Preterm Preterm Prelabor Rupture Of Membranes Research Articles

Safety of Monoclonal Antibodies as Treatment for Coronavirus Disease 2019 (COVID-19) During Pregnancy

OBJECTIVE: Pregnant patients are at increased risk of severe illness, in-hospital mortality, and preterm birth in the setting of coronavirus disease 2019 (COVID-19); however, they often are excluded from clinical trials that analyze improved therapeutics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Thus, there are relatively few available data that examine the safety of monoclonal antibodies (mAbs) in pregnant patients with COVID-19, which we aimed to explore in this systematic review. DATA SOURCES: We searched PubMed, Cochrane, EMBASE, and Google Scholar on September 30, 2022. Included studies encompassed English-language case reports with at least five participants, cross-sectional studies, case–control studies, cohort studies, retrospective or prospective chart reviews, and randomized controlled trials that enrolled pregnant women who received SARS-CoV-2–targeted mAbs. Studies were screened for eligibility using Covidence according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines and were subsequently evaluated for risk of bias with the JBI critical appraisal checklist. TABULATION, INTEGRATION, AND RESULTS: Initial search yielded 616 studies; 13 publications were ultimately eligible. Pregnant patients were treated with SARS-CoV-2–neutralizing mAbs casirivimab-imdevimab, bamlanivimab, or bamlanivimab-etesevimab. A total of 365 patients were treated with casirivimab-imdevimab, 13 were treated with bamlanivimab, and 11 were treated with bamlanivimab-etesevimab. There were no cases of maternal mortality. Eighteen of the 389 patients had adverse effects related to mAb administration—all resolved. Of the patients treated with casirivimab-imdevimab, there were 35 preterm deliveries, two fetal deaths, one neonatal death due to sepsis, five cases of preterm prelabor rupture of membranes (PROM), one case of PROM, and 24 neonatal intensive care unit (NICU) admissions. Of the patients treated with bamlanivimab, there was one case of preterm PROM and one preterm delivery. There were no NICU admissions in the bamlanivimab or bamlanivimab-etesevimab cohorts. CONCLUSION: Preliminary data suggest that neutralizing mAb treatment for COVID-19 in pregnant patients is safe. However, treatment-associated events support the importance of clinical trials to determine the statistical significance of maternal and fetal outcomes in pregnant patients treated with SARS-CoV-2–targeted mAbs.

Maternal Outcomes Following Active vs. Expectant Management of Previable Preterm Pre-Labor Rupture of Membranes: A Meta-Analysis.

The diagnosis of previable preterm pre-labor rupture of membranes (PROM) is known to be associated with poor outcomes for both the mother and the fetus. Following previable preterm PROM, patients are generally offered either active management through the termination of the pregnancy or expectant management to increase the chances of fetal survival. It is difficult to counsel patients because there is a lack of data directly comparing maternal outcomes following active vs. expectant management. Using the data in the current literature, the goal of the present meta-analysis was to determine if there were any differences in terms of maternal risks when active versus elective management was chosen. PubMed, Google Scholar, EMBASE, and Scopus were searched. We found four studies accounting for a total of 506 patients. The risk ratio (RR) of chorioamnionitis in active vs. expectant management was 0.30 (with a 95% confidence interval, CI, of 0.09-1.02). The heterogeneity of the study results was 81% (I2). A sub-analysis of two included studies revealed an RR of postpartum hemorrhage in active vs. expectant management of 0.75 (95% CI 0.27-2.07) and an RR of maternal sepsis of 0.23 (95% CI 0.04-1.28). The heterogeneity of the study results for this sub-analysis was 68% (I2) for postpartum hemorrhage and 0% (I2) for maternal sepsis. Overall, there was no statistically significant difference in the risk of chorioamnionitis, postpartum hemorrhage, or maternal sepsis when active management was chosen over expectant management in previable preterm PROM at <24 weeks. The scarcity and the high heterogeneity of the available data likely contributed to the lack of statistical significance and calls for further work directly comparing maternal outcomes following active vs. expectant management.

Outcomes in Twins Compared With Singletons Subsequent to Preterm Prelabor Rupture of Membranes.

To compare maternal and neonatal outcomes after preterm prelabor rupture of membranes (PROM) from 23 to 34 weeks of gestation in twin compared with singleton gestations. We conducted a secondary analysis of an obstetric cohort of 115,502 individuals and their singleton or twin neonates born in 25 hospitals nationwide (2008-2011). Those with preterm PROM from 23 0/7 through 33 6/7 weeks of gestation were included; neonates with major fetal anomalies were excluded. The coprimary outcomes for this analysis were composite maternal morbidity (chorioamnionitis, blood transfusion, postpartum endometritis, wound infection, sepsis, venous thromboembolism, intensive care unit admission, or death) and composite major neonatal morbidity (persistent pulmonary hypertension, intraventricular hemorrhage grade III or IV, seizures, hypoxic-ischemic encephalopathy, necrotizing enterocolitis stage II or III, bronchopulmonary dysplasia, stillbirth subsequent to admission, or neonatal death before discharge). Logistic regression was used to estimate unadjusted and adjusted odds ratios (ORs) with 95% CIs for twin compared with singleton gestations. Of 1,531 (1.3%) individuals who met eligibility criteria for this analysis, 218 (14.2%) had twin gestations. The median gestational age at preterm PROM was similar between those with twins and singletons (31.2 weeks [interquartile range 27.4-32.9] vs 30.6 weeks [interquartile range 26.9-32.7], P=.23); however, those with twin gestations had a shorter median latency period (2.0 days [interquartile range 1.0-5.0] vs 3.0 days [interquartile range 2.0-8.0], P<.001). After adjustment for potential confounders, odds of experiencing composite maternal morbidity (17.9% vs 19.3%, adjusted OR 0.97, 95% CI 0.66-1.42) or composite neonatal morbidity (20.4% vs 20.5%, OR 0.97, 95% CI 0.72-1.31) did not differ between groups. In a large, diverse cohort, the likelihood of composite maternal or neonatal morbidity per fetus after preterm PROM was similar for twin and singleton gestations.

Antibiotic Use Without Indication During Delivery Hospitalizations in the United States.

To analyze trends in unindicated antibiotic use during vaginal delivery hospitalization. This study used an administrative database to analyze antibiotic use during delivery hospitalizations from January 2006 to March 2015. Women were classified by mode of delivery and whether they had an evidence-based indication for antibiotics. Indications for antibiotics included preterm prelabor rupture of membranes (PROM), cesarean delivery, group B streptococcus (GBS) colonization, chorioamnionitis, endometritis, urinary tract infections, and other infections. The Cochran-Armitage test was used to assess trends of antibiotic administration. Unadjusted and adjusted analyses for antibiotic receipt including demographic, hospital, and obstetric and medical factors were performed with unadjusted and adjusted risk ratios (RRs) with 95% CIs as measures of association. A total of 5,536,756 delivery hospitalizations, including 2,872,286 vaginal deliveries without an indication for antibiotics, were analyzed. The most common indication for antibiotics was cesarean delivery (33.6% of the entire cohort), followed by GBS colonization (15.8%), chorioamnionitis (1.7%), preterm PROM (1.6%), endometritis (1.2%), urinary tract infections (0.6%), and other infections (total less than 0.5%). The proportion of women receiving unindicated antibiotics decreased 44.4%, from 38.1% in 2006 to 21.2% in 2015. Adjusted risk for receipt of unindicated antibiotics was lower in 2015 vs 2006 (adjusted RR 0.56, 95% CI 0.55-0.57). Use of antibiotics during vaginal delivery hospitalizations without an indication for antibiotic use declined significantly based on an analysis of a large administrative data set.

Risk of preterm birth after the excisional surgery for cervical lesions: a propensity-score matching study in Japan

Introduction There is a paucity of data on the risk of preterm birth subcategorized by gestational age in pregnancies after the pre-pregnancy excisional treatment for cervical lesions. In addition, little is known about the effect of prophylactic cerclage on the risk of preterm birth. The aim of this study was to investigate the risk of preterm birth stratified by gestational period and its reduction by the prophylactic cerclage in women with prior excisional surgery. Materials and methods We retrospectively analyzed a cohort of singleton pregnancies in the Japan Perinatal Registry Network Database (2013–2014, n = 307,001). Cases included pregnancies after the surgery (i.e. conization and loop electrosurgical excision procedure). Controls comprised the propensity-score matched pregnancies without pre-pregnancy surgery. The main outcome was the occurrence of preterm birth. The effect of prophylactic cervical cerclage on the risk of preterm birth after the excisional surgery was also examined using cases. Results In the propensity-score matched population (cases, n = 1389; controls, n = 1389), cases exhibited a higher risk of preterm birth and preterm prelabor rupture of membranes (PROM), compared with controls (preterm birth: 25.3 versus 10.6%; preterm PROM: 14.0 versus 3.5%: both p < .0001). Odds ratios (OR; 95% confidence interval [CI]) for preterm birth at 22–27 weeks, 28–31 weeks, 32–33 weeks, and 34–36 weeks were 3.4 [1.8–6.5], 4.6 [2.7–7.7], 2.2 [1.4–3.5], and 2.1 [1.6–2.7], respectively. The association was stronger for preterm PROM at earlier gestational age (22–27 weeks, 28–31 weeks, 32–33 weeks, and 34–36 weeks: 5.2 [2.3–11.8], 7.1 [3.4–15.0], 3.8 [1.7–8.3], and 3.9 [1.8–4.6], respectively). In cases, 171 underwent the prophylactic cervical cerclage. The occurrence of preterm birth and preterm PROM was comparable between those with and without the cerclage (28.7 versus 24.2, and 12.9 versus 13.3%, respectively). Conclusions Pre-pregnancy excisional cervical surgery was associated with the increased risk of preterm birth, especially before 32 weeks of gestation. The prophylactic cerclage did not reduce the risk of preterm birth.

Preterm Prelabor Rupture of Membranes: Outcomes with Expectant Management until 34 versus 35 Weeks

To evaluate outcomes with expectant management of preterm prelabor rupture of membranes (PROM) until 35 weeks versus immediate delivery at ≥34 weeks. This was a multicenter retrospective cohort study of singletons with preterm PROM at >20 weeks from 2011 through 2017. Groups were defined as expectant management until 35 weeks versus immediate delivery at ≥34 weeks. Primary outcome was composite neonatal morbidity: need for respiratory support, culture positive neonatal sepsis, or antibiotic administration for >72 hours. Univariate and general estimating equation models were used with p < 0.05 considered significant. A total of 280 mother-infant dyads were included. There was no difference in composite neonatal outcome in pregnancies managed with expectant management compared with immediate delivery (43.4 vs. 37.5%; p = 0.32). Those with expectant management had shorter length of neonatal intensive care unit (NICU) admission but higher rates of neonatal antibiotics for > 72 hours, endometritis, and histological chorioamnionitis. There were no cases of fetal demise, neonatal death, or maternal sepsis, and only three cases of neonatal sepsis. There is no difference in composite neonatal morbidity in pregnancies with preterm PROM managed with expectant management until 35 weeks as compared with immediate delivery at 34 weeks. Expectant management is associated with a decreased length of NICU admission but increased short-term infectious morbidity.

Long-term Trends in Singleton Preterm Birth in South Australia From 1986 to 2014.

To describe long-term trends in the prevalence of preterm birth and rates of preterm birth in singleton pregnancies complicated by hypertensive disorders of pregnancy, small for gestational age (SGA), and preterm prelabor rupture of membranes (PROM) in South Australia. We conducted a retrospective population study including all singleton live births in the state of South Australia from 1986 to 2014. Long-term trends for preterm birth, hypertensive disorders of pregnancy, SGA, preterm PROM as well as stillbirth were assessed using joinpoint regression analyses. Trends in maternal age, body mass index (BMI), ethnic diversity, parity, and smoking over time were also assessed. From 1986 to 2014, with a total of 539,234 singleton births, the overall preterm birth rates increased from 5.1% to 7.1% (P<.001) and for iatrogenic preterm birth increased from 1.6% to 3.2% (P<.001). The incidence of hypertensive disorders of pregnancy decreased from 8.7% to 7.2%. Among pregnancies complicated by hypertensive disorders of pregnancy, the proportion of preterm birth increased (10.4-17.5%, P<.001). The incidence of SGA decreased from 11.1% to 8.0%. Among pregnancies complicated by SGA, the proportion of preterm birth increased (2.9-5.4%, P<.001). The incidence of preterm PROM increased from 1.4% to 2.2%. Among pregnancies complicated by preterm PROM, the proportion of preterm birth remained stable. Preterm stillbirth rates declined (4.23-2.32%, P<.001). Maternal age, BMI, and ethnic diversity have all increased since 1986, whereas maternal smoking has decreased. In South Australia, the preterm birth rate among singletons increased from 1986 to 2014 by 40%, with iatrogenic preterm birth being responsible for 80% of this increase. Incidence of hypertensive disorders of pregnancy and SGA declined. Among pregnancies complicated by hypertensive disorders of pregnancy and SGA, the proportions of preterm birth increased, indicating earlier interventions in these women. The diagnosis of preterm PROM increased from 1% to 2%, and greater than 80% of preterm PROM was associated with preterm birth after 1990. Increasing iatrogenic delivery may be attributable, in part, to changing maternal phenotype and to altered clinicians' behavior. However, improvements in fetal surveillance, particularly ultrasonography, and advanced neonatal care may underpin perinatal clinical decision-making and the likelihood of iatrogenic birth.

Pregnancy Outcomes in Women With a History of Previable, Preterm Prelabor Rupture of Membranes.

To characterize subsequent pregnancy outcomes among women with a history of previable, preterm prelabor rupture of membranes (PROM) and assess factors associated with recurrent preterm birth. This was a retrospective cohort study of women cared for with a history of one or more singleton pregnancy complicated by preterm PROM at less than 24 weeks of gestation between 2002 and 2013 who were cared for in two tertiary care health systems by a single group of maternal-fetal medicine specialists. Women were identified using International Classification of Diseases, 9th Revision codes and obstetric databases. Those with iatrogenic preterm PROM and those whose index preterm PROM at less than 24 weeks of gestation was preceded by advanced cervical dilation were excluded. All women with one or more pregnancies reaching the second trimester after an index previable, preterm PROM pregnancy were included. The primary outcome was recurrent preterm birth at less than 37 weeks of gestation. Data were analyzed by χ, Fisher exact, t test, Wilcoxon rank-sum, and logistic regression. Two hundred ninety-four women had one or more pregnancies complicated by previable, preterm PROM. One hundred eight of 294 (37%) had one or more subsequent pregnancies in our health care systems and 50 of 108 (46%) had two or more. In the pregnancy immediately after the index delivery, the risk of prematurity was high: 50 (46%) delivered at less than 37 weeks of gestation, 31 (30%) at less than 34 weeks of gestation, 25 (23%) at less than 28 weeks of gestation, and 18 (17%) before 24 weeks of gestation. Fewer than half (n=49 [45%]) of women received preterm birth prophylaxis (progesterone or cerclage) in a subsequent pregnancy; rates of recurrent preterm birth were similar among women who received preterm birth prophylaxis compared with those who did not. In regression models, the only factor significantly associated with recurrent preterm birth at less than 37 weeks of gestation was a history of preterm birth preceding previable, preterm PROM delivery (adjusted odds ratio 3.23, 95% confidence interval 1.32-7.93). Patients with a history of previable, preterm PROM are at high risk of recurrent preterm birth.

WITHDRAWN: Vaginal fluid IL-6 concentrations as a point-of-care test is of value in women with preterm PROM

The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.ajog.2016.07.001 . The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal

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.

Endoglin in Amniotic Fluid as a Risk Factor for the Subsequent Development of Bronchopulmonary Dysplasia

Cross-talk between inflammation and angiogenesis pathways has been recently reported. The objectives of this study were to: (i) examine whether amniotic fluid (AF) concentrations of soluble endoglin (sEng), a protein with anti-angiogenic properties, change during pregnancy, parturition, or intra-amniotic infection and/or inflammation (IAI); (ii) determine whether an increase in sEng in the AF of patients with preterm labor (PTL) and preterm prelabor rupture of membranes (PROM) is associated with adverse neonatal outcomes; and (iii) investigate potential sources of sEng in AF. A cross-sectional study was conducted to include patients in the following groups: (i) mid-trimester (n=20); (ii) PTL with term delivery (n=95); (iii) PTL leading to preterm delivery with (n=40) and without IAI (n=46); (iv) preterm PROM with (n=37) and without IAI (n=37); (v) term in labor (n=48) and not in labor (n=44). AF concentrations of sEng were determined by enzyme-linked immunosorbent assay. Chorioamniotic membranes, umbilical cord blood, and AF macrophages were examined for the expression of endoglin. (i) Patients with IAI had a higher median AF concentration of sEng than those without IAI (P=0.02 for PTL and 0.06 for preterm PROM); (ii) AF concentrations of sEng in the 3rd and 4th quartiles were associated with IAI (OR 2.5 and 7.9, respectively); (iii) an AF sEng concentration ≥779.5pg/mL was associated with bronchopulmonary dysplasia (BPD) (OR 7.9); (iv) endoglin was co-localized with CD14+ macrophages in AF pellets of patients with IAI by immunofluorescence and flow cytometry; and (v) the concentration of sEng in the supernatant was significantly increased after the treatment of macrophages with endotoxin or TNF-α. Soluble endoglin participates in the host response against IAI. Activated macrophages may be a source of sEng concentrations in the AF of patients with IAI. An increase of sEng in the AF is associated with BPD and adverse neonatal outcomes.

Damage-associated molecular patterns (DAMPs) in preterm labor with intact membranes and preterm PROM: a study of the alarmin HMGB1

Objective. Preterm parturition is a syndrome caused by multiple etiologies. Although intra-amniotic infection is causally linked with intrauterine inflammation and the onset of preterm labor, other patients have preterm labor in the absence of demonstrable infection. It is now clear that inflammation may be elicited by activation of the Damage-Associated Molecular Patterns (DAMPs), which include pathogen-associated molecular patterns (PAMPs) as well as “alarmins” (endogenous molecules that signal tissue and cellular damage). A prototypic alarmin is high-mobility group box 1 (HMGB1) protein, capable of inducing inflammation and tissue repair when it reaches the extracellular environment. HMGB1 is a late mediator of sepsis, and blockade of HMGB1 activity reduces mortality in an animal model of endotoxemia, even if administered late during the course of the disorder. The objectives of this study were to: (1) determine whether intra-amniotic infection/inflammation (IAI) is associated with changes in amniotic fluid concentrations of HMGB1; and (2) localize immunoreactivity of HMGB1 in the fetal membranes and umbilical cord of patients with chorioamnionitis. Methods. Amniotic fluid samples were collected from the following groups: (1) preterm labor with intact membranes (PTL) with (n = 42) and without IAI (n = 84); and (2) preterm prelabor rupture of membranes (PROM) with (n = 38) and without IAI (n = 35). IAI was defined as either a positive amniotic fluid culture or amniotic fluid concentration of interleukin-6 (IL-6) ≥2.6 ng/mL. HMGB1 concentrations in amniotic fluid were determined by ELISA. Immunofluorescence staining for HMGB1 was performed in the fetal membranes and umbilical cord of pregnancies with acute chorioamnionitis. Results. (1) Amniotic fluid HMGB1 concentrations were higher in patients with IAI than in those without IAI in both the PTL and preterm PROM groups (PTL IAI: median 3.1 ng/mL vs. without IAI; median 0.98 ng/mL; p < 0.001; and preterm PROM with IAI median 7.3 ng/mL vs. without IAI median 2.6 ng/mL; p = 0.002); (2) patients with preterm PROM without IAI had a higher median amniotic fluid HMGB1 concentration than those with PTL and intact membranes without IAI (p < 0.001); and (3) HMGB1 was immunolocalized to amnion epithelial cells and stromal cells in the Wharton’s jelly (prominent in the nuclei and cytoplasm). Myofibroblasts and macrophages of the chorioamniotic connective tissue layer and infiltrating neutrophils showed diffuse cytoplasmic HMGB1 immunoreactivity. Conclusions. (1) intra-amniotic infection/inflammation is associated with elevated amniotic fluid HMGB1 concentrations regardless of membrane status; (2) preterm PROM was associated with a higher amniotic fluid HMGB1 concentration than PTL with intact membranes, suggesting that rupture of membranes is associated with an elevation of alarmins; (3) immunoreactive HMGB1 was localized to amnion epithelial cells, Wharton’s jelly and cells involved in the innate immune response; and (4) we propose that HMGB1 released from stress or injured cells into amniotic fluid may be responsible, in part, for intra-amniotic inflammation due to non-microbial insults.

Evidence in support of a role for anti-angiogenic factors in preterm prelabor rupture of membranes

Objective. Vaginal bleeding, placental abruption, and defective placentation are frequently observed in patients with preterm prelabor rupture of membranes (PROM). Recently, a role of vascular endothelial growth factor (VEGF) and its receptor, VEGF receptor (VEGFR)- 1 has been implicated in the mechanisms of membrane rupture. The purpose of this study was to determine whether the soluble form of VEGFR-1 and -2 concentrations in amniotic fluid (AF) change with preterm PROM, intra-amniotic infection/inflammation (IAI), or parturition.Study design. This cross-sectional study included 544 patients in the following groups: (1) midtrimester (MT) (n = 48); (2) preterm labor (PTL) leading to term delivery (n = 143); (3) PTL resulting in preterm delivery with (n = 72) and without IAI (n = 100); (4) preterm PROM with (n = 46) and without IAI (n = 42); (5) term in labor (n = 48); and (6) term not in labor (n = 45). The concentrations of sVEGFR-1 and sVEGFR-2 were determined by ELISA. Non-parametric statistics and logistic regression analysis were applied.Results. (1) Preterm PROM (with and without IAI) had a lower median AF concentration of sVEGFR-1 than patients with PTL who delivered at term (p < 0.001 for each comparison); (2) A decrease in AFsVEGFR-1 concentrations per each quartile was associated with PROM after adjusting for confounders (OR 1.8; 95%CI 1.4–2.3); (3) IAI, regardless of the membrane status, was not associated with a change in the median AF concentrations of sVEGFR-1 and sVEGFR-2 (p > 0.05 for each comparison); and (4) Spontaneous term and PTL did not change the median sVEGFR-1 and sVEGFR-2 concentrations (p > 0.05 for each comparison).Conclusion. (1) This is the first evidence that preterm PROM is associated with a lower AF concentration of sVEGFR-1 than patients with PTL intact membranes. These findings cannot be attributed to gestational age, labor, or IAI; and (2) AF concentrations of sVEGFR-2 did not change with preterm PROM, IAI, or labor at term and preterm.

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.

Pentraxin 3 in amniotic fluid: a novel association with intra-amniotic infection and inflammation

Pentraxin 3 (PTX3) is a soluble pattern recognition receptor (PRR) that has an important role in immunoregulation and vascular integrity. The aim of this study was to determine if PTX3 is present in amniotic fluid (AF) and whether its concentration changes with gestational age (GA), in the presence of preterm or term labor, and in cases of intra-amniotic infection/inflammation (IAI) associated with spontaneous preterm labor (PTL) or preterm prelabor rupture of membranes (PROM). This cross-sectional study included the following groups: 1) mid-trimester (n=45); 2) uncomplicated pregnancies at term with (n=48) and without (n=40) spontaneous labor; 3) women with PTL and intact membranes who: a) delivered at term (n=44); b) delivered preterm without IAI (n=40); or c) delivered preterm with IAI (n=62); 4) women with preterm PROM with (n=63) and without (n=36) IAI. PTX3 concentration in AF was determined by ELISA. Non-parametric statistics were used for analyses. 1) Among women with PTL and intact membranes, the median AF PTX3 concentration was significantly higher in women with IAI than in those without IAI (7.95 ng/mL vs. 0.38 ng/mL; P<0.001) and than in those who delivered at term (0.55 ng/mL; P<0.001); 2) women with preterm PROM and IAI had a higher median AF PTX3 concentration than those without IAI (9.12 ng/mL vs. 0.76 ng/mL; P<0.001); 3) the median AF PTX3 concentration did not change with GA (mid-trimester: 0.79 ng/mL vs. term not in labor: 0.58 ng/mL; P=0.09); and 4) labor at term was not associated with a significant change of AF PTX 3 concentration (in labor: 0.54 ng/mL vs. not in labor: 0.58 ng/mL, P=0.9). PTX3 is a physiologic constituent of the AF, and its median concentration is elevated in the presence of IAI, suggesting that PTX3 may play a role in the innate immune response against IAI.

Fragment Bb in amniotic fluid: evidence for complement activation by the alternative pathway in women with intra-amniotic infection/inflammation

Objective. Fragment Bb is an activator of the alternative pathway of the complement system. Recently, increased first trimester maternal plasma concentrations of this fragment were reported in patients destined to have a spontaneous preterm delivery before 34 weeks of gestation. The aim of this study was to determine whether the amniotic fluid (AF) concentrations of fragment Bb change with gestational age, spontaneous labor (term and preterm) and in the presence of intra-amniotic infection/inflammation (IAI).Study design. This cross-sectional study included patients in the following groups: (1) mid-trimester (n = 64); (2) term in spontaneous labor (n = 70); (3) term not in labor (n = 43); (4) spontaneous preterm labor (PTL) who delivered at term (n = 76); (5) PTL without IAI who delivered preterm (n = 73); (6) PTL with IAI (n = 76); (7) preterm prelabor rupture of membranes (PROM) without IAI (n = 71); and (8) preterm PROM with IAI (n = 71). Fragment Bb concentration in AF was determined by an enzyme-linked immunoassay. Non-parametric statistics were used for analyses.Results. (1) Fragment Bb was detected in all AF samples (n = 544); (2) The median AF concentration of fragment Bb in patients at term not in labor was significantly higher than that of those in the mid-trimester [2.42 μg/ml, interquartile range (IQR) 1.78–3.22 vs. 1.64 μg/ml, IQR 1.06–3.49; p < 0.001]; (3) Among patients with PTL, those with IAI had a higher median AF fragment Bb concentration than that of woman without IAI, who delivered preterm (4.82 μg/ml, IQR 3.32–6.08 vs. 3.67 μg/ml, IQR 2.35–4.57; p < 0.001) and than that of women with an episode of PTL, who delivered at term (3.21 μg/ml, IQR 2.39–4.16; p < 0.001); (4) Similarly, among patients with preterm PROM, the median AF fragment Bb concentration was higher in individuals with IAI than in those without IAI (4.24 μg/ml, IQR 2.58–5.79 vs. 2.79 μg/ml, IQR 2.09–3.89; p < 0.001). (5) Among patients at term, the median AF fragment Bb concentration did not differ between women with spontaneous labor and those without labor (term in labor: 2.47 μg/ml, IQR 1.86–3.22; p = 0.97).Conclusions. (1) Fragment Bb, an activator of the alternative complement pathway, is a physiologic constituent of the AF, and its concentration increases with advancing gestational age; (2) AF concentrations of fragment Bb are higher in pregnancies complicated with IAI; and (3) labor at term is not associated with changes in the AF concentrations of fragment Bb. These findings suggest a role for fragment Bb in the host immune response against IAI.

Amniotic fluid heat shock protein 70 concentration in histologic chorioamnionitis, term and preterm parturition

Objective. Heat shock protein (HSP) 70, a conserved member of the stress protein family, is produced in almost all cell types in response to a wide range of stressful stimuli, and its production has a survival value. Evidence suggests that extracellular HSP70 is involved in the activation of the innate and adaptive immune response. Furthermore, increased mRNA expression of HSP70 has been observed in human fetal membranes following endotoxin stimulation. This study was conducted to determine the changes in amniotic fluid HSP70 concentrations during pregnancy, term and preterm parturition, intra-amniotic infection (IAI), and histologic chorioamnionitis.Study design. A cross-sectional study was conducted in 376 pregnant women in the following groups: (1) women with a normal pregnancy who were classified into the following categories: (a) women in the mid-trimester (14–18 weeks) who underwent amniocentesis for genetic indications and delivered normal infants at term (n=72); (b) women at term not in labor (n = 23); and (c) those at term in labor (n = 48). (2) Women with spontaneous preterm labor and intact membranes who were subdivided into the following categories: (a) preterm labor who delivered at term without IAI (n = 42); (b) preterm labor who delivered preterm without IAI (n = 57); and (c) preterm labor and delivery with IAI (n = 30). (3) Women with preterm prelabor rupture of membranes (PROM) with (n = 50) and without (n = 54) IAI. Among patients with preterm labor with intact membranes and preterm PROM who delivered within 72 hours of amniocentesis, placenta, umbilical cord, and chorioamniotic membranes were collected and assessed for the presence or absence of acute inflammatory lesions in the extraplacental membranes (histologic chorioamnionitis) and/or umbilical cords (funisitis). HSP70 concentrations in amniotic fluid were determined using a sensitive and specific immunoassay. Non-parametric statistics were used for analysis. A p value of <0.05 was considered statistically significant.Results. Immunoreactive HSP70 was detected in 88% (332/376) of amniotic fluid samples. The median amniotic fluid HSP70 concentration was significantly higher in women at term without labor than in those in the mid-trimester (term no labor: median 34.9 ng/mL, range 0–78.1 ng/mL vs. mid-trimester; median 6.6 ng/mL, range 0–20.8 ng/mL; p<0.001). Among patients with spontaneous preterm labor and preterm PROM, those with IAI had a significantly higher median amniotic fluid HSP70 concentration than those without IAI (preterm labor with IAI: median 82.9 ng/mL, range 0–500 ng/mL vs. preterm labor without IAI: median 41.7 ng/mL, range 0–244 ng/mL; p = 0.001; preterm PROM with IAI: median 86.5 ng/mL, range 0–428 ng/mL vs. preterm PROM without IAI: median 55.9 ng/mL, range 14.9–299.9 ng/mL; p = 0.007). There was no significant difference in the median amniotic fluid HSP70 concentration between patients with preterm labor who delivered preterm without IAI and those who delivered at term (p = 0.6). However, among patients with preterm labor without IAI, there was an inverse relationship between amniotic fluid concentration of HSP70 and the amniocentesis-to-spontaneous delivery interval (Spearman's Rho = −0.26; p = 0.02). Patients with histologic chorioamnionitis/funisitis had a significantly higher median amniotic fluid HSP70 concentration than those without inflammation (inflammation: median 108.7 ng/mL, range 0–500 ng/mL vs. without inflammation: median 67.9 ng/mL, range 7.1–299.9 ng/mL; p = 0.02). Women at term in labor had a median amniotic fluid concentration of HSP70 significantly higher than those not in labor (term in labor: median 60.7 ng/mL, range 0–359.9 ng/mL vs. term not in labor: median 34.9 ng/mL, range 0–78.1 ng/mL; p = 0.02).Conclusions. Intra-amniotic infection, histologic chorioamnionitis, and term parturition are associated with elevated amniotic fluid HSP70 concentrations. HSP70 plays a role in the host defense mechanism by activating the innate arm of the immune response in women with intrauterine infection. The mechanisms of preterm and term parturition in humans may involve extracellular HSP70.

Clinical significance of the presence of amniotic fluid ‘sludge’ in asymptomatic patients at high risk for spontaneous preterm delivery

To determine the clinical significance of the presence of amniotic fluid (AF) 'sludge' among asymptomatic patients at high risk for spontaneous preterm delivery. This retrospective case-control study included 281 patients with (n = 66) or without (n = 215) AF 'sludge', who underwent transvaginal ultrasound examination between 13 and 29 completed weeks of gestation. Patients with threatened preterm labor, multiple gestation, fetal anomalies, placenta previa or uterine contractions were excluded. The prevalence of AF 'sludge' in the study population was 23.5% (66/281). The rates of spontaneous preterm delivery at < 28 weeks, < 32 weeks, < 35 weeks and < 37 weeks of gestation were 14.7% (29/197), 21.3% (46/216), 28.7% (62/216) and 42.1% (91/216), respectively. Patients with 'sludge' had: (1) a higher rate of spontaneous preterm delivery at < 28 weeks (46.5% (20/43) vs. 5.8% (9/154); P < 0.001), < 32 weeks (55.6% (25/45) vs. 12.3% (21/171); P < 0.001) and < 35 weeks (62.2% (28/45) vs. 19.9% (34/171); P < 0.001); (2) a higher frequency of clinical chorioamnionitis (15.2% (10/66) vs. 5.1% (11/215); P = 0.007), histologic chorioamnionitis (61.5% (40/65) vs. 28% (54/193); P < 0.001) and funisitis (32.3% (21/65) vs. 19.2% (37/193); P = 0.03); (3) a higher frequency of preterm prelabor rupture of membranes (PROM) (39.4% (26/66) vs. 13.5% (29/215); P < 0.001), lower gestational age at preterm PROM (median 24.7 (interquartile range (IQR), 22.3-28.1) weeks vs. 32.3 (IQR, 27.7-34.8) weeks; P < 0.001); and (4) shorter median ultrasound-to-delivery interval ('sludge' positive 127 days (95% CI, 120-134 days) vs. 'sludge' negative 161 days (95% CI, 153-169 days); P < 0.001) and ultrasound-to-preterm PROM interval ('sludge' positive 23 days (95% CI, 7-39 days) vs. 'sludge' negative 57 days (95% CI, 38-77 days); P = 0.003) than those without 'sludge'. AF 'sludge' was an independent explanatory variable for the occurrence of spontaneous preterm delivery at < 28 weeks, < 32 weeks and < 35 weeks, preterm PROM, microbial invasion of the amniotic cavity (MIAC) and histologic chorioamnionitis. Moreover, the combination of a cervical length < 25 mm and 'sludge' conferred an odds ratio of 14.8 and 9.9 for spontaneous preterm delivery at < 28 weeks and < 32 weeks, respectively. AF 'sludge' is an independent risk factor for spontaneous preterm delivery, preterm PROM, MIAC and histologic chorioamnionitis in asymptomatic patients at high risk for spontaneous preterm delivery. Furthermore, the combination of 'sludge' and a short cervix confers a higher risk for spontaneous preterm delivery at < 28 weeks and < 32 weeks than a short cervix alone.

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

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

Repeated Courses of Steroids in Preterm Membrane Rupture Do Not Increase the Risk of Histologic Chorioamnionitis

Antenatal administration of steroids (betamethasone 12 mg i.m. twice q 24 hr) enhances fetal lung maturation and reduces neonatal morbidity in preterm prelabor rupture of membranes (PROM). However, the risks of repeated administration of steroids 7 days after the initial course are unknown. We evaluated the prevalence of histologic evidence of chorioamnionitis in patients receiving single versus multiple courses of steroids for fetal lung maturation. We performed a retrospective analysis of consecutive cases of preterm PROM at or = 2 courses of steroids (n = 89). Placental pathology examination was performed after delivery, and histologic evidence of acute placental inflammation was determined and scored semiquantitatively on a scale of 0-4, as previously described. Potential confounding variables considered were: presence of oligohydramnios (vertical pocket of amniotic fluid < or = 1 cm at ultrasound), onset of labor prior to delivery, gestational age at delivery, and mode of delivery. The three groups were comparable for gestational age at membrane rupture and at delivery, rate of oligohydramnios, labor prior to delivery, and mode of delivery. Administration of multiple courses of steroids was associated with a decrease in the rate of clinical chorioamnionitis (p < 0.0001) and severity of histologic acute placental inflammation (mean +/- SD total score of acute inflammation: 10.7 +/- 7.2 vs. 7.3 +/- 6.0 vs. 6.9 +/- 6.0, p = 0.005) compared with the groups receiving no steroids or administration of a single course of steroids. In preterm PROM at < 32 weeks, repeated administration of courses of steroids is not associated with an increase in the prevalence of clinical or histologic evidence of infectious outcome. These findings may reflect a greater likelihood for noninfected patients to remain quiescent and thus receive repeated courses of steroids.