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Perinatal Infections With Ureaplasma
Abstract
Ureaplasma species are increasingly recognized as relevant pathogens in prenatal, perinatal and postnatal morbidity. They are commonly found as commensals on the mucous membranes of the lower urogenital tract of pregnant women, but when ascending, they can cause bacterial vaginosis, chorioamnionitis, premature birth and postnatal morbidities such as bronchopulmonary dysplasia, and early-onset neonatal sepsis and meningitis. The detection of Ureaplasma species is challenging and is not covered by routine diagnostics, and current empiric antibiotic treatment in neonates suspected of infection is not directed against Ureaplasma species. The aim of this review is to discuss the pathophysiology of Ureaplasma infections, the clinical consequences and the current difficulties in diagnosis and treatment by providing an overview of the current literature.
... In these cases, U. parvum is the most common bacterium found in the amniotic cavity [1,3]. In the neonate, these microorganisms may cause bronchopulmonary dysplasia, necrotizing enterocolitis, premature retinopathy or brain lesions, among other clinical manifestations [1,2,8,9]. Although Ureaplasma spp. ...
... They are fastidious microorganisms that require special culture methods because of their growth requirements [2]. Molecular techniques offer advantages over other methods, such a higher diagnostic sensitivity, the capacity to distinguish between species and quantify results [9]. Betalactam antibiotics are ineffective due to the lack of a cell wall [2,3,9]. ...
... Molecular techniques offer advantages over other methods, such a higher diagnostic sensitivity, the capacity to distinguish between species and quantify results [9]. Betalactam antibiotics are ineffective due to the lack of a cell wall [2,3,9]. There are limited, effective, non-teratogenic therapies available; being macrolides the most widely used family of antibiotics, especially azithromycin and clarithromycin [2,3]. ...
Objectives
Ureaplasma species are the most frequently isolated microorganisms in cases of spontaneous preterm labor, premature rupture of the membranes, or chorioamnionitis.
Case presentation
A woman at 28 ⁺⁶ weeks of gestation with no apparent history of interest presented at the hospital with contractions. Upon suspicion of chorioamnionitis, the patient was admitted for a low segment transverse cesarean section, which was completed without any complications. The patient was discharged at 7 days. The newborn remained stable and showed no clinical signs of infection. However, on suspicion of chorioamnionitis, empirical treatment with intravenous ampicillin (2 g every 6 h) and gentamicin (5 mg/kg once daily) was initiated. Samples of pharyngeal/tonsillar, ear, and anal/rectal exudates were collected. At 24 h, all samples were positive for Ureaplasma parvum . Empirical treatment was suspended, and treatment with intravenous azithromycin was initiated (12 mg once daily). Endocervical and placental exudates were also positive for U. parvum . Fifty-two days after birth, the newborn was discharged.
Conclusions
The relationship between Ureaplasma spp. colonization and perinatal disease seem to be clear. However, the high frequency of vaginal Ureaplasma spp . colonization and high rates of term labor among pregnant women with this colonization make further studies necessary.
... Pese a ser colonizadores habituales del tracto genital, las especies de Ureaplasma son los microorganismos más frecuentemente relacionados con casos de parto prematuro espontáneo, rotura prematura de membranas o corioamnionitis [1,2,5,7], siendo U. parvum la especie que invade con mayor frecuencia la cavidad amniótica [1,3]. En el neonato pueden causar displasia broncopulmonar, enterocolitis necrosante, retinopatía prematura o lesiones cerebrales, entre otros cuadros clínicos [1,2,8,9]. Ureaplasma spp. posee varios factores de virulencia, pero ninguno de ellos ha podido relacionarse directamente como causa de parto prematuro [3]. ...
... Además, se trata de microorganismos fastidiosos que requieren medios de cultivo complejos para satisfacer sus requerimientos nutricionales [2]. Por todo ello, las técnicas de diagnóstico molecular ofrecen ventajas en el diagnóstico, como una mayor sensibilidad y la capacidad de obtener una identificación a nivel de especie, incluso la posibilidad de cuantificar el resultado [9]. La ausencia de pared celular hace que los antibióticos betalactámicos resulten ineficaces [2,3,9]. ...
... Por todo ello, las técnicas de diagnóstico molecular ofrecen ventajas en el diagnóstico, como una mayor sensibilidad y la capacidad de obtener una identificación a nivel de especie, incluso la posibilidad de cuantificar el resultado [9]. La ausencia de pared celular hace que los antibióticos betalactámicos resulten ineficaces [2,3,9]. Las opciones terapéuticas válidas y no teratógenas son limitadas, siendo los macrólidos la familia de antibióticos más utilizados, sobre todo azitromicina y claritromicina [2,3]. ...
Resumen
Objetivos
Las especies de Ureaplasma son los microorganismos más frecuentemente relacionados con casos de parto prematuro espontáneo, rotura prematura de membranas o corioamnionitis.
Caso clínico
Gestante de 28 + 6 semanas, sin antecedentes personales de interés, que acude al hospital por contracciones. Ante la sospecha clínica de corioamnionitis ingresa para cesárea segmentaria transversa, transcurriendo sin nada reseñable y siendo dada de alta a los siete días del ingreso. El neonato permanece estable y sin datos clínicos de infección. No obstante, ante la sospecha clínica de corioamnionitis se pauta tratamiento empírico con ampicilina (2 g/6 h) y gentamicina (5 mg/kg/24 h) intravenosas y se toman muestras de exudados faríngeo/amigdalar, ótico y anal/rectal. A las 24 horas se detecta en todas las muestras Ureaplasma parvum , suspendiéndose el tratamiento empírico e iniciando azitromicina intravenosa (12 mg/24 h). También se detecta U. parvum en muestra de exudado endocervical y de placenta. Tras 52 días de ingreso el lactante es dado de alta.
Conclusiones
Aunque parece clara la relación entre la colonización por estos microorganismos y el desarrollo de enfermedad perinatal, el elevado porcentaje de colonización vaginal existente y el hecho de que la mayoría de embarazadas colonizadas den a luz a término, sin ningún tipo de complicación, hacen necesarios más estudios.
... The most dangerous species for the offspring are Mycoplasma hominis (MH), Ureaplama ureatylicum (UU), and Ureaplasma parvum (UP). Ureaplasma species are being increasingly recognized as pathogens raising prenatal, perinatal and postnatal morbidity [346]. UU is part of the lower urogenital tract flora, but in occasions ascends and cause bacterial vaginosis, chorioamnionitis increasing the adverse outcomes of pregnancy such as preterm birth [346]. ...
... Ureaplasma species are being increasingly recognized as pathogens raising prenatal, perinatal and postnatal morbidity [346]. UU is part of the lower urogenital tract flora, but in occasions ascends and cause bacterial vaginosis, chorioamnionitis increasing the adverse outcomes of pregnancy such as preterm birth [346]. Several reports agree that UU leads to infection of the chorioamnion which associates with premature spontaneous labor and delivery [347][348][349]. ...
... Several reports agree that UU leads to infection of the chorioamnion which associates with premature spontaneous labor and delivery [347][348][349]. It plays an important role in perinatal and postnatal morbidities increasing bronchopulmonary dysplasia, neonatal sepsis and meningitis [346]. Though reports in the pathogenesis of bronchopulmonary dysplasia in the offspring were initially controversial, most of the evidence is consistent with a role of UU in the pathogenesis of this disease [350][351][352]. ...
The molecular evolution of life on earth along with changing environmental, conditions has rendered mankind susceptible to endemic and pandemic emerging infectious diseases. The effects of certain systemic viral and bacterial infections on morbidity and mortality are considered as examples of recent emerging infections. Here we will focus on three examples of infections that are important in pregnancy and early childhood: SARS-CoV-2 virus, Zika virus, and Mycoplasma species. The basic structural characteristics of these infectious agents will be examined, along with their general pathogenic mechanisms. Coronavirus infections, such as caused by the SARS-CoV-2 virus, likely evolved from zoonotic bat viruses to infect humans and cause a pandemic that has been the biggest challenge for humanity since the Spanish Flu pandemic of the early 20th century. In contrast, Zika Virus infections represent an expanding infectious threat in the context of global climate change. The relationship of these infections to pregnancy, the vertical transmission and neurological sequels make these viruses highly relevant to the topics of this special issue. Finally, mycoplasmal infections have been present before mankind evolved, but they were rarely identified as human pathogens until recently, and they are now recognized as important coinfections that are able to modify the course and prognosis of various infectious diseases and other chronic illnesses. The infectious processes caused by these intracellular microorganisms are examined as well as some general aspects of their pathogeneses, clinical presentations, and diagnoses. We will finally consider examples of treatments that have been used to reduce morbidity and mortality of these infections and discuss briefly the current status of vaccines, in particular, against the SARS-CoV-2 virus. It is important to understand some of the basic features of these emerging infectious diseases and the pathogens involved in order to better appreciate the contributions of this special issue on how infectious diseases can affect human pregnancy, fetuses and neonates.
... The most dangerous species for the offspring are Mycoplasma hominis (MH), Ureaplama ureatylicum (UU), and Ureaplasma parvum (UP). Ureaplasma species are being increasingly recognized as pathogens raising prenatal, perinatal and postnatal morbidity [346]. UU is part of the lower urogenital tract flora, but in occasions ascends and cause bacterial vaginosis, chorioamnionitis increasing the adverse outcomes of pregnancy such as preterm birth [346]. ...
... Ureaplasma species are being increasingly recognized as pathogens raising prenatal, perinatal and postnatal morbidity [346]. UU is part of the lower urogenital tract flora, but in occasions ascends and cause bacterial vaginosis, chorioamnionitis increasing the adverse outcomes of pregnancy such as preterm birth [346]. Several reports agree that UU leads to infection of the chorioamnion which associates with premature spontaneous labor and delivery [347][348][349]. ...
... Several reports agree that UU leads to infection of the chorioamnion which associates with premature spontaneous labor and delivery [347][348][349]. It plays an important role in perinatal and postnatal morbidities increasing bronchopulmonary dysplasia, neonatal sepsis and meningitis [346]. Though reports in the pathogenesis of bronchopulmonary dysplasia in the offspring were initially controversial, most of the evidence is consistent with a role of UU in the pathogenesis of this disease [350][351][352]. ...
Murine B16 melanoma sublines have been cloned or selected in vivo for preference of bloodborne metastatic colonization of lung, ovary, or brain. These sublines show differing metastatic properties and cell surface alterations that correlate with a preference for metastatic colonization sites. When the sensitivities of these selected sublines to certain drugs (beta-all-trans retinoic acid or 1,3-bis (2-chlorethyl)-1-nitrosourea (BCNU) were examined, the in vivo-selected sublines were more resistant to growth inhibition in vitro by cytostatic (retinoic acid) or cytotoxic (BCNU) drugs than was the parental B16 line.
... In the context of perinatal medicine, ascending Ureaplasma infections are relevant triggers of chorioamnionitis, which itself is one of the main risk factors for preterm birth. 1 Of the two known Ureaplasma species, Ureaplasma parvum and Ureaplasma urealyticum (Uu), U. parvum is more frequently detected in cases of chorioamnionitis, preterm birth, and neonatal CNS infections. 2 Neonatal colonization results in increased morbidity, particularly due to the development of congenital pneumonia, septicemia, and meningitis, as well as increased overall mortality. 3 Respiratory colonization with Uu in extremely low birth weight infants (ELBWI) increases the risk of developing bronchopulmonary dysplasia (BPD). ...
Ureaplasma urealyticum (Uu) has rarely been described as a cause of ventriculitis in preterm infants. We report a preterm infant in whom Uu was detected in the tracheal secretion. Concurrent intraventricular hemorrhage III° with posthemorrhagic hydrocephalus occurred, necessitating the bilateral insertion of ventriculostomy access devices for treatment. Persisting high cerebrospinal fluid (CSF) protein and pleocytosis in the otherwise clinically unremarkable neonate subsequently led to the targeted detection of Uu in the CSF. Normalization of CSF parameters occurred only after prolonged intravenous and oral macrolide therapy.
... It has been postulated that chorioamnionitis can potentially influence the development and maturation of the neonatal immune system and that in utero exposure to an inflammatory state such as chorioamnionitis, even in the absence of infection, may "prime" the developing immune system, resulting in a more activated immunophenotype, potentially increasing the susceptibility of the infant to later childhood diseases, altering their response to vaccination, or contributing to the development of immunopathological disorders [17]. It has been shown that the offspring of mothers who have chorioamnionitis during labor are at higher risk for short-term perinatal infectious morbidity like sepsis and meningitis [18][19][20]. However, to the best of our knowledge, we found no previous studies evaluating whether these children also suffer long-term childhood infectious morbidity. ...
Background: Chorioamnionitis during labor exposes the fetus to an intrauterine state that may alter the future immune response and may expose the offspring to future susceptibility to infectious disease. We evaluated the long-term pediatric infectious morbidity of children born at term to mothers who have chorioamnionitis during labor. Methods: This was a population-based cohort analysis including only term singleton deliveries at a regional tertiary hospital between the years 1991 and 2021. Offspring to mothers with and without a diagnosis of chorioamnionitis during labor were compared. Offspring hospitalizations up to the age of 18 years involving infectious morbidity were evaluated using the Kaplan–Meier survival curve and a Cox regression model to control possible confounders. Results: A total of 331,598 deliveries were included, 988 (0.3%) of which were of mothers diagnosed with chorioamnionitis during labor. All infectious morbidity rates included in the analysis were comparable between groups. The Kaplan–Meier survival curves were similar for both groups (log-rank = 0.881) and the multivariable analysis ascertained that chorioamnionitis during labor was not a risk factor for offspring’s long-term infectious morbidity (HR 0.929, 95%CI 0.818–1.054, p = 0.254). Conclusions: In our cohort, term chorioamnionitis during labor was not associated with a higher risk of pediatric hospitalization due to infections. The infectious/inflammatory state during labor did not expose nor increase the susceptibility of the term offspring to future infectious morbidity.
... U. urealyticum is becoming an increasingly recognized pathogen in perinatal infection [17]. In sheep studies, the multiple banded antigen, the proposed virulence factor of U. urealyticum, has been associated with placental inflammation [18]. ...
Objective
To identify bacteria in umbilical cord tissue and investigate the association with placental inflammation and neonatal sepsis risk score.
Study design
Retrospective cohort study from 2017–2019. RNA was extracted from umbilical cord tissue and NanoString nCounter used to identify seven bacteria genera. Sepsis risk score was calculated using the Kaiser sepsis calculator. Placental histopathology was abstracted from medical records.
Results
Detection of bacterial RNA in the umbilical cord (n = 96/287) was associated with high-stage maternal and fetal acute placental inflammation (maternal 35.4% vs 22.5%, p = 0.03 and fetal 34.4% vs 19.4%, p < 0.01) and maternal vascular malperfusion (36.5% vs 23.0%, p = 0.02). Detection of Ureaplasma spp. was also associated with increased sepsis risk score (1.5/1000 [0.6, 8.6] vs 0.9/1000 [0.2, 2.9], p = 0.04).
Conclusion
Umbilical cord bacterial pathogens are linked to fetal and maternal placental inflammation and maternal vascular malperfusion during gestation and associated with increased sepsis risk score in the neonate.
... Tenericutes and Mollicutes are primarily associated with infections in pregnant women and newborns. Several studies have shown that mycoplasma infections can cause puerperal sepsis (35), and in newborns, these infections are linked to an increased risk of bronchopulmonary dysplasia, early-onset neonatal sepsis, and meningitis (36,37). In contrast, Lentisphaerae (phylum), Lentisphaeria (class), and Victivallales (order) are relatively under-studied bacterial groups. ...
Background
There is a growing body of evidence that suggests a connection between the composition of gut microbiota and sepsis. However, more research is needed to better understand the causal relationship between the two. To gain a deeper insight into the association between gut microbiota, C-reactive protein (CRP), and sepsis, we conducted several Mendelian randomization (MR) analyses.
Methods
In this study, publicly available genome-wide association study (GWAS) summary statistics were examined to determine the correlation between gut microbiota and sepsis, including various sepsis subgroups (such as under 75, 28-day death, Critical Care Units (ICU), 28-day death in ICU). Initially, two-sample and reverse Mendelian randomization (MR) analyses were conducted to identify causality between gut microbiota and sepsis. Subsequently, multivariable and two-step MR analyses revealed that the relationship between microbiota and sepsis was mediated by CRP. The robustness of the findings was confirmed through several sensitivity analyses.
Findings
In our study, we revealed positive correlations between 24 taxa and different sepsis outcomes, while 30 taxa demonstrated negative correlations with sepsis outcomes. Following the correction for multiple testing, we found that the Phylum Lentisphaerae (OR: 0.932, p = 2.64E-03), class Lentisphaeria, and order Victivallales (OR: 0.927, p = 1.42E-03) displayed a negative relationship with sepsis risk. In contrast, Phylum Tenericutes and class Mollicutes (OR: 1.274, p = 2.89E-03) were positively related to sepsis risk and death within 28 days. It is notable that Phylum Tenericutes and class Mollicutes (OR: 1.108, p = 1.72E-03) also indicated a positive relationship with sepsis risk in individuals under 75. From our analysis, it was shown that C-reactive protein (CRP) mediated 32.16% of the causal pathway from Phylum Tenericutes and class Mollicutes to sepsis for individuals under 75. Additionally, CRP was found to mediate 31.53% of the effect of the genus Gordonibacter on sepsis. Despite these findings, our reverse analysis did not indicate any influence of sepsis on the gut microbiota and CRP levels.
Conclusion
The study showcased the connection between gut microbiota, CRP, and sepsis, which sheds new light on the potential role of CRP as a mediator in facilitating the impact of gut microbiota on sepsis.
... Furthermore, M. hominis, U. urealyticum, and U. parvum are examples of pathogens that can invade pregnant mothers and are closely associated with neonatal pneumonia (Waites et al., 2005). In pregnant mothers, U. urealyticum is found in the lower urogenital tract flora, occasionally, it ascends and causes bacterial vaginosis, chorioamnionitis, and premature birth (Stol et al., 2021). In the fetus, it causes neonatal sepsis and meningitis (Ferreira et al., 2021). ...
Mycoplasmas as economically important and pantropic pathogens can cause similar clinical diseases in different hosts by eluding host defense and establishing their niches despite their limited metabolic capacities. Besides, enormous undiscovered virulence has a fundamental role in the pathogenesis of pathogenic mycoplasmas. On the other hand, they are host-specific pathogens with some highly pathogenic members that can colonize a vast number of habitats. Reshuffling mycoplasmas genetic information and evolving rapidly is a way to avoid their host’s immune system. However, currently, only a few control measures exist against some mycoplasmosis which are far from satisfaction. This review aimed to provide an updated insight into the state of mycoplasmas as pathogens by summarizing and analyzing the comprehensive progress, current challenge, and future perspectives of mycoplasmas. It covers clinical implications of mycoplasmas in humans and domestic and wild animals, virulence-related factors, the process of gene transfer and its crucial prospects, the current application and future perspectives of nanotechnology for diagnosing and curing mycoplasmosis, Mycoplasma vaccination, and protective immunity. Several questions remain unanswered and are recommended to pay close attention to. The findings would be helpful to develop new strategies for basic and applied research on mycoplasmas and facilitate the control of mycoplasmosis for humans and various species of animals.
Sexually Transmitted Infections (STIs) are an important and growing public health concern. Implementation of screening programmes and awareness campaigns are crucial to mitigate this problem. A university in the central region of Portugal has devised a health-promotion programme, named Protection+, specifically directed towards the sexual health of the university community. The present study aimed to evaluate the results of the different actions undertaken as part of the health-promotion programme during the 2023–2024 academic year. Chlamydia, gonorrhoea, trichomoniasis and infection with Mycoplasma genitalium were assessed through real-time polymerase chain reaction protocols. Syphilis, infection with HIV, HBV and HCV were assessed through immunological assays. The adherence to the health-promotion programme after the awareness campaigns was also evaluated. STIs have been diagnosed in 13.7% of the 475 screened participants. Chlamydia was the STI most frequently diagnosed (8.4%), followed by infection with M. genitalium (2.3%), T. pallidum (2.0%) and N. gonorrhoeae (1.1%). HIV, HBV and HCV were diagnosed in a residual number of cases, and T. vaginalis was not detected in any of the screened participants. At the time of diagnosis, more than half of the infected patients were asymptomatic. After the implementation of awareness campaigns, an increase in the adherence to STI screening was observed, with the expected simultaneous increase in STI diagnoses. The high prevalence of STIs, particularly chlamydia, in the university population, along with the asymptomatic nature of these infections, demonstrated the importance of STI screenings and the implementation of campaigns that raise awareness on the prevention and consequences of untreated STIs.
Intrauterine Ureaplasma infection is associated with chorioamnionitis and preterm birth. The difficulty of detecting Ureaplasma species by conventional culture methods makes definitive diagnosis of clinical infection challenging. Thus far, quantitative tests for Ureaplasma have been performed using adult cervical samples, amniotic fluid, and pediatric bronchial secretions, but quantification of bacterial count in central nervous system infections caused by Ureaplasma species has not been unreported. We report a case of culture-negative Ureaplasma meningitis in a preterm infant in whom novel techniques to identify this pathogen and quantify bacterial count were effective. We suspected meningitis based on a sustained reduction in cerebrospinal fluid (CSF) glucose levels. Multiple CSF cultures were sterile. We confirmed infection by Ureaplasma species using the melting temperature mapping method. Treatment with erythromycin and ciprofloxacin resulted in a gradual decrease in the bacterial count in the CSF to 0. Our study highlights the potential utility of the melting temperature mapping method as a new diagnostic tool for culture-negative Ureaplasma meningitis and establishes the utility of serial quantification of bacterial count to monitor response to therapy.
Background
Bronchopulmonary dysplasia (BPD) is the most prevalent chronic lung disease in preterm infants. Studies have shown that Ureaplasma urealyticum (UU) infection is linked to its pathogenesis. However, it remains controversial whether UU colonization in preterm infants increases the risk of developing BPD.
Objective
This study aimed to conduct a systematic review and meta-analysis to summarize the correlation between UU and BPD.
Methods
We searched PubMed, Embase, the Cochrane Library, Web of Science, Wanfang Database, Chinese National Knowledge Infrastructure Database, Chinese Science and Technique Journal Database, and the China Biology Medicine disc from their inception to March 15, 2024. We included cohort and case-control studies investigating the association between UU infections and BPD in preterm infants, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The Newcastle-Ottawa Scale was used for quality assessment. The outcome was defined as the continued need for oxygen or respiratory support at 28 days after birth (BPD28) or at 36 weeks postmenstrual age (BPD36). Considering the potential publication bias in observational studies, we used a random-effects meta-analysis model, assessed heterogeneity (I²), performed subgroup analyses, evaluated publication bias, and graded the quality of evidence.
Results
The meta-analysis included 36 cohort studies encompassing 5,991 participants. Among these, 20 reported on BPD28, 13 on BPD36, and 3 on both. The results indicated a significant association between UU colonization and BPD28 (odds ratio (OR): 2.26, 95% confidence interval (CI): 1.78–2.85, P < 0.00001, 23 studies, very low certainty of evidence) and BPD36 (OR: 2.13, 95% CI: 1.47–3.07, P < 0.0001, 16 studies, very low certainty of evidence).
Conclusion
There is a correlation between UU colonization and the development of BPD in preterm infants. Future research should prioritize well-designed, large-scale, high-quality randomized controlled trials (RCTs) to comprehensively assess the risk of BPD in neonates following UU infection and to provide stronger evidence for clinical screening and prevention strategies to improve the prognosis of affected newborns.
Systematic Review Registration
https://www.crd.york.ac.uk/, identifier (CRD42024524846).
Background
Globally, over 400,000 neonatal deaths in 2015 were attributed to sepsis, however, the incidence and etiologies of these infections are largely unknown in low-middle income countries. We aimed to determine incidence and etiology of community-acquired early-onset (<72 hours age) sepsis (EOS) using culture and molecular diagnostics.
Methods
This was a prospective observational study, in which we conducted a surveillance for pathogens using a combination of blood culture and a polymerase chain reaction (PCR)-based test. Blood culture was performed on all neonates with suspected EOS. Among the subset fulfilling criteria for protocol-defined EOS, blood and nasopharyngeal (NP) respiratory swabs were tested by quantitative real-time reverse-transcriptase PCR using a Taqman Array Card (TAC) with 15 bacterial and 12 viral targets. Blood and NP samples from 312 healthy newborns were also tested by TAC to estimate background positivity rates. We used variant latent-class methods to attribute etiologies and calculate pathogen-specific proportions and incidence rates.
Results
We enrolled 2,624 neonates with suspected EOS and from these 1,231 newborns met criteria for protocol-defined EOS (incidence- 39.3/1,000 live-births). Using the partially latent-class modelling, only 26.7% cases with protocol-defined EOS had attributable etiology, and the largest pathogen proportion were Ureaplasma spp. (5.4%; 95%CI: 3.6–8.0) and group B Streptococcus (GBS) (4.8%; 95%CI: 4.1–5.8), and no etiology was attributable for 73.3% of cases. Blood cultures were positive in 99/1,231 (8.0%) with protocol-defined EOS (incidence- 3.2/1,000 live-births). Leading pathogens on blood culture included GBS (35%) and viridans streptococci (24%). Ureaplasma spp. was the most common organism identified on TAC among cases with protocol-defined EOS.
Conclusion
Using a combination of blood culture and a PCR-based test the common pathogens isolated in neonates with sepsis were Ureaplasma spp. and GBS. Despite documenting higher rates of protocol-defined EOS and using a combination of tests, the etiology for EOS remains elusive.
Background: Controversy remains concerning the impact of Ureaplasma on preterm neonatal morbidity.
Methods: Prospective single-center study in very low birth weight infants <30 weeks' gestation. Cord blood and initial nasopharyngeal swabs were screened for Ureaplasma parvum and U. urealyticum using culture technique and polymerase chain reaction. Neonatal outcomes were followed until death or discharge. Multi-analyte immunoassay provided cord blood levels of inflammatory markers. Using multivariate regression analyses, perinatal Ureaplasma exposure was evaluated as risk factor for the development of bronchopulmonary dysplasia (BPD), other neonatal morbidities until discharge and systemic inflammation at admission.
Results: 40/103 (39%) infants were positive for Ureaplasma in one or both specimens, with U. parvum being the predominant species. While exposure to Ureaplasma alone was not associated with BPD, we found an increased risk of BPD in Ureaplasma-positive infants ventilated ≥5 days (OR 1.64; 95% CI 0.12–22.98; p = 0.009). Presence of Ureaplasma was associated with a 7-fold risk of late onset sepsis (LOS) (95% CI 1.80–27.39; p = 0.014). Moreover, Ureaplasma-positive infants had higher I/T ratios (b 0.39; 95% CI 0.08–0.71; p = 0.014), increased levels of interleukin (IL)-17 (b 0.16; 95% CI 0.02–0.30; p = 0.025) and matrix metalloproteinase 8 (b 0.77; 95% CI 0.10–1.44; p = 0.020), decreased levels of IL-10 (b −0.77; 95% CI −1.58 to −0.01; p = 0.043) and increased ratios of Tumor necrosis factor-α, IL-8, and IL-17 to anti-inflammatory IL-10 (p = 0.003, p = 0.012, p < 0.001).
Conclusions: Positive Ureaplasma screening was not associated with BPD. However, exposure contributed to BPD in infants ventilated ≥5 days and conferred an increased risk of LOS and imbalanced inflammatory cytokine responses.
Background:
Ureaplasma spp. is a known risk factor for bronchopulmonary dysplasia (BPD). However, little is known about the effect of different degrees of maternal Ureaplasma colonization and their adverse outcomes. Hence, the aim of this study was to determine the effects of different degrees of maternal Ureaplasma colonization on BPD.
Methods:
A retrospective cohort study of preterm infants delivered at <32 weeks' gestational age (GA) was performed. The infants were divided according to maternal Ureaplasma status as follows: high-colonization (≥104 CCU/ml, UUH), low-colonization (<104 CCU/ml, UUL), and noncolonization (controls). Subgroup analysis according to neonatal respiratory Ureaplasma (n-UU) was also performed to evaluate vertical transmission.
Results:
In total, 245 infants were included in this study (UUH = 105, UUL = 47, controls = 93). The rates of preterm labor and histological chorioamnionitis were significantly different. The rate of BPD was significantly high in UUH (P = 0.044). The transmission rate of n-UU colonization was 36% in UUH and 32% in UUL (P = 0.609). The rate of BPD was 78% in n-UU (+) of UUH but 43% in n-UU (-) of UUL (P = 0.027).
Conclusions:
High-degree colonization of maternal Ureaplasma was associated with preterm labor, histological chorioamnionitis, and neonatal BPD. The incidence of BPD was significantly higher in Ureaplasma-colonized infants born to women with high-degree colonization.
Background:
More than 500 000 neonatal deaths per year result from possible serious bacterial infections (pSBIs), but the causes are largely unknown. We investigated the incidence of community-acquired infections caused by specific organisms among neonates in south Asia.
Methods:
From 2011 to 2014, we identified babies through population-based pregnancy surveillance at five sites in Bangladesh, India, and Pakistan. Babies were visited at home by community health workers up to ten times from age 0 to 59 days. Illness meeting the WHO definition of pSBI and randomly selected healthy babies were referred to study physicians. The primary objective was to estimate proportions of specific infectious causes by blood culture and Custom TaqMan Array Cards molecular assay (Thermo Fisher, Bartlesville, OK, USA) of blood and respiratory samples.
Findings:
6022 pSBI episodes were identified among 63 114 babies (95·4 per 1000 livebirths). Causes were attributed in 28% of episodes (16% bacterial and 12% viral). Mean incidence of bacterial infections was 13·2 (95% credible interval [CrI] 11·2-15·6) per 1000 livebirths and of viral infections was 10·1 (9·4-11·6) per 1000 livebirths. The leading pathogen was respiratory syncytial virus (5·4, 95% CrI 4·8-6·3 episodes per 1000 livebirths), followed by Ureaplasma spp (2·4, 1·6-3·2 episodes per 1000 livebirths). Among babies who died, causes were attributed to 46% of pSBI episodes, among which 92% were bacterial. 85 (83%) of 102 blood culture isolates were susceptible to penicillin, ampicillin, gentamicin, or a combination of these drugs.
Interpretation:
Non-attribution of a cause in a high proportion of patients suggests that a substantial proportion of pSBI episodes might not have been due to infection. The predominance of bacterial causes among babies who died, however, indicates that appropriate prevention measures and management could substantially affect neonatal mortality. Susceptibility of bacterial isolates to first-line antibiotics emphasises the need for prudent and limited use of newer-generation antibiotics. Furthermore, the predominance of atypical bacteria we found and high incidence of respiratory syncytial virus indicated that changes in management strategies for treatment and prevention are needed. Given the burden of disease, prevention of respiratory syncytial virus would have a notable effect on the overall health system and achievement of Sustainable Development Goal.
Funding:
Bill & Melinda Gates Foundation.
Background: Ureaplasma species have been associated with chorioamnionitis and preterm birth and have been implicated in the pathogenesis of neonatal short and long-term morbidity. However, being mostly commensal bacteria, controversy remains on the pro-inflammatory capacity of Ureaplasma. Discussions are ongoing on the incidence and impact of prenatal, perinatal, and postnatal infection. The present study addressed the impact of Ureaplasma isolates on monocyte-driven inflammation.
Methods: Cord blood monocytes of term neonates and adult monocytes, either native or LPS-primed, were cultured with Ureaplasma urealyticum (U. urealyticum) serovar 8 (Uu8) and Ureaplasma parvum serovar 3 (Up3). Using qRT-PCR, cytokine flow cytometry, and multi-analyte immunoassay, we assessed mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-8, IL-12p40, IL-10, and IL-1 receptor antagonist (IL-1ra) as well as Toll-like receptor (TLR) 2 and TLR4.
Results: Uu8 and Up3 induced mRNA expression and protein release of TNF-α, IL-1β and IL-8 in term neonatal and adult monocytes (p < 0.01 and p < 0.05). Intracellular protein expression of TNF-α, IL-1β and IL-8 in Ureaplasma-stimulated cells paralleled those results. Ureaplasma-induced cytokine levels did not significantly differ from LPS-mediated levels except for lower intracellular IL-1β in adult monocytes (Uu8: p < 0.05). Remarkably, ureaplasmas did not induce IL-12p40 response and promoted lower amounts of anti-inflammatory IL-10 and IL-1ra than LPS, provoking a cytokine imbalance more in favor of pro-inflammation (IL-1β/IL-10, IL-8/IL-10 and IL-8/IL-1ra: p < 0.01, vs. LPS). In contrast to LPS, both isolates induced TLR2 mRNA in neonatal and adult cells (p < 0.001 and p < 0.05) and suppressed TLR4 mRNA in adult monocytes (p < 0.05). Upon co-stimulation, Uu8 and Up3 inhibited LPS-induced intracellular IL-1β (p < 0.001 and p < 0.05) and IL-8 in adult monocytes (p < 0.01), while LPS-induced neonatal cytokines were maintained or aggravated (p < 0.05).
Conclusion: Our data demonstrate a considerable pro-inflammatory capacity of Ureaplasma isolates in human monocytes. Stimulating pro-inflammatory cytokine responses while hardly inducing immunomodulatory and anti-inflammatory cytokines, ureaplasmas might push monocyte immune responses toward pro-inflammation. Inhibition of LPS-induced cytokines in adult monocytes in contrast to sustained inflammation in term neonatal monocytes indicates a differential modulation of host immune responses to a second stimulus. Modification of TLR2 and TLR4 expression may shape host susceptibility to inflammation.
Objective: The aim of this study was to evaluate clusterin concentrations in amniotic fluid in pregnancies complicated by preterm prelabor rupture of membranes (PPROM) with respect to the presence of the microbial invasion of the amniotic cavity (MIAC), intra-amniotic inflammation (IAI), and microbial-associated IAI.
Methods: One hundred thirty-six women with singleton pregnancies complicated by preterm prelabor rupture of membranes were included in this study. Amniotic fluid samples were obtained by transabdominal amniocentesis. Amniotic fluid clusterin concentrations were assessed by enzyme-linked immunosorbent assay (ELISA). MIAC was determined by a non-cultivation approach. IAI was defined as an amniotic fluid bedside interleukin-6 concentration ≥ 745 pg/mL. Microbial-associated IAI was characterized as the presence of both MIAC and IAI.
Result: Women with MIAC, IAI, and microbial-associated IAI had lower amniotic fluid clusterin concentrations than women without these complications (with MIAC: median 1314 ng/mL vs. without MIAC: median 1633 ng/mL, p = 0.003; with IAI: median 1281 ng/mL vs. without IAI: median 1575 ng/mL, p = 0.04; with microbial associated-IAI: median 1220 ng/mL vs. without microbial-associated IAI: median 1575 pg/mL; p = 0.008). A week negative correlation between amniotic fluid clusterin concentrations and gestational age at sampling was revealed (rho=-0.30; p = 0.0005).
Conclusions: The presence of MIAC, IAI, and microbial-associated IAI was characterized by lower amniotic fluid clusterin concentrations in pregnancies complicated by PPROM.
Background
Although Ureaplasma species are the most common organisms associated with prematurity, their effects on the maternal and fetal immune system remain poorly characterized.
Methods
Rhesus macaque dams at ∼80% gestation were injected intra-amniotically with 10⁷ CFU Ureaplasma parvum (UP) or saline (control). Fetuses were delivered surgically 3 or 7 days later. We performed comprehensive assessments of inflammation and immune effects in multiple fetal and maternal tissues.
Results
Although UP grew well in amniotic fluid, there was minimal chorioamnionitis. UP colonized the fetal lung, but fetal systemic microbial invasion was limited. Fetal lung inflammation was mild with elevations in CXCL8, TNFα, and CCL2 levels in alveolar washes at d7. Inflammation was not detected in the fetal brain. Significantly, UP decreased regulatory T-cells (Treg) and activated interferon γ production in these Tregs in the fetus. UP was detected in uterine tissue by d7, and induced mild inflammation and increased expression of connexin-43, a gap junction protein involved with labor.
Conclusions
UP colonized the amniotic fluid and caused uterine inflammation, but without overt chorioamnionitis. UP caused mild fetal lung inflammation, but had a more profound effect on the fetal immune system, decreasing Treg and polarizing them toward a Th-1 phenotype.
Objective:
The human Ureaplasma species are the most frequently isolated microbe from placentae of women who deliver preterm. The role of Ureaplasma spp. has been investigated in pregnancies <32 weeks, currently no studies have determined the prevalence of ureaplasmas in the moderate/late preterm period - the largest cohort of preterm infants.
Study design:
Women delivering moderate/late preterm (n=477) and their infants/placentae (n=535) were recruited and swabs of chorioamnion tissue, chorioamnion tissue and cord blood were obtained at delivery. Swabs and tissues were utilized for culture and 16S rRNA PCR for the presence of microorganisms, while cord blood was analysed for the presence of cytokines, chemokines and growth factors.
Results:
We detected microorganisms in 10.6% of all placentae (delivered late preterm (n=443) and at term (n=92)). Significantly, Ureaplasma spp. were the most prevalent microorganisms detected and their presence alone was associated with histological chorioamnionitis in moderate/late preterm and term placentae (p<0.001). The presence of ureaplasmas within the chorioamnion was also associated with elevated levels of granulocyte colony-stimulating factor (G-CSF) (p=0.02).
Conclusions:
These findings have important implications for infection and adverse pregnancy outcomes throughout gestation, and should be of major consideration for obstetricians and neonatologists.
Objective:
To evaluate the influence of microbial invasion of the amniotic cavity (MIAC) and histological chorioamnionitis (HCA) on short-term neonatal outcome in women with preterm prelabor rupture of membranes before 34 weeks of gestation.
Methods:
A prospective observational cohort study including 122 pregnant women with PPROM between 24+0 and 34+0. MIAC was defined as a positive PCR result for Ureaplasma species, Mycoplasma hominis and Chlamydia trachomatis and/or positive PCR result for the 16S rRNA gene in the amniotic fluid. HCA was defined according to the Salafia classification. Maternal and short-term neonatal outcomes were evaluated according to the presence or absence of MIAC and/or HCA.
Results:
The presence of both MIAC and HCA was observed in 36% (45/122) of women, HCA alone in 34% (41/122) and MIAC in 5% (6/122). A significantly higher incidence of early onset sepsis was observed in newborns born from women with both MIAC and HCA [33% (15/45)] compared with women with HCA alone [12% (5/41)] or MIAC alone [0% (0/6)] or women without MIAC or HCA detected [0% (0/30); p = 0.001].
Conclusions:
The presence of both MIAC and HCA increases the risk of early onset sepsis in pregnancies complicated by preterm prelabor rupture of membranes before 34 weeks of gestation.
Significance
The human indigenous microbial communities (microbiota) play critical roles in health and may be especially important for mother and fetus during pregnancy. Using a case-control cohort of 40 women, we characterized weekly variation in the vaginal, gut, and oral microbiota during and after pregnancy. Microbiota membership remained relatively stable at each body site during pregnancy. An altered vaginal microbial community was associated with preterm birth; this finding was corroborated by an analysis of samples from an additional cohort of nine women. We also discovered an abrupt change in the vaginal microbiota at delivery that persisted in some cases for at least 1 y. Our findings suggest that pregnancy outcomes might be predicted by features of the microbiota early in gestation.
Pre-term birth (PTB) associated with intrauterine infection and inflammation (IUI) is the major cause of early PTB less than 32 weeks of gestation. Ureaplasma spp. are common commensals of the urogenital tract in pregnancy and are the most commonly identified microorganisms in amniotic fluid of pre-term pregnancies. While we have an understanding of the causal relationship between intra-amniotic infection, inflammation and PTB, we are still unable to explain why vaginal Ureaplasma sp. colonization is tolerated in some women but causes PTB in others. It is now known that placental tissues are frequently colonized by bacteria even in apparently healthy pregnancies delivered at term; usually this occurs in the absence of a significant local inflammatory response. It appears, therefore, that the site, nature, and magnitude of the immune response to infiltrating microorganisms are key in determining pregnancy outcome. Some evidence exists that the maternal serological response to Ureaplasma sp. colonization may be predictive of adverse pregnancy outcome, although issues such as the importance of virulence factors (serovars) and the timing, magnitude, and functional consequences of the immune response await clarification. This mini-review discusses the evidence linking the maternal immune response to risk of PTB and the potential applications of maternal serological analysis for predicting obstetric outcome.
A novel multiplex quantitative real-time polymerase chain reaction (qPCR) for simultaneous detection of U. urealyticum and U. parvum was developed and compared with quantitative culture in Shepard's 10 C medium for ureaplasmas in urethral swabs from 129 men and 66 women, and cervical swabs from 61 women. Using culture as the gold standard, the sensitivity of the qPCR was 96% and 95% for female urethral and cervical swabs, respectively. In male urethral swabs the sensitivity was 89%. The corresponding specificities were 100%, 87% and 99%. The qPCR showed a linear increasing DNA copy number with increasing colour-changing units. Although slightly less sensitive than culture, this multiplex qPCR assay detecting U. urealyticum and U. parvum constitutes a simple and fast alternative to the traditional methods for identification of ureaplasmas and allows simultaneous species differentiation and quantitation in clinical samples. Furthermore, specimens overgrown by other bacteria using the culture method can be evaluated in the qPCR.
Abstract Objective: To evaluate Ureaplasma species and Mycoplasma hominis DNA in the umbilical cord blood and its correlation with its microbial load in the amniotic fluid, as a measure of microbial burden in fetal inflammatory response and neonatal outcome in pregnancies complicated by preterm prelabor rupture of membranes (pPROM). Study design: A retrospective study of 158 women with singleton pregnancies complicated by pPROM between 24(0/7) and 36(6/7) weeks was conducted. Amniotic fluid was obtained from all women by transabdominal amniocentesis, and umbilical cord blood was obtained by venipuncture from umbilical cords immediately after the delivery of the neonates. The Ureaplasma species and Mycoplasma hominis DNA was quantitated using absolute quantification techniques. Result: Ureaplasma species and Mycoplasma hominis DNA was identified in 9% of the umbilical cord blood samples. No correlation between the amniotic fluid and umbilical cord blood microbial load of was observed. The presence of Ureaplasma species and Mycoplasma hominis DNA in the umbilical cord blood had no impact on short-term neonatal morbidity. Conclusions: A high microbial load of genital mycoplasma Ureaplasma species DNA in the umbilical cord in pregnancies complicated by pPROM is not associated with a high fetal inflammatory response and is therefore not associated with serious neonatal morbidity.
There are no well-matched, controlled studies comparing azithromycin with doxycycline for the treatment of complicated scrub
typhus. A retrospective propensity score-matched case-control study was performed for patients who presented with complicated
scrub typhus and were treated with doxycycline or azithromycin between 2001 and 2011. Data on comorbidities, clinical manifestations,
laboratory studies, treatments, and outcomes were extracted for analysis. The clinical characteristics and outcomes of the
azithromycin-treated group (n = 73) were compared to those of the doxycycline-treated group (n = 108). Of 181 patients, 73 from each group were matched by propensity scores. There were no significant differences in baseline
characteristics between the matched groups. The treatment success and survival rates were not significantly different (89%
[65/73 patients] versus 96% [70/73 patients] and 96% [70/73 patients] versus 96% [70/73 patients], respectively [P > 0.05]). No difference was observed in the time to defervescence or length of hospital stay between the two groups (P > 0.05). In complicated scrub typhus patients (n = 181), multivariate analysis showed that only APACHE II score was an independent risk factor for mortality (95% confidence
interval, 1.11 to 1.56; P < 0.001). Our data suggest that outcomes of azithromycin therapy are comparable to those of doxycycline therapy in patients
with complicated scrub typhus.
Preterm birth is a major cause of perinatal mortality and long-term morbidity. Chorioamnionitis is a common cause of preterm birth. Clinical chorioamnionitis, characterised by maternal fever, leukocytosis, tachycardia, uterine tenderness, and preterm rupture of membranes, is less common than subclinical/histologic chorioamnionitis, which is asymptomatic and defined by inflammation of the chorion, amnion, and placenta. Chorioamnionitis is often associated with a fetal inflammatory response. The fetal inflammatory response syndrome (FIRS) is defined by increased systemic inflammatory cytokine concentrations, funisitis, and fetal vasculitis. Clinical and epidemiological studies have demonstrated that FIRS leads to poor cardiorespiratory, neurological, and renal outcomes. These observations are further supported by experimental studies that have improved our understanding of the mechanisms responsible for these outcomes. This paper outlines clinical and experimental studies that have improved our current understanding of the mechanisms responsible for chorioamnionitis-induced preterm birth and explores the cellular and physiological mechanisms underlying poor cardiorespiratory, neural, retinal, and renal outcomes observed in preterm infants exposed to chorioamnionitis.
Little is known about the outcomes of extremely low birth weight (ELBW) preterm infants with congenital heart defects (CHDs). The aim of this study was to assess the mortality, morbidity, and early childhood outcomes of ELBW infants with isolated CHD compared with infants with no congenital defects. Participants were 401-1,000 g infants cared for at National Institute of Child Health and Human Development Neonatal Research Network centers between January 1, 1998, and December 31, 2005. Neonatal morbidities and 18-22 months' corrected age outcomes were assessed. Neurodevelopmental impairment (NDI) was defined as moderate to severe cerebral palsy, Bayley II mental or psychomotor developmental index <70, bilateral blindness, or hearing impairment requiring aids. Poisson regression models were used to estimate relative risks for outcomes while adjusting for gestational age, small-for-gestational-age status, and other variables. Of 14,457 ELBW infants, 110 (0.8 %) had isolated CHD, and 13,887 (96 %) had no major birth defect. The most common CHD were septal defects, tetralogy of Fallot, pulmonary valve stenosis, and coarctation of the aorta. Infants with CHD experienced increased mortality (48 % compared with 35 % for infants with no birth defect) and poorer growth. Surprisingly, the adjusted risks of other short-term neonatal morbidities associated with prematurity were not significantly different. Fifty-seven (52 %) infants with CHD survived to 18-22 months' corrected age, and 49 (86 %) infants completed follow-up. A higher proportion of surviving infants with CHD were impaired compared with those without birth defects (57 vs. 38 %, p = 0.004). Risk of death or NDI was greater for ELBW infants with CHD, although 20 % of infants survived without NDI.
Multiplex, real-time PCR for the identification of Ureaplasma urealyticum and Ureaplasma parvum was performed on nucleic acids extracted from sequential endotracheal aspirates obtained from preterm neonates born at <29
weeks of gestation and ventilated for more than 48 h admitted to two level 3 neonatal intensive care units. Specimens were
obtained shortly after birth and sequentially up until extubation. One hundred fifty-two specimens (93.8%) contained material
suitable for analysis. Ureaplasma spp. were identified in 5 of 13 neonates studied. In most cases, the DNA load of the detected Ureaplasma species was low and decreased over time. In addition, changes in detectable Ureaplasma species DNA did not relate to changes in the inflammatory marker C-reactive protein (CRP) or respiratory status. All but
two blood samples obtained at times of suspected sepsis were culture positive for other microorganisms; the species cultured
were typically coagulase-negative staphylococci and were associated with increased levels of CRP (>10 mg/liter). This study
was limited by the small number of patients examined and does not have the power to support or contradict the hypothesis that
postnatal lung infection with Ureaplasma parvum is causally related to bronchopulmonary dysplasia (BPD) or adverse respiratory outcomes after preterm birth. However, in
this study, increases in CRP levels were not associated with patients in whom Ureaplasma parvum was detected, in contrast to the detection of other bacterial species.
This report presents data from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network on care of and morbidity and mortality rates for very low birth weight infants, according to gestational age (GA).
Perinatal/neonatal data were collected for 9575 infants of extremely low GA (22-28 weeks) and very low birth weight (401-1500 g) who were born at network centers between January 1, 2003, and December 31, 2007.
Rates of survival to discharge increased with increasing GA (6% at 22 weeks and 92% at 28 weeks); 1060 infants died at <or=12 hours, with most early deaths occurring at 22 and 23 weeks (85% and 43%, respectively). Rates of prenatal steroid use (13% and 53%, respectively), cesarean section (7% and 24%, respectively), and delivery room intubation (19% and 68%, respectively) increased markedly between 22 and 23 weeks. Infants at the lowest GAs were at greatest risk for morbidities. Overall, 93% had respiratory distress syndrome, 46% patent ductus arteriosus, 16% severe intraventricular hemorrhage, 11% necrotizing enterocolitis, and 36% late-onset sepsis. The new severity-based definition of bronchopulmonary dysplasia classified more infants as having bronchopulmonary dysplasia than did the traditional definition of supplemental oxygen use at 36 weeks (68%, compared with 42%). More than one-half of infants with extremely low GAs had undetermined retinopathy status at the time of discharge. Center differences in management and outcomes were identified.
Although the majority of infants with GAs of >or=24 weeks survive, high rates of morbidity among survivors continue to be observed.
Ureaplasma respiratory tract colonization stimulates prolonged, dysregulated inflammation in the lungs of preterm infants, contributing to bronchopulmonary dysplasia (BPD) pathogenesis. Surfactant protein-A (SP-A), a lung collectin critical for bacterial clearance and regulating inflammation, is deficient in the preterm lung. To analyze the role of SP-A in modulating Ureaplasma-mediated lung inflammation, SP-A deficient (SP-A-/-) and WT mice were inoculated intratracheally with a mouse-adapted U. parvum isolate and indices of inflammation were sequentially assessed up to 28 d postinoculation. Compared with infected WT and noninfected controls, Ureaplasma-infected SP-A-/- mice exhibited an exaggerated inflammatory response evidenced by rapid influx of neutrophils and macrophages into the lung, and higher bronchoalveolar lavage TNF-alpha, mouse analogue of human growth-related protein alpha (KC), and monocyte chemotactic factor (MCP-1) concentrations. However, nitrite generation in response to Ureaplasma infection was blunted at 24 h and Ureaplasma clearance was delayed in SP-A-/- mice compared with WT mice. Coadministration of human SP-A with the Ureaplasma inoculum to SP-A-/- mice reduced the inflammatory response, but did not improve the bacterial clearance rate. SP-A deficiency may contribute to the prolonged inflammatory response in the Ureaplasma-infected preterm lung, but other factors may contribute to the impaired Ureaplasma clearance.
Ureaplasma urealyticum, a common commensal of the urogenital tract of sexually mature humans, is gaining recognition as an important opportunistic pathogen during pregnancy. While its etiologic significance in many aspects of adverse pregnancy remains controversial, recent evidence indicates that U. urealyticum in the absence of other organisms is a cause of chorioamnionitis. Furthermore, ureaplasmal infection of the chorioamnion is significantly associated with premature spontaneous labor and delivery. In at least some cases, it appears to be causal. Present evidence indicates that U. urealyticum is a cause of septicemia, meningitis, and pneumonia in newborn infants, particularly those born prematurely. There is strong but not definitive evidence that ureaplasmal infection of the lower respiratory tract can lead to development of chronic lung disease in very low-birth-weight infants. Although risk factors for colonization of the lower genitourinary tract have been identified, little information is available concerning risk factors for intrauterine infection and host immune responses to invasive infection. Recent establishment of animal models of respiratory and central nervous system diseases should provide an opportunity to evaluate risk factors, pathogenic mechanisms, and operative immune mechanisms. However, the most critical need is additional information concerning indications for diagnosis and treatment as well as efficacy of treatment.
In this study, the phylogenetic relationships between the two biovars and 14 serovars of Ureaplasma urealyticum were studied using the sequences of four different genes or genetic regions, namely: 16S rRNA genes; 16S-23S rRNA gene spacer regions; urease gene subunits ureA, ureB, partial ureC and adjoining regions upstream of ureA, ureA-ureB spacer and ureB-ureC spacer; the 5'-ends of the multiple-banded antigen (MBA) genes. U. urealyticum genotypes, based on all four genomic sequences, could be clearly separated into two clusters corresponding with currently recognized biovars 1 and 2. Sequences were generally conserved within each biovar. However, there was heterogeneity within the 5'-end regions of the MBA genes of the four serovars of biovar 1; the sequence of serovar 3 was identical with the previously published sequence and differed by only three bases from that of serovar 14; but there were significant differences between the sequences of serovars 3 and 14 and those of serovars 1 and 6. Based on the phylogenetic analysis, support is given to previous recommendations that the two biovars of U. urealyticum be classified as distinct species, namely U. parvum and U. urealyticum for biovars 1 and 2, respectively. In the future, the relationship between the new species and clinical manifestations of ureaplasma infections should be studied.
We previously observed that Ureaplasma urealyticum respiratory tract colonization in infants with a birth weight of < or =1,250 g was associated with increases in the tracheal aspirate proinflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and interleukin-8 (IL-8) relative to the counterregulatory cytokine IL-6 during the first week of life (A. M. Patterson, V. Taciak, J. Lovchik, R. E. Fox, A. B. Campbell, and R. M. Viscardi, Pediatr. Infect. Dis. J. 17:321-328, 1998). We hypothesized that U. urealyticum alters the host immune response in the presence of a coinflammatory stimulus (e.g., bacterial infection or hyperoxia) by shifting the balance of cytokine expression towards the proinflammatory cytokines. To test this hypothesis, we compared the release of TNF-alpha, IL-8, IL-6, and IL-10 in vitro by unstimulated and U. urealyticum (with or without lipopolysaccharide [LPS])-stimulated human monocytes from adult peripheral blood and from term and preterm cord blood. U. urealyticum alone and in combination with LPS induced concentration- and development-dependent changes in cytokine release. In vitro inoculation with low-inoculum U. urealyticum (10(3) color-changing units [CCU]) (i) partially blocked the LPS-stimulated IL-6 release by all cells and reduced LPS-stimulated IL-10 release by preterm cells, (ii) stimulated TNF-alpha and IL-8 release by preterm cells, and (iii) augmented LPS-stimulated TNF-alpha release in all cells. In preterm cells, high-inoculum U. urealyticum (10(6) CCU) (i) stimulated TNF-alpha and IL-8, but not IL-6 or IL-10, release and (ii) augmented LPS-stimulated TNF-alpha and IL-8 release. High-inoculum U. urealyticum (i) stimulated release of all four cytokines in term cells and IL-8 release in adult cells and (ii) augmented LPS-induced TNF-alpha, IL-10, and IL-8 release in term cells but did not significantly affect LPS-induced cytokine release in adult cells. We speculate that U. urealyticum enhances the proinflammatory response to a second infection by blocking expression of counterregulatory cytokines (IL-6 and IL-10), predisposing the preterm infant to prolonged and dysregulated inflammation, lung injury, and impaired clearance of secondary infections.
Fetal inflammatory response has been implicated as a mechanism of multi-system organ injury in preterm and term neonates. Microbial invasion of the amniotic cavity (MIAC) is frequently associated with a fetal inflammatory response. However, there are no studies comparing the fetal response to MIAC in term and preterm gestations. The purpose of this study was to compare the umbilical cord plasma interleukin-6 (IL-6) concentrations in term and preterm neonates in the presence or absence of MIAC.
Umbilical cord blood was obtained at birth from 252 neonates whose mothers had an amniocentesis within 48 h of delivery (preterm delivery, n = 62; term delivery, n = 190). MIAC was defined as a positive amniotic fluid culture for bacteria or genital mycoplasmas. IL-6 was measured by a sensitive and specific immunoassay.
The median IL-6 concentration in umbilical cord plasma was significantly higher in preterm neonates than in term neonates (median 13.4 pg/ml, range 0.1-676 pg/ml vs. median 3.2 pg/ml, range 0.1-408 pg/ml; p < 0.0001). In the context of MIAC, the median umbilical cord plasma IL-6 concentration was significantly higher in preterm than in term neonates (median 31.6 pg/ml, range 1.4-676 pg/ml vs. median 11.7 pg/ml, range 1.3-82 pg/ml, respectively; p < 0.05). Neonates born to mothers with a positive amniotic fluid culture had a significantly higher median IL-6 concentration than neonates born to mothers with a negative amniotic fluid culture (preterm: median 31.6, range 1.4-676 pg/ml vs. median 8.0, range 0.1-656 pg/ml; p < 0.05 and term: median 11.7, range 1.3-82 pg/ml vs. median 3.1, range 0.1-408 pg/ml; p < 0.01, respectively).
The preterm fetus is capable of mounting a systemic cytokine response as measured by IL-6 in its peripheral blood. In the setting of MIAC, a fetal IL-6 response is higher in preterm than in term gestation.
Objectives
To determine the relationship between the intensity of the intra-amniotic inflammatory response and the gestational age at the time of diagnosis in cases with preterm premature rupture of membranes (PROM) and intra-amniotic infection caused by Ureaplasma spp.
Methods
A retrospective cohort study was conducted which included 71 women with preterm PROM and a positive amniotic fluid culture with Ureaplasma spp. Women with mixed intra-amniotic infections were excluded. The study population was classified into three groups according to gestational age: group 1, <26 weeks (extreme preterm PROM, n = 17); group 2, 26.0–33.9 weeks (moderate preterm PROM, n = 39); group 3, 34.0–36.9 weeks (late preterm PROM, n = 15). The intensity of the intra-amniotic and maternal inflammatory response was compared among the three groups. The intensity of the intra-amniotic inflammatory response was assessed by the concentration of amniotic fluid matrix metalloproteinase-8 (MMP-8) and white blood cell (WBC) count. The maternal inflammatory response was assessed by the concentration of C-reactive protein (CRP) and WBC count in maternal blood at the time of amniocentesis.
Results
(1) The median values of amniotic fluid MMP-8 concentration and WBC count were the highest in the extreme preterm PROM group and the lowest in the late preterm PROM group (P < 0.001 and P = 0.01, respectively); (2) the intensity of the maternal inflammatory response measured by maternal blood WBC count and CRP concentration was not significantly associated with gestational age at the time of diagnosis.
Conclusion
The earlier the gestational age at the time of PROM, the higher the intensity of the intra-amniotic inflammatory response in women with preterm PROM and intra-amniotic infection caused by Ureaplasma spp.
Background:
Ureaplasma species (spp) are the bacteria most often isolated from the amniotic cavity of women with preterm labor or preterm premature rupture of membranes; thus, the link between intrauterine Ureaplasma spp infection and adverse pregnancy outcome clearly is established. However, because vaginal Ureaplasma spp colonization is very common in pregnant women, the reason that these microorganisms cause ascending infections in some cases but remain asymptomatic in most pregnancies is not clear. Previous studies suggested an association between vaginal colonization with Ureaplasma parvum as opposed to U urealyticum and preterm delivery. However, because of the high frequency of vaginal Ureaplasma spp colonization during pregnancy, additional risk factors are needed to select a group of women who might benefit from treatment.
Objective:
To further identify pregnant women who are at increased risk for preterm delivery, the aim of the present study was to investigate U parvum serovar-specific pathogenicity in a large clinical cohort.
Study design:
We serotyped 1316 samples that were positive for U parvum using a high-resolution melt polymerase chain reaction assay, and results were correlated with pregnancy outcome.
Results:
Within U parvum positive samples, serovar 3 was the most common isolate (43.3%), followed by serovar 6 (31.4%) and serovar 1 (25.2%). There was a significantly increased risk for spontaneous preterm birth at very low (<32 weeks gestation; P<.005) and extremely low (<28 weeks gestation; P<.005) gestational age in the group with vaginal U parvum serovar 3 colonization compared with the control group of pregnant women who tested negative for vaginal Ureaplasma spp colonization. This association was found for neither serovar 1 nor serovar 6. The combination of vaginal U parvum serovar 3 colonization and diagnosis of bacterial vaginosis in early pregnancy or a history of preterm birth further increased the risk for adverse pregnancy outcome.
Conclusion:
Colonization with U parvum serovar 3, but not serovar 1 or serovar 6, in early pregnancy is associated with preterm delivery at very and extremely low gestational age. The combination of U parvum serovar 3 colonization and a history of preterm birth or bacterial vaginosis further increases the risk for spontaneous preterm birth at low gestational age and may define a target group for therapeutic intervention studies.
Objectives
To summarize evidence regarding microbial dysbiosis of the airway associated with bronchopulmonary dysplasia (BPD) and to explore heterogeneity among studies.
Study design
We included studies that evaluated the airway microbiome in preterm infants who developed BPD using culture-independent molecular techniques and reported alpha- and beta-diversity metrics and microbial profiles.
Results
The 6 included studies had substantial clinical and methodological heterogeneity. Most studies reported the presence of an airway microbiome early after birth and an evolution in the first weeks of life with increasing bacterial loads. The early airway microbiome was dominated by Staphylococcus and Ureaplasma spp. Two studies reported differences in alpha- and beta- diversity indices in preterm infants with BPD compared with those who did not develop BPD. Increased microbial community turnover, changes in the relative abundance of Proteobacteria and Firmicutes, and decreased Lactobacilli were reported with BPD progression. Most included infants were born by cesarean delivery, and a majority were exposed to postnatal antibiotics. No data regarding feeding human milk or correlations with the development of gut microbiota (gut-lung axis) were available.
Conclusions
Microbial dysbiosis may be associated with BPD progression and severity, and further study of microbiome optimization in preterm infants at risk for BPD is warranted.
Aim:
Ureaplasma parvum, Ureaplasma urealyticum and Mycoplasma hominis are also known as genital mycoplasmas. Acute chorioamnionitis is an inflammation of the placenta associated with miscarriage. We retrospectively evaluated a possible association between genital mycoplasmas detection, acute chorioamnionitis and fetal pneumonia from second and third trimester spontaneous abortions.
Methods:
One hundred and thirty placenta and fetal lung samples were evaluated for histological examination. The placenta samples, along with corresponding fetal tracheo-bronchial aspirates, also underwent bacterial and fungal culture and real-time polymerase chain reaction (PCR) assay for the detection of genital mycoplasmas.
Results:
Acute chorioamnionitis and pneumonia were diagnosed in 80/130 (61.5%) and 22/130 (16.9%) samples, respectively. Among samples positive for acute chorioamnionitis, the proportion of samples positive by real-time PCR and/or culture, was significantly higher than that of negative controls [54/80 (67.5%) vs. 26/80 (32.5%); P<0.001]. Ureaplasma parvum detection was significantly associated with acute chorioamnionitis compared to controls [9/11 (81.8%) vs. 2/11 (18.2%); P=0.019], as well as U. urealyticum [6/7 (85.7%) vs. 1/7 (14.3%); P=0.039]. Among tracheo-bronchial aspirates from abortions with pneumonia, the proportion of real-time PCR and/or culture positive samples was significantly higher than that of controls [13/22 (59.1%) vs. 9/22 (40.9%); P=0.029].
Conclusions:
A strong association was found between acute histologic chorioamnionitis and microbial invasion with U. parvum and/or U. urealyticum.
There is growing global concern regarding the rise of antibiotic-resistant organisms. Many of these reports have focused on various Gram-positive and Gram-negative pathogens, with little attention to the genus Ureaplasma. Ureaplasma spp. are associated with numerous infectious diseases affecting pregnant women, neonates and the immunocompromised. Treatment options are extremely limited due to high levels of intrinsic resistance resulting from the unique physiology of these organisms and further restricted in cases of the developing fetus or neonate, often limiting therapeutic options to predominantly macrolides or rarely fluoroquinolones. The increasing presence of macrolide- and fluoroquinolone-resistant strains among neonatal infections may result in pan-drug resistance and potentially untreatable conditions. Here, we review the requirements for accurate measurement of antimicrobial susceptibility, provide a comprehensive review of the antimicrobial resistance (AMR) for Ureaplasma species in the literature and contextualize these results relative to some investigators' reliance on commercial kits that are not CLSI compliant when determining AMR. The dramatic variation in the resistance patterns and impact of high levels of AMR amongst neonatal populations suggests the need for continued surveillance. Commercial kits represent an excellent tool for initial antibiotic susceptibility determination and screening. However, AMR reporting must utilize internationally standardized methods, as high-titre samples, or Mycoplasma hominis-contaminated samples routinely give false AMR results. Furthermore, there is a requirement for future reports to determine the underlying AMR mechanisms and determine whether expanding AMR is due to spontaneous mutation, transmission of resistance genes on mobile elements or selection and expansion of resistant clones.
Isolation of Ureaplasma spp. from preterm neonates and the association with development of bronchopulmonary dysplasia has been previously investigated. However, few studies have contrasted the nature of infection in twins. In this article, we report that dizygotic twins (1 girl, 1 boy) born at 24 weeks gestation both yielded culturable Ureaplasma from endotracheal secretions. The samples were part of a serial blind collection cohort of ventilated premature neonates, and analysis of repeat cultures showed stable, separate infections over a period of 17 and 21 days, respectively. Immunoblot and probe-specific quantitative polymerase chain reaction analysis determined that Twin 1 was solely infected with Ureaplasma parvum (specifically, serovar 6 by gene sequencing), whereas Twin 2 was solely infected with Ureaplasma urealyticum (specifically, genotype A- serovars 2, 5, and 8 by gene sequencing). Immunoblot analysis found that the major surface antigen (multiple-banded antigen) altered relative mass for both strains during the course of infection. Quantitative polymerase chain reaction analysis of extracted endotracheal aspirates confirmed no evidence of mixed infection for either twin. Failure of sentinel ventilated preterm infants on the same ward to acquire Ureaplasma infection after the first week of birth suggests no cot-to-cot transfer of Ureaplasma infection occurred. This study demonstrated not only a contrasting clinical outcome for a set of twins infected with 2 separate species of Ureaplasma, but also the first real-time demonstration of multiple-banded antigen alteration and evolution of Ureaplasma over the course of a clinical infection.
Background:
Synthetic surfactants represent a promising alternative to animal-derived preparations in the treatment of neonatal respiratory distress syndrome. The synthetic surfactant CHF5633 has proven biophysical effectiveness and, moreover, demonstrated anti-inflammatory effects in LPS-stimulated monocytes. With ureaplasmas being relevant pathogens in preterm lung inflammation, the present study addressed immunomodulatory features on Ureaplasma-induced monocyte cytokine responses.
Methods:
Ureaplasma parvum-stimulated monocytes were exposed to CHF5633. TNF-α, IL-1β, IL-8, IL-10, TLR2 and TLR4 expression were analyzed using qPCR and flow cytometry.
Results:
CHF5633 did not induce pro-inflammation, and did not aggravate Ureaplasma-induced pro-inflammatory cytokine responses. It suppressed U. parvum-induced intracellular TNF-α (p<0.05) and IL-1β (p<0.05) in neonatal monocytes and inhibited Ureaplasma-induced TNF-α mRNA (p<0.05), TNF-α protein (p<0.001), and IL-1β (p=0.05) in adult monocytes. Ureaplasma-modulated IL-8, IL-10, TLR2 and TLR4 were unaffected.
Conclusion:
CHF5633 does neither act pro-apoptotic nor pro-inflammatory in native and Ureaplasma-infected monocytes. Suppression of Ureaplasma-induced TNF-α and IL-1β underlines anti-inflammatory features of CHF5633.
Unlabelled:
Ureaplasma spp. are a common vaginal microorganism causally linked to inflammation-driven preterm birth (PTB). The nature of the immune response to Ureaplasma spp. may influence PTB risk. This study sought to define maternal T cell cytokine responses to in vitro stimulation with Ureaplasma parvum serovar 3 (UpSV3) in vaginally colonised (UP+) and non-colonised (UP-) pregnant women. Whole blood flow cytometry demonstrated an increase (p=0.027) in the baseline frequency of IFNγ-positive CD3(+)CD4(-)(CD8(+)) T cells in UP+ women. UpSV3 stimulation resulted in a significant and specific increase (p=0.001) in the frequency of IFNγ-positive CD3(+)CD4(-)(CD8(+)) T cells, regardless of vaginal colonisation status. UpSV3 stimulation also increased the frequency of IFNγ-positive CD3(+)CD4(+) T cells, particularly in the UP+ group (p=0.003). This is the first published study to examine T cell responses to Ureaplasma spp.
Exposure:
Future appropriately-powered studies are needed to assess whether insufficient priming or a loss of tolerance to Ureaplasma spp. is occurring in UP+ women at risk of PTB.
In January 2015, the Eunice Kennedy Shriver National Institute of Child Health and Human Development invited an expert panel to a workshop to address numerous knowledge gaps and to provide evidence-based guidelines for the diagnosis and management of pregnant women with what had been commonly called chorioamnionitis and the neonates born to these women. The panel noted that the term chorioamnionitis has been used to label a heterogeneous array of conditions characterized by infection and inflammation or both with a consequent great variation in clinical practice for mothers and their newborns. Therefore, the panel proposed to replace the term chorioamnionitis with a more general, descriptive term: "intrauterine inflammation or infection or both," abbreviated as "Triple I." The panel proposed a classification for Triple I and recommended approaches to evaluation and management of pregnant women and their newborns with a diagnosis of Triple I. It is particularly important to recognize that an isolated maternal fever is not synonymous with chorioamnionitis. A research agenda was proposed to further refine the definition and management of this complex group of conditions. This article provides a summary of the workshop presentations and discussions.
Objective:
To assess the association of vaginal commensal and low-grade pathogenic bacteria including Ureaplasma parvum, Ureaplasma urealyticum, Mycoplasma hominis, Mycoplasma genitalium, Group B streptococcus (GBS), and Gardnerella vaginalis, in women who delivered preterm at less than 37-week gestation in the presence or absence of inflammation of the chorioamnionitic membranes.
Methods:
A case control study involving women who delivered before 37-week gestation with and without inflammation of chorioamnionitic membranes. A total of 57 placental samples were histologically examined for polymorphonuclear leukocyte infiltration of placental tissue for evidence of chorioamnionitis, and by type-specific nucleic acid amplification for evidence of infection with one or more of the target bacteria. Demographic data were collected for each mother.
Results:
Among the 57 placental samples, 42.1% had chorioamnionitis and 24.6% delivered in the second trimester of pregnancy; U. parvum, U. urealyticum, G. vaginalis, and GBS were all detected in the study with respective prevalence of 19.3%, 3.5%, 17.5%, and 15.8%; M. genitalium and M. hominis were not detected. U. parvum was significantly associated with chorioamnionitis (p = 0.02; OR 5.0; (95% CI 1.2-21.5) and was more common in women who delivered in the second (35.7%) compared to the third trimester of pregnancy (13.9%). None of the other bacteria were associated with chorioamnionitis or earlier delivery, and all G. vaginalis-positive women delivered in the third trimester of pregnancy (p = 0.04).
Conclusions:
The detection of U. parvum in placental tissue was significantly associated with acute chorioamnionitis in women presenting in extreme preterm labor.
Background and objective:
Ureaplasma spp. infection has been associated with bronchopulmonary dysplasia (BPD) in preterm infants. Macrolides have been used for the treatment of Ureaplasma spp. infection, with an intention to prevent BPD. The objective of this meta-analysis is to evaluate the use of macrolides in the prevention of BPD in preterm infants.
Methods:
We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials, abstracts of the major pediatric society meetings and bibliographies of retrieved articles. We included randomized controlled trials assessing the effects of macrolides therapy on BPD in preterm infants. A random/fixed-effect model was used to synthesize predefined outcomes.
Results:
Six studies involving 469 preterm infants were eligible for the analysis. Macrolides when used prophylactically (4 studies) did not show significant reduction in BPD (risk ratio, RR, 0.88, 95% confidence interval, CI, 0.75-1.03), death (RR 0.89, 95% CI 0.79-1.01) or in the composite outcome of BPD/death. Similarly, there was no significant reduction in BPD (RR 0.64, 95% CI 0.31-1.31) or the composite outcome of BPD/death (RR 0.41, 95% CI 0.05-3.13), when macrolides were used in Ureaplasma-positive infants. However, prophylactic azithromycin therapy (3 studies) was associated with significant reduction in BPD (RR 0.83, 95% CI 0.71-0.97; number needed to treat, NNT, 10) and composite outcome of BPD/death (RR 0.86, 95% CI 0.77-0.97; NNT 10).
Conclusion:
This meta-analysis demonstrates prophylactic azithromycin therapy was associated with statistically significant reduction in BPD and the composite outcome of BPD/death in preterm infants. However, given the limited information on pharmacokinetics and potential harmful effects, further studies should be done before routine use of azithromycin in the neonatal population.
Our understanding of the bacterial species inhabiting the female genital tract has been limited primarily by our ability to detect them. Early investigations using microscopy and culture-based techniques identified lactobacilli as the predominant members of the vaginal microbiota and suggested that these organisms might serve a protective function at the mucosal surface. Improvements in cultivation techniques and the development of molecular-based detection strategies validated these early findings and enabled us to recognize that the microbiota of the female genital tract is much more complex than previously suspected. Disruption of the vaginal microbial community due to invasion of exogenous organisms or by overgrowth of one or more endogenous species has important health implications for both the mother and newborn.
Ureaplasma respiratory tract colonization is associated with bronchopulmonary dysplasia (BPD) in preterm infants. Whether the 4 Ureaplasma parvum and 10 Ureaplasma urealyticum serovars differ in virulence is unknown. This study was conducted to determine the distribution of Ureaplasma serovars in respiratory secretions of a prospective cohort of preterm infants and to assess whether any of the serovars are associated with BPD.
Serial endotracheal and/or nasopharyngeal aspirates were obtained for Ureaplasma culture and PCR from 136 infants of gestational age <33 weeks. All positive samples were speciated and serovars were determined by real-time PCR.
A total of 51 (37.5%) infants were Ureaplasma-positive one or more times during the first month of life. Respiratory colonization was inversely related to gestational age. Sixty-five percent of infants <26 weeks compared with 31% infants ≥ 26 weeks were culture or PCR positive. U. parvum was more common (N = 32, 63%) than U. urealyticum (N = 17, 33%); both species were present in 2 samples. Serovars 3 and 6 alone and in combination accounted for 96% U. parvum isolates. U. urealyticum isolates were commonly a mixture of multiple serovars, with serovar 11 alone or combined with other serovars (10/17, 59%) being the most common serovar. No individual species or serovars or serovar mixtures were associated with moderate-to-severe BPD.
U. parvum serovars 3 and 6 and U. urealyticum serovar 11 were the most common serovars detected in respiratory samples from a prospective cohort of preterm infants.
The significance of Ureaplasma species as pathogens in neonatal meningitis remains contentious. Using an illustrative case of a premature infant with Ureaplasma parvum meningitis, confirmed by cerebrospinal fluid cultures and both specific and 16s rDNA polymerase chain reaction, we discuss the epidemiology of Ureaplasma species, the difficulties involved in diagnosis and establishing pathogenicity, and the challenges in defining appropriate treatment.
Ureaplasma spp. is detected in the urogenital tract, including the vagina, cervix, chorioamnion, and placenta. Their colonization is associated with histologic chorioamnionitis (CAM), often observed in placentas from preterm delivery. We isolated Ureaplasma spp. from 63 preterm placentas among 151 specimens, which were delivered at <32 wk of gestation. Of the 63 placentas, 52 (83%) revealed CAM in cultures positive for Ureaplasma spp., however, CAM was observed only in 30% (26/88) of cultures negative for Ureaplasma spp. (p < 0.01). Colonization by Ureaplasma spp. was an independent risk factor for CAM (OR, 11.27; 95% CI, 5.09-24.98). Characteristic neutrophil infiltration was observed in the amnion and subchorion (bistratified pattern) in cultures positive for Ureaplasma spp. FISH analysis of CAM placenta with male infant pregnancy indicated that bistratified infiltrated neutrophils showed the XX karyotype and umbilical vein infiltrated neutrophils showed XY karyotype. The distribution of sulfoglycolipid, the receptor of Ureaplasma spp., was mainly detected in the amnion. Ureaplasmal urease D protein and ureB gene were both detected in the amnion, indicating direct colonization by Ureaplasma spp.
To study the role of Mycoplasma hominis and T-mycoplasmas (Ureaplasma urealyticum) in chorioamnionitis, we obtained culture from 249 puerperal women and their babies. The placentas were examined histologically. Infants whose placentas showed inflammation (chorioamnionitis) had cultures positive for T-mycoplasmas more frequently (37.5 per cent) than those with normal placentas (19.0 per cent) (P = 0.021). Colonization with M. hominis was found in 16.0 per cent of the babies and was not significantly associated with chorioamnionitis. Material colonization with mycoplasmas was more frequent (73.4 per cent) and was not correlated with placental inflammation. We conclude that a substantial proportion of cases of chorioamnionitis may be caused by prenatal infection with T-mycoplasmas. The fact that these organisms are not highly virulent could explain the frequent finding of inflammed placentas from otherwise normal pregnacies. No adverse clinical effects of the placental lesions or of mycoplasmal colonization could be detected in this small study.
We performed a metaanalysis to determine whether there is an association between Ureaplasma urealyticum and chronic lung disease of prematurity (CLD); most studies involved small sample sizes, and the reported lack of statistical significance could have been due to inadequate power.
Articles were identified from the literature through a search of MEDLINE, Excerpta Medica, and Reference Update, with the search terms "Ureaplasma urealyticum," "CLD," and "bronchopulmonary dysplasia." The search was initially conducted in June 1994 and updated in March 1995. Abstracts were identified through a hand search of proceedings from two meetings for the years 1987 through 1994. Summary data on frequency of CLD in U. urealyticum-colonized and uncolonized babies were independently determined by the three authors. Preterm and term neonates were included. Colonization required recovery of U. urealyticum from a respiratory or surface specimen. The presence of CLD at 28 or 30 days was determined.
Seventeen publications comprising 13 full publications and 4 abstracts were included in the analysis. The estimates for relative risk (RR) exceeded one in all studies, although the lower confidence interval included one in seven studies. The RR for the development of CLD in colonized neonates was 1.72 (95% confidence interval, 1.5 to 1.96) times that for uncolonized neonates. The RR was not significantly different for abstracts versus full publications; studies focusing on extremely premature, low birth weight neonates versus studies including all neonates; and studies in which only endotracheal aspirates were used to define colonization versus others. The RR since surfactant use was somewhat lower than in studies in which receipt of surfactant was unknown.
This metaanalysis supports a significant association between U. urealyticum colonization and subsequent development of CLD. A randomized, controlled trial showing a reduction in CLD through the use of an antibiotic effective against U. urealyticum would provide further support of a causative role for this agent.
The aim of the present study was to determine the association between the presence of Ureaplasma urealyticum in endotracheal aspirates and bronchopulmonary dysplasia (BPD). In addition, a review of similar studies from the English literature is presented. During the period February 1990 until March 1991, 108 mechanically-ventilated infants were included in a prospective study. Endotracheal aspirates were cultured for U. urealyticum. Birth weight, gestational age and development of BPD was recorded. Cultures were positive in 23 infants, resulting in a 21% colonization. The infants with positive cultures had a significantly lower gestational age (mean 28.9 vs 31.5 weeks; range 25-40 vs 25-42 weeks; p=0.0014). A positive U. urealyticum culture was not associated with a low birth weight (mean 1,390 vs 1,690 g; range 675-4,090 vs 700-3,600 g; p=0.0712). A positive U. urealyticum culture was significantly associated with BPD (p=0.0373). However, after correction for gestational age by logistic regression analysis, BPD failed to correlate with the presence of positive U. urealyticum cultures. A MEDLINE search of the English language literature was performed to identify all studies having the association of U. urealyticum colonization and BPD. Fourteen controlled studies were found. Five studies found no significant association between U. urealyticum colonization and BPD. In two studies, after correction for gestational age, the association between U. urealyticum colonization and BPD did not remain significant. In five studies with a significant association between U. urealyticum colonization and BPD, no correction for gestational age had taken place. In conclusion, U. urealyticum colonization is not associated with the development of bronchopulmonary dysplasia. U. urealyticum is often associated with gestational age and/or low birth weight; to investigate the association between U. urealyticum and bronchopulmonary dysplasia correction for both parameters should be made.
To determine whether Ureaplasma urealyticum respiratory tract colonization in very low birth weight infants during the first week of life is associated with changes in tracheal aspirate concentrations of the cytokines interleukin 1-beta (IL-1-beta), tumor necrosis factor alpha (TNF-alpha) and IL-6.
Infants with birth weights < or =1250 g were prospectively enrolled. Samples were obtained from the endotracheal tube or nasopharynx on Day 1 and again between Days 7 and 10 for U. urealyticum culture. The concentrations of IL-1-beta, TNF-alpha and IL-6 were measured in tracheal aspirate samples by enzyme-linked immunosorbent assay.
There were 18 positive cultures for U. urealyticum from 15 of 96 infants (15.6%). IL-1-beta in tracheal aspirates expressed as concentration per volume or as a ratio of IL-1-beta to IL-6 were 7- and 14.9-fold higher, respectively, in Ureaplasma-positive infants than in Ureaplasma-negative infants (P < 0.05). The TNF-alpha/IL-6 ratio was 18.9 and 15.5 times higher in the Ureaplasma-positive aspirates than in the Ure aplasma-negative aspirates on Day 1 and Days 7 to 10 (P < 0.05). Concentrations of IL-1-beta and TNF-alpha were significantly correlated on Day 1 and Days 7 to 10. Although there was no clinical association demonstrated between U. urealyticum colonization and the development of bronchopulmonary dysplasia (BPD) in this study, infants who developed BPD had significantly higher IL-1-beta concentrations and ratios of IL-1-beta to IL-6 in Day 1 aspirates than infants who did not develop BPD. Conclusions. Isolation of U. urealyticum from the respiratory tract is associated with increased IL-1-beta concentrations and IL-1-beta-IL-6 ratios on Day 1 and increased TNF-alpha-IL-6 ratios on Days 1 and 7 to 10 in tracheal aspirates of colonized infants. Infants who developed BPD had higher IL-1-beta concentrations and IL-1-beta-IL-6 ratios, suggesting that these may be early markers of lung inflammation.
To determine the relationship between the presence of Ureaplasma urealyticum in the amniotic cavity and adverse maternal and perinatal outcome in women with preterm labor.
Amniocentesis was performed in 181 patients with preterm labor and intact membranes. Amniotic fluid (AF) was cultured for aerobic and anaerobic bacteria and mycoplasmas. Patients were divided into three groups according to the results of AF culture: those with negative AF cultures (n=160), those with positive AF cultures and in whom the only microbial isolate was U urealyticum (n=11), and those with positive cultures for non-ureaplasmas or mixed microorganisms (n=10). Survival techniques were used for analysis.
The prevalence of positive AF cultures in which the only microbial isolate was Uurealyticum was 6.1% (11 of 181), and of positive cultures with non-ureaplasmas or mixed microorganisms was 5.5% (10 of 181). The amniocentesis-to-delivery interval was significantly shorter in patients with positive cultures limited to U urealyticum than in those with negative cultures (median 7 [range 0.1-149] hours versus median 264 [0.1-2659] hours, P < .001). Preterm delivery within 48 hours, 72 hours, and 7 days was more frequent in patients with U urealyticum in the AF than in those with sterile AF (48 hour: 91% versus 33%; 72 hour: 91% versus 36%; 7 days: 100% versus 45%, P < .001 for each). Patients with positive AF cultures limited to U urealyticum had a significantly higher rate of adverse perinatal outcome than those with negative culture. Adverse outcomes included low gestational age at birth, low birth weight, histologic chorioamnionitis, significant neonatal morbidity, and perinatal death.
Microbial invasion of the amniotic cavity with U urealyticum is a risk factor for impending preterm delivery and adverse perinatal outcome.
Ureaplasma urealyticum is the microorganism most frequently isolated from the amniotic fluid of women with preterm labor and preterm premature rupture of the membranes, yet the significance of amniotic fluid infection exclusively caused by this microorganism is unclear. This study was conducted to examine the presence and intensity of the inflammatory response in the fetal, amniotic, and maternal compartments in patients with preterm premature rupture of membranes and amniotic fluid infection with U urealyticum.
One hundred twenty patients with preterm premature rupture of the membranes who delivered preterm neonates (gestational age </=36 weeks) within 5 days of amniocentesis were included. Amniotic fluid was cultured for aerobic and anaerobic bacterias and mycoplasmas. The intensity of the inflammatory response was evaluated by amniotic fluid concentrations of interleukin-6, tumor necrosis factor-alpha, interleukin-1beta, amniotic fluid white blood cell count, histologic chorioamnionitis, and interleukin-6 concentrations of umbilical cord plasma at birth. Cytokines were measured by sensitive and specific immunoassays.
The prevalence of a positive amniotic fluid culture in which the only microbial isolate was U urealyticum was 21% (25/120) and that of positive cultures with other or mixed microorganisms was 9% (11/120). Intrauterine inflammatory response was significantly more intense in patients with positive amniotic fluid cultures limited to U urealyticum than in those with a negative culture (median and range of amniotic fluid interleukin-6, 13.4 [0.7-115.2] ng/mL vs 0.9 [0.001-137.2] ng/mL; median and range of amniotic fluid tumor necrosis factor-alpha, 85.5 [0.9-1600] pg/mL vs 2.4 [0-1142] pg/mL; median and range of amniotic fluid interleukin-1beta, 274.0 [0.3->80,000] pg/mL vs 3.4 [0-1449] pg/mL; median and range of amniotic fluid white blood cell count, 306 [0-19,764] cells/mm3 vs 3 [0-7956] cells/mm3; median and range of cord interleukin-6, 20.0 [2. 3-1199.6] pg/mL vs 6.7 [0-5550] pg/mL; histologic chorioamnionitis, 100% [22/22] vs 42% [30/72]; P <.01 for each) but was similar to values of patients with a positive amniotic fluid culture for other bacteria or mixed microorganisms.
Patients with preterm premature rupture of membranes and microbial invasion of the amniotic cavity with U urealyticum are associated with a robust host inflammatory response in the fetal, amniotic, and maternal compartments.
Ureaplasma urealyticum and its association with chronic lung disease (CLD) of prematurity has remained a controversial topic. To readdress this question, we performed a longitudinal study using culture and polymerase chain reaction to detect U urealyticum in the respiratory tract of very low birthweight infants throughout their neonatal intensive care unit hospitalizations.
We screened 125 infants weighing <1500 g and/or <32 weeks' gestational age over a 12-month period, collecting endotracheal, nasopharyngeal, and throat specimens on days of age 1, 3, 7, and weekly thereafter. CLD was defined as dependency on supplemental oxygen at 28 days and at 36 weeks' postconceptional age.
Forty infants (32%) had 1 or more positive specimens by culture or polymerase chain reaction. We identified 3 patterns of U urealyticum colonization: persistently positive (n = 18), early transient (n = 14), and late acquisition (n = 8). We compared the rates of CLD in each of the 3 colonized groups with the rate of CLD in the noncolonized group. We found a significantly higher rate of CLD at 28 days of age (odds ratio: 8.7; 95% confidence interval: 3.3, 23) and at 36 weeks' postconception (odds ratio: 38.5, 95% confidence interval: 4.0, 374) only for infants with persistently positive colonization.
This study demonstrates that the risk of developing CLD varies with the pattern of U urealyticum colonization. Only the persistently positive colonization pattern, which accounted for 45% of the U urealyticum-positive infants, was associated with a significantly increased risk of development of CLD.
Ureaplasma urealyticum is the microorganism most frequently isolated from the amniotic fluid of women in preterm labor. The relationship between
intra-amniotic U. urealyticum in healthy second-trimester pregnant women and subsequent pregnancy outcome was investigated. Transabdominal amniotic fluid
obtained from 254 asymptomatic women at 15–17 weeks’ gestation were tested by polymerase chain reaction (PCR). U. urealyticum was identified in 29 subjects (11.4%). A subsequent preterm labor occurred in 17 U. urealyticum–positive women (58.6%), compared with 10 (4.4%) U. urealyticum–negative women (P<.0001). Preterm birth was documented in 7 (24.1%) U. urealyticum–positive women compared with only 1 U. urealyticum–negative woman (0.4%) (P<.0001). U. urealyticum–positive women also had a higher prevalence of preterm labor in a prior pregnancy (20.7%) than did the negative women (2.7%;
P=.0008). PCR testing of second-trimester amniotic fluid for U. urealyticum can identify women at risk for subsequent preterm labor and delivery