Cervical length assessment in women with idiopathic polyhydramnios.

OBJECTIVE: The aims of the study were to determine cervical length among patients with polyhydramnios and to assess the relationship between the severity of polyhydramnios, cervical length and gestational age at delivery. PATIENTS AND METHODS: A prospective study was designed including 92 consecutive singleton pregnancies with polyhydramnios between 24 and 40 weeks' gestation. Cervical length was measured using transvaginal sonography. Polyhydramnios was defined when amniotic fluid index (AFI) was equal to or greater than 20 cm. A single sonologist performed all the examinations of the cervical length and the AFI. RESULTS: The median cervical length and AFI were 37.5 (range, 7-52) mm and 28.8 (range, 20-43) cm, respectively. A significant gradual shortening of the cervical length was observed with advancing gestational age (P=0.027). No significant association was found between AFI and cervical length (P=0.24). A cut-off of 15 mm (n=5) was associated with a significantly lower gestational age at delivery (30+/-2.6 weeks vs. 37.2+/-4.2 weeks, respectively, P<0.001). CONCLUSIONS: Women with polyhydramnios have a gradual shortening of cervical length with advancing gestational age. However, this finding is not related to the severity of polyhydramnios.

Intraplacental choriocarcinoma metastasizing to the maternal lung.

BACKGROUND: Although normal pregnancy is the precursor of 25% of cases of maternal choriocarcinoma, intraplacental choriocarcinoma in an otherwise normal placenta associated with viable pregnancy has rarely been reported. CASE: Examination of the placenta after delivery of a pale and small-for-date infant at term revealed intraplacental choriocarcinoma. There was no evidence of metastatic disease in the mother or child, but the mother exhibited postpartum rising levels of beta-HCG. The mother refused chemotherapy and disappeared from follow-up. Nine months later, she presented with metastatic choriocarcinoma of the lung. Eleven courses of the multi-drug EMA CO regimen effected a decrease of beta-HCG to normal and disappearance of lung metastases. To date, 28 months after the end of chemotherapy, the patient is alive and without evidence of gestational trophoblastic disease. Moreover, since then she has given birth to an additional two children. CONCLUSIONS: This case is an example of natural disease progression of intraplacental choriocarcinoma metastasizing to the mother. Furthermore, it supports common knowledge that the multi-drug EMA CO regimen is effective treatment in poor prognosis metastatic choriocarcinoma.

Fetal cardiac dysfunction in preterm premature rupture of membranes.

BACKGROUND: Preterm premature rupture of membranes (PROM) is associated with one-third of preterm births. In about 50% of preterm PROM cases, the fetuses will elicit a fetal inflammatory response syndrome (FIRS). FIRS is associated with the impending onset of preterm labor, periventricular leukomalacia, neonatal sepsis, and long-term handicap, including the development of bronchopulmonary dysplasia and cerebral palsy. The fetal myocardium is a potential target organ of proinflammatory cytokines released during FIRS. The objective of this study was to determine whether preterm PROM is associated with functional changes in the fetal heart, as determined by fetal echocardiography. METHODS: A retrospective study was conducted to assess the diastolic function of fetuses with preterm PROM with documented microbial invasion of the amniotic cavity (n = 25), preterm PROM without microbial invasion of the amniotic cavity (n = 42), and fetuses from normal pregnancies (control group = 150). Pregnancies with multiple gestation, fetal distress, fetuses that were small for gestational age, and major congenital anomalies were excluded. Fetal echocardiography studies were performed with two-dimensional ultrasound, color Doppler imaging and pulsed Doppler ultrasound. Non-parametric statistics were used for comparisons. A p value of < 0.05 was considered significant. RESULTS: The prevalence of positive amniotic fluid cultures for micro-organisms in patients with preterm PROM was 35.8% (24/67). Ureaplasma urealyticum was the most frequent isolate, either alone (41.7%; 10/24) or with other micro-organisms (29.2%; 7/24). Fetuses with preterm PROM had a higher delta early diastolic filling/atrial contraction (E/A) peak velocity ratio, a higher delta E/A velocity-time integral (VTI) ratio, a lower delta A peak velocity, a lower delta A VTI, and a lower A VTI/total VTI ratio in the mitral valve compared to those with uncomplicated pregnancies. The delta E/A peak velocity ratio was significantly higher and the delta A VTI significantly lower in fetuses with preterm PROM and microbial invasion of the amniotic cavity than in those with preterm PROM without microbial invasion of the amniotic cavity. CONCLUSIONS: Preterm PROM is associated with changes in fetal cardiac function consistent with increased left ventricular compliance. These observations were also noted in fetuses with microbial invasion of the amniotic cavity. Our findings suggest that fetal cardiac function is altered in preterm PROM and, in particular, in cases with intra-amniotic infection.

Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome.

OBJECTIVE: To determine whether there is a relationship between the presence of histological signs of inflammation in the extraplacental membranes and umbilical cord and the concentrations of fetal plasma interleukin-6 (IL-6). METHODS: The study examined a cohort of patients who were admitted with preterm labor or preterm premature rupture of the membranes (PROM) and who underwent cordocentesis. Inclusion criteria included fetal plasma available for IL-6 determination, histological examination of the umbilical cord and placenta, and delivery within 48 h of the procedure. This last criterion was used to preserve a meaningful temporal relationship between fetal plasma IL-6 and the results of histological examination of the placenta. Fetal plasma IL-6 was determined by a high sensitivity ELISA. Forty-five patients were available for study: 18 patients had preterm labor with intact membranes and 27 had preterm PROM. RESULTS: The incidence of funisitis was 44.4% (20/45): 27.8% (5/18) in patients with preterm labor and intact membranes and 55.6% (15/27) in patients with preterm PROM. The median values of fetal plasma IL-6 in patients with funisitis, chorioamnionitis without funisitis, and non-inflamed membranes were 51.4, 18.4 and 5.2 pg/ml, respectively. After log transformation of the fetal plasma IL-6 concentration, the means differed significantly from each other (ANOVA, p < 0.02). There was no difference in log fetal plasma IL-6 concentration between patients with funisitis and those with chorioamnionitis without funisitis. The difference in mean concentration of log fetal plasma IL-6 between patients with funisitis or chorionic vasculitis and those without inflammation was highly significant (post-hoc test, p = 0.01 and p < 0.01, respectively). Fetuses with fetal plasma IL-6 > 11 pg/ml had a significantly higher rate of histological signs of inflammation in the extra-placental membranes and umbilical cord than those with fetal plasma IL-6 < 11 pg/ml (funisitis: 55.6% (15/27) vs. 27.8% (5/18), p < 0.05; chorionic vasculitis: 55.6% (15/27) vs. 12.5% (2/16), p < 0.01; chorioamnionitis only: 25.9% (7/27) vs. 16.7% (3/18), p < 0.05; no inflammation: 18.5% (5/27) vs. 55.6% (10/18), p < 0.05, respectively). Fetuses with funisitis had significantly higher rates of clinical and histological chorioamnionitis, and neonatal infectious morbidity (proven + suspected sepsis) than fetuses without funisitis (40% (8/20) vs. 8% (2/25), 90% (18/20) vs. 36% (9/25), and 40% (8/20) vs. 4% (1/25), respectively; p < 0.01 for each). Fetuses with chorionic vasculitis had significantly higher rates of clinical and histological chorioamnionitis as well as neonatal infectious morbidity (proven + suspected sepsis) than fetuses without chorionic vasculitis (100% (17/17) vs. 42.3% (11/26), p < 0.01; 82.4% (14/17) vs. 50.0% (13/26), p = 0.05; and 41.2% (7/17) vs. 7.7% (2/26), p = 0.01). CONCLUSION: Fetal plasma IL-6 concentration is significantly associated with the presence of inflammatory lesions in the extraplacental membranes and umbilical cord. Fetuses with fetal plasma IL-6 > 11 pg/ml had a significantly higher rate of funisitis and/or chorionic vasculitis than fetuses with fetal plasma IL-6 < 11 pg/ml. These findings suggest that funisitis/chorionic vasculitis is the histological manifestation of the fetal inflammatory response syndrome.

Maternal intravascular inflammation in preterm premature rupture of membranes.

OBJECTIVE: Intrauterine inflammation has been implicated in the mechanisms responsible for preterm premature rupture of membranes (PROM). However, it is unclear whether this inflammatory process remains localized to the uterus, at the site of membrane rupture, or extends to the maternal compartment. Flow cytometric analysis is a sensitive method to assess the presence and magnitude of in vivo inflammation. This study was conducted to determine whether preterm PROM is associated with changes in the phenotypic and metabolic characteristics of maternal granulocytes and monocytes consistent with the presence of maternal intravascular inflammation. STUDY DESIGN: A prospective cross-sectional study was performed including patients with preterm PROM (n = 43) and normal pregnancy (n = 51). Maternal intravascular inflammation was studied using flow cytometry. Maternal blood was assayed to determine granulocyte and monocyte phenotype using monoclonal antibodies, which included cluster differentiation (CD) markers CD11b, CD14, CD15, CD16, CD18, CD49d, CD62L, CD64, CD66b and human leukocyte antigen (HLA)-DR. The quantities of basal intracellular reactive oxygen species (iROS) and oxidative burst was assessed. Statistical analysis was conducted with the use of non-parametric methods. A p value < 0.01 was considered significant. RESULTS: Preterm PROM was associated with a significant increase in the median mean channel brightness (MCB) of CD11b, CD14, CD64 and CD66b on granulocytes and median MCB of CD11b on monocytes. The oxidative burst and the stimulation index in both cell types were higher in preterm PROM than in normal pregnancy (p < 0.01). CONCLUSION: Preterm PROM is associated with phenotypic and metabolic changes in circulating granulocytes and monocytes.

Phenotypic and metabolic characteristics of monocytes and granulocytes in normal pregnancy and maternal infection.

OBJECTIVE: Normal pregnancy has been proposed to be a state of physiologic activation of the innate limb of the immune response. Recent studies have concluded that normal pregnancy produces inflammatory changes in peripheral blood leukocytes akin to those of sepsis. This unexpected observation has implications that are critical to understanding the susceptibility of pregnant women to sepsis, the pathophysiology of preeclampsia, and the biology of normal pregnancy. This study was designed to examine the phenotypic and metabolic characteristics of monocytes and granulocytes in normal pregnancy and in pregnant patients with acute infection. STUDY DESIGN: A cross-sectional study was conducted that included nonpregnant women (n = 20), normal pregnant women (n = 57), and pregnant women with a positive blood culture and/or pyelonephritis (n = 16). Phenotypic and metabolic characteristics of monocytes and granulocytes were studied with the use of flow cytometry and monoclonal antibodies against surface markers (CD11b, CD14, CD15, CD16, CD18, CD49d, CD62L, CD64, CD66b, and HLA-DR). Intracellular reactive oxygen species were measured at basal conditions and after stimulation (oxidative burst). The stimulation index (ratio of intracellular reactive oxygen species after oxidative burst over basal state) was calculated. Nonparametric statistics were used. A probability value of <.01 was considered statistically significant. RESULTS: Granulocytes from normal pregnant women had a higher median mean channel brightness for CD14 and CD64, but lower median mean channel brightness for CD16 and HLA-DR than granulocytes of nonpregnant women. Granulocytes of patients with acute infection had a higher median mean channel brightness for CD64 and CD66b than granulocytes of normal pregnant women. Monocytes from patients with acute infection had a higher mean channel brightness for CD11b, CD16, CD18, CD49d, CD64, and CD66b than monocytes of normal pregnant women. Baseline intracellular reactive oxygen species, oxidative burst, and stimulation index values were significantly higher in the granulocytes and monocytes of normal pregnant women than in the granulocytes and monocytes of nonpregnant women. Similarly, baseline intracellular reactive oxygen species, oxidative burst, and stimulation index values were higher in women with acute infections than in normal pregnant women. CONCLUSION: Normal pregnancy was associated with phenotypic and metabolic changes of granulocytes and monocytes; pregnant women with acute infection had more marked phenotypic and metabolic changes of leukocytes than normal pregnant women. These qualitative differences indicate that the innate limb of the immune response is not maximally activated during normal pregnancy.

Phenotypic and metabolic characteristics of maternal monocytes and granulocytes in preterm labor with intact membranes.

OBJECTIVE: Experimental and clinical studies support a role for the fetus in the control of the onset of labor. Fetal systemic inflammation, but not a maternal inflammatory response, has been linked to the onset of preterm labor and delivery on the basis of the determination of inflammatory cytokines in fetal and maternal blood. We propose that parturition requires fetomaternal cooperation and that inflammation is an integral part of the parturitional process. This study used flow cytometry, a sensitive technique for the detection of intravascular inflammation, to assess whether maternal inflammation is present in preterm labor. STUDY DESIGN: A prospective cross-sectional study was performed including patients with preterm labor (n = 55) and women with normal pregnancy (n = 50). Intravascular inflammation was studied by using flow cytometry. Maternal blood was assayed to determine granulocyte and monocyte phenotype by using monoclonal antibodies, which included the following cluster of differentiation (CD) markers: CD11b, CD14, CD15, CD16, CD18, CD49d, CD62L, CD64, CD66b, and HLA-DR. Oxidative burst and generation of basal intracellular oxygen radical species were assessed. Statistical analysis was conducted with the use of nonparametric methods. A P value of <.01 was considered statistically significant. RESULTS: Preterm labor was associated with a significant increase in the median mean channel brightness of CD11b, CD15, and CD66b on granulocytes and median mean channel brightness of CD11b and CD15 on monocytes. The ratio of oxidative burst over basal intracellular oxygen radical species in both granulocytes and monocytes was increased in preterm labor (P <. 01). CONCLUSION: Preterm labor with intact membranes is associated with phenotypic and metabolic changes of maternal granulocytes and monocytes.

Value of amniotic fluid neutrophil collagenase concentrations in preterm premature rupture of membranes.

OBJECTIVE: Neutrophils in amniotic fluid are thought to be of fetal origin, and therefore the detection of these cells and/or their products in amniotic fluid may reflect the fetal inflammatory status. We propose that amniotic fluid neutrophil collagenase (matrix metalloproteinase-8) is a useful parameter to predict adverse neonatal outcome, impending preterm labor/delivery, and intrauterine infection in the setting of preterm premature rupture of the membranes. STUDY DESIGN: Amniotic fluid was obtained by transabdominal amniocentesis from 101 patients with preterm premature rupture of the membranes (gestational age, 24-36 weeks). Fluid was cultured for aerobic and anaerobic bacteria and Mycoplasmas. Amniotic fluid analysis included Gram stain, white blood cell count, and determination of interleukin-6 and matrix metalloproteinase-8 concentrations (enzyme-linked immunosorbent assay). RESULTS: Neonates with adverse neonatal outcome were born to mothers with a significantly higher median amniotic fluid matrix metalloproteinase-8 concentration than those without adverse neonatal outcome (median, 54.4 ng/mL; range, 0.82-14,500 ng/mL vs median, 28.9 ng/mL; range, 0.78-2451.8 ng/mL; P <.05, respectively). The higher the amniotic fluid matrix metalloproteinase-8 concentrations, the shorter the interval to delivery (Cox proportional hazards model adjusting for gestational age at delivery; hazard ratio, 1.9; 95% CI, 1.1-3.5; P <.03). Amniotic fluid matrix metalloproteinase-8 concentration was more sensitive than an amniotic fluid white blood cell count and interleukin-6 in the detection of microbiologically proven intra-amniotic infection. CONCLUSION: Increased concentrations of neutrophil collagenase (matrix metalloproteinase-8) in amniotic fluid are associated with intra-amniotic infection, impending preterm delivery, and adverse neonatal outcome in patients with preterm premature rupture of the membranes. Moreover, matrix metalloproteinase-8 in amniotic fluid is a stronger predictor for the duration of pregnancy and intra-amniotic inflammation than interleukin-6 and an amniotic fluid white blood cell count.

Amniotic fluid matrix metalloproteinase-8 in preterm labor with intact membranes.

OBJECTIVE: Intra-amniotic inflammation is a major determinant of maternal and neonatal outcome in patients with preterm labor. Matrix metalloproteinase-8 is a sensitive marker of inflammation in body fluids. This study was conducted to examine the value of amniotic fluid matrix metalloproteinase-8 determinations in patients with preterm labor and intact membranes. STUDY DESIGN: Amniotic fluid was obtained by transabdominal amniocentesis from 371 patients with preterm labor. Fluid was cultured for aerobic and anaerobic bacteria and Mycoplasmas. Amniotic fluid analysis included Gram stain examination, white blood cell count, and matrix metalloproteinase-8 (enzyme-linked immunosorbent assay) determination. Nonparametric statistics were used for analysis. RESULTS: The rate of preterm delivery was 54% (200/371) and that of intra-amniotic infection was 9.2% (34/371). The median amniotic fluid matrix metalloproteinase-8 concentration was more than 50-fold higher in patients with intra-amniotic infection than in patients with no intra-amniotic infection (median, 605.6 ng/mL; range, 0.65-15,000 ng/mL vs median, 10.6 ng/mL; range, <0.06-16,600 ng/mL, respectively; P <.0001). The matrix metalloproteinase-8 amniotic fluid concentrations were significantly higher in patients who delivered preterm than in patients who delivered at term (median, 19.5 ng/mL; range, <0.06-16,600 ng/mL vs median, 2.1 ng/mL; range, <0.06-500 ng/mL, respectively; P <.001). After exclusion of patients with intra-amniotic infection, patients who delivered preterm had a significantly higher median amniotic fluid matrix metalloproteinase-8 than patients who delivered at term (P <.05). An amniotic fluid matrix metalloproteinase-8 level of >30 ng/mL was an independent predictor for the occurrence of neonatal morbidity (odds ratio, 3.4; 95% CI, 1.9-5.8; P <.01). CONCLUSION: Increased amniotic fluid matrix metalloproteinase-8 concentrations identify patients at risk for intra-amniotic infection, impending preterm delivery, and adverse neonatal outcome.

Phenotypic and metabolic characteristics of monocytes and granulocytes in preeclampsia.

OBJECTIVE: The maternal syndrome of preeclampsia has recently been attributed to a systemic intravascular inflammatory response and endothelial cell activation and dysfunction. This novel hypothesis has considerable clinical and biological implications. This study was designed to determine whether women with preeclampsia have evidence of intravascular inflammation by examination of the phenotypic and metabolic activity of granulocytes and monocytes. STUDY DESIGN: A cross-sectional study was performed that included patients with preeclampsia (n = 31) and normal pregnancies (n = 58) matched for gestational age at blood draw. Intravascular inflammation was studied with use of flow cytometry. Peripheral venous blood was assayed to determine granulocyte and monocyte phenotype with the use of monoclonal antibodies for selective cluster differentiation (CD) antigens. The panel of antibodies included CD11b, CD14, CD16, CD18, CD49d, CD62L, CD64, CD66b, and HLA-DR. The quantity of basal intracellular reactive oxygen species and oxidative burst was assessed. Results were reported as mean channel brightness or intensity of detected fluorescence. Analysis was conducted with nonparametric statistics. A P value <.01 was considered to be significant. RESULTS: Preeclampsia was associated with a significant increase in mean channel brightness for CD11b on granulocytes and monocytes but lower mean channel brightness for CD62L on granulocytes than those from women with normal pregnancy (P <.01 for each). Basal intracellular reactive oxygen species were increased in monocytes but not in granulocytes. The oxidative burst was higher in both cell types. CONCLUSION: Preeclampsia is associated with phenotypic and metabolic changes in granulocytes and monocytes.

A role for the 72 kDa gelatinase (MMP-2) and its inhibitor (TIMP-2) in human parturition, premature rupture of membranes and intraamniotic infection.

OBJECTIVE: Degradation of the extracellular matrix in fetal membranes has been implicated in the process of parturition and rupture of membranes. Matrix metalloproteinases (MMPs) are enzymes capable of degrading extracellular matrix including collagen. Tissue inhibitors of matrix metalloproteinases (TIMPs) inhibit the activity of MMPs by covalently binding to the enzymes. MMP-2 degrades Type IV collagen and TIMP-2 is its specific inhibitor. The objective of this study was to determine if human parturition, rupture of membranes (term and preterm) and microbial invasion of the amniotic cavity (MIAC) are associated with changes in the concentrations of MMP-2 and TIMP-2 in amniotic fluid. STUDY DESIGN: A cross-sectional study was conducted with women in the following categories: 1) term with intact membranes, in labor and not in labor; 2) preterm labor and intact membranes who delivered at term, who delivered preterm and preterm labor with MIAC; 3) preterm premature rupture of membranes (PROM) with and without infection; 4) term and preterm PROM not in labor; and 5) midtrimester. MMP-2 and TIMP-2 concentrations in amniotic fluid were determined using sensitive and specific immunoassays. RESULTS: The concentration of TIMP-2 increased with advancing gestational age (r = 0.6, p < 0.001). No correlation was found between MMP-2 concentrations and gestational age. Human parturition and rupture of membranes (term and preterm) and in patients with intact membranes were not associated with changes in the amniotic fluid MMP-2 concentrations. In contrast, 1) patients with spontaneous labor (term and preterm) had significantly lower median concentrations of TIMP-2 compared to those not in labor (p < 0.05 for both); 2) MIAC in women with preterm labor and preterm PROM was associated with a significant decrease in amniotic fluid TIMP-2 concentrations (p < 0.04 for both comparisons); 3) Rupture of the membranes (term and preterm) was also associated with a significant decrease in the amniotic fluid TIMP-2 concentrations (p < 0.05 and p < 0.03, respectively). CONCLUSIONS: Human parturition (preterm and term), rupture of fetal membranes (term and preterm) and intraamniotic infection are associated with a significant decrease in amniotic fluid TIMP-2 concentrations.

Does cervical cerclage prevent preterm delivery in patients with a short cervix?

OBJECTIVE: Our purpose was to determine whether cerclage placement in women with a short cervix on transvaginal ultrasonography reduces the rate of preterm delivery. STUDY DESIGN: A retrospective cohort study identified patients with an ultrasonographic short cervix (cervical length < or =15 mm) between 14 and 24 weeks' gestation. Cerclage placement was performed at the discretion of the attending physician. Clinical characteristics and outcome with and without cerclage were compared. RESULTS: Seventy patients met inclusion criteria; 25 (36%) underwent cerclage placement. Patients managed with cerclage had a lower gestational age at diagnosis (19.6 weeks vs 21.3 weeks, P <.01) but had a similar median cervical length, presence of funneling, and a history of cervical surgery, in comparison with those managed without cerclage. The rate of spontaneous preterm delivery was not different between groups. Patients with cerclage had a higher rate of preterm premature rupture of membranes than those without cerclage (65.2% vs 36.4%, P <.05). CONCLUSION: Cervical cerclage in patients with a short cervix did not reduce the rate of spontaneous preterm delivery and increased the risk of preterm premature rupture of membranes.

Further observations on the fetal inflammatory response syndrome: a potential homeostatic role for the soluble receptors of tumor necrosis factor alpha.

OBJECTIVE: The fetal inflammatory response syndrome is a subclinical condition frequently present in preterm labor and preterm premature rupture of the membranes and is associated with increased perinatal morbidity and mortality. Tumor necrosis factor alpha is a mediator of septic shock and death, and it exerts its biologic effects by interacting with 2 receptors, TNF-R1 and TNF-R2. Soluble tumor necrosis factor receptors can buffer the biologic activity and protect against the deleterious effects of tumor necrosis factor alpha. The purpose of this study was to determine the behavior of soluble tumor necrosis factor receptors in fetuses with and without fetal inflammatory response syndrome. STUDY DESIGN: Fetal blood sampling was performed in patients with preterm labor (n = 95) and preterm premature rupture of the membranes (n = 39). Control samples were obtained from fetuses who were undergoing blood sampling for clinical indications and had normal outcomes (n = 21). Fetal inflammatory response syndrome was defined as a fetal plasma interleukin 6 concentration >11 pg/mL. Concentrations of interleukin 6 and TNF-R1 and TNF-R2 were determined by use of sensitive and specific immunoassays. Analysis of covariance was used for statistical analysis. RESULTS: (1) TNF-R1 and TNF-R2 were detectable in all samples, and their concentrations decreased with advancing gestational age (r = -0.8 and r = -0.7; P<.0001 and P<.001, respectively). (2) The mean fetal plasma concentrations of TNF-R1 and TNF-R2 were significantly higher in fetuses with fetal inflammatory response syndrome than in those without the syndrome after adjustment for gestational age and fetal membrane status (TNF-R1: no fetal inflammatory response syndrome, mean +/- SE, 3473.7+/-128.8 pg/mL; vs fetal inflammatory response syndrome, mean +/- SE, 4079.9+/-190.7 pg/mL; P<.005; TNF-R2: no fetal inflammatory response syndrome, mean +/- SE, 6033.2+/-235.4 pg/mL; vs. fetal inflammatory response syndrome, mean +/- SE, 7783.1+/-342.8 pg/mL; P<.0001). (3) Fetuses of patients who delivered within 72 hours of cordocentesis had significantly higher concentrations of TNF-R1 and TNF-R2 receptors than those with longer latency periods (P<.05 for each). CONCLUSION: The fetal inflammatory response syndrome is associated with increased availability of the soluble receptors of tumor necrosis factor alpha in fetal plasma. These factors may attenuate the deleterious effects of tumor necrosis factor alpha.

Participation of the novel cytokine interleukin 18 in the host response to intra-amniotic infection.

OBJECTIVE: Interleukin 18 is a proinflammatory pleiotropic cytokine that has been implicated in the host defense against infection. This study was undertaken to determine whether interleukin 18 concentrations change in the maternal, fetal, and amniotic fluid compartments with labor (term and preterm) and microbial invasion of the amniotic cavity. STUDY DESIGN: Amniotic fluid was assayed for interleukin 18 in samples obtained from 285 patients in the following groups: (1) term not in labor (n = 22), in labor (n = 19), and with microbial invasion of the amniotic cavity (n = 16); (2) preterm labor who delivered at term (n = 38), who delivered preterm but without microbial invasion of the amniotic cavity (n = 41), and preterm labor with microbial invasion of the amniotic cavity (n = 24); (3) preterm premature rupture of membranes without microbial invasion of the amniotic cavity (n = 30) and with microbial invasion of the amniotic cavity (n = 34); (4) term premature rupture of membranes not in labor (n = 20) and term premature rupture of membranes in labor (n = 19); and (5) midtrimester (n = 22). In addition, cord and maternal plasma samples from women at term not in labor (n = 20) and in labor (n = 20) were assayed for interleukin 18. RESULTS: (1) Interleukin 18 was detectable in all amniotic fluid samples and maternal and umbilical cord blood samples. (2) Interleukin 18 concentrations increased with advancing gestational age (r = 0.47; P <.0001). (3) Microbial invasion of the amniotic cavity in either preterm or term parturition was associated with a significant increase in the amniotic fluid concentration of interleukin 18 (preterm labor without microbial invasion of the amniotic cavity: median, 14.95 pg/mL; range, 3.9-277.0 pg/mL; vs preterm labor with microbial invasion of the amniotic cavity: median, 20.75 pg/mL; range, 5.53-160.21 pg/mL; P <.02; term labor without microbial invasion of the amniotic cavity: median, 18.73 pg/mL; range, 5.09-95.44 pg/mL; vs term labor with microbial invasion of the amniotic cavity: median, 24.35 pg/mL; range, 10.07-144.42 pg/mL; P<.004). (4) Both term and preterm parturition were associated with a modest increase in amniotic fluid interleukin 18 concentrations, although this trend did not reach statistical significance. (5) Rupture of membranes at term was associated with a significant decrease in amniotic fluid interleukin 18 concentrations (intact membranes: median, 14.96 pg/mL; range, <3.89-26.07 pg/mL; vs rupture of membranes: median, 10.1 pg/mL; range, 4.29-21.44 pg/mL; P <.001). CONCLUSION: (1) Interleukin 18 is increased in cases of microbial invasion of the amniotic cavity. (2) Interleukin 18 is detectable in the amniotic, maternal, and fetal compartments. (3) We propose that this novel cytokine plays a role in the host defense against infection.

Evidence of in vivo differential bioavailability of the active forms of matrix metalloproteinases 9 and 2 in parturition, spontaneous rupture of membranes, and intra-amniotic infection.

OBJECTIVE: Matrix metalloproteinases (MMP-9 and MMP-2) have been implicated in the digestion of fetal membranes. The purpose of this study was to determine the amniotic fluid concentrations of active forms of MMP-2 and MMP-9 and to explore the participation of these enzymes in labor (term and preterm), rupture of membranes (term and preterm), and microbial invasion of the amniotic cavity. STUDY DESIGN: A cross-sectional study was conducted with 291 women in the following categories: (1) term not in labor, (2) term in labor, (3) preterm labor and intact membranes who delivered at term, (4) preterm labor who delivered preterm, (5) preterm labor with microbial invasion of the amniotic cavity, (6) preterm premature rupture of membranes without microbial invasion of the amniotic cavity, (7) preterm premature rupture of membranes with microbial invasion of the amniotic cavity, (8) term premature rupture of membranes not in labor, and (9) mid trimester. Active forms of MMP-2 and MMP-9 were measured by a novel assay that uses a substrate developed by protein engineering. RESULTS: (1) MMP-2 and MMP-9 were detected in 88% and 96% of amniotic fluid samples, respectively (255/291 and 279/291). (2) The concentrations of active forms of MMP-2 and MMP-9 changed with advancing gestational age. (3) Spontaneous term parturition was associated with a significant increase in the median concentration of the active forms of MMP-9 (P <.005) and a significant decrease in the median concentration of the active forms of MMP-2 (P <.003). (4) Preterm labor with intact membranes leading to preterm delivery in the absence of infection was associated with a significant increase in the median concentration of the active forms of MMP-9 (P <.005) but not of the active forms of MMP-2 (P =.2). (5) Rupture of membranes (either term or preterm) was associated with a significant increase in the concentration of the active forms of MMP-9 and with a significant decrease in the concentration of the active forms of MMP-2 (P <.005 for term and P <.03 and P <.003 for preterm, respectively). (6) Microbial invasion of the amniotic cavity in women with preterm premature rupture of membranes was also associated with a significant increase in the concentration of the active forms of MMP-9 (P <.03) and a decrease in the concentration of the active forms of MMP-2 (P <.05). (7) Microbial invasion of the amniotic cavity in patients with preterm labor was associated with a significant increase in the median concentration of the active forms of MMP-9 (P <.005) but not of the active forms of MMP-2 (P =.6). CONCLUSION: Spontaneous rupture of membranes (either term or preterm), parturition (either term or preterm), and microbial invasion of the amniotic cavity were associated with significant increases in the amniotic fluid concentration of the active forms of MMP-9. In contrast, the concentration of the active forms of MMP-2 either decreased or remained the same in these conditions. Our observations provide evidence for a novel regulation of gelatinolytic activity in vivo.

Lactoferrin in intrauterine infection, human parturition, and rupture of fetal membranes.

OBJECTIVE: Lactoferrin is an iron-binding protein with antimicrobial properties. This study was undertaken to determine whether amniotic fluid concentrations of this protein change with gestational age, infection, labor, and rupture of membranes. STUDY DESIGN: This cross-sectional study included women who underwent transabdominal amniocentesis (n = 268) in the following groups: (1) mid trimester of pregnancy; (2) preterm labor who delivered at term, preterm labor who delivered preterm with intra-amniotic infection, and preterm labor who delivered preterm without intra-amniotic infection; (3) preterm premature rupture of membranes in the presence or absence of intra-amniotic infection; (4) term with intact membranes not in labor, in labor, and in labor with intra-amniotic infection; and (5) premature rupture of membranes at term not in labor. In addition, lactoferrin concentrations were determined in maternal plasma and cord blood of patients at term not in labor. Lactoferrin concentration was measured with an immunoassay. RESULTS: (1) Lactoferrin was detectable in 85.4% (229/268) of amniotic fluid samples, not detectable in all fluid obtained in the mid trimester, and detectable in all maternal and cord plasma samples. (2) The concentration of lactoferrin increased with advancing gestational age (r = 0.68; P <.0001). (3) Intra-amniotic infection was associated with significant increases in amniotic fluid lactoferrin concentrations in patients with preterm labor (no intra-amniotic infection median, 1641.2 ng/mL; range, <1.24-35,090.0 ng/mL; vs intra-amniotic infection median, 3833.6 ng/mL; range, 746.0-47,020.0 ng/mL; P <.001), term labor (no intra-amniotic infection median, 2085.8 ng/mL; range, 425.0-23,230.0 ng/mL; vs intra-amniotic infection median, 5627.0 ng/mL; range, <1.24-19,220.0 ng/mL; P <. 001), and preterm premature rupture of membranes (no intra-amniotic infection median, 2190 ng/mL; range, <1.24-7456.1 ng/mL; vs intra-amniotic infection median, 3449.3 ng/mL; range, <1.24-83,600. 0; P <.01). (4) Spontaneous labor at term but not preterm was associated with a significant decrease in amniotic fluid lactoferrin concentration (P <.05). (5) Spontaneous term parturition was associated with a significant increase in umbilical cord plasma lactoferrin concentration (P <.005). CONCLUSION: (1) Intra-amniotic infection was consistently associated with dramatically increased concentrations of lactoferrin in amniotic fluid. (2) Term parturition was associated with a significant increase in lactoferrin concentration in the fetal compartment (umbilical cord blood) and a decrease in the amniotic compartment. We propose that lactoferrin is part of the repertoire of host defense mechanisms against intra-amniotic infection.

Evidence for the participation of interstitial collagenase (matrix metalloproteinase 1) in preterm premature rupture of membranes.

OBJECTIVE: Rupture of membranes is thought to result from the effects of physical forces in localized areas of the membranes weakened by the degradation of structural collagens. Matrix metalloproteinases are enzymes that degrade extracellular matrix components and have been implicated in membrane rupture. The objective of this study was to determine whether spontaneous rupture of membranes is associated with a change in the amniotic fluid concentration of interstitial collagenase (matrix metalloproteinase 1 [MMP-1]), a major collagenase. STUDY DESIGN: A cross-sectional study was conducted to determine MMP-1 concentrations in amniotic fluid from 353 women in the following categories: (1) term with intact membranes not in labor and in labor, (2) preterm labor who delivered at term, (3) preterm labor who delivered preterm without microbial invasion of the amniotic cavity, (4) preterm labor who delivered preterm with microbial invasion of the amniotic cavity, (5) preterm premature rupture of membranes with and without microbial invasion of the amniotic cavity, (6) term premature rupture of membranes not in labor and in labor, and (7) mid trimester of pregnancy. Microbial invasion of the amniotic cavity was determined by an amniotic fluid culture positive for microorganisms. MMP-1 concentrations in amniotic fluid were determined by means of sensitive and specific immunoassays. RESULTS: (1) MMP-1 was detectable in 81.3% of amniotic fluid samples (287/353), and its concentrations increased with advancing gestational age (r = 0.4; P <.001). (2) Preterm premature rupture of membranes was associated with a significant increase in the median amniotic fluid concentration of MMP-1 (P =.02). (3) Women with term premature rupture of membranes had a significantly lower amniotic fluid MMP-1 concentration than those with intact membranes at term not in labor (P <.001). (4) Microbial invasion of the amniotic cavity in patients in preterm labor with intact membranes and in patients with preterm premature rupture of membranes was also associated with significant increases in the median amniotic fluid MMP-1 concentrations (P <.05 and P <.01, respectively). (5) Patients with preterm premature rupture of membranes and microbial invasion of the amniotic cavity had a significantly higher median amniotic fluid MMP-1 concentration than those with intact membranes and microbial invasion of the amniotic cavity (P =.01). (6) Neither term nor preterm parturition was associated with changes in amniotic fluid MMP-1 concentrations (P =.6 and P =.3, respectively). CONCLUSION: (1) Collagenase 1 (MMP-1) is a physiologic constituent of amniotic fluid. (2) Preterm premature rupture of membranes (in both the presence and absence of infection) was associated with an increase in the amniotic fluid MMP-1 concentrations. (3) Neither term nor preterm parturition was associated with a significant increase in the amniotic fluid concentration of MMP-1.

Breech presentation is a risk factor for intrapartum and neonatal death in preterm delivery.

OBJECTIVES: To determine the prevalence of malpresentation among preterm births and to evaluate the clinical significance of malpresentation as a predictor of neonatal complications in preterm delivery. STUDY DESIGN: A cross-sectional study was conducted comparing 692 nonvertex preterm deliveries of singleton births (24-36 weeks) to 4685 vertex preterm deliveries. Women with gestational age less than 24 weeks and birthweight <500 g were excluded from the study. RESULTS: The study population included 5377 women who met the inclusion criteria. The prevalence of malpresentation was 12.8% (692/5377); 73% in the breech presentation, 22% in the transverse lie, and 5% in other positions. The mean gestational age at birth was significantly lower in the nonvertex group (32.4+/- 3.5 vs. 34.2+/-2.6; P<0.0001). Higher rates of perinatal mortality (23.1% vs. 10.1%; P<0.0001) were observed in the nonvertex group when compared with vertex births, as well as other complications such as oligohydroamnion (9.2% vs. 3.2%; P<0.0001); small-for-gestational-age; (10.5% vs. 5.9%; P<0.001); congenital anomalies (11% vs. 5.9%; P<0.001); placental abruption (8.7% vs. 4. 1%; P<0.0001); placenta previa (6.8% vs. 2.5%; P<0.0001); premature rupture of membranes (25.4% vs. 16.6%; P<0.0001); chorioamnionitis (7.9% vs. 2.9%; P<0.001); prolapse of cord (2.3% vs. 0.6%; P<0.0001) and cesarean section rate (63.9% vs. 19.1%; P<0.0001). Neonatal mortality was found to be higher for breech presentation, odds ratio (OR)=4 (confidence interval [CI]=2.76-4; P<0.0001), transverse lie, OR=2.1 (1.1-4.12; P<0.02) and for other malpositions, OR=7.3 (2. 72-20; P<0.0001). After multivariate adjustment for birthweight, cesarean section, placental pathology and chorioamnionitis, a strong association remained between the presence of breech presentation and neonatal mortality, with an adjusted OR of 2.2 (CI=1.36-3.63; P<0.01). The adjusted OR for the two other groups of malpresentation was not statistically significant. CONCLUSION: Breech presentation in preterm delivery is an independent risk factor for neonatal mortality after simultaneous adjustment for birthweight, chorioamnionitis and placental pathology. Cesarean section was found to have a protective effect on neonatal mortality rates.

Human neutrophil collagenase (matrix metalloproteinase 8) in parturition, premature rupture of the membranes, and intrauterine infection.

OBJECTIVES: The mechanisms by which microbial invasion of the amniotic cavity leads to membrane weakening and rupture are poorly understood. Recently, endogenous host enzymes have been implicated in this process. Matrix metalloproteinases are a family of potent enzymes that degrade components of the extracellular matrix. Collagen type I provides the main tensile strength of the fetal membranes. Matrix metalloproteinase 8 (MMP-8), or neutrophil collagenase, degrades interstitial collagens, acting preferentially on collagen type I. This study was undertaken (1) to determine whether MMP-8 is present in amniotic fluid and whether its concentrations are changed in preterm and term labor and membrane rupture with and without intra-amniotic infection and (2) to determine whether the amniotic fluid concentrations of MMP-8 in labor at term are different in the lower and upper uterine compartments. STUDY DESIGN: A cross-sectional study was conducted and transabdominal amniocentesis was performed in women in the following categories: (1) midtrimester (n = 25), (2) preterm labor in the presence and absence of microbial invasion of the amniotic cavity (n = 86), (3) preterm premature rupture of the membranes in the presence and absence of microbial invasion of the amniotic cavity (n = 51), (4) term patients in labor and not in labor (n = 51), and (5) term premature rupture of membranes (n = 20). Additional paired samples of amniotic fluid were retrieved by transabdominal amniocentesis (upper compartment) and transvaginal amniocentesis (lower or forebag compartment) from 14 term patients (28 samples) in spontaneous labor with intact membranes. Amniotic fluid MMP-8 concentrations were determined with a sensitive and specific immunoassay. RESULTS: MMP-8 was detected in 95.4% (249/261) of all samples. (1) Spontaneous human parturition was associated with a significant increase in amniotic fluid concentrations of MMP-8 in both term and preterm gestation. Term (no labor median, 3.3 ng/mL; range, <0.06-38.6 ng/mL; vs labor median, 16.6 ng/mL; range, 0. 33-1650 ng/mL; P <.05). Patients with preterm labor who delivered preterm (in the absence of microbial invasion of the amniotic cavity) had a significantly higher median amniotic fluid MMP-8 concentration than those with preterm labor who delivered at term (preterm labor, term delivery median, 3.1 ng/mL; range, <0.06-415.1 ng/mL; vs preterm labor, preterm delivery median, 32.5 ng/mL; range, <0.06-6006.6 ng/mL;P <.003). (2) Spontaneous rupture of membranes in preterm gestation but not in term gestation was associated with elevated amniotic fluid concentrations of MMP-8. Preterm gestation (preterm labor, intact membranes median, 3.1 ng/mL; range, <0.06-415. 1 ng/mL; vs preterm premature rupture of membranes median, 35.1 ng/mL; range, 0.71-1184.1 ng/mL; P <.05). Term gestation (intact membranes median, 3.3 ng/mL; range, 0.24-38.6 ng/mL; vs rupture of membranes median, 5.6 ng/mL; range, 0.22-19.8 ng/mL; P =.9). (3) Microbial invasion of the amniotic cavity was associated with a significant increase in amniotic fluid MMP-8 concentration in patients with preterm labor and intact membranes, as well as in patients with preterm premature rupture of membranes. Preterm labor (no microbial invasion of the amniotic cavity, preterm delivery median, 32.5 ng/mL; range, <0.06-6006.6 ng/mL; vs microbial invasion of the amniotic cavity median, 208.1 ng/mL; range, 4.2-14,600 ng/mL; P <.001). Preterm premature rupture of membranes (no microbial invasion of the amniotic cavity median, 35.1 ng/mL; range, 0.71-1184. 1 ng/mL; vs microbial invasion of the amniotic cavity median, 317.9 ng/mL; range, 2.16-14,500 ng/mL; P <.01). (4) The median amniotic fluid MMP-8 concentrations were significantly higher in fluid obtained from the forebag compartment than in that obtained from the upper compartment (median, 66.2 ng/mL; range, 7.4-170 ng/mL; vs median, 13.3 ng/mL; range, 2-170 ng/mL; respectively; P <.01). (ABSTRACT TRUNCATED)

Matrilysin (matrix metalloproteinase 7) in parturition, premature rupture of membranes, and intrauterine infection.

OBJECTIVE: Matrix metalloproteinases are enzymes capable of degrading extracellular matrix components. Matrilysin (matrix metalloproteinase 7), a novel member of this family, degrades fibronectin and proteoglycans. The objective of this study was to determine whether parturition (either term or preterm), premature rupture of the membranes, and microbial invasion of the amniotic cavity are associated with changes in the amniotic fluid concentration of matrilysin. STUDY DESIGN: A cross-sectional study was conducted with 275 women in the following categories: (1) second trimester, (2) term not in labor, (3) term in labor, (4) term with microbial invasion of the amniotic cavity, (5) preterm labor with intact membranes without microbial invasion of the amniotic cavity who delivered at term, (6) preterm labor without microbial invasion of the amniotic cavity who delivered preterm, (7) preterm labor with microbial invasion of the amniotic cavity, (8) preterm premature rupture of membranes with and without microbial invasion of the amniotic cavity, and (9) term premature rupture of membranes not in labor and without microbial invasion of the amniotic cavity. Matrilysin concentrations were measured with a sensitive specific immunoassay that was validated for amniotic fluid. RESULTS: Matrilysin was detectable in 97.4% (268/275) of the samples. The concentration of matrilysin increased with advancing gestational age (r = 0.8; P <.001). Parturition at term was not associated with a significant increase in amniotic fluid concentration of matrilysin. Preterm parturition in the absence of microbial invasion of the amniotic cavity was associated with a significant increase in amniotic fluid concentration of matrilysin (preterm labor with preterm delivery: median, 1.7 ng/mL; range, 0.45-21.6 mg/mL; vs preterm labor with term delivery: median, 1.2 ng/mL; range, 0.17-42. 1 ng/mL; P <.05). Premature rupture of membranes without microbial invasion of the amniotic cavity (either term or preterm) was not associated with a significant change in the amniotic fluid matrilysin concentration. Intra-amniotic infection was associated with a significant increase in amniotic fluid matrilysin among both patients with preterm labor and patients with preterm premature rupture of membranes (preterm labor with microbial invasion of the amniotic cavity: median, 3.2 ng/mL; range, 0.16-21.9 ng/mL; vs preterm labor and delivery without microbial invasion of the amniotic cavity: median, 1.7 ng/mL; range, 0.45-21.6 ng/mL; vs preterm labor with term delivery: median, 1.2 ng/mL; range, 0.17-42. 1 ng/mL; P <.01 for each comparison; and preterm premature rupture of membranes without microbial invasion of the amniotic cavity: median, 1.7 ng/mL; range, 0.29-13.9 ng/mL; vs preterm premature rupture of membranes with microbial invasion of the amniotic cavity: median, 3.6 ng/mL; range, 0.59-20.3 ng/mL; P <.01). CONCLUSION: Matrilysin is a physiologic constituent of amniotic fluid, and its concentration increases with advancing gestational age. Microbial invasion of the amniotic cavity in preterm gestations was associated with a significant increase in amniotic fluid concentration of matrilysin. Matrilysin therefore may play a role in the host defense mechanism.