Amniotic fluid total antioxidant capacity and nitric oxide in emergency cerclage

Objective: Nitric oxide (NO) is one of the reactive oxygen species (ROS) that has been associated with inflammation. Total antioxidant capacity (TAC) neutralizes ROS. We evaluated that amniotic fluid (AF) TAC and NO correlate with the outcome of emergency cerclage.

Methods: Thirty-six women with cervical dilatation (≥2?cm) and bulging membranes between 16 and 24 weeks underwent emergency cerclage. Sixty-seven women between 16 and 24 weeks who had amniocentesis for chromosomal test provided control samples. AF samples were tested for TAC, and NO, and then correlated with pregnancy outcome.

Results: AF TAC was significantly lower in cerclage group than control group (cerclage: 92.6 mmol/L versus control: 127.2 mmol/L, p?<?0.001). Higher levels of AF TAC were associated with a longer latency from cerclage to delivery (r?=?0.62, p?<?0.001). NO was similar between two groups (p?=?0.35). The mean gestational age at delivery of control group was better than cerclage group (cerclage: 29.5 weeks versus control: 39.4 weeks, p?<?0.01).

Conclusion: Higher levels of AF TAC are correlated with longer prolongation days after cerclage. However, AF NO and iNOS are not different between two groups.     

Cerclage retention versus removal following preterm premature rupture of membranes and association with amniotic fluid markers

Objective

To evaluate whether amniotic fluid markers can aid the decision of whether to retain or remove a cervical cerclage after preterm premature rupture of membranes (PPROM).

Methods

A retrospective cohort study included pregnancies involving PPROM after diagnostic amniocentesis and cerclage placement. Cerclage was retained for more than 12 hours after PPROM in the study group (n = 18); the comparison group comprised women who underwent immediate cerclage removal after PPROM (n = 22). Analyses were performed using concentrations of interleukin (IL)-6, glucose, and white blood cells (WBCs) in the amniotic fluid to measure relationships with adverse outcomes.

Results

The latency period from PPROM to delivery was significantly shorter in the group that underwent immediate cerclage removal (P < 0.005). Latency periods of more than 48 hours (P < 0.001) and more than 7 days (P < 0.01), and chorioamnionitis (P < 0.05) were associated with cerclage retention. Neonatal outcomes were not significantly different between the study group and the comparison group. However, elevated IL-6 levels were associated with cumulative neonatal morbidity (P < 0.05). Low IL-6 (P < 0.001) and WBC (P < 0.05) levels were significantly associated with a latency period of more than 7 days.

Conclusion

Amniotic fluid levels of IL-6 and WBCs may be of clinical value for individualizing the management of patients with PPROM after cerclage.     

Elevated midtrimester α-fetoprotein and delivery markers of inflammation in a preterm population

Objective: Determine whether elevated second trimester maternal serum α-fetoprotein (AFP) is associated with clinical and histopathologic markers of inflammation at preterm delivery. Methods: 105 women <32 weeks’ gestation were included. AFP levels were dichotomized at 2.0 multiples of the median (MoM). Rates of neonatal morbidities, clinical chorioamnionitis, cord blood IL-6 level, and placental inflammatory findings were compared. Results: Thirteen (12.4%) had elevated AFP. Fewer women with AFP ≥2 MoM had histologic placental or membrane rupture site inflammation, funisitis, or placental culture positive for Mycoplasma and Ureaplasma species, compared to those with normal AFP. Neonatal death was increased in the elevated AFP group (23.1% vs. 2.27%, RR 10.6). Elevated AFP was associated with a nonsignificant increase in indicated birth (54% vs. 35%; p = 0.225). Virtually all inflammatory findings were confined to the spontaneous delivery group. Conclusion: Elevated midtrimester AFP conveyed significant risk of neonatal death, but was negatively associated with clinical or histopathologic inflammation in preterm infants.     

Relationship between the neonatal white blood cell count and histologic chorioamnionitis in preterm newborns

Objective: The aim was to examine the relationship between neonatal white blood cell (WBC) count and the diagnosis of histologic chorioamnionitis (HCA). Design: We measured WBC, a widely used marker of inflammation, to evaluate whether the values at birth were associated with HCA. Setting: NICU, Department of Pediatrics of Padua University, Padua, Italy. Subjects: WBC count was evaluated in 71 preterm neonates (<32 weeks of gestation) with HCA and in a control group without HCA on day 1, 3, and 6 after delivery. Logistic regression analysis and diagnostic accuracy analysis were used to assess the association between WBC counts and HCA. Main results: WBC levels were significantly higher in infants with HCA than in those without HCA (Median IQR, WBC (x10⁹/l): day 1, 13.2 (6.2–21.8) vs 8.1 (6–11.4), p < 0.001; day 3, 17.4 (11.4–26.9) vs 6.3 (5.2–8.3), p < 0.001; day 6, 18.4 (11.1–31) vs 6.5 (4.4–9), p < 0.0001). The neonatal WBC count on the third day of life was the most sensitive parameter associated with HCA (sensitivity: 0.80; specificity: 0.88). The cut-off value based on the ROC curve was 10 (x10⁹/l). Conclusions: WBC count in the third day of life is strongly associated with HCA.     

Predictive value of intra-amniotic and serum markers for inflammatory lesions of preterm placenta

Objective

To compare the relative predictive values of amniotic fluid (AF) matrix metalloproteinase-9 (MMP-9), interleukin-6 (IL-6), and serum C-reactive protein (CRP) for histologic chorioamnionitis and intra-amniotic infection in women with preterm labor or preterm premature rupture of membranes (PROM).

Study design

This retrospective cohort study included 99 consecutive women with preterm labor or preterm PROM (21–35 weeks’ gestation) who delivered within 72 h of transabdominal amniocentesis. The AF was cultured for aerobic and anaerobic bacteria and for genital mycoplasmas and was assayed for MMP-9 and IL-6 levels. Maternal serum CRP was measured immediately after amniocentesis. The placentas were examined histologically.

Main outcome measures

histologic chorioamnionitis and intra-amniotic infection.

Results

The prevalence of histologic chorioamnionitis and a positive AF culture was 44% (44/99) and 28% (28/99), respectively. In predicting intra-amniotic infection, AF MMP-9 had a significantly higher area under the curve (AUC: 0.94 [95% CI, 0.87–0.98]) than AF IL-6 (0.87 [95% CI, 0.78–0.84]; P < 0.05) and serum CRP (0.76 [95% CI, 0.66–0.84]; P < 0.001) and a higher sensitivity and specificity than serum CRP (P < 0.01, respectively). However, in predicting histologic chorioamnionitis, there were no significant differences in AUCs among the three tests (AF MMP-9: 0.78 [95% CI, 0.68–0.85]; AF IL-6: 0.76 [95% CI, 0.66–0.84]; serum CRP: 0.76 [95% CI, 0.66–0.84]). In a sub-analysis of 71 women without intra-amniotic infection, histologic chorioamnionitis was associated with an elevated serum CRP level (P < 0.05), but not with the level of AF IL-6 or MMP-9 (P = 0.232 and P = 0.402, respectively).

Conclusions

The AF MMP-9 has a better overall diagnostic performance than the AF IL-6 and maternal serum CRP in predicting intra-amniotic infection. However, the serum CRP level obtained up to 72 h before delivery appears to be an important marker for early identification of histologic chorioamnionitis in women without 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 extraplacental 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.     

Amniotic fluid soluble human leukocyte antigen-G in term and preterm parturition,and intra-amniotic infection/inflammation

Objective.?Circulating soluble human leukocyte antigen-G (sHLA-G) has been associated with pregnancy complications, and determination of sHLA-G concentrations in amniotic fluid (AF) has been reported in normal pregnancies. Our aim was to determine if the AF concentrations of sHLA-G change with advancing gestation, spontaneous labor at term, and in patients with spontaneous preterm labor (PTL) with intact membranes, as well as in those with preterm prelabor rupture of membranes (PROM), in the presence or absence of intra-amniotic infection/inflammation (IAI).

Study design.?This cross-sectional study included the following groups: (1) mid-trimester (n?=?55); (2) normal pregnancy at term with (n?=?50) and without (n?=?50) labor; (3) spontaneous PTL with intact membranes divided into: (a) PTL who delivered at term (n?=?153); (b) PTL who delivered preterm without IAI (n?=?108); and (c) PTL with IAI (n?=?84); and (4) preterm PROM with (n?=?46) and without (n?=?44) IAI. sHLA-G concentrations were determined by ELISA. Non-parametric statistics were used for analysis.

Results.?(1) Among patients with PTL, the median AF sHLA-G concentration was higher in patients with IAI than in those without IAI or women that delivered at term (p?<?0.001 for both comparisons); (2) Similarly, patients with preterm PROM and IAI had higher median AF sHLA-G concentrations than those without IAI (p?=?0.004); (3) Among patients with PTL and delivery, those with histologic chorioamnionitis and/or funisitis had a higher median AF sHLA-G concentration than those without histologic inflammation (p?<?0.001); and (4) The median AF sHLA-G concentration did not change with advancing gestational age.

Conclusions.?AF sHLA-G concentrations are elevated in preterm parturition associated to IAI as well as in histologic chorioamnionitis. We propose that sHLA-G may participate in the regulation of the host immune response against intra-amniotic infection.     

Elevated amniotic fluid ferritin levels are associated with inflammation-related pregnancy loss following mid-trimester amniocentesis

Objective: Occult infection accounts for up to 12% of pregnancy losses following genetic amniocentesis. Elevated serum and cervical fluid levels of ferritin, an acute-phase reactant, have been associated with spontaneous preterm delivery. We determined the association between amniotic fluid (AF) ferritin levels and post-amniocentesis pregnancy loss. Methods: We performed a case-control study involving 66 women with a non-anomalous fetus who had a spontaneous pregnancy loss within 30 days following genetic amniocentesis and 66 term controls matched for maternal age, gestational age, time of test and indication for amniocentesis. Amniotic fluid ferritin and interleukin-6 (IL-6) levels were measured using commercially available kits. Results: Mean (± SD) AF ferritin levels were similar between the cases (19.3 ± 21.4 ng/ml) and the controls (19.8 ± 22.7 ng/ml) (p = 0.9). Mean (± SD) AF IL-6 levels were significantly higher in the women with post-amniocentesis pregnancy loss (4.0 ± 13.1 ng/ml) than in controls (0.5 ± 0.7 ng/ml) (p = 0.04). A significant proportion (12.1%, 8/66) of the women with postamniocentesis pregnancy loss had elevated amniotic fluid IL-6 levels (> 3 SD, 2.5 ng/ml) indicating inflammation, as compared to none in the control group (p = 0.01). In this subgroup of women with pregnancy loss and elevated IL-6 levels, AF ferritin levels were significantly elevated (52.0 ± 45.5 ng/ml) compared to the level in women who had a term delivery (19.8 ± 22.7 ng/ml) (p = 0.002), and were strongly correlated with IL-6 levels among the cases (r = 0.67, p < 0.001). Conclusion: The strong correlation of AF ferritin with IL-6 levels, along with the high ferritin values in cases with high AF IL-6, indicates that ferritin is a marker of inflammation in asymptomatic women destined to have an early pregnancy loss.     

Good prognosis of cerclage in cases of cervical insufficiency when intra-amniotic inflammation/infection is ruled out

Objective: To determine if absence of sub-clinical intra-amniotic inflammation improves the prognosis of rescue cerclage in cases of bulging membranes.

Methods: Cohort study with all women with bulging membranes admitted into our hospital between 2009 and 2013. Patients underwent amniocentesis to quantify amniotic glucose, leukocytes, IL-6 and leukocyte esterase levels and for microbiological culture. All patients without intra-amniotic inflammation or sub-clinical chorioamnionitis were proposed a physical examination-indicated cervical cerclage. Those who did not accept were treated with bed rest.

Results: We enrolled 31 women. Median gestational age at diagnosis was 23?+?1 (21–25?+?4) weeks. Median interval until delivery was 12 (3–52.5) d. IL-6 had the highest diagnostic accuracy for good prognosis. Patients with IL6 <2.90?ng/ml were diagnosed later in pregnancy and presented a longer interval until delivery (89 versus 4?d), higher gestational age at delivery (35?+?1 versus 23?+?3 weeks) and a lower rate of prematurity (54.5% versus 100%) and perinatal mortality (0% versus 80%) than those with IL-6 ≥2.90?ng/ml. Rescue cerclage and low Il-6 were the best predictors of good outcome.

Conclusion: IL-6 levels in amniotic fluid may be of clinical value for individualizing the management of patients with bulging membranes for placement of rescue cerclage.     

An elevated amniotic fluid prostaglandin F2α concentration is associated with intra-amniotic inflammation/infection,and clinical and histologic chorioamnionitis,as well as impending preterm delivery in patients with preterm labor and intact membranes

Objective: To determine whether an elevated amniotic fluid concentration of prostaglandin F_2α (PGF_2α) is associated with intra-amniotic inflammation/infection and adverse pregnancy outcomes in patients with preterm labor and intact membranes.

Materials and methods: The retrospective cohort study included 132 patients who had singleton pregnancies with preterm labor (<?35 weeks of gestation) and intact membranes. Amniotic fluid was cultured for aerobic and anaerobic bacteria as well as for genital mycoplasmas. Intra-amniotic inflammation was defined by an elevated amniotic fluid matrix metalloproteinase-8 (MMP-8) concentration (>23?ng/mL). PGF_2α was measured with a sensitive and specific immunoassay. The amniotic fluid PGF_2α concentration was considered elevated when it was above the 95th percentile among pregnant women at 15–36 weeks of gestation who were not in labor (≥170?pg/mL).

Results: (1) The prevalence of an elevated amniotic fluid PGF_2α concentration was 40.2% (53/132) in patients with preterm labor and intact membranes; (2) patients with an elevated amniotic fluid PGF_2α concentration had a significantly higher rate of positive amniotic fluid culture [19% (10/53) versus 5% (4/79); p?=?0.019], intra-amniotic inflammation/infection [49% (26/53) versus 20% (16/79); p?=?0.001], spontaneous preterm delivery, clinical and histologic chorioamnionitis, and funisitis, as well as a higher median amniotic fluid MMP-8 concentration and amniotic fluid white blood cell count and a shorter amniocentesis-to-delivery interval than those without an elevated concentration of amniotic fluid PGF_2α (p?<?0.05 for each); and (3) an elevated amniotic fluid PGF_2α concentration was associated with a shorter amniocentesis-to-delivery interval after adjustment for the presence of intra-amniotic inflammation/infection [hazard ratio 2.1, 95% confidence interval (CI) 1.4–3.1; p?=?0.001].

Conclusion: The concentration of PGF_2α was elevated in the amniotic fluid of 40.2% of patients with preterm labor and intact membranes and is an independent risk factor for intra-amniotic inflammation/infection, impending preterm delivery, chorioamnionitis, and funisitis.     

Pregnancy outcomes after cerclage placement in nulliparous women with a short cervix on transvaginal ultrasonography

Objective: Little is known about pregnancy outcomes associated with a short cervix and cerclage placement in nulliparous women.

Methods: An electronic query of our ultrasound database was used to identify patients whose cervical length measured <?25?mm between 16–24 weeks of gestation. Any nulliparous women, with no prior pregnancy lasting beyond 13 weeks 6 d gestational age, were included in the analysis. The primary outcome was the interval of time from the diagnosis of a short cervix (<25?mm) to the time of delivery.

Results: Our query identified 70 patients for analysis. The interval of time from diagnosis of a short cervix to delivery was observed to be 85 d (12.1 weeks) in the cerclage group and 116 d (16.6 weeks) in the expectantly managed group (p?=?0.02). In those women receiving a cerclage, there was a statistically significant risk of spontaneous preterm birth <32 weeks gestational age (R.R. 6.7 [95% CI 1.45–30.6]).

Conclusions: The impact of a short cervix is largely unknown in patients with an uncomplicated obstetrical history. Our investigation would suggest that in this subset of patients, cerclage would not be beneficial in preventing preterm delivery.     

Fetal fibronectin,cervical length,and the risk of preterm birth in patients with an ultrasound or physical exam indicated cervical cerclage

Objective: The objective of this study is to estimate the risk of preterm birth in patients with an ultrasound or physical exam indicated cervical cerclage based on the results of fetal fibronectin (fFN) and cervical length (CL) screening.

Methods: Retrospective cohort of patients with a singleton pregnancy and an ultrasound or physical exam indicated Shirodkar cerclage placed by one maternal–fetal medicine practice from November 2005 to January 2015. Patients routinely underwent serial CL and fFN testing from 22 to 32 weeks. Based on ROC curve analysis, a short CL was defined as?≤15?mm. All fFN and CL results included are from after the cerclage placement.

Results: One hundred and four patients were included. Seventy eight (75%) patients had an ultrasound-indicated cerclage and 26 (25%) patients had a physical exam-indicated cerclage. A positive fFN was associate with preterm birth?<32 weeks (15.6% versus 4.2%, p?=?0.043), <35 weeks (37.5% versus 11.1%, p?=?0.002), <37 weeks (65.6% versus 20.8%, p?<?0.001), and earlier gestational ages at delivery (35.2?±?3.9 versus 37.4?±?2.9, p?=?0.001). A short CL was also associated with preterm birth?<35 weeks (50.0% versus 11.9%, p?<?0.01), preterm birth?<37 weeks (55.0% versus 29.8%, p?=?0.033), and earlier gestational ages at delivery (34.8?±?4.1 versus 37.2?±?3.0, p?=?0.004). The risk of preterm birth?<32, <35, and?<37 weeks increased significantly with the number of abnormal markers.

Conclusion: In patients with an ultrasound or physical exam indicated cerclage, a positive fFN and a short CL are both associated with preterm birth. The risk of preterm birth increases with the number of abnormal biomarkers.     

Amniotic fluid prostaglandin F2 increases even in sterile amniotic fluid and is an independent predictor of impending delivery in preterm premature rupture of membranes

Objective.?To determine whether amniotic fluid (AF) concentration of prostaglandins (PGs) increases in patients with intra-amniotic inflammation and/or proven AF infection in preterm PROM, and can predict impending delivery.

Methods.?AF PGF2a concentrations were determined by ELISA in 140 singleton pregnancies with preterm premature rupture of membranes (PROM) (≤35 weeks). AF was cultured for aerobic and anaerobic bacteria, and genital mycoplasmas. Intra-amniotic inflammation was defined as an elevated AF matrix metalloproteinase-8 concentration (>23 ng/ml).

Results.?(1) Patients with intra-amniotic inflammation and a negative AF culture had a significantly higher median AF PGF2a than those without intra-amniotic inflammation and with a negative culture (p < 0.001); (2) However, there was no difference in the median AF PGF2a between patients with intra-amniotic inflammation with a negative culture and those with culture-proven AF infection (p > 0.1); (3) Patients with an elevated AF PGF2a had a significantly shorter interval-to-delivery than those with a low AF PGF2a (≤170 pg/mL) (p < 0.001); (4) An elevated AF PGF2a (≤170 pg/mL) concentration was a significant predictor of the duration of pregnancy after adjusting for gestational age and AF inflammation/infection (p < 0.005).

Conclusions.?AF PGF2a (≥170 pg/mL) concentration increased in patients with intra-amniotic inflammation regardless of AF culture results. Moreover, an elevated AF PGF2a concentration was an independent predictor of impending delivery in preterm PROM.     

The Involvement of Human Amnion in Histologic Chorioamnionitis is an Indicator that a Fetal and an Intra-Amniotic Inflammatory Response is More Likely and Severe: Clinical Implications

ObjectiveAmnionitis (inflammation of the amnion) is the final stage of extra-placental chorioamniotic inflammation. We propose that patients with “amnionitis”, rather than “chorionitis” have a more advanced form of intra-uterine inflammation/infection and, thus, would have a more intense fetal and intra-amniotic inflammatory response than those without “amnionitis”.Study designThe relationship between the presence of amnionitis, and a fetal and an intra-amniotic inflammatory response was examined in 290 singleton preterm births (≤36 weeks) with histologic chorioamnionitis. The fetal inflammatory response was determined by plasma C-reactive protein (CRP) concentrations in umbilical cord and the presence of funisitis. The intra-amniotic inflammatory response was assessed by matrix metalloproteinase-8 (MMP-8) concentration and white blood cell (WBC) count in 156 amniotic fluid (AF) samples obtained within 5 days of birth. AF was cultured for aerobic and anaerobic bacteria and genital mycoplasmas. The CRP concentration was measured with a highly sensitive immunoassay.Results(1) Amnionitis was present in 43.1% of cases with histologic chorioamnionitis. (2) Patients with amnionitis had a significantly higher rate of funisitis and positive AF culture and a higher median umbilical cord plasma CRP, AF MMP-8 level and AF WBC count than those without amnionitis (p < 0.001 for each). (3) Among cases with amnionitis, the presence or absence of funisitis was not associated with significant differences in the median cord plasma CRP, AF MMP-8 level and AF WBC count. (4) However, the presence of amnionitis in cases with funisitis was associated with a higher median umbilical cord plasma CRP, AF MMP-8 level and AF WBC count than the absence of amnionitis in those with funisitis (p < 0.05 for each). (5) Multiple logistic regression analysis demonstrated that amnionitis was a better independent predictor of proven or suspected early-onset neonatal sepsis (odds ratio 3.8, 95% confidence interval (CI) 1.1–13.2, p < 0.05) than funisitis (odds ratio 1.8, 95% CI 0.5–6.1, not significant) after correction for the contribution of other potential confounding variables.ConclusionThe involvement of the amnion in the inflammatory process of the extraplacental membranes is associated with a more intense fetal and intra-amniotic inflammatory response than chorionitis alone. This observation has clinical implications because it allows staging of the severity of the inflammatory process and assessment of the likelihood of fetal involvement.     

Maternal serum concentrations of s-Endoglin and IL-6 in pregnancy complicated by preterm premature membrane rupture

Objective: This study aimed to investigate maternal serum concentrations of s-Endoglin and compare s-Endoglin with other inflammatory markers in prediction of time to delivery, in pregnancies complicated by preterm premature rupture of membranes (PPROM).

Materials and methods: Fifty five patients complicated by PPROM whose gestational age were between 2433 weeks and 44 matched healthy pregnant women were included in present study. Maternal concentrations of s-Endoglin concentrations were measured by an enzyme-linked immunosorbent assay (ELISA) and compared with maternal inflammatory markers including interleukin-6 (IL-6), white blood cell (WBC) count and serum C-reactive protein (CRP). The best variable for prediction of preterm birth was computed.

Results: Mean s-Endoglin levels in PPROM were lower than control groups (0.24?±?0.12?pg/ml and 0.69?±?0.25?pg/ml, respectively, p?<?0.01). Besides IL-6 (p?<?0.01), WBC (p?=?0.016) and CRP (p?=?0.010) levels were higher in PPROM group. In PPROM group, ROC analysis results of s-Endoglin for prediction of preterm delivery <48 h, <7 days, <32 weeks were not different (p?>?0.05). For predicting preterm birth before 48 h and 7 days, only IL-6 at cut off value >0.70 (pg/ml) and >0.55 (pg/ml) had area under curve (AUC); 0.871 (0.7750.965), p?<?0.01, AUC; 0.925 (0.8560.993), p?<?0.001, respectively.

Conclusion: s-Endoglin as an anti-angiogenic marker seemed to have a role in pathogenesis but results of present study showed that, unlike IL-6, it was unsatisfactory for estimating time to delivery in PPROM.     

Funisitis in term pregnancy is associated with microbial invasion of the amniotic cavity and intra-amniotic inflammation

Objective.?Funisitis is the histologic counterpart of the fetal inflammatory response syndrome, which is a multisystemic disorder associated with impending preterm delivery and adverse neonatal outcome. The purpose of this study was to examine the relationship between funisitis and the microbiologic status of amniotic fluid (AF) and AF white blood cell (WBC) count in patients at term.

Methods.?The relationship between the presence of funisitis, AF culture, and AF WBC count was examined in 832 consecutive patients who delivered a term neonate within 72 hours of amniocentesis. AF was cultured for aerobic and anaerobic bacteria, as well as for mycoplasmas. Funisitis was diagnosed in the presence of neutrophil infiltration into the umbilical vessel walls or Wharton's jelly. AF WBC count was analyzed in a hemocytometer chamber. Nonparametric statistics were used for data analysis.

Results.?Funisitis was present in 4% (30/832) of cases. A positive AF culture was more common in cases with funisitis than in those without funisitis (17% vs. 5%; p < 0.05). Patients with funisitis had a significantly higher median AF WBC count than those without funisitis (median >1000 cells/mm³ vs. median 2 cells/mm³; p < 0.001). The frequency of funisitis and of a positive AF culture was 1% in women without labor and with intact membranes and the frequencies and the median AF WBC count increased in the presence of labor or rupture of membranes.

Conclusion.?Funisitis is present in 4% of women at term and is associated with microbial invasion of the amniotic cavity (MIAC) and inflammation as reflected by increased AF WBC count.     

Sterile and microbial-associated intra-amniotic inflammation in preterm prelabor rupture of membranes

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 were Sneathia species and Ureaplasma 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.     

Outcomes after periviable ultrasound-indicated cerclage

Background: Cerclage placed for a sonographically short cervix has been shown to reduce the risk of preterm delivery in women with a history of prior preterm birth. While short cervix is traditionally placed before viability, the threshold gestational age at which viability is achieved continues to decrease, and, as a result, a larger subset of women may be ineligible to receive this potentially beneficial procedure.

Objective: To evaluate the association between obstetric outcomes and perioperative complications after placement of an ultrasound-indicated cerclage at periviability compared to placement in the previable period.

Methods: This retrospective cohort study of patients who underwent ultrasound-indicated cerclage evaluated obstetric outcomes and perioperative complications based on gestational age at cerclage placement. Ultrasound-indicated cerclage was considered to have been placed at periviability if placed at 22 to <24 weeks (exposed) and at previability if placed at 16 to <22 weeks gestational age (unexposed). The primary outcome was preterm delivery <36 weeks. Secondary outcomes included mean gestational age at delivery, preterm delivery <32 weeks, <28, and <24 weeks, preterm premature rupture of membranes (PPROM), chorioamnionitis, and perioperative complications. Adjusted analyses were performed to account for demographic and obstetric factors.

Results: Of the 426 patients included in the analysis, 94 (22%) had cerclage placed between ≥22 weeks to <24 weeks, while 332 (78%) had cerclage placed at <22 weeks. On univariate analysis, women who had a periviable cerclage placed were less likely to have a recurrent preterm delivery <36 weeks compared to women with previable cerclage placement (26.6 versus 38.3%, respectively, p?=?.04). The adjusted model did not demonstrate a significant difference in risk for preterm delivery <36 weeks associated with periviable versus previable cerclage (odds ratio 0.66, 95%CI 0.37–1.17). Secondary outcomes were similar between the previable and periviable groups, including mean gestational age at delivery (35.1 versus 36.2 weeks, respectively, p?=?.08) and preterm delivery before 32-week gestation (20.7 versus 13.8%, respectively, p?=?.17). Intraoperative and postoperative complications were rare and rates were similar between groups.

Conclusions: Obstetric outcomes between patients receiving periviable and previable cerclage are similar. Ultrasound-indicated cerclage placement is associated with a relatively low rate of complications. Given the evidence supporting benefit of cerclage for women with short ultrasound cervical length and prior preterm birth, our findings demonstrate that benefits of placement at ≥22 weeks to <24 weeks may outweigh risks.     

Maternal plasma interleukin-6, interleukin-1β and C-reactive protein as indicators of tocolysis failure and neonatal outcome after preterm delivery

Objective. To investigate whether maternal serum interleukin-6 (IL-6), interleukin-1β (IL-1β) and high sensitive C-reactive protein (CRP) could be used as markers of tocolysis failure and adverse neonatal outcome in pregnancies with preterm labor (PL).

Methods. Forty-seven maternal blood samples taken because of PL at admission and delivery were analyzed. Control samples were taken from 20 gravidas with normal pregnancies. Differences in interleukins and CRP levels with or without chorioamnionitis, connatal infection or periventricular leukomalacia (PVL) were analyzed. Cut-off values were estimated for prediction of tocolysis failure and adverse neonatal outcome.

Results. All three parameters were significantly higher in patients delivering prematurely than in patients delivering at term. All three parameters were significantly higher with than without histologic chorioamnionitis (p < 0.001), with than without connatal infection (p < 0.01), with than without PVL (p < 0.01 for IL-6 and IL-1β, p < 0.05 for CRP), and in pregnancies with preterm premature rupture of membranes (PPROM) delivered within 48 hours compared to those more prolonged (p < 0.01). Choosing 50.9 pg/mL of IL-6 and a CRP of 19.7 as cut-offs in maternal blood admission concentrations for neonatal PVL, resulted in sensitivity of 81% and specificity of 91% and sensitivity of 91% and specificity of 81%, respectively. At respective maternal blood admission cut-off levels of 27.8 pg/mL of IL-6 and 8.9 of CRP, both parameters were effective predictors of connatal infection.

Conclusions. Maternal blood IL-6 and CRP could become useful in predicting tocolysis failure and intrauterine treat for the fetus.     

The Frequency and Clinical Significance of Intra-Uterine Infection and Inflammation in Patients with Placenta Previa and Preterm Labor and Intact Membranes

ObjectiveHistologic placental and/or intra-amniotic inflammation is frequently documented during ascending intra-uterine infections in patients with preterm labor and intact membranes. Placenta previa can be a clinical situation that shows the successive schema of histologic placental and intra-amniotic inflammation during the process of ascending intra-uterine infections. However, a paucity of information exists about the frequency and clinical significance of intra-uterine infections and inflammation in patients with placenta previa and preterm labor and intact membranes. The purpose of this study was to examine this issue.Study designAmniocentesis was performed on 42 patients with placenta previa and preterm labor and intact membranes (gestational age < 37 weeks). Amniotic fluid (AF) was cultured for aerobic and anaerobic bacteria and genital mycoplasmas, and AF white blood cell (WBC) count and matrix metalloproteinase-8 (MMP-8) concentrations were determined. The diagnosis of intra-amniotic inflammation was made in patients with an elevated AF MMP-8 (≥23 ng/ml). Non-parametric statistics were used for analysis.Results1) Intra-amniotic inflammation was present in 16.7% (7/42), proven AF infection in 4.9% (2/41), and histologic chorioamnionitis in 19.0% (8/42) of patients with placenta previa and preterm labor; 2) Patients with intra-amniotic inflammation had significantly higher rates of a positive AF culture, histologic chorioamnionitis, funisitis, and a shorter interval-to-delivery than those without intra-amniotic inflammation (p < 0.05 for each); 3) Among patients with histologic chorioamnionitis, inflammation of the choriodecidua, which was exposed to the cervical canal, existed in all cases (8/8), but inflammation of the chorionic plate existed in 63% of patients (5/8); 4) Patients with inflammation of the chorionic plate had significantly higher median AF MMP-8 concentrations and WBC counts, and higher rates of intra-amniotic inflammation than those in whom inflammation was restricted to choriodecidua (p < 0.05 for each).ConclusionsPlacental inflammation was present in 19.0% and intra-amniotic inflammation was present in 16.7% of patients with placenta previa and preterm labor and intact membranes. The intra-amniotic inflammatory response was stronger when inflammation was present in the chorionic plate and choriodecidua, than when it was restricted to the choriodecidua only, which was exposed to the cervical canal in placenta previa.