.0 vs. normal pregnancy: median 40.2%, range 11.2-67.3; p = 0.01). There was no significant difference in the percentage of cells with dual expression (CD45RA+/CD45RO+) between the study groups. CONCLUSION: Prior exposure to microbial products (bacterial or viral) or other unidentified antigens may result in a shift of the sub-population of 'naive-like' T cells to 'memory-like' T cells in mothers with unexplained fetal death.

Maternal and fetal inflammatory responses in unexplained fetal death.

OBJECTIVE: The role of intra-amniotic infection in the etiology of fetal death has been proposed. This study was conducted to determine the prevalence of microbial invasion of the amniotic cavity (MIAC) and the frequency of maternal and/or fetal inflammation in patients presenting with a fetal death. METHODS: A prospective study was conducted in patients with a fetal death. Amniocenteses were performed for clinical indications (karyotype), as well as to assess the microbiological and cytological state of the amniotic cavity. Fluid was cultured for aerobic and anaerobic bacteria and genital mycoplasmas. An amniotic fluid white blood cell count and glucose determinations were also performed. Histological examination of the placenta was conducted to identify a maternal inflammatory response (acute chorioamnionitis) or a fetal inflammatory response (funisitis). RESULTS: This study included 44 patients with intrauterine fetal death. The median gestational age at diagnosis was 30.1 weeks (range 16.3-40.4 weeks). One patient had documented MIAC (1/44). Acute histological chorioamnionitis was found in 20.9% (9/43), but a fetal inflammatory response was observed in only 2.3% (1/43) of cases. One patient had a positive amniotic fluid culture for Streptococcus agalactiae (group B streptococcus). CONCLUSION: Histological chorioamnionitis was present in 20.9% of cases, but MIAC could be demonstrated with conventional microbiological techniques in only one case. A fetal inflammatory response was nine times less frequent than a maternal inflammatory response (maternal 20.9% vs. fetal 2.3%, p = 0.008) in cases of fetal death.

Evidence of in vivo generation of thrombin in patients with small-for-gestational-age fetuses and pre-eclampsia.

OBJECTIVE: Thrombotic lesions in the maternal or fetal compartments are frequently observed in the placentas of patients with small-for-gestational-age (SGA) fetuses and in pre-eclampsia. The objective of this study was to determine whether there was evidence of in vivo generation of thrombin, the rate-limiting enzyme responsible for the formation of fibrin. The plasma concentrations of thrombin-antithrombin (TAT) complexes were used as an index of thrombin generation. METHODS: TAT complexes were measured in the plasma from 68 women from the following groups: normal pregnancy (n = 29); pre-eclampsia (n = 26); and SGA (defined as estimated fetal weight below the 10th centile for gestational age, which was confirmed by neonatal birth weight) (n = 13). TAT complex plasma concentrations were determined with a specific and sensitive immunoassay. Statistical analysis was performed with non-parametric statistics. RESULTS: The median plasma TAT complex concentrations were significantly higher in patients who delivered SGA neonates than in normal pregnant women (SGA, median 24.2 microg/l; range 11.9-788.7 vs. normal pregnancy, median: 14.4 microg/l; range 6.8-26.9; p = 0.001). Patients with pre-eclampsia had a higher median plasma TAT complex concentration than normal pregnant women (pre-eclampsia, median 18.1 microg/l; range 10.0-75.2 vs. normal pregnancy, median 14.4 microg/l; range 6.8-26.9; p = 0.02). CONCLUSION: In vivo generation of thrombin, determined by the plasma concentrations of TAT complexes, is higher in patients with SGA fetuses and patients with pre-eclampsia than in normal pregnancy.

Activation of coagulation system in preterm labor and preterm premature rupture of membranes.

OBJECTIVE: Thrombin, originally discovered as a coagulation factor, is a multifunctional protease capable of inducing myometrial contractions in vitro and in vivo. This enzyme has been implicated in the mechanisms of premature labor. Plasma concentrations of thrombin-antithrombin (TAT) complexes are an index of in vivo thrombin generation. The purpose of this study was to determine whether patients with premature labor and preterm premature rupture of membranes (PROM) have evidence of increased thrombin generation in maternal blood, as determined by the TAT complex concentrations. METHODS: A cross-sectional study was designed to determine plasma concentrations of TAT complexes in 110 women in the following groups: non-pregnant women (n = 20); normal pregnant women (n = 30); women in preterm labor with intact membranes (n = 30); and women with preterm PROM (n = 30). TAT complex concentrations were determined with a sensitive and specific immunoassay. Statistical analysis was conducted with non-parametric statistics. RESULTS: Patients with preterm labor and intact membranes had a significantly higher median plasma TAT complex concentration than normal pregnant women (women in preterm labor, median 19.1 microg/l; range 7.4-406 vs. normal pregnant women, median 15 microg/l; range 6.8-32.5; p = 0.03). Patients with preterm PROM had a higher median TAT complex concentration than normal pregnant women (preterm PROM, median 19.1 microg/l; range 4.7-738.6 vs. normal pregnant women, median 15 microg/l; range 6.8-32.5; p = 0.03). Normal pregnancy was associated with a higher median plasma TAT complex concentration than the non-pregnant state (normal pregnant women, median 15 microg/l; range 6.8-32.5 vs. non-pregnant women, median 2.7 microg/l; range 0.9-14.2; p < 0.001). CONCLUSION: Preterm labor and preterm PROM are associated with an excess generation of thrombin.

Evidence of participation of soluble CD14 in the host response to microbial invasion of the amniotic cavity and intra-amniotic inflammation in term and preterm gestations.

OBJECTIVE: Endotoxin has been implicated in the mechanism responsible for the setting of infection in preterm labor. To exert its biological effects, endotoxin binds to a circulating protein known as lipopolysaccharide binding protein (LBP) and presents endotoxin monomers to CD14, which may be a membrane-bound receptor or a soluble molecule. The endotoxin-LBP-CD14 complex interacts with Toll-like receptor 4 and other regulatory proteins leading to cellular activation and an inflammatory response. The purpose of this study was to determine whether microbial invasion of the amniotic cavity (MIAC)/intra-amniotic inflammation (both preterm and term) and parturition at term are associated with changes in the amniotic fluid and umbilical plasma soluble concentrations of CD14 (sCD14). STUDY DESIGN: Amniotic fluid was retrieved by amniocentesis from 88 patients in the following groups: group 1, preterm labor with intact membranes with MIAC/intra-amniotic inflammation (n = 18) and without these conditions (n = 26); group 2, term gestations not in labor without MIAC/intra-amniotic inflammation (n = 11), in labor without MIAC/intra-amniotic inflammation (n = 12) and in labor with MIAC/intra-amniotic inflammation (n = 13); and group 3, patients who underwent genetic amniocentesis at mid-trimester (n = 8). A sample of cord blood was obtained after delivery in all patients except those in group 3. sCD14 was assayed with a sensitive and specific immunoassay. Non-parametric statistics were used for analysis. A p value of < 0.05 was considered significant. RESULTS: sCD14 was detectable in 97% (85/88) of the amniotic fluid samples. Amniotic fluid sCD14 concentrations were lower in patients at term than in the mid-trimester of pregnancy (mid-trimester: median 482 ng/ml, range 258-838 ng/ml vs. term no labor: median 7 ng/ml, range 2-274 ng/ml, p = 0.01). Among patients with preterm labor with intact membranes, the median amniotic fluid sCD14 level of patients with MIAC/intra-amniotic inflammation was higher than in patients without these conditions (median 1568 ng/ml, range 98-5887 ng/ml vs. median 645 ng/ml, range 0-3961 ng/ml, respectively; p = 0.01). Among women at term in labor, those with MIAC/intra-amniotic inflammation had a higher median amniotic fluid sCD14 concentration than those without these conditions (median 85 ng/ml, range 2-1113 ng/ml vs. median 17 ng/ml, range 0-186 ng/ml; p = 0.01). MIAC/intra-amniotic inflammation in women with preterm labor with intact membranes was associated with a higher median umbilical venous plasma sCD14 concentration (median 744 ng/ml, range 0-3620 ng/ml vs. median 0 ng/ml, range 0-2060 ng/ml; p = 0.04). sCD14 was undetectable in plasma from umbilical cords of all neonates born to women at term. An increase in amniotic fluid concentration of sCD14 was observed in cases of intrauterine infection, not only by gram-negative bacteria, but also gram-positive bacteria and Ureaplasma spp. CONCLUSION: sCD14 is a physiological constituent of amniotic fluid, and its concentrations at term are lower than in the mid-trimester. Intrauterine infection/inflammation is associated with a higher median amniotic fluid sCD14 concentration in both preterm and term parturition. Neonates born from mothers with preterm labor with intact membranes and MIAC/intra-amniotic inflammation had a higher median concentration of sCD14 in umbilical cord plasma than those without these conditions. sCD14 concentrations are increased in the amniotic fluid and umbilical cord blood even in the absence of a microbiologically proven gram-negative infection. CD14 appears to participate in the host response to intrauterine infection even in cases involving genital mycoplasmas.

Differences in the fetal interleukin-6 response to microbial invasion of the amniotic cavity between term and preterm gestation.

BACKGROUND/OBJECTIVE: Fetal inflammatory response has been implicated as a mechanism of multi-system organ injury in preterm and term neonates. Microbial invasion of the amniotic cavity (MIAC) is frequently associated with a fetal inflammatory response. However, there are no studies comparing the fetal response to MIAC in term and preterm gestations. The purpose of this study was to compare the umbilical cord plasma interleukin-6 (IL-6) concentrations in term and preterm neonates in the presence or absence of MIAC. STUDY DESIGN: Umbilical cord blood was obtained at birth from 252 neonates whose mothers had an amniocentesis within 48 h of delivery (preterm delivery, n = 62; term delivery, n = 190). MIAC was defined as a positive amniotic fluid culture for bacteria or genital mycoplasmas. IL-6 was measured by a sensitive and specific immunoassay. RESULTS: The median IL-6 concentration in umbilical cord plasma was significantly higher in preterm neonates than in term neonates (median 13.4 pg/ml, range 0.1-676 pg/ml vs. median 3.2 pg/ml, range 0.1-408 pg/ml; p < 0.0001). In the context of MIAC, the median umbilical cord plasma IL-6 concentration was significantly higher in preterm than in term neonates (median 31.6 pg/ml, range 1.4-676 pg/ml vs. median 11.7 pg/ml, range 1.3-82 pg/ml, respectively; p < 0.05). Neonates born to mothers with a positive amniotic fluid culture had a significantly higher median IL-6 concentration than neonates born to mothers with a negative amniotic fluid culture (preterm: median 31.6, range 1.4-676 pg/ml vs. median 8.0, range 0.1-656 pg/ml; p < 0.05 and term: median 11.7, range 1.3-82 pg/ml vs. median 3.1, range 0.1-408 pg/ml; p < 0.01, respectively). CONCLUSIONS: The preterm fetus is capable of mounting a systemic cytokine response as measured by IL-6 in its peripheral blood. In the setting of MIAC, a fetal IL-6 response is higher in preterm than in term gestation.