Immunolocalization of the Inducible Nitric Oxide Synthase Isoform in Human Fetal Membranes

PROBLEM: Nitric oxide (NO) synthesized by fetal membranes may protect the fetus from maternal infection or immune challenge or have a tocolytic effect on myometrium. The sites of synthesis and enzymes responsible for NO production in human fetal membranes remain unidentified. METHOD OF STUDY: Fetal membranes were obtained from four groups of patients: term (>37 weeks gestation) or preterm (<37 weeks gestation), both either in labor or not in labor. Frozen sections of membrane rolls were immunostained for inducible (iNOS) and endothelial (eNOS) nitric oxide synthase isoforms and the monocyte/macrophage marker CD14. RESULTS: Positive iNOS immunostaining was found in fibroblasts of amnionic and chorionic mesenchyme and in decidual macrophages identified by CD14 from all four groups of tissues. No iNOS immunostaining was seen in amnion epithelium or chorion trophoblast. Very intense iNOS staining was seen with evidence of monocyte/macrophage invasion of membranes. eNOS immunostaining was only found in decidual vascular endothelium. CONCLUSIONS: Constitutive expression of iNOS in decidual macrophages and fetal membrane fibroblasts may form an immune barrier against maternal insult. In chorioamnionitis, macrophage recruitment and NO expression may be part of the maternal immune response.     

以羊水中粒细胞集落刺激因子预测绒毛膜羊膜炎的价值

目的：通过检测分娩时羊水中GCSF和IL-6的含量及其与病理诊断为绒毛膜羊膜炎（CAM）的关系，研究测定羊水中G-CSF和IL-6的含量用以预测CAM的价值。方法：将研究对象按是否胎膜早破分为两组，均排除产科并发症及内外科合并症。两组产妇于分娩时抽取羊水5ml,用ELISA法检测羊水中G-CSF和IL-6的含量，同时两组产妇均于产后留取胎膜，用HE染色法检测是否存在CAM。结果：胎膜早破（PROM）组与对照组在年龄、孕周间差异无显著性的条件下，PROM组羊水中G-CSF和IL-6的含量高于对照组，差异有显著性，并且随着破膜时间延长而增高，各组间差异有显著性；CAM组羊水中G-CSF和IL-6的含量高于非CAM组，并且随着病理级别的增加，羊水中G-CSF和IL-6的的含量增加，其水平高低和胎盘炎症的组织学分级有明显的线性关系，组间差异有显著性；G-CSF与IL-6相比有较高的敏感性和特异性。结论：羊水中C-CSF、IL-6可作为CAM的早期诊断指标，且G-CSF优于IL-6。羊水中G-CSF、IL-6可作为反映绒毛膜羊膜炎严重程度的指标。     

宫颈环扎术并发症

宫颈环扎术是治疗宫颈机能不全的唯一有效方法,其并发症发生率低,相关报道少,严重并发症罕见。最常见的并发症包括胎膜早破、绒毛膜羊膜炎、子宫内膜炎、围手术期出血、宫颈裂伤、环扎线或环扎带移位等,少见的并发症有膀胱宫颈瘘、输尿管宫颈瘘等,经阴道环扎的并发症较经腹环扎多。并发症的发生率因宫颈环扎的时机及适应证的不同而异。并发症常随孕周的增加及宫颈的扩张而增多,当胎膜破裂或宫颈扩张时行环扎术会增加并发症的发生风险。故应严格掌握适应证与禁忌证,选择适合的手术时机。已证明宫颈环扎的穿刺点和环扎带的位置直接影响妊娠结局,环扎带越接近宫颈内口效果越好。宫颈环扎后一般要限制体力活动,适当卧床休息,若子宫的敏感性增高给予孕酮和保胎药物,有感染病史及感染迹象者给予抗生素,重视阴道感染的筛查与治疗,密切监测母胎情况,关注宫颈环扎可能出现的并发症。开腹或腹腔镜环扎需剖宫产分娩,如有产兆,应即刻施术,避免发生宫颈裂伤或子宫破裂。     

Chorioamnionitis following vaccination in the Vaccine Adverse Event Reporting System

BackgroundIn October 2012, the Advisory Committee on Immunization Practices (ACIP) recommended a dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) during each pregnancy, irrespective of the woman's prior history of receiving Tdap. A retrospective cohort study to assess the safety of Tdap vaccination in pregnant women in two Vaccine Safety Datalink (VSD) sites during 2010–2012 found a small but statistically significant increased risk of chorioamnionitis.ObjectiveWe conducted a review of the VAERS database to describe reports of chorioamnionitis following receipt of any vaccines.MethodsWe searched the VAERS database for reports of chorioamnionitis after any vaccine in the United States during the period from July 1, 1990 through February 2, 2014.ResultsVAERS received 31 reports of chorioamnionitis out of 3389 pregnancy reports in 24 years. The three most common vaccines in these reports were 2009 H1N1 inactivated influenza, quadrivalent human papillomavirus (HPV4), and Tdap vaccines in 32%, 29% and 26% of reports, respectively. Fifty-eight percent of reports had at least one reported risk factor for chorioamnionitis. Chorioamnionitis was identified in 3 reports of spontaneous abortions and 6 stillbirths, 6 reports of preterm birth (two of whom died) and 16 reports of term birth; maternal outcomes included two reports of postpartum hemorrhage and one report of maternal admission to the intensive care unit. No maternal deaths were reported.ConclusionChorioamnionitis was found to be uncommonly reported, representing 1% of pregnancy reports to VAERS. A majority of reports had at least one risk factor for chorioamnionitis.     

血清β-hCG与CRP水平在预测胎膜早破宫内感染及预后的应用比较

目的 探讨血清β-绒毛膜促性腺激素(β-hCG)和C-反应蛋白(CRP)水平,在预测胎膜早破宫内感染和预后的应用比较.方法 入选2009年3月-2011年5月在医院妇产科孕足月住院发生胎膜早破的孕妇146例,产前抽取静脉血5 ml,用免疫分析法分别检测血清β-hCG和CRP,产后留取胎膜组织和胎盘组织,检查是否存在组织绒毛膜炎,将146例胎膜早破孕妇分为感染组与非感染组,比较两组血清β-hCG和CRP,以评价β-hCG、CRP在预测胎膜早破宫内感染和预后中的临床价值.结果 146例胎膜早破孕妇中,血清β-hCG阳性者47例,发生感染33例,感染率为70.2％,阴性者99例,发生感染19例,感染率为19.2％ ;CRP阳性者63例,发生感染41例,感染率为65.1％；阴性者83例,发生感染11例,感染率为13.3％,差异均有统计学意义(P＜0.05),血清β-hCG预测胎膜早破感染敏感度为63.5％,特异度为85.1％,二者与CRP检查差异无统计学意义,146例胎膜早破的孕妇分娩顺利,血清β-hCG和CRP阳性者预后较阴性者差,抗菌药物使用时间长,剂量大,住院时间延长,但是血清β-hCG和CRP在评价预后无差异.结论 血清β-hCG和CRP均能较好地预测胎膜早破孕妇是否发生感染和评价预后,二者之间没有差异,临床上结合血清β-hCG和CRP能够更迅速、更准确地诊断胎膜早破并发感染,并能更好地评价预后.     

Neonatal Morbidities Associated with Histologic Chorioamnionitis Defined Based on the Site and Extent of Inflammation in Very Low Birth Weight Infants

Conflicting results on the influences of histologic chorioamnionitis (HC) on neonatal morbidities might be partly originated from using different definition of HC. The aim of this study was to determine the relationship between HC and neonatal morbidities using definition of HC that reflects the site and extent of inflammation. This was a retrospective cohort study of 261 very low birth weight (VLBW) infants admitted at a tertiary academic center. Based on the site of inflammation, HC was categorized: any HC; amnionitis; funisitis; amnionitis+funisitis. The extent of inflammation in each site was reflected by sub-defining high grade (HG). The incidences of morbidities in infants with and without HC were compared. The bronchopulmonary dysplasia (BPD) rate was significantly higher in infants with amnionitis and the severe retinopathy of prematurity (ROP) rate was significantly higher in infants with any HC and funisitis. After adjustment for both gestational age and birth weight, the respiratory distress syndrome (RDS) rate was significantly lower in infants with all categories of HC except for HG amnionitis and HG funisitis, which are not associated with lower RDS rate. HG amnionitis was significantly associated with increased BPD rate but the association of HC with severe ROP disappeared. In conclusion, HC is significantly associated with decreased RDS and HG amnionitis with increased BPD while lacking association with other neonatal morbidities in VLBW infants. The association with HC and neonatal morbidities differs by the site and extent of chorioamnionitis.

Graphical Abstract

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Sensorineural hearing loss in very low birth weight infants with histological chorioamnionitis

Objective: Histological chorioamnionitis (HCAM) has been associated with inflammatory diseases of preterm infants. Recently we have observed that it increased the risk of speech delay and hearing loss. So the aim of this study was to evaluate the relationship between sensorineural hearing loss (SNHL) of VLBW infants and HCAM.

Methods: We performed an observational study on VLBW infants admitted to the NICU of Padua. Each patient with HCAM was matched with one control without HCAM. All infants underwent hearing screening before discharge by means of automated transient–evoked otoacustic emissions and automated auditory brainstem responses, which were repeated at 3 and 6 months of age with tympanometry measurement. Incidence of SNHL at 6 months of age was compared in the 2 groups and risk factors for hearing loss were studied.

Results: Two of 77 (2.6%) newborns with HCAM e 6/73 (8.2%) without it presented SNHL at 6 months of corrected age (p?=?0.16). Multivariable logistic regression analysis identified surgical ligation of patent ductus arteriosus (PDA) as independent predictors of SNHL (OR: 5.75, 95% CI 1.34–24.84, p?=?0.02), whereas the effect of HCAM on SNHL was only near to statistical significance level.

Conclusions: Surgical ligation of PDA is associated with an increased risk of SNHL in VLBW infants, regardless of HCAM.     

Tdap vaccination during pregnancy and risk of chorioamnionitis and related infant outcomes

IntroductionAn increased risk of chorioamnionitis in people receiving tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine during pregnancy has been reported. The importance of this association is unclear as additional study has not demonstrated increased adverse infant outcomes associated with Tdap vaccination in pregnancy.MethodsWe conducted a retrospective observational cohort study of pregnant people ages 15–49 years with singleton pregnancies ending in live birth who were members of 8 Vaccine Safety Datalink (VSD) sites during October 2016–September 2018. We used a time-dependent covariate Cox model with stabilized inverse probability weights applied to evaluate associations between Tdap vaccination during pregnancy and chorioamnionitis and preterm birth outcomes. We used Poisson regression with robust variance with stabilized inverse probability weights applied to evaluate the association of Tdap vaccination with adverse infant outcomes. We performed medical record reviews on a random sample of patients with ICD-10-CM-diagnosed chorioamnionitis to determine positive predictive values (PPV) of coded chorioamnionitisfor “probable clinical chorioamnionitis,” “possible clinical chorioamnionitis,” or “histologic chorioamnionitis.”ResultsWe included 118,211 pregnant people; 103,258 (87%) received Tdap vaccine during pregnancy; 8098 (7%) were diagnosed with chorioamnionitis. The adjusted hazard ratio for chorioamnionitis in the Tdap vaccine-exposed group compared to unexposed was 0.96 (95% CI 0.90–1.03). There was no association between Tdap vaccine and preterm birth or adverse infant outcomes associated with chorioamnionitis. Chart reviews were performed for 528 pregnant people with chorioamnionitis. The PPV for clinical (probable or possible clinical chorioamnionitis) was 48% and 59% for histologic chorioamnionitis. The PPV for the combined outcome of clinical or histologic chorioamnionitis was 81%.Conclusions and relevanceTdap vaccine exposure during pregnancy was not associated with chorioamnionitis, preterm birth, or adverse infant outcomes. ICD-10 codes for chorioamnionitis lack specificity for clinical chorioamnionitis and should be a recognized limitation when interpreting results.     

Umbilical cord prostaglandins in term and preterm parturition

Objective: Prostaglandins (PGs) are considered the universal mediators of parturition. Amniotic fluid PGE₂ and PGF_2α concentrations increase before the onset of spontaneous labor at term, as well as during labor. This study was conducted to determine if the concentrations of umbilical cord PGE₂ and PGF₂α change with advancing gestational age, spontaneous labor at term, and preterm labor (with and without funisitis).

Methods: Umbilical cord (UC) tissue samples were obtained from women (N?=?158) with singleton pregnancies in the following groups: (1) term deliveries without labor (TNL; n?=?20); (2) term deliveries with labor (TIL; n?=?20); (3) spontaneous preterm deliveries (sPTD) with (n?=?20) and without acute funisitis (n?=?20); and (4) preeclampsia without labor (n?=?78). The concentrations of PGs were determined in different locations of the UC. PGE₂ and PGF_2α were measured by specific immunoassays. Non-parametric statistics were used for analysis.

Results: (1) In spontaneous preterm deliveries, the median UC PGE₂ concentration was higher in cases with funisitis than in those without funisitis (233.7?pg/µg versus 87.4?pg/µg of total protein, p?=?0.001); (2) the median UC PGE₂ concentration in sPTD with funisitis was also higher than that obtained from samples who had undergone labor at term (233.7?pg/µg versus 116.1?pg/µg of total protein, p?=?0.03); (3) the UC PGE₂ and PGF_2α concentration increased as a function of advancing gestational age before 36 weeks (PGE₂: ρ?=?0.59, p?<?0.001; PGF_2α: ρ?=?0.39, p?=?0.01), but not after 36 weeks (PGE₂: ρ?=??0.1, p?=?0.5; PGF_2α: ρ?=??0.2, p?=?0.2); (4) the median UC concentrations of PGE₂ and PGF_2α at term was similar in samples obtained from women with and without labor (PGE₂: TNL 133.7?pg/µg versus TIL 116.1?pg/µg of total protein, p?=?0.9; PGF_2α: TNL 8.4?pg/µg versus TIL 8.1?pg/µg of total protein, p?=?0.7); and (5) there was no correlation between UC PG concentration and gestational age at term pregnancy (PGE₂: ρ?=?0.01, p?=?0.9; PGF_2α: ρ?=?0.07, p?=?0.7).

Conclusions: (1) PGE₂ concentrations in the UC are higher in the presence of acute funisitis than in the absence of this lesion; (2) spontaneous labor at term was not associated with a change in the UC concentration of PGE₂ and PGF_2α; and (3) the UC concentrations of PGE₂ and PGF_2α increased as a function of gestational age. We propose that UC PGs act as inflammatory mediators generated in the context of fetal systemic inflammation.