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Abstract

To examine the relationships between clinical or histological chorioamnionitis and cerebral palsy using a meta-analysis approach. A systematic review of the literature appeared in PubMed between 2000 and 2009 was conducted using the search terms "cerebral palsy" and "infection," with broad-scope variations in terminology of "white matter damage," "periventricular leukomalacia," "cystic periventricular leukomalacia," "chorioamnionitis," "intrauterine infection," "intraventricular hemorrhage," "funisitis," "fetal inflammatory response," "early neonatal sepsis," "neurological impairment," "virus," "bacteria," "fungi," and "protozoa," with variations of suffixes (eg, "viral," "bacterial," "fungal," "protozoan," etc), and "urinary tract infection," "bacterial vaginosis," "bacteriuria," and "cytokines." The related key words "gestational age," "small for gestational age," "preterm," and "low birth weight" also were added to the search terms. Only studies published in English were included. Three hundred eight articles were retrieved and systematically reviewed independently by two authors. Application of four inclusion criteria led to 15 studies being considered for data abstraction. An exposure was considered relevant if it met the established criteria for clinical or histological chorioamnionitis. The outcome was a diagnosis of cerebral palsy in accordance with established criteria. The data were abstracted onto standard forms, correlated according to eight characteristics, and tabulated. Twelve of the 15 studies contained information on the association between clinical chorioamnionitis and cerebral palsy, and eight studies included information on the association between histological chorioamnionitis and cerebral palsy. The results indicated that there were significant associations between clinical chorioamnionitis or histological chorioamnionitis and cerebral palsy, for clinical chorioamnionitis (chi1=13.91; P<.001) with a pooled odds ratio of 2.42 (95% confidence interval 1.52-3.84), and for histological chorioamnionitis (chi1=6.86; P=.009) with a pooled odds ratio of 1.83 (95% confidence interval, 1.17-2.89). The data suggested increased risks of 140% and 80% for neonates exposed to clinical chorioamnionitis or histological chorioamnionitis, respectively. The significant association of clinical or histological chorioamnionitis with cerebral palsy suggested that clinical strategies to prevent or reduce chorioamnionitis would lead to a reduction in cerebral palsy. The culture techniques currently used to diagnose the presence of pathogenic microorganisms during pregnancy need to improve, both in their methodology and in the length of time they require.

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... Further, preterm babies who are exposed to inflammation and/or infection causing chorioamnionitis usually need greater requirement for respiratory support, with a greater risk to develop severe neurological damage with respect to those neonates who are not exposed to chorioamnionitis [13][14][15][16][17]. ...
... Chorioamnionitis is defined as a perinatal condition presenting with inflammation of the fetal membrane, including the chorion and the amnion [13][14][15][16][17]. The clinical presentation of this disease can vary based on microbiologic, histologic, and clinical features, which interact among one another to varying degrees [13][14][15][16][17]. ...
... Chorioamnionitis is defined as a perinatal condition presenting with inflammation of the fetal membrane, including the chorion and the amnion [13][14][15][16][17]. The clinical presentation of this disease can vary based on microbiologic, histologic, and clinical features, which interact among one another to varying degrees [13][14][15][16][17]. ...
Article
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Background: The present manuscript aims to be a narrative review evaluating the association between inflammation in chorioamnionitis and damage on respiratory centers, peripheral airways, and lungs, explaining the pathways responsible for apnea in preterm babies born by delivery after chorioamnionitis. Methods: A combination of keywords and MESH words was used, including: “inflammation”, “chorioamnionitis”, “brainstem”, “cytokines storm”, “preterm birth”, “neonatal apnea”, and “apnea physiopathology”. All identified papers were screened for title and abstracts by the two authors to verify whether they met the proper criteria to write the topic. Results: Chorioamnionitis is usually associated with Fetal Inflammatory Response Syndrome (FIRS), resulting in injury of brain and lungs. Literature data have shown that infections causing chorioamnionitis are mostly associated with inflammation and consequent hypoxia-mediated brain injury. Moreover, inflammation and infection induce apneic episodes in neonates, as well as in animal samples. Chorioamnionitis-induced inflammation favors the systemic secretion of pro-inflammatory cytokines that are involved in abnormal development of the respiratory centers in the brainstem and in alterations of peripheral airways and lungs. Conclusions: Preterm birth shows a suboptimal development of the brainstem and abnormalities and altered development of peripheral airways and lungs. These alterations are responsible for reduced respiratory control and apnea. To date, mostly animal studies have been published. Therefore, more clinical studies on the role of chorioamninitis-induced inflammation on prematurity and neonatal apnea are necessary.
... C erebral palsy (CP), the most common cause of motor deficiency in young children, occurs in about 5% of very premature births. [1][2][3] It has been suggested that chorioamnionitis, either clinical or histologic, is associated with CP. 4,5 Definitions of prenatal inflammation/infection vary widely, and its impact on the fetal brain remains controversial. 6 Three metaanalyses have shown conflicting results about an association between chorioamnionitis and CP in infants born premature. ...
... 6 Three metaanalyses have shown conflicting results about an association between chorioamnionitis and CP in infants born premature. 5,[7][8][9] Most previous studies have included children born prematurely without distinguishing the causes of these preterm deliveries, primarily, placental vascular disease, preterm premature rupture of membranes (PPROM), or preterm labor. 10,11 However, the clinical path leading to preterm birth, including fetal and obstetric complications and mode of delivery, differs in women with vascular disorders and those with preterm labor and PPROM. ...
... Interestingly, the strength of this association increased with the accuracy of the clinical criteria used to define clinical chorioamnionitis. 5,7 The association between histologic chorioamnionitis and CP is even more controversial, and the most recent meta-analysis yielded discordant results, with aORs ranging from 0.35 to 2.48. 9,29,30 Our findings come from the largest nationwide population-based prospective study we are aware of; its data about clinical chorioamnionitis and histologic chorioamnionitis are accurate and its practices consistent with current worldwide recommendations (ie, antenatal cortico-steroids for preterm labor or PPROM and antibiotics for PPROM). ...
Article
Objective To assess whether chorioamnionitis is associated with cerebral palsy (CP) or death at 2 years' corrected age in infants born before 32 weeks of gestation after spontaneous birth. Study design EPIPAGE-2 is a national, prospective, population-based cohort study of children born preterm in France in 2011; recruitment periods varied by gestational age. This analysis includes infants born alive after preterm labor or preterm premature rupture of membranes from 240/7 to 316/7 weeks of gestation. We compared the outcomes of CP, death at 2 years' corrected age, and “CP or death at age 2” according to the presence of either clinical chorioamnionitis or histologic chorioamnionitis. All percentages were weighted by the duration of the recruitment period. Results Among 2252 infants born alive spontaneously before 32 weeks of gestation, 116 (5.2%) were exposed to clinical chorioamnionitis. Among 1470 with placental examination data available, 639 (43.5%) had histologic chorioamnionitis. In total, 346 infants died before 2 years and 1586 (83.2% of the survivors) were evaluated for CP at age 2 years. CP rates were 11.1% with and 5.0% without clinical chorioamnionitis (P = .03) and 6.1% with and 5.3% without histologic chorioamnionitis (P = .49). After adjustment for confounding factors, CP risk rose with clinical chorioamnionitis (aOR 2.13, 95% CI 1.12-4.05) but not histologic chorioamnionitis (aOR 1.21, 95% 0.75-1.93). Neither form was associated with the composite outcome “CP or death at age 2.” Conclusions Among infants very preterm born spontaneously, the risk of CP at a corrected age of 2 years was associated with exposure to clinical chorioamnionitis but not histologic chorioamnionitis.
... Exposure to HCA is associated with an increased risk of medical problems later in life including cerebral palsy, developmental delay, asthma, and allergic disorders (6)(7)(8)(9)(10)(11)(12)(13). Although the mechanism of this increased risk is not yet known, alteration in gene expression secondary to differential DNA methylation may contribute to this increased risk. ...
... Previous studies have also shown that HCA is associated with neurodevelopmental impairment and cerebral palsy (8)(9)(10)13). Several genes involved in nervous system development and function, neurological diseases, and neurological pathways were found to be differentially methylated in cord blood mononuclear leukocytes after exposure to HCA. ...
Article
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Background: Histological chorioamnionitis (HCA) is an infection/inflammation of fetal membranes and complicates 5.2–28.5% of all live births. Exposure to HCA can have long-term consequences including abnormal neurodevelopment and an increased risk for allergic disorders and asthma later in childhood. HCA may incite epigenetic changes, which have the potential to modulate both the immune and neurological systems as well as increase the risk of related disorders later in life. However, there is limited data on the impact of HCA on epigenetics, in particular DNA methylation, and changes to immune and neurological systems in full-term human neonates. Objective: To determine differential DNA methylation in cord blood mononuclear leukocytes from neonates exposed to HCA. Methods: Cord blood was collected from 10 term neonates (5 with HCA and 5 controls without HCA) and mononuclear leukocytes were isolated. Genome-wide DNA methylation screening was performed on Genomic DNA extracted from mononuclear leukocytes. Results: Mononuclear leukocytes from cord blood of HCA-exposed neonates showed differential DNA methylation of 68 probe sets compared to the control group (44 hypermethylated, 24 hypomethylated) with a p ≤ 0.0001. Several genes involved in immune modulation and nervous system development were found to be differentially methylated. Important canonical pathways as revealed by Ingenuity Pathway Analysis (IPA) were CREB Signaling in Neurons, FcγRIIB Signaling in B Lymphocytes, Cell Cycle: G1/S Checkpoint Regulation, Interleukin-1, 2, 3, 6, 8, 10, 17, and 17A signaling, p53 signaling, dopamine degradation, and serotonin degradation. The diseases and disorders picked up by IPA were nervous system development and function, neurological disease, respiratory disease, immune cell trafficking, inflammatory response, and immunological disease. Conclusions: HCA induces differential DNA methylation in cord blood mononuclear leukocytes. The differentially methylated genes may contribute to inflammatory, immunological and neurodevelopmental disorders in neonates exposed to HCA.
... Previous systematic reviews have demonstrated an association between clinical chorioamnionitis and the development of cerebral palsy. 6,92,93 However, this systematic review is the first to find an association between intrapartum hyperthermia of any cause and neonatal brain injury. ...
... 97 Previous meta-analyses found that, whilst there is often an association between clinical chorioamnionitis and cerebral palsy, this is not seen to the same extent with histological chorioamnionitis. 6,92,93 This hints that it is the hyperthermia itself, rather than the underlying disease process, that has the greater impact on neonatal neurological outcome. The finding in the present meta-analysis that intrapartum hyperthermia of any cause is associated with neonatal brain injury adds weight to this argument. ...
Article
Background Epidural analgesia is associated with intrapartum hyperthermia, and chorioamnionitis is associated with neonatal brain injury. However, it is not known if epidural hyperthermia is associated with neonatal brain injury. This systematic review and meta-analysis investigated three questions: (1) does epidural analgesia cause intrapartum hyperthermia, (2) is intrapartum hyperthermia associated with neonatal brain injury, and (3) is epidural-induced hyperthermia associated with neonatal brain injury? Methods PubMed, ISI Web of Knowledge, The Cochrane Library, and Embase were searched from inception to January 2020 using Medical Subject Headings (MeSH) terms relating to epidural analgesia, hyperthermia, labour, and neonatal brain injury. Studies were reviewed independently for inclusion and quality by two authors (Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach). Two meta-analyses were performed using the Mantel–Haenszel fixed effect method to generate odds ratios (ORs) and 95% confidence intervals (CIs). Results Forty-one studies were included for Question 1 (646 296 participants), 36 for Question 2 (11 866 021 participants), and two studies for Question 3 (297 113 participants). When the mode of analgesia was randomised, epidural analgesia was associated with intrapartum hyperthermia (OR: 4.21; 95% CI: 3.48–5.09). There was an association between intrapartum hyperthermia and neonatal brain injury (OR: 2.79; 95% CI: 2.54–2.3.06). It was not possible to quantify the association between epidural-induced hyperthermia and neonatal brain injury. Conclusions Epidural analgesia is a cause of intrapartum hyperthermia, and intrapartum hyperthermia of any cause is associated with neonatal brain injury. Further work is required to establish if epidural-induced hyperthermia is a cause of neonatal brain injury.
... A wealth of literature describes epidemiologic associations between maternal inflammation (with or without intrauterine infection), neonatal brain injury and long-term neurologic and neuropsychiatric morbidities, including CP, neurodevelopmental delay, epilepsy, and psychiatric disease (Dammann and Leviton, 2000;Yoon and Romero, 1996;Yoon et al., 1997a;Anblagan et al., 2016;Ophelders et al., 2020;Hagberg et al., 2015;Gotsch et al., 2007;Shatrov et al., 2010;Shi et al., 2017;Edwards and Tan, 2006;Leviton et al., 2010a;Xing et al., 2019;Venkatesh et al., 2020;Malaeb and Dammann, 2009;Burd et al., 2012;Raghavan et al., 2019). For instance, the risk of CPthe late sequelae of central nervous system (CNS) WMI and a complication of prematurityis increased in the setting of maternal prenatal infection (Wu and Colford, 2001;Mann et al., 2009;Walstab et al., 2002;Miller et al., 2013). ...
... Moreover, at least two recent studies from Europe have showed lack of association between chorioamnionitis and neurodevelopmental outcomes in preterm infants (Källén et al., 2015;Schlapbach et al., 2010). However, results from four systematic reviews and meta-analyses have found positive associations between histologic or clinical chorioamnionitis and CP or cPVL in preterm infants ( Table 1) (Shatrov et al., 2010;Wu, 2002). ...
Article
Preterm newborns are exposed to several risk factors for developing brain injury. Clinical studies have suggested that the presence of intrauterine infection is a consistent risk factor for preterm birth and white matter injury. Animal models have confirmed these associations by identifying inflammatory cascades originating at the maternofetal interface that penetrate the fetal blood-brain barrier and result in brain injury. Acquired diseases of prematurity further potentiate the risk for cerebral injury. Systems biology approaches incorporating ante- and post-natal risk factors and analyzing omic and multiomic data using machine learning are promising methodologies for further elucidating biologic mechanisms of fetal and neonatal brain injury.
... Notably, more than 40% of the prematurity is triggered by IUI (2,(5)(6)(7). In addition to maternal morbidity, IUI enhances the risk for fetal and newborn brain injury (8)(9)(10), necrotizing enterocolitis (11), and chronic lung disease (12). ...
Article
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Preterm birth (PTB) is a major cause of neonatal mortality and morbidity, often triggered by chorioamnionitis or intrauterine inflammation (IUI) with or without infection. Recently, there has been a strong association of IL-1 with PTB. We hypothesized that IL-1R-associated kinase 1 (IRAK1), a key signaling mediator in the TLR/IL-1 pathway, plays a critical role in PTB. In human fetal membranes (FM) collected immediately after birth from women delivering preterm, p-IRAK1 was significantly increased in all the layers of FM with chorioamnionitis, compared with no-chorioamnionitis subjects. In a preterm rhesus macaque model of IUI given intra-amniotic LPS, induction of p-IRAK1 and downstream proinflammatory signaling mediators were seen in the FM. In a C57BL/6J wild-type PTB mouse model of IUI given intrauterine LPS, an IRAK1 inhibitor significantly decreased PTB and increased live birth in a dose-dependent manner. Furthermore, IRAK1 knockout mice were protected from LPS-induced PTB, which was seen in wild-type controls. Activation of IRAK1 was maintained by K63-mediated ubiquitination in preterm FM of humans with chorioamnionitis and rhesus and mouse IUI models. Mechanistically, IRAK1 induced PTB in the mouse model of IUI by upregulating expression of COX-2. Thus, our data from human, rhesus, and mouse demonstrates a critical role IRAK1 in IUI and inflammation-associated PTB and suggest it as potential therapeutic target in IUI-induced PTB.
... Future studies should classify histologic chorioamnionitis by site and location and by molecular diagnostics and be designed in ways that will assess the extent to which early detection and treatment of chorioamnionitis can affect infant neurodevelopment. 52 We also employed rigorous standardized outcome ascertainments in contrast to previous studies. In the ELGAN study cohort, almost two-thirds of children who had a subnormal IQ (<70) at the age of 2 years as assessed with the Bayley Scales were no longer considered to have such a low IQ when assessed with the outcome at 10 years used for this report. ...
Article
Background Children born extremely preterm whose placenta had histologic evidence of chorioamnionitis have early brain dysfunction, but little is known about neurological development at 10 years of age. Objective We investigated the association between histologic chorioamnionitis and neurodevelopmental impairment at 10 years among children born <28 weeks gestation (extremely preterm). Methods The multicenter Extremely Low Gestational Age Newborn (ELGAN) Study enrolled extremely preterm newborns from 2002-2004 at 14 U.S. hospitals. Chorioamnionitis was defined by histologic stage (early, moderate, and advanced) and grade (mild/moderate and severe) of chorionic plate and umbilical cord inflammation. The children were evaluated for cerebral palsy at 2 years, and autism spectrum disorder, cognitive impairment (intelligence quotient >2 standard deviations below the mean), and epilepsy at age 10 years by blinded evaluators using validated measures. Multivariable logistic regression with generalized estimating equations was used. Results Among 805 placenta, 43% (347/805) had histologic chorioamnionitis by moderate or advanced maternal stage, 36% (286/805) by severe maternal grade, 18% (132/737) by moderate or advanced fetal stage, and 1% (10/737) by severe fetal grade. The frequencies of impairments were 11% (88/767) for cerebral palsy, 7% (56/773) for autism spectrum disorder, 15% (120/788) for cognitive impairment, and 7% (52/763) for epilepsy. Adjusted for maternal age, body mass index, race, insurance status, maternal education, tobacco use, infant sex, and multiple gestations, the adjusted odds (AOR) for the association between histologic chorioamnionitis and cerebral palsy years was increased with advanced maternal stage (AOR 2.5, 95% CI 1.6 to 3.9), severe maternal grade (AOR 2.0, 95% CI 1.2 to 3.4), moderate fetal stage (AOR 2.20, 95% CI 2.1 to 2.2), and mild or moderate fetal grade (AOR 1.5, 95% CI 1.0 to 2.2). Similarly, the AOR for the association between histologic chorioamnionitis and epilepsy was increased with advanced maternal stage (AOR 1.5, 95% CI 1.3 to 1.6) and severe fetal grade (AOR 5.9, CI 1.9 to 17.8). In addition, the AOR for the association between histologic chorioamnionitis and autism spectrum disorder was increased with mild or moderate fetal grade (AOR 1.7, 95% CI 1.0 to 2.9). Histologic chorioamnionitis was not associated with cognitive impairment. These findings held after adjustment for gestational age at delivery. In contrast to histological chorioamnionitis, a clinical diagnosis of chorioamnionitis was not associated with neurodevelopmental impairment. Conclusion Histologic chorioamnionitis may be associated with some forms of neurodevelopmental impairment at 10 years of life among infants born <28 weeks gestation.
... symptomatic) and histologic (i.e. mostly asymptomatic) chorioamnionitis are associated with increased risks of, respectively, 140 % and 80 % for the neonate to develop CP in the population (i.e. term and preterm births combined) (Shatrov et al., 2010). Moreover, term newborns (4.7-fold increase) seem to be more affected by CP than those born prematurely (1.9-fold increase), when exposed to chorioamnionitis in-utero (Wu and Colford, 2000). ...
Thesis
Although some bacteria can be beneficial for the host immune system, others can cause harm during pregnancy. The perinatal period involves highly elaborate and time-specific neurodevelopmental processes, which can be disrupted by many types of environmental insults such as maternofetal immune activation. Changes in placental histology may impact fetal outcomes by altering nutrient transport, hormone production, as well as inflammatory factor released in the fetal circulation, potentially directly or indirectly affecting the fetal brain. Placental inflammation – termed chorioamnionitis – is associated with increased risks of preterm delivery, intra-uterine growth retardation (IUGR) and brain injury related to neurobehavioural disabilities such as cerebral palsy (CP), autism spectrum disorders (ASD), and attention-deficit/hyperactivity disorder (ADHD). Chorioamnionitis is a significant threat to the neonates, potentially causing brain injury and other morbidities that are affecting males more often than females for poorly known reasons. Group B Streptococcus (GBS) is one of the most common bacteria isolated in human chorioamnionitis. The two most prevalent GBS isolates are serotypes Ia and III, the latter being associated with worse clinical outcomes in the neonate. The Sébire Laboratory was among the first to design preclinical models of GBS-induced chorioamnionitis. Using these rat models, we showed a sexually dichotomous, ASD-like phenotype in the male but not female offspring exposed to GBS serotype Ia in-utero. GBS serotype Ia-exposed females presented white matter brain damage and behavioural impairments such as increased sociability and impaired sensorimotor integrations during adolescence. In this thesis, I hypothesised that placental inflammation triggered by GBS varies according to fetal sex and that GBS exposure leads to serotype- and sex-specific neurodevelopmental impairments in the offspring. I aimed to (1) investigate neurobehavioural outcomes in the female and male offspring in-utero-exposed to the two most common GBS serotypes, and (2) identify the key innate immune pathways involved in sex-specific GBS-induced inflammation in the maternal-placental-fetal axis. This thesis presents for the first time that: (i) females exposed in-utero to GBS serotype Ia displayed ADHD-like behaviours post-puberty, (ii) in-utero exposure to GBS serotype III impacted negatively fetal growth and led to sex-specific CP-like neuromotor impairments in the IUGR offspring, and (iii) the GBS-induced placental and fetal inflammatory response varies according to fetal sex, with a stronger pro-inflammatory response in male compared to female tissues. These results demonstrated for the first time a correlation between the maternal and the fetal circulation in the intensity of interleukin-1β response following placental infection by GBS, providing a potential translational biomarker. This thesis opens a new research avenue to better understand the sex-differentiated vulnerability of the immature brain to frequent, and modifiable, environmental factors such as GBS. Our results pave the way to develop, adapted to fetal sex, new placento- and neuro-protective therapies, which are critically needed. Teams already showed that human recombinant interleukin-1 Receptor antagonist was a safe and efficient anti-inflammatory strategy to prevent chorioamnionitis and subsequent brain injuries triggered by lipopolysaccharides from Escherichia coli. Demonstrating the same benefits against a placental infection by live GBS bacteria – rather than non-infectious bacterial components – would bring us to the threshold of preclinical data required for proposing this anti-inflammatory treatment as a placento- and neuro-protective drug. This treatment would alleviate the heavy burden of neurodevelopmental disabilities associated with chorioamnionitis from two of the primary bacteria involved in placental infections (i.e. GBS and E. coli).
... Chorioamnionitis is associated with increased maternal and perinatal morbidity and mortality [15]. Neonatal morbidity and mortality related to chorioamnionitis is inversely proportional to gestational age at birth and includes: neonatal sepsis, pneumonia, intraventricular hemorrhage, and cerebral white matter damage with possible short and long-term sequelae, such as cerebral palsy [16]. PROM, at term or preterm, is associated with an increase in neonatal sepsis [17]. ...
... It is possible that more infants in the non-HDP group had poor prognostic factors such as severe CAM, placental abruption and fetal distress. CAM is well-known to be associated with poor neurological outcomes in preterm infants [24][25][26] . However, we found that excluding women with histological CAM from both groups resulted in similar outcomes when all women were included. ...
Article
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To evaluate the impact of maternal hypertensive disorders of pregnancy (HDP) on mortality and neurological outcomes in extremely and very preterm infants using a nationwide neonatal database in Japan. This population-based retrospective study was based on an analysis of data collected by the Neonatal Research Network of Japan from 2003 to 2015 of neonates weighing 1,500 g or less at birth, between 22 and 31 weeks’ gestation. A total of 21,659 infants were randomly divided into two groups, HDP (n = 4,584) and non-HDP (n = 4,584), at a ratio of 1:1 after stratification by four factors including maternal age, parity, weeks of gestation, and year of delivery. Short-term (neonatal period) and medium-term (3 years of age) mortality and neurological outcomes were compared between the two groups by logistic regression analyses. In univariate analysis, HDP was associated with an increased risk for in-hospital death (crude odds ratio [OR], 1.31; 95% confidence interval, 1.04–1.63) and a decreased risk for severe intraventricular haemorrhage (0.68; 0.53–0.87) and periventricular leukomalacia (0.60; 0.48–0.77). In multivariate analysis, HDP was significantly associated with a lower risk for in-hospital death (adjusted OR, 0.61; 0.47–0.80), severe intraventricular haemorrhage (0.47; 0.35–0.63), periventricular leukomalacia (0.59; 0.45–0.78), neonatal seizures (0.40; 0.28–0.57) and cerebral palsy (0.70; 0.52–0.95) at 3 years after adjustment for covariates including birth weight. These results were consistent with those of additional analyses, which excluded cases with histological chorioamnionitis and which divided the infants into two subgroups (22–27 gestational weeks and 28–31 gestational weeks). Maternal HDP was associated with an increased risk for in-hospital death without adjusting for covariates, but it was also associated with a lower risk for mortality and adverse neurological outcomes in extremely and very preterm infants if all covariates except HDP were identical.
... In spite of a lack of early symptoms, exposure to chorioamnionitis, and FIRS in particular, has been linked to an increased risk for severe neonatal morbidities (12)(13)(14), preterm brain injury (11,15), and long term adverse outcomes (16,17), suggesting that inflammatory mechanisms may contribute to injury. In addition to a possible risk of inflammationinduced injury, chorioamnionitis may also affect the immune response and the risk of severe infections in the preterm infant (18). ...
Article
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Background: Preterm infants exposed to chorioamnionitis and with a fetal inflammatory response are at risk for neonatal morbidity and adverse outcome. Alarmins S100A8, S100A9, and S100A12 are expressed by myeloid cells and have been associated with inflammatory activation and monocyte modulation. Aim: To study S100A alarmin expression in cord blood monocytes from term healthy and preterm infants and relate results to clinical findings, inflammatory biomarkers and alarmin protein levels, as well as pathways identified by differentially regulated monocyte genes. Methods: Cord blood CD14+ monocytes were isolated from healthy term (n = 10) and preterm infants (<30 weeks gestational age, n = 33) by MACS technology. Monocyte RNA was sequenced and gene expression was analyzed by Principal Component Analysis and hierarchical clustering. Pathways were identified by Ingenuity Pathway Analysis. Inflammatory proteins were measured by Multiplex ELISA, and plasma S100A proteins by mass spectrometry. Histological chorioamnionitis (HCA) and fetal inflammatory response syndrome (FIRS) were diagnosed by placenta histological examination. Results: S100A8, S100A9, and S100A12 gene expression was significantly increased and with a wider range in preterm vs. term infants. High S100A8 and S100A9 gene expression (n = 17) within the preterm group was strongly associated with spontaneous onset of delivery, HCA, FIRS and elevated inflammatory proteins in cord blood, while low expression (n = 16) was associated with impaired fetal growth and physician-initiated delivery. S100A8 and S100A9 protein levels were significantly lower in preterm vs. term infants, but within the preterm group high S100A gene expression, spontaneous onset of labor, HCA and FIRS were associated with elevated protein levels. One thousand nine hundred genes were differentially expressed in preterm infants with high vs. low S100A alarmin expression. Analysis of 124 genes differentially expressed in S100A high as well as FIRS and HCA groups identified 18 common pathways and S100A alarmins represented major hubs in network analyses. Conclusion: High expression of S100A alarmins in cord blood monocytes identifies a distinct clinical risk group of preterm infants exposed to chorioamnionitis and with a fetal inflammatory response. Gene and pathway analyses suggest that high S100A alarmin expression also affects monocyte function. The connection with monocyte phenotype and inflammation-stimulated S100A expression in other cell types (e.g., neutrophils) warrants further investigation.
... Multiple studies have proven that early antenatal screening for early detection of CA identification and implementation of effective treatment protocol will possibly provide a better prognosis for neonates born to a mother with a history of CA [10][11] . Similarly, Tita AT et al. in their study stated that clinical CA is estimated to affect 1-4% of pregnancies worldwide in developed countries 16 , although data is lacking in these countries, and is expected to be higher than this rate [10][11]17 . ...
Article
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Objective: The aim of this study was to determine the impact of chorioamnionitis on neonatal outcome. Methods: This cross-section descriptive study was conducted in the neonatal intensive care unit (NICU) of the Department of Pediatrics, Liaquat National Hospital Karachi from June 1 st , 2016 to De-cember 31st, 2016. Neonates (infants < 28 days of age) with maternal risk factors indicative of chorioamnionitis (maternal febrile illness in last trimester, high WBC count in maternal blood, lower abdominal pain or tenderness, and foul-smelling discharge) were included in the study. The neo-nates with an inborn error of metabolism and congenital anomalies were excluded from this study. The neonates were further categorized by gestational age as a term (gestational age >37 weeks) and preterm (gestational age <37 weeks). The neonatal outcome is classified into binary categories; dead or alive. Data were recorded by the data collectors in the predesigned proforma. The data were entered and analyzed using SPSS version 22. Results: During the study period, 1200 women delivered a singleton baby, out of which 400 were admitted at NICU. Of 400 infants, a total of 68 neonates of mothers with the indication of chorioamnionitis were enrolled in the study. The mean age of enrolled neonates was 2.55 ± 1.22 days. Out of 68 neonate babies, 33 (48.5%) were males and 35 (51.5%) were females. Only 43 (63%) were delivered, pre-term babies. The morbidities identified were respiratory distress syndrome (33.8%), sepsis (27.9%), intraventricular hemorrhage (10.3%), persistent pulmonary hypertension of newborns (11.8%) and necrotizing enterocolitis (7.4%). A total of 16 (23.5%) neonates died. Out of 16 newborns who died, 32.6% were preterm and 8% were born at term. It was noted that weight, body mass index, fronto-occipital circumference, and gestational age were significant contributors to the mortality. Conclusion: In conclusion, chorioamnionitis is an important contributor to neonatal mortality and morbidity. The neonates of a mother with indications of chorioamnionitis are at an increased risk of respiratory distress syndrome.
... [13][14][15][16] The difficulties in assessing the results are illustrated by current meta-analyses reaching completely opposite conclusions. 17,18 Possible explanations for these inconsistencies are different definitions of chorioamniotis, limited sample sizes with varying inclusion criteria, confounding factors such as severe neonatal morbidities, short follow-up, and a lack of detailed follow-up data. ...
Article
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Chorioamnionitis is an important cause of preterm delivery. Data on neurodevelopmental outcome in exposed infants are inconsistent due to difficulties in diagnosing intrauterine infection/inflammation and lack of detailed long-term follow-up. We investigate cognitive and motor function in preterm infants at early school age and relate the findings to bacteria in amniotic fluid obtained by amniocentesis (microbial invasion of the amniotic cavity (MIAC)) or placenta findings of histological chorioamnionitis (HCA) or fetal inflammatory response syndrome (FIRS). Sixty-six infants with gestational age <34 weeks at birth and without major disabilities were assessed using WISC-III and the Bruininks–Oseretsky Test of Motor Proficiency. Results were corrected for gestational age and sex. Children exposed to MIAC had significantly lower scores for full-scale IQ and verbal IQ compared to the non-MIAC group and the difference in full-scale IQ remained after correction for confounding factors. The MIAC group had also significantly lower motor scores after correction. In contrast, motor function was not affected in infants exposed to HCA or FIRS and differences between groups for cognitive scores were lost after corrections. Exposure to bacteria in amniotic fluid is associated with lower motor and cognitive scores in school age preterm infants without major disabilities.
... 7,8 Given that intraamniotic infection is associated with both maternal and neonatal complications, it is important to examine if amnioinfusion is associated with increased odds of intraamniotic infection. [9][10][11] In addition, little is known whether amnioinfusion is associated with increased odds of postpartum hemorrhage as amnioinfusion can lead to uterine distension, a known risk factor for this obstetric complication. 12 Therefore, we sought to examine whether an amnioinfusion is associated with increased odds of intraamniotic infection or postpartum hemorrhage compared with intrauterine pressure catheter placement alone. ...
Article
Objective This study aimed to examine the rates of intraamniotic infection between intrauterine pressure catheter with amnioinfusion and intrauterine pressure catheter alone. Study Design This was a retrospective cohort study of all women who had an intrauterine pressure catheter placement during labor at a tertiary referral hospital from January 2016 to June 2018. Outcomes were compared between women who had an intrauterine pressure catheter with amnioinfusion and intrauterine pressure catheter placement alone. The primary outcome was the rate of intraamniotic infection. Secondary outcomes included postpartum endometritis, postpartum hemorrhage (blood loss of ≥1,000 mL), quantitative blood loss (mL), and cesarean delivery. Multivariable logistic regression analysis was performed to calculate adjusted odds ratios (aOR) and 95% confidence interval (95% CI), controlling for age, race, body mass index, gestational age, and length of time of rupture of membranes. Results Of 1,268 women with an intrauterine pressure catheter, 298 (23.5%) also had an amnioinfusion. Women who had amnioinfusion through an intrauterine pressure catheter compared with those who had intrauterine pressure catheter alone had similar rates of intraamniotic infection (5.4 vs. 8.0%, crude p = 0.12, aOR 0.69; 95% CI 0.39–1.21), as well as secondary outcomes such as postpartum endometritis (3.0 vs. 2.5%, crude p = 0.61, aOR 1.12; 95% CI 0.49–2.53), postpartum hemorrhage (16.1 vs. 15.8%, crude p = 0.89, aOR 1.07; 95% CI 0.75–1.54), blood loss (479.5 vs. 500 mL, adjusted p = 0.89), and cesarean delivery (40.6 vs. 43.1%, crude p = 0.45, aOR 0.90; 95% CI 0.68–1.19). Conclusion Amnioinfusion was not associated with increased odds of intraamniotic infection compared with intrauterine pressure catheter placement alone. Key Points
... Maternal chorioamnionitis (bacterial infection of the amniotic fluid) together with fetal systemic inflammatory response syndrome [14] has been linked with numerous morbidities in very preterm neonates. These morbidities include an increase of PVL/Cerebral palsy [15,16], IVH [17][18][19], ROP [20], NEC [18,21] and EONS [19,22,23]. Chorioamnionitis is protective of LONS [23] probably through hastening the immune maturation. ...
Article
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The mortality rate of very preterm infants with birth weight <1500 g is as high as 15%. The survivors till discharge have a high incidence of significant morbidity, which includes necrotising enterocolitis (NEC), early-onset neonatal sepsis (EONS) and late-onset neonatal sepsis (LONS). More than 25% of preterm births are associated with microbial invasion of amniotic cavity. The preterm gut microbiome subsequently undergoes an early disruption before achieving bacterial maturation. It is postulated that bacterial gut colonisation at birth and postnatal intestinal dysbacteriosis precede the development of NEC and LONS in very preterm infants. In fact, bacterial colonization patterns in preterm infants greatly differ from term infants due to maternal chorioamnionitis, gestational age, delivery method, feeding type, antibiotic exposure and the environment factor in neonatal intensive care unit (NICU). In this regard, this review provides an overview on the gut bacteria in preterm neonates' meconium and stool. More than 50% of preterm meconium contains bacteria and the proportion increases with lower gestational age. Researchers revealed that the gut bacterial diversity is reduced in preterm infants at risk for LONS and NEC. Nevertheless, the association between gut dysbacteriosis and NEC is inconclusive with regards to relative bacteria abundance and between-sample beta diversity indices. With most studies show a disruption of the Proteobacteria and Firmicutes preceding the NEC. Hence, this review sheds light on whether gut bacteria at birth either alone or in combination with postnatal gut dysbacteriosis are associated with mortality and the morbidity of LONS and NEC in very preterm infants.
... Inflammationrelated apoptosis may affect all organ systems, including the fetal brain. Two systematic reviews including case control and cohort studies found that both clinical and histological chorioamnionitis are associated with an increased risk for CP [39,40]. The relevance of gestational age and related neurologic development for the occurrence of brain damage in the context of an inflammatory response is also well known [41]. ...
... Genital mycoplasmas (Ureaplasma and Mycoplasma species) are the most common isolates [7,8] and anaerobes, enteric gram negative bacilli and group B streptococcus are other frequent pathogens [7]. Intra-amniotic infection is associated with a significant increase of serious short-term neonatal complications including pneumonia, meningitis, intraventricular hemorrhage, sepsis and death as well as long-term neonatal outcomes such as bronchopulmonary dysplasia, cerebral palsy and periventricular leukomalacia [9,10]. Moreover, chorioamnionitis can also result in maternal complications such as maternal sepsis, endometritis, wound infection, postpartum hemorrhage and increased risk of cesarean delivery [4,11]. ...
Article
Introduction: To evaluate the effect of antibiotic regimens for chorioamnionitis on maternal and neonatal outcomes. Material and methods: We conducted a systematic review, wherein we searched six bibliographic databases until June 2020 and included randomized clinical trials describing antibiotic regimens for treating chorioamnionitis. Risk of bias was assessed using the Cochrane Risk of Bias tool V2.0. Random-effects meta-analysis was performed and results were presented as risk ratio (RR) and mean differences (MD) with 95% confidence intervals. Results: Fourteen trials at low-to-high risk of bias were included. Three trials (n=244), comparing different intrapartum antibiotic regimens, showed no difference in outcomes except for lower composite maternal morbidity (endometritis, pneumonia, sepsis, blood transfusion and ileus) with ampicillin/sulbactam vs. ampicillin/gentamicin in one study [0/43 vs. 6/49, p=0.03]. Three trials (n=295) comparing different doses of intrapartum antibiotics showed no differences in maternal and neonatal outcomes, although one study showed a shorter duration of antibiotic treatment in the experimental [4mg/kg gentamicin q24hours + 1200mg clindamycin q12hours] vs. conventional [1.33mg/kg gentamicin + 800mg clindamycin q8hours] arms [48.0±36 vs. 55.2±48 hours, p=0.04]. Four trials (n=484) comparing postpartum antibiotics vs. no antibiotics showed no difference in outcomes except shorter hospital stay [two studies, MD -7.90 (-13.52 to -2.27) hours]. Three trials (n=447) comparing single vs. multiple doses of postpartum antibiotics showed shorter hospital stay [MD -19.14 (-29.88 to -8.41) hours], but no differences in treatment failure [RR 1.73 (0.69-4.30)] or total antibiotic dose [MD -9.24 (-19.49 to 1.01)]. One trial (n=48) comparing intrapartum vs. postpartum initiation of treatment found benefits to intrapartum (vs. postpartum) initiation of antibiotics, in terms of postpartum maternal hospital stay [MD -24 (-45.56 to -1.44) hours], neonatal hospital stay [MD -45.6 (-93.84 to -11.76) hours] and neonatal pneumonia or sepsis [RR 0.06 (0.00-0.95)]. Conclusions: Upon diagnosis of chorioamnionitis, there is limited evidence to recommend prompt initiation of intrapartum antibiotics, and to consider a single dose of postpartum antibiotics over multiple doses or no treatment. Well-designed trials using standard definitions of chorioamnionitis, outcome measures and newer antibiotics, are required to inform clinical practice with regard the preferred antibiotic regimen, dose and duration to optimize maternal and neonatal outcomes.
... Clinical studies indicate that intrauterine inflammation, such as chorioamnionitis, is a risk factor for both CP and cystic periventricular leukomalacia, 1 and increases the risk of CP in term and preterm infants. [2][3][4] However, the pathogenesis of intrauterine inflammation-induced WMI during brain development is complex and not fully understood. ...
Article
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White matter injury (WMI) induced by intrauterine inflammation can cause adverse neurological outcomes. Fibrinogen-like protein 2 (FGL2)/fibroleukin is an important trigger of inflammatory responses and is involved in some cerebral diseases. However, the role of FGL2 in intrauterine inflammation-induced WMI remains unclear. Lipopolysaccharide (LPS) was intraperitoneally injected into wild-type and FGL2 knockout mice to induce intrauterine inflammation. Body weight and brain weight of offspring were monitored. Major basic protein (MBP) expression was evaluated to demonstrate the myelination of offspring. To investigate the regulatory mechanism of FGL2, cytokine expression, microglial polarization, and the activation of mitogen-activated protein kinase (MAPK) signaling pathway in the offspring were analyzed. Upon LPS exposure, FGL2 knockout offspring showed a significant increase in body weight loss. MBP reduction induced by LPS was prevented in FGL2 knockout offspring. Expression levels of proinflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α, and M1 marker CD86 were suppressed, while the expression levels of anti-inflammatory cytokines IL-10 and M2 marker CD206 were increased. FGL2 deficiency significantly inhibited the phosphorylation of p38MAPK and c-Jun N-terminal kinase (JNK) protein. FGL2 deficiency can ameliorate WMI induced by intrauterine inflammation, reducing inflammatory cascade and improving hypomyelination, through the regulation of microglial polarization and MAPK signaling pathways. Intrauterine inflammation induces WMI leading to severe neurological sequelae. FGL2 plays an important role in the progression of WMI induced by intrauterine inflammation. FGL2 deficiency can protect against WMI by inhibiting p38 MAPK and JNK phosphorylation, regulating microglia polarization, and reducing inflammation response. FGL2 could be a novel molecular target for protecting against WMI induced by intrauterine inflammation.
... The impacts of these agents on the processes of brain development are diverse and the productive time extends from prenatal to adolescent period [85]. Prenatal exposure to carbofuran, a carbamate pesticide, decreases nestin expression, histone-H3 phosphorylation, and the number of glial fibrillary acidic protein and SOX-2 co-labeled cells, which further leads to neurodegeneration and cognitive deficits in offspring [87]; Maternal application of dicholoacetonitrile (a disinfectant in our drinking water), benzyl benzoate (a antiparasitic insecticide), and trimethyltin (a stabilizer for plastics in paints) may induce oxidative stress and then result in neurodegeneration in fetal brain [88][89][90]; maternal infection is associated with the increased levels of proinflammatory cytokines in the amniotic fluid [91], umbilical cord plasma [92], and cerebral palsy [93,94] as well as neurodevelopmental disorders such as schizophrenia [95] and autism spectrum disorders [96]. The findings in experimental models of maternal infection manifest the role of inflammatory response in the alteration of fetal neuronal morphology [97], astrocytosis, ventriculomegaly, changes in oligodendrocyte precursors [98], reduction of oligodendrocyte number, hypomyelination of brain [99] and a decrease of dopaminergic and serotoninergic neurons in the offspring [100], all of which are capable of leading to brain formative deficits. ...
Chapter
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The brain is not only a control center of the body but also a part of the way that the body can communicate with external environments. The spatial and temporal events of brain development are well-defined. These processes are sequentially regulated by intrinsic and external factors, such as gene. Disruption of these steps results in malformation and malfunction of the brain. Neurotoxin may affect our developing nervous system as a kind of endogenous and exogenous factor. For classical neurotoxins, such as heavy metals, snake venom, and bacterial toxins, the underlying toxin-mediated physiological pathways are relatively clear, and their antidotes are usually available. However, for atypical neurotoxins, such as air pollutants, food additives, and manufactural compounds, their effects on the nervous system are ordinarily extended and not easy to detect. In addition, the corresponding mechanism is too complex to define. A single and effective antidote against these atypical neurotoxins is uncommon, so prevention is better than cure with this kind of toxin. This chapter starts with the introduction of endogenous and exogenous neurotoxins, how they affect nervous system and their potential antidotes, followed by the impact of atypical neurotoxins in fetal brain development and their possible preventative or therapeutic methods.
... Diagnosis of histological chorioamnionitis (HCA) is mostly based on the infiltration of neutrophils and lymphocytes into the placenta and associated membranes. Many studies have associated chorioamnionitis with various short-and long-term adverse outcomes, such as intrauterine growth restriction, cerebral palsy, chronic lung disease, wheezing or asthma later in life [3,4]. However, the outcomes are inconsistent across studies. ...
Article
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Background Chorioamnionitis is associated with various neonatal short- and long-term morbidities. The effect of chorioamnionitis on premature children’s outcomes remains controversial. The aim of this study is to investigate the relationship between histological chorioamnionitis (HCA) and physiological development, wheezing, and atopic diseases in preterm children. Methods Singleton, preterm children (< 34 weeks), whose mother underwent pathological placental examinations, were retrospectively enrolled and the outcomes were assessed at 24–40 months during follow-up. Wheezing and atopic diseases including eczema, food allergies, and allergic rhinitis were screened by a questionnaire along with medical diagnosis. Anthropometric indexes and blood pressure were measured. Cognitive and behavioural developments were assessed by the Gesell Development and Diagnosis Scale. Blood IgE and routine examination were analyzed with venous blood and serum metabolomic profiling was assessed via liquid chromatography-mass spectrometry (LC-MS). A multivariate logistic regression model was used to estimate the association between HCA and the current outcomes. Results Among the 115 enrolled children, 47 were exposed to HCA. The incidence of wheezing was significantly higher in children exposed to HCA, as 38.30% of children who were exposed to HCA and 16.18% of children who were not had been diagnosed with wheezing. After adjusting for related confounders in the multivariate logistic regression model, there remained a 2.72-fold increased risk of wheezing in children with HCA (adjusted odds ratio, aOR, 2.72; 95% confidence interval, 1.02–7.23). Moreover, 163 differential metabolites, such as butanoic acid, annotemoyin 1 and charine, were identified in the HCA exposed children’s serum. Enrichment analysis revealed that these compounds participated in diverse key metabolomic pathways relating to physical and neuro- developments, including glycerophospholipid, alpha-linolenic acid and choline metabolisms. There were no significant differences in atopic diseases, serum IgE, eosinophils’ level, anthropometric indexes, blood pressure, or cognitive or behavioural developments between the two groups. Conclusion HCA exposure is associated with an increased risk of wheezing in preterm children less than 34 gestational weeks.
... The stress, and cytokines on glial cells have been speculated to be the contributory exact nature of cellular and molecular mechanisms of sepsis-Benha Journal Of Applied Sciences, Vol.(4) Issue(1) (2019( induced encephalopathy is still elusive. The impairment of cerebral autoregulation, damage to blood-brain barrier [BBB], and the direct inflammatory effects of free radicals, oxidative factors [11]. ...
... 14 In mothers, chorioamnionitis may result in septic shock, disseminated intravascular coagulation (DIC) and death. 15,16 The maternal serum is an easy way to approach and obtain the material required for diagnosis in a minimally invasive manner. C-reactive protein (CRP), counting of white blood cells, TNF-α, IL-6, IL-10 and G-CSF markers that can be tested from maternal serum. ...
Article
Objective: To determine the diagnostic accuracy of procalcitonin in maternal plasma to detect early intra-amniotic infection in Preterm premature rupture of the membranes (PPROM) with respect of high vaginal swab as gold standard. Methods: A cross-sectional study was conducted at Liaquat National Hospital, Karachi, from February to August 2017. The blood sample of women with PPROM were collected to measure procalcitonin level. PCT1 and PCT2 were run along with the sample for the accuracy of the results. Sensitivity, specificity, PPV, NPV, and diagnostic accuracy of procalcitonin were calculated taking HVS C/S as gold standard. Results: Out of total 150 women, mean age was 28.78±4.79 years. Mean gestational age was 30.79±3.07 weeks. Mean procalcitonin level was 0.13±0.24 ng/ml. Intra-amniotic infection was diagnosed in 48.7% cases through procalcitonin levels and 51.3% through HVS culture and sensitivity. Sensitivity, Specificity, PPV (Positive predictive value), NPV (Negative predictive value) and accuracy were 87%, 91.8%, 91.78%, 87%, and 89.3% respectively. For females with gestational age ≤32 weeks, sensitivity, specificity, and diagnostic accuracy were 83.9%, 90.4%, and 87.03% respectively. For females with gestational age >32 weeks, sensitivity, specificity, and diagnostic accuracy were 95.2%, 92.5%, and 95.23% respectively. Conclusion: Diagnostic accuracy of maternal blood procalcitonin levels were found satisfactory in detection of early intra-amniotic infection in PPROM.
... The stress, and cytokines on glial cells have been speculated to be the contributory exact nature of cellular and molecular mechanisms of sepsis-Benha Journal Of Applied Sciences, Vol.(4) Issue(1) (2019( induced encephalopathy is still elusive. The impairment of cerebral autoregulation, damage to blood-brain barrier [BBB], and the direct inflammatory effects of free radicals, oxidative factors [11]. ...
... Preterm infants have a distinct immune profile in umbilical cord blood and cerebrospinal fluid that includes higher levels of pro-inflammatory cytokines and lower levels of growth factors when compared to term-born controls, but there is uncertainty about the extent to which this is influenced by antenatal factors, environmental exposures and/or developmental regulation (4)(5)(6). Histologic chorioamnionitis (HCA), defined as inflammation of the chorioamniotic membranes, is strongly associated with preterm birth (7,8) and increases the risk of neonatal morbidities including lung disease, intraventricular hemorrhage, sepsis and necrotizing enterocolitis (9)(10)(11)(12)(13)(14). HCA has also been implicated in the development of white matter injury, cerebral palsy and neurodevelopmental impairment (15)(16)(17)(18) and we have previously reported that this may be mediated by a distinct cord blood immune profile in preterm infants (19). When HCA involves a fetal inflammatory response (FIR), these risks appear to be increased further, suggesting that organ injury is mediated by a systemic fetal inflammatory response syndrome (FIRS). ...
Article
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Introduction Preterm infants are at increased risk of exposure to histologic chorioamnionitis (HCA) when compared to term-born controls, and this is associated with several neonatal morbidities involving brain, lungs and gut. Preterm infants could benefit from immunomodulatory therapies in the perinatal period, but development of rational treatment strategies requires improved characterization of the perinatal response to HCA. We had two objectives: The first, to characterize the umbilical cord blood immune profile in preterm infants compared to term-born controls; the second, to investigate the postnatal immune response in preterm infants exposed to HCA versus those who were not. Population For objective one 59 term infants [mean gestational age (GA) 39 ⁺⁴ (37 ⁺³ to 42 ⁺⁰ )] and 55 preterm infants [mean GA29 ⁺⁰ (23 ⁺³ to 32 ⁺⁰ )] with umbilical cord samples available were included; for objective two we studied 96 preterm infants [mean GA29 ⁺¹ (23 ⁺² to 32 ⁺⁰ )] for whom placental histology and postnatal blood samples were available. Methods Placental histopathology was used to identify reaction patterns indicative of HCA, and a customized immunoassay of 24 inflammatory markers and trophic proteins selected to reflect the perinatal immune response was performed on umbilical cord blood in term and preterm participants and postnatal day 5 blood in the preterm group. Results The umbilical cord blood immune profile classified gestational age category with 86% accuracy (95% CI 0.78-0.92), p-value=1.242x10 ⁻¹⁴ . Pro-inflammatory proteins IL-6, MCP-1 and CRP were elevated in the cord blood of preterm infants whilst BDNF, C3, C9, IL-18, MMP-9 and RANTES were decreased, compared to infants born at term. In preterm infants, exposure to HCA was associated with elevations in 8 immune proteins on postnatal day 5 (BDNF, C3, C5a, C9, IL-8, MCP-1, MIP-1β and MMP-9) when compared to preterm infants who were not exposed. Conclusion Preterm birth is associated with a distinct immune profile in umbilical cord blood and preterm infants exposed to HCA with evidence of a fetal inflammatory response have specific alterations in immune function that are apparent on day 5 of postnatal life.
... The prevalence of Bacterial vaginosis (BV) in the general population is high globally, ranging from 23% to 29% across regions (Europe and Central Asia, 23%; East Asia and Pacific, 24%; Latin America and Caribbean, 24%; Middle East and North Africa, 25%; sub-Saharan Africa, 25%; North America, 27%; South Asia, 29%) [1][2][3][4]. Chorioamnionitis (CAM), an increasingly common intrauterine infection often derived from ongoing BV, has been shown to have a positive correlation with cerebral palsy [5,6]. Although transplantation of fetal brain cells has been used as a potential therapy for Parkinson disease, fetal brain damage or cerebral palsy, may result from different risk factors including gestational age of <32 weeks, low birth weight, asphyxia, infection, and inflammation induced by lipopolysaccharide (LPS) [7][8][9][10][11][12]. ...
Article
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Chorioamnionitis (CAM) is an increasingly common disease affecting pregnant women which derives from bacterial vaginosis. In different clinical cases, it has been shown that CAM can cause multiple risk factors for fetal brain damage, such as infection, and intra-uterine asphyxia. However, the molecular mechanism remains unknown. In this study, we established a novel CAM mouse model by exposing pregnant mice to a combination of three risk factors: vaginal lipopolysaccharides (LPS), amniotic LPS, and ischemic reperfusion. We found amniotic LPS caused Parkinson’s disease-like fetal brain damage, in a dose and time-dependent manner. Moreover, the mechanism of this fetal brain damage is apoptosis induced by amniotic LPS but it was inhibited by being pretreated with a vaginal LPS challenge before amniotic LPS injection. In contrast, amniotic LPS with continuous ischemic reperfusion caused a higher level of apoptotic cell death than amniotic LPS alone. In particular, a potential neuroprotective biomarker phosphorylation (p)-CREB (ser133) appeared in only vaginal LPS preconditioned before amniotic LPS, whereas ischemic reperfusion triggered IKK phosphorylation after amniotic LPS. Despite the need for many future investigations, this study also discussed a developed understanding of the molecular mechanism of how these phenotypes occurred.
... The placenta is a dynamic feto-maternal organ, and the role of the maternal-fetal unit (mother-placenta-fetus) is complex and interactive, so the effect of one compartment on outcomes may not be straight forward or linear. Clinical studies have repeatedly demonstrated an association between placental abnormalities and neurodevelopmental outcomes in term and pre-term infants (8)(9)(10)(11). ...
Article
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Background: Placental abnormalities are associated with inflammation and have been linked to brain injury in preterm infants. We studied the relationship between placental pathology and the temporal profiles of cytokine levels in extremely pre-term infants. Study Design: We prospectively enrolled 55 extremely preterm infants born between June 2017 and July 2018. Levels of 27 cytokines were measured in blood drawn from the umbilical artery at birth and from infants at 1–3 and 21–28 days of life. Placental pathology was grouped as normal (N), inflammation (I), vasculopathy (V), or combined vasculopathy and inflammation (V+I). Results: Complete data was available from 42 patients. Cord blood median levels of cytokines differed between groups with the highest levels observed in group V+I as compared to groups N, I and V for the following: Eotaxin ( p = 0.038), G-CSF ( p = 0.023), IFN-γ ( p = 0.002), IL-1ra ( p < 0.001), IL-4 ( p = 0.005), IL-8 ( p = 0.010), MCP-1 ( p = 0.011), and TNFα ( p = 0.002). Post-hoc analysis revealed sex differences between and within the placental pathology groups. Conclusion: Specific types of placental pathology may be associated with differential cytokine profiles in extremely pre-term infants. Sampling from cord blood may help assess the pathological status of the placenta and potentially infer outcome risks for the infant.
... It is a complication of up to 60% of preterm premature rupture of membrane (PPROM) cases [2]. Chorioamnionitis leads to fetal inflammatory response syndrome, which is associated with higher rates of neonatal morbidity (cerebral palsy, intracranial hemorrhage, sepsis, respiratory distress syndrome, necrotizing enterocolitis, and neurodevelopmental disorders) and mortality [3,4]. ...
Article
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Background: Earlier chorioamnionitis diagnosis is crucial to improve maternal and neonatal health outcomes. This study was conducted to evaluate the inlerleukin-6 (IL-6), tumor necrosis factor α (TNF-α), and matrix metalloproteinase 8 (MMP-8) levels in vaginally obtained amniotic fluid to investigate their prognostic value and to determine the most appropriate cut-off values for the prediction of chorioamnionitis. Methods: This case control study included women who were diagnosed with preterm premature rupture of the membranes before 34 weeks of gestation and were admitted to Vilnius University Hospital Santaros Klinikos. Free-leaking amniotic fluid was obtained vaginally with a sterile speculum less than 48h before delivery. Amniotic fluid IL-6, TNF-α, and MMP-8 levels were determined by the Enzyme Linked Immunosorbent Assay. Diagnosis of chorioamnionitis was confirmed by histological examination of the placenta and membranes after delivery. Results: The study included 156 women, 65 patients in the histological chorioamnionitis group (Group I) and 91 in a group without diagnosed histological chorioamnionitis (Group II). The median concentrations of IL-6, MMP-8, and TNF-α in amniotic fluid were statistically significantly higher in Group I than in Group II (p-value < 0.001). The area under the curve of TNF-α and MMP-8 were higher than the area under the curve of IL-6 (0.91, 0.89, and 0.81, respectively). No statistically significant difference was found when comparing the receiver operating characteristic (ROC) curves of TNF-α and MMP-8. The optimum cut-off values for the prediction of chorioamnionitis were found to be 1389.82 pg/mL for IL-6, 21.17 pg/mL for TNF-α, and 172.53 ng/mL for MMP-8. The sensitivity, specificity, positive prognostic value (PPV), and negative prognostic value (NPV) of the IL-6 cut-off for chorioamnionitis were 88%, 70%, 67%, and 89%, respectively. The sensitivity, specificity, PPV, and NPV of the TNF-α cut-off were 88%, 84%, 79%, and 90%, respectively. The sensitivity, specificity, PPV, and NPV of the MMP-8 cut-off were 80%, 87%, 81%, and 86%, respectively. Conclusions: The vaginally obtained amniotic fluid IL-6, MMP-8, and TNF-α seem to be good predictors for chorioamnionitis of patients with preterm premature rupture of membranes before 34 weeks of gestation. The noninvasive technique of sampling amniotic fluid could be alternative method to invasive amniocentesis.
Article
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Preterm birth is a leading cause of neurodevelopmental and neurocognitive impairment in childhood and is closely associated with psychiatric disease. The biological and environmental factors that confer risk and resilience for healthy brain development and long‐term outcome after preterm birth are uncertain, which presents challenges for risk stratification and for the discovery and evaluation of neuroprotective strategies. Neonatal magnetic resonance imaging reveals a signature of preterm birth that includes dysconnectivity of neural networks and atypical development of cortical and deep grey matter structures. Here we provide a brief review of perinatal factors that are associated with the MRI signature of preterm birth. We consider maternal and fetal factors including chorioamnionitis, fetal growth restriction, socioeconomic deprivation, and prenatal alcohol, drug and stress exposures; and neonatal factors including co‐morbidities of preterm birth, nutrition, pain and medication during neonatal intensive care, and variation conferred by the genome/epigenome. Association studies offer the first insights into pathways to adversity and resilience after preterm birth. Future challenges are to analyse quantitative brain MRI data with collateral biological and environmental data in study designs that support causal inference, and ultimately to use the output of such analyses to stratify infants for clinical trials of therapies designed to improve outcome.
Article
Objective: To evaluate whether women with protracted active phase labor longer than 6 hours have an increased risk of adverse maternal and neonatal outcomes after the implementation of new labor management guidelines. Methods: This was a retrospective study of nulliparous, term, singleton, vertex deliveries at Cedars Sinai Medical Center from August 2016 to September 2017. Women were included if they progressed to active phase labor, defined by cervical dilation of 6 cm or more. Women then were divided into three groups based on the time course of cervical change between 6 and 10 cm: 1) normal active phase: cervical change 1 cm or more within 4 hours throughout active labor; 2) mildly protracted active phase: cervical change 1 cm or less over 4-6 hours; and 3) very protracted active phase: cervical change 1 cm or less over 6 hours. Rate of change was assessed between cervical examinations. Primary outcome was a composite of maternal morbidity by study group. Secondary outcome was a composite of neonatal morbidity. We hypothesized that women with very protracted active phase had higher rates of adverse outcomes when compared with normal active phase. Regression analyses were performed to compare maternal and neonatal outcomes by study group. Results: There were 2,559 deliveries, of which 2,378 (90.8%) were vaginal deliveries. Composite maternal and neonatal morbidity was higher with longer labor. Maternal morbidity-very protracted active phase (42.0%) compared with normal active phase (22.6%) adjusted odds ratio (aOR) 2.15 (95% CI 1.62-2.86); mildly protracted active phase (39.5%) compared with normal active phase (22.6%) aOR 2.18 (95% CI 1.67-2.84). Neonatal morbidity: very protracted active phase (19.8%) compared with normal active phase (13.8%) aOR 1.38 (95% CI 0.98-1.96); mildly protracted active phase (19.4%) compared with normal active phase (13.8%) aOR 1.44; (95% CI 1.04-1.99). Composite maternal and neonatal morbidity was not different between mildly protracted and very protracted groups. Conclusion: Composite maternal morbidity was greater in women with cervical change consistent with mildly protracted (4-6 hours) and very protracted (more than 6 hours) labor compared with cervical change in the normal active phase (less than 4 hours) group. However, composite maternal and neonatal morbidity was not different between mildly protracted and very protracted groups.
Article
Pregnancy itself is an inflammatory process that is carefully regulated by the placenta via immunomodulation and cell-to-cell communication of maternal and fetal tissues. Exosomes, types of extracellular vesicles, facilitate the intercellular communication and traffic biologically modifying cargo within the maternal-placental-fetal axis in normal and pathologic pregnancies. Chorioamnionitis is characterized by inflammation of chorioamniotic membranes that produces systemic maternal and fetal inflammatory responses of cytokine dysregulation and has been associated with brain injury and neurodevelopmental disorders. This review focuses on how pathologic placental exosomes propagate acute and chronic inflammation leading to brain injury. The evidence reviewed here highlights the need to investigate exosomes from pathologic pregnancies and those with known brain injury to identify new diagnostics, biomarkers, and potential therapeutic targets.
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Numerous litigations against hospitals and obstetricians take place in which the placental findings become an important participant in advising the disputing parties on perinatal circumstances. These litigations are initiated most often on behalf of children with neurologic problems including cerebral palsy, but also occasionally with malformations, stillbirth, or with other less than optimal or expected outcomes (Rosenblatt and Hurst Obstet Gynecol. 74:710–4, 1989; Richards and Thomasson Obstet Gynecol 80:313–6, 1992). A well-done initial placental examination with good documentation and reporting can prove to be of great importance in many cases; however, family and pregnancy history, antenatal factors, peripartum events, and neonatal status deserve careful consideration. “The examination of the placenta may be viewed as a diary of the pregnancy,” as Gillan (Curr Opin Obstet Gynecol 4:286–94, 1992) has aptly stated, and the placenta has therefore become an increasingly important organ in adjudicating medicolegal allegations. The use of the placenta in the understanding of perinatal injury. In: Fisher DSM, editor. Risk management techniques and neonatal practice. Armonk: Futura Publishing Co; 1996. p. 325–45; (Kaplan, Forensic aspects in pediatric pathology. Karger, Basel, 1995). An important meeting of pathologists, perinatologists, and the legal profession resulted in literature that attempts to address the complexity of the medicolegal aspects of placental pathology (Travers and Schmidt Arch Pathol Lab Med 115:660–731, 1991; Langston et al. Arch Pathol Lab Med 121:449–476, 1997), Boyd and Baergen Placental pathology and the etiology of fetal and neonatal brain injury. In: Stevenson D, Benitz W, Sunshine P, Hintz S, Druzin M, editors. Fetal and neonatal brain injury. 5th ed. Cambridge: Cambridge University Press; 2018.). These reviews were further expanded by the work of Redline (Redline Pediatr Dev Pathol 11:456–64, 2008) who has specifically studied infants with cerebral palsy. He found significant correlations with inflammatory lesions, fetal vascular lesions, and lesions of uteroplacental underperfusion, particularly when multiple processes were present (Redline et al. Pediatr Dev Pathol 10:282–92, 2007; Redline, Pediatr Dev Pathol 11:456–64, 2008). The increasing population of smaller, younger preterm babies who survive with current neonatal care has led to many cases with cerebral palsy and other neurologic deficits (Anonymous, Lancet 2:1251–2, 1989; Kuban and Leviton N Engl J Med 330:188–195, 1994). The increased usage of fertility assistance has led to women bearing children at older ages and increased multiple births, both of which contribute to this group. The incidence of cerebral palsy in term infants has been less affected by changes in obstetrical care and these are a major component of litigated cases.
The fetal inflammatory response syndrome (FIRS) is characterized by umbilical cord inflammation and elevated fetal pro-inflammatory cytokines. Surviving neonates, especially very preterm infants, have increased rates of neonatal morbidity including neurodevelopmental impairment. The mechanism of brain injury in FIRS is complex and may involve “multiple hits.” Exposure to in utero inflammation initiates a cascade of the fetal immune response, where pro-inflammatory cytokines can cause direct injury to oligodendrocytes and neurons. Activation of microglia results in further injury to vulnerable pre-myelinating oligodendrocytes and influences the integrity of the fetal and newborn’s blood-brain barrier, resulting in further exposure of the brain to developmental insults. Newborns exposed to FIRS are frequently exposed to additional perinatal and postnatal insults that can result in further brain injury. Future directions should include evaluations for new therapeutic interventions aimed at reducing brain injury by dampening FIRS, inhibition of microglial activation, and regeneration of immature oligodendrocytes.
Individuals born extremely preterm (before 28 weeks of gestation) comprise only about 0.7% of births in the United States and an even lower proportion in other high resource countries. However, these individuals account for a disproportionate number of children with cerebral palsy, intellectual deficit, autism spectrum disorder, attention deficit hyperactivity disorder, and epilepsy. This review describes two large multiple center cohorts comprised of individuals born extremely preterm: the EPICURE cohort, recruited 1995 in the United Kingdom and the Republic of Ireland, and the Extremely Low Gestational Age Newborn (ELGAN), recruited 2002–2004 in five states in the United States. The primary focus of these studies has been neurodevelopmental disorders, but also of interest are growth, respiratory illness, and parent- and self-reported global health and well-being. Both of these studies indicate that among individuals born extremely preterm the risks of most neurodevelopmental disorders are increased. Early life factors that contribute to this risk include perinatal brain damage, some of which can be identified using neonatal head ultrasound, bronchopulmonary dysplasia, and neonatal systemic inflammation. Prenatal factors, particularly the family's socioeconomic position, also appear to contribute to risk. For most adverse outcomes, the risk is higher in males. Young adults born extremely preterm who have neurodevelopmental impairment, as compared to those without such impairment, rate their quality of life lower. However, young adults born extremely preterm who do not have neurodevelopmental impairments rate their quality of life as being similar to that of young adults born at term. Finally, we summarize the current state of interventions designed to improve the life course of extremely premature infants, with particular focus on efforts to prevent premature birth and on postnatal efforts to prevent adverse neurodevelopmental outcomes
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Fetuses exposed to an inflammatory environment are predisposed to long‐term adverse neurological outcomes. However, the mechanism by which intrauterine inflammation (IUI) is responsible for abnormal fetal brain development is not fully understood. The mTOR signaling pathway is closely associated with fetal brain development. We hypothesized that mTOR signaling might be involved in fetal brain injury and malformation when fetuses are exposed to the IUI environment. A well‐established IUI model was utilized by intrauterine injection of lipopolysaccharide (LPS) to explore the effect of IUI on mTOR signaling in mouse fetal brains. We found that microglia activation in LPS fetal brains was increased, as demonstrated by elevated Iba‐1 protein level and immunofluorescence density. LPS fetal brains also showed reduced neuronal cell counts, decreased cell proliferation demonstrated by low Ki67‐positive density, and elevated neuron apoptosis evidenced by high expression of cleaved Caspase 3. Furthermore, we found that mTOR signaling in LPS fetal brains was elevated at 2h after LPS treatment, declined at 6h and showed overall inhibition at 24h. In summary, our study revealed that LPS‐induced IUI leads to increased activation of microglia cells, neuronal damage, and dynamic alterations in mTOR signaling in the mouse fetal brain. Our findings indicate that abnormal changes in mTOR signaling may underlie the development of future neurological complications in offspring exposed to prenatal IUI.
Article
[Abstract] [Introduction] Ex-vivo uterine environment (EVE) therapy is an experimental intensive care strategy for extremely preterm infants born between 21 and 24 weeks of gestation. Gas exchange is performed by membranous oxygenators connected by catheters to the umbilical vessels. The fetus is submerged in a bath of synthetic amniotic fluid. The lungs remain fluid-filled and pulmonary respiration does not occur. Intrauterine inflammation is strongly associated with extremely early preterm birth and fetal injury. Presently, there are no data of which we are aware to show that artificial placenta-based systems can be used to support extremely preterm fetuses compromised by exposure to intrauterine inflammation. [Objectives] To evaluate the ability of our EVE therapy platform to support extremely preterm ovine fetuses (95 d gestational age; approximately equivalent to 24 weeks of human gestation) exposed to intrauterine inflammation for a period of 120 hours, the following primary endpoints were chosen: i) maintenance of key physiological variables within normal ranges; ii) absence of infection and inflammation; iii) absence of brain injury; and iv) gross fetal growth and cardiovascular function matching that of age-matched in utero controls. [Study Design] Ten ewes with singleton pregnancies were each given a single intraamniotic injection of 10 mg E.coli lipopolysaccharides (LPS) under ultrasound guidance 48h before undergoing surgical delivery for adaptation to EVE therapy at 95d gestation (term=150d). Fetuses were adapted to EVE therapy and maintained for 120h with constant monitoring of key vital parameters (EVE Group) before being euthanised at 100d equivalent gestational age. Umbilical artery blood samples were regularly collected to assess blood gas data, differential counts, biochemical parameters, inflammatory markers and microbial load to exclude infection. Ultrasound was conducted at 48 h after intraamniotic LPS (before surgery) to confirm fetal viability and at the conclusion of the experiments (before euthanasia) to evaluate cardiac function. Brain injury was evaluated by gross anatomical and histopathological investigations. Eight singleton pregnant control animals were similarly exposed to intraamniotic LPS at 93d gestation and were euthanized at 100 d gestation to allow comparative post-mortem analyses (Control Group). Bio-banked samples from age-matched saline-treated animals served as an additional comparison group. Successful instillation of LPS into the amniotic fluid exposure was confirmed by amniotic fluid analysis at the time of administration, and by analyzing cytokine levels in fetal plasma and amniotic fluid. Data were tested for mean differences with ANOVA. [Results] Six out of eight LPS Control Group (75%) and eight out of ten EVE Group fetuses (80%) successfully completed their protocols. Six of eight EVE Group fetuses required dexamethasone phosphate treatment to manage profound refractory hypotension. Weight and crown rump length was reduced in EVE Group fetuses at euthanasia compared to LPS Control Group fetuses (p<0.05). There were no biologically significant differences in cardiac ultrasound measurement, differential leucocyte counts (p>0.05), plasma tumour necrosis factor α (TNF-α), monocyte chemoattractant protein-1 (MCP-1) concentrations (p>0.05), or liver function tests between groups. Daily blood cultures were negative for aerobic and anaerobic growth in all EVE Group animals. No cases of intraventricular haemorrhage were observed. White matter injury was identified in three of six LPS Control Group fetuses and three of eight EVE Group fetuses. [Conclusions] We report the use of an artificial placenta-based system to support extremely preterm lambs compromised by exposure to intrauterine inflammation. Our data highlight key challenges (refractory hypotension, growth restriction and white matter injury) to be overcome in the development and use of artificial placenta technology for extremely early preterm infants. As such challenges appear largely absent from studies based on healthy pregnancies, additional experiments of this nature using clinically relevant model systems are essential for further development of this technology and its eventual clinical application.
Article
Background There is growing evidence to support an association between placental inflammation and neurologic sequelae of preterm infants. The goal of this study is to evaluate the relationship between placental pathology, Doppler cerebral resistive indices (RI’s) and intraventricular hemorrhage (IVH) in premature infants. Methods A cohort study of preterm infants 23 0/7 and 32 6/7 weeks gestation at Parkland Hospital were examined with placental pathology and serial ultrasound Doppler to evaluate for the primary outcome of IVH and death. Results 255 infants were recruited and 166 (65%) had at least one significant placental pathology, most commonly chorioamnionitis. Infants with placental pathologies were significantly more likely to have mothers with clinical chorioamnionitis and to have lower gestational ages. There was no observed association between placental pathology and IVH or death. Secondary analysis demonstrated resistive indices obtained from the 1st and 2nd HUS were not different in infants with IVH. Conclusion In this study, we observed a high rate of placental pathologies but no alterations in cerebral indices on ultrasound, nor differences in rates of IVH or death. Additional studies are necessary to delineate the relationship between placental pathology, white matter brain injury and outcomes.
Clinical signs and neuroimaging patterns associated with the fetal inflammatory response syndrome (FIRS) worsen or mimic the clinical repertoire after intrapartum hypoxic-ischemic encephalopathy (HIE) during labor and/or parturition. Diagnostic considerations expressed as neonatal encephalopathy (NE) must consider chronic as well as acute factors associated with FIRS. Trimester-specific factors adversely alter the interactions of the maternal/placental/fetal (MPF) triad and influence the postnatal phenotype of FIRS. Anticipatory guidance for families by clinicians caring for survivors with FIRS, as well as researchers, must consider acute and chronic effects that influence neurologic outcome. Novel neurotherapeutic interventions must include prenatal preventive as well as peripartum/postnatal rescue and repair strategies to effectively reduce the presence and severity of sequelae from FIRS.
Article
Perinatal brain injury is a multifactorial process. In utero placental physiology plays a major role in neuroprotection and the normal development of the fetal central nervous system. Advances in placental pathology have clarified several specific mechanisms of injury and the histologic lesions most strongly associated with them. This review provides an updated summary of the relevant placental anatomy and physiology, the specific placental pathways leading to brain injury, the revised Amsterdam classification system for placental pathology, and the known associations of specific placental lesions with subtypes of adverse neurologic outcomes.
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Intra-amniotic infection (IAI) is a major cause of preterm birth with a poor perinatal prognosis. We aimed to determine whether analyzing vaginal microbiota can evaluate the risk of chorioamnionitis (CAM) in preterm labor cases. Vaginal discharge samples were collected from 83 pregnant women admitted for preterm labor. Based on Blanc’s classification, the participants were divided into CAM (stage ≥ II; n = 46) and non-CAM (stage ≤ I; n = 37) groups. The 16S rDNA amplicons (V1–V2) from vaginal samples were sequenced and analyzed. Using a random forest algorithm, the bacterial species associated with CAM were identified, and a predictive CAM (PCAM) scoring method was developed. The α diversity was significantly higher in the CAM than in the non-CAM group (P < 0.001). The area under the curve was 0.849 (95% confidence interval 0.765–0.934) using the PCAM score. Among patients at < 35 weeks of gestation, the PCAM group (n = 22) had a significantly shorter extended gestational period than the non-PCAM group (n = 25; P = 0.022). Multivariate analysis revealed a significant difference in the frequency of developmental disorders in 3-year-old infants (PCAM, 28%, non-PCAM, 4%; P = 0.022). Analyzing vaginal microbiota can evaluate the risk of IAI. Future studies should establish appropriate interventions for IAI high-risk patients to improve perinatal prognosis.
Article
Importance: Intra-amniotic infection (IAI) is a common condition with potentially devastating maternal and neonatal complications. However, there are incomplete data regarding the most effective antimicrobial treatment regimen for this condition. Objective: This article aims to review the current evidence and recommendations for intrapartum and postpartum management of IAI. Evidence acquisition: Original research articles, review articles, and guidelines on IAI were reviewed. Results: Numerous known risk factors for IAI exist, some of which are modifiable. Serious neonatal complications can result from exposure to IAI including increased risk of preterm birth and neonatal death. Possible maternal complications include increased risk of cesarean delivery, postpartum hemorrhage, and postpartum endometritis. Antibiotics are the mainstay of treatment for IAI for both mothers and neonates, although there is no consensus on which antimicrobial agents are best and the appropriate duration of therapy. Conclusions and relevance: Monitoring patients for signs of IAI, proper treatment, and communication of the diagnosis with the pediatric team are essential for preventing maternal and neonatal complications of IAI. More research is needed to determine the proper treatment regimens for both mothers diagnosed with IAI and their neonates.
Article
Recent studies implicate microbiota-brain communication as an essential factor for physiology and pathophysiology in brain function and neurodevelopment. One of the pivotal mechanisms about gut to brain communication is through the regulation and interaction of gut microbiota on the host immune system. In this review, we will discuss the role of microbiota-immune system-interactions in human neurological disorders. The characteristic features in the development of neurological diseases include gut dysbiosis, the disturbed intestinal/ blood-brain barrier (BBB) permeability, the activated inflammatory response, and the changed microbial metabolites. Neurological disorders contribute to gut dysbiosis and some relevant metabolites in a top-down way. In turn, the activated immune system induced by the change of gut microbiota may deteriorate the development of neurological diseases through the disturbed gut/BBB barrier in a down-top way. Understanding the characterization and identification of microbiome-immune- brain signaling pathways will help us to yield novel therapeutic strategies by targeting the gut microbiome in neurological disease.
The fetal inflammatory response syndrome (FIRS) is a condition whereby the fetus mounts an inflammatory response to intrauterine infection/inflammation. Clinical consequences include preterm premature rupture of membranes (PPROM), spontaneous preterm delivery, neonatal sepsis, bronchopulmonary dysplasia, and brain and other organ injury. Mechanisms leading to brain injury in FIRS have been investigated in animal and human studies. We review the neuroimaging findings of brain injury in FIRS, which overlap those of hypoxic-ischemic injury, and clinical correlation is necessary for a correct diagnosis. FIRS should be considered the primary diagnosis when neuroimaging findings such as periventricular leukomalacia are identified in preterm children born as a consequence of PPROM and spontaneous preterm labor. Additionally, FIRS should be considered in term infants who do not have most common features of HIE (e.g. a sentinel event). Systematic histopathologic examination of the placenta and umbilical cord and/or detection of characteristic inflammatory markers in such cases are needed to establish the correct diagnosis.
Article
Objectives: Intra-amniotic infection, defined by the presence of microorganisms in the amniotic cavity, is often accompanied by intra-amniotic inflammation. Occasionally, laboratories report the growth of bacteria or the presence of microbial nucleic acids in amniotic fluid in the absence of intra-amniotic inflammation. This study was conducted to determine the clinical significance of the presence of bacteria in amniotic fluid samples in the absence of intra-amniotic inflammation. Methods: A retrospective cross-sectional study included 360 patients with preterm labor and intact membranes who underwent transabdominal amniocentesis for evaluation of the microbial state of the amniotic cavity as well as intra-amniotic inflammation. Cultivation techniques were used to isolate microorganisms, and broad-range polymerase chain reaction coupled with electrospray ionization mass spectrometry (PCR/ESI-MS) was utilized to detect the nucleic acids of bacteria, viruses, and fungi. Results: Patients whose amniotic fluid samples evinced microorganisms but did not indicate inflammation had a similar perinatal outcome to those without microorganisms or inflammation [amniocentesis-to-delivery interval (p=0.31), spontaneous preterm birth before 34 weeks (p=0.83), acute placental inflammatory lesions (p=1), and composite neonatal morbidity (p=0.8)]. Conclusions: The isolation of microorganisms from a sample of amniotic fluid in the absence of intra-amniotic inflammation is indicative of a benign condition, which most likely represents contamination of the specimen during the collection procedure or laboratory processing rather than early colonization or infection.
Article
The aim of this review was to examine the existing evidence about interventions proposed for the treatment of clinical chorioamnionitis, with the goal of developing an evidence-based contemporary approach for the management of this condition. Most trials that assessed the use of antibiotics in clinical chorioamnionitis included patients with a gestational age ≥34 weeks and in labor. The first-line antimicrobial regimen for the treatment of clinical chorioamnionitis is ampicillin combined with gentamicin, which should be initiated during the intrapartum period. In the event of a cesarean delivery, patients should receive clindamycin at the time of umbilical cord clamping. The administration of additional antibiotic therapy does not appear to be necessary after vaginal or cesarean delivery. However, if post-delivery antibiotics are prescribed, there is support for the administration of an additional dose. Patients should receive antipyretics, mainly acetaminophen, even though there is no clear evidence of their benefits. Current evidence suggests that the administration of antenatal corticosteroids for fetal lung maturation and of magnesium sulfate for fetal neuroprotection to patients with clinical chorioamnionitis between 24 0/7 and 33 6/7 weeks of gestation, and possibly between 23 0/7 and 23 6/7 weeks, has an overall beneficial effect on the infant. However, delivery should not be delayed in order to complete the full course of corticosteroids and magnesium sulfate. Once the diagnosis of clinical chorioamnionitis has been established, delivery should be considered, regardless of the gestational age. Vaginal delivery is the safer option and cesarean delivery should be reserved for standard obstetric indications. The time interval between the diagnosis of clinical chorioamnionitis and delivery is not related to most adverse maternal and neonatal outcomes. Patients may require a higher dose of oxytocin to achieve adequate uterine activity and/or greater uterine activity to effect a given change in cervical dilation. The benefit of using continuous electronic fetal heart rate monitoring in these patients is unclear. We identified the following promising interventions for the management of clinical chorioamnionitis: (1) an antibiotic regimen including ceftriaxone, clarithromycin, and metronidazole that provides coverage against the most commonly identified microorganisms in patients with clinical chorioamnionitis; (2) vaginal cleansing with antiseptic solutions before cesarean delivery with the aim of decreasing the risk of endometritis and, possibly, postoperative wound infection; and (3) antenatal administration of N-acetylcysteine, an antioxidant and anti-inflammatory agent, to reduce neonatal morbidity and mortality. Well-powered randomized controlled trials are needed to assess these interventions in patients with clinical chorioamnionitis.
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The patterns of fetal neurobehavior and neurodevelopment have not been entirely established after plenty of years of scientific research, remaining at present an evolving challenge. The disclosures regarding fetal movements and fetal morphology had concluded that the fetal neurobehavioral patterns are interconnected with the maturation and development stages of the fetal central nervous system and can predict with a high accuracy neurological and organic disorders. Nowadays, with the introduction of four-dimensional ultrasonography in clinical practice, obstetricians can forecast fetal neurodevelopment dysfunctions and brain impairments through the assessment of the quality and quantity of general movements, facial expressions, the opening of the eyes, and primary reflexes. Kurjak Antenatal Neurodevelopmental Test (KANET) combines general movement’s evaluation and the Amiel-Tison Neurological Assessment at Term to detect normal from abnormal or borderline at normal and high-risk pregnancies. Although KANET is an important tool for fetal neurological evaluation, further research is needed to completely understand the applicability of four-dimensional ultrasonography to fetal neurobehavior and neurodevelopment.
Article
With few exceptions, adherence to ethical, outcomes-focused, evidence-based, and cost-effective medicine does not support placental pathology examination.
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Infection occurring during the prenatal, perinatal, and early postnatal periods of life can cause cerebral palsy (CP). Gestational age may be an associated risk factor, but both preterm and term infants can be affected. Injury to the brain causing CP can be the result of both direct and secondary pathogenesis from infectious etiologies. Direct infection of the central nervous system, damaging immune-mediated inflammatory response to maternal or congenital infection, or sequelae from infection such as hypoxic-ischemic events can all lead to insult to the brain. Pathogens causing these CP-related congenital infections can vary but are usually neurotropic viruses including cytomegalovirus (CMV). Maternal bacterial infections such as chorioamnionitis or urinary tract infection and neonatal bacterial infections such as sepsis and meningitis have been associated with CP and may correlate with specific subtypes of CP. Distinct clinical manifestations and stigmata can help identify these infections, in addition to diagnostics such as serology and molecular testing. However, treatments and therapies can be limited and toxic and may have little direct effect on the development of CP and its long-term outcomes.
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Aim: To investigate intrapartum fetal heart rate (FHR) patterns in women with chorioamnionitis at or beyond 34 weeks of gestation in relation to neonatal outcome and to compare clinical and subclinical chorioamnionitis. Methods: A retrospective questionnaire survey on deliveries during 2015 was conducted by the Perinatology Committee of the Japan Society of Obstetrics and Gynecology from 2016 to 2018. A total of 498 singleton births complicated by chorioamnionitis delivered at ≥34 weeks of gestation without major congenital malformations were included. The subjects were divided into clinical and subclinical chorioamnionitis groups based on Lencki's criteria. Poor perinatal outcome was defined as death or brain damage. We analyzed clinical features, FHR patterns in the last 2 h before delivery, gestational age, birthweight, Apgar score, umbilical arterial blood gas analysis, and infant's outcome. Results: Incidence of chorioamnionitis at ≥34 weeks of gestation was 0.59% (522/87827). Clinical and subclinical chorioamnionitis comprised 240 and 258 cases, respectively. Abnormal FHR patterns (late deceleration or decreased baseline variability) were significantly associated with poor perinatal outcome. Combined late deceleration and decreased variability showed low positive predictive value (12.8%) and high negative predictive value (99.5%), and was significantly associated with long-term poor outcome in clinical chorioamnionitis only (odds ratio: 29.4, p < 0.01). Poor perinatal outcome showed no significant difference between the clinical and subclinical chorioamnionitis groups. Conclusions: Combined late deceleration and decreased variability could predict poor perinatal outcome in clinical chorioamnionitis. Poor perinatal outcome occurred in infants born to mothers with clinical and subclinical chorioamnionitis.
Article
Background: The source and clearance of cytokines in the fetal circulation in term pregnancies complicated by chorioamnionitis remains unclear as are the contributions of placental transport, synthesis, and clearance. The objectives of the study were to determine (1) fetal and/or placental contributions to synthesis and/or clearance of inflammatory and anti-inflammatory cytokines in term pregnancies complicated by chorioamnionitis and (2) whether this differs in pregnancies further complicated by fetal hypoxia. Methods: Prospective cohort study of pregnancies >37 weeks gestational age that included: Group 1, uncomplicated cesarean delivery without labor (n = 20); Group 2, uncomplicated vaginal delivery (n = 30); Group 3, pregnancies complicated by chorioamnionitis (n = 10); Group 4, complicated by chorioamnionitis + fetal hypoxia (n = 10). Umbilical arterial (UmA) and venous (UmV) blood were assayed for IL-1β, IL-2, IL-6, IL-8, TNFα, and IL-10. Results: IL-6 and IL-8 were below assay detection in UmA and UmV blood in Group 1 and increased in Group 2 (P < 0.01), UmA»UmV (P < 0.01). Their concentrations increased further in Groups 3 and 4 (P = 0.003), UmA»UmV. Placental clearance was concentration dependent that approaches saturation in the presence of chorioamnionitis. Conclusions: Marked increases in fetal synthesis of IL-6 and IL-8 occur in chorioamnionitis. Synthesis increase further when complicated by fetal hypoxia. Cytokine removal occurs via placental concentration-dependent mechanisms, potentially contributing to adverse fetal effects. Impact: The source and role of the placenta in synthesis and/or clearance of inflammatory mediators in term pregnancies complicated by clinical chorioamnionitis are unclear; however, conventional wisdom suggests the placenta is their source. This is the first study demonstrating that circulating concentrations of fetal IL-6 and IL-8 in clinical chorioamnionitis ± birth asphyxia in term pregnancies are of fetal origin. Circulating fetal inflammatory cytokines are cleared by concentration-dependent placental mechanisms that are nearly saturated in chorioamnionitis ± fetal hypoxia. These observations provide additional insight into understanding the fetal immune response in term pregnancies complicated by clinical chorioamnionitis.
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The association between clinical chorioamnionitis and increased risk of cerebral palsy (CP) in term and near-term infants was determined in 109 children with CP not due to postnatal brain injury or developmental abnormalities compared to 218 controls, in a study at University of California, San Francisco, and Kaiser Permanente Division of Research, Oakland, CA.
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Because of the pressure for timely, informed decisions in public health and clinical practice and the explosion of information in the scientific literature, research results must be synthesized. Meta-analyses are increasingly used to address this problem, and they often evaluate observational studies. A workshop was held in Atlanta, Ga, in April 1997, to examine the reporting of meta-analyses of observational studies and to make recommendations to aid authors, reviewers, editors, and readers. Twenty-seven participants were selected by a steering committee, based on expertise in clinical practice, trials, statistics, epidemiology, social sciences, and biomedical editing. Deliberations of the workshop were open to other interested scientists. Funding for this activity was provided by the Centers for Disease Control and Prevention. We conducted a systematic review of the published literature on the conduct and reporting of meta-analyses in observational studies using MEDLINE, Educational Research Information Center (ERIC), PsycLIT, and the Current Index to Statistics. We also examined reference lists of the 32 studies retrieved and contacted experts in the field. Participants were assigned to small-group discussions on the subjects of bias, searching and abstracting, heterogeneity, study categorization, and statistical methods. From the material presented at the workshop, the authors developed a checklist summarizing recommendations for reporting meta-analyses of observational studies. The checklist and supporting evidence were circulated to all conference attendees and additional experts. All suggestions for revisions were addressed. The proposed checklist contains specifications for reporting of meta-analyses of observational studies in epidemiology, including background, search strategy, methods, results, discussion, and conclusion. Use of the checklist should improve the usefulness of meta-analyses for authors, reviewers, editors, readers, and decision makers. An evaluation plan is suggested and research areas are explored.
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Context Chorioamnionitis has been implicated in the pathogenesis of cerebral palsy, but most studies have not reported a significant association. Cystic periventricular leukomalacia (cPVL) is believed to be a precursor of cerebral palsy in preterm infants.Objectives To determine whether chorioamnionitis is associated with cerebral palsy or cPVL and to examine factors that may explain differences in study results.Data Sources Searches of MEDLINE (1966-1999), Index Medicus (1960-1965), Doctoral Dissertation Abstracts On-Line (1861-1999), bibliographies, and online conference proceedings (1999) were performed for English-language studies with titles or abstracts that discussed prenatal risk factors for cerebral palsy or cPVL.Study Selection Of 229 initially identified publications, meta-analyses were performed on studies that addressed the association between clinical (n = 19) or histologic (n = 7) chorioamnionitis and cerebral palsy or cPVL in both preterm and full-term infants. Inclusion criteria were: presence of appropriate exposure and outcome measures, case-control or cohort study design, and provision of sufficient data to calculate relative risks (RRs) or odds ratios with 95% confidence intervals (CIs). Studies evaluating risk of cerebral palsy following maternal fever, urinary tract infection, or other maternal infection were collected, but not included in the meta-analysis.Data Extraction Information from individual studies was abstracted using standardized forms by 2 independent observers blinded to authors' names, journal titles, and funding sources.Data Synthesis Using a random effects model, clinical chorioamnionitis was significantly associated with both cerebral palsy (RR, 1.9; 95% CI, 1.4-2.5) and cPVL (RR, 3.0; 95% CI, 2.2-4.0) in preterm infants. The RR of histologic chorioamnionitis and cerebral palsy was 1.6 (95% CI, 0.9-2.7) in preterm infants, and histologic chorioamnionitis was significantly associated with cPVL (RR, 2.1; 95% CI, 1.5-2.9). Among full-term infants, a positive association was found between clinical chorioamnionitis and cerebral palsy (RR, 4.7; 95% CI, 1.3-16.2). Factors explaining differences in study results included varying definitions of clinical chorioamnionitis, extent of blinding in determining exposure status, and whether individual studies adjusted for potential confounders.Conclusion Our meta-analysis indicates that chorioamnionitis is a risk factor for both cerebral palsy and cPVL. Figures in this Article Despite improvements in perinatal medicine, the prevalence of cerebral palsy has increased over the last 2 decades,1 and the etiology of cerebral palsy remains poorly understood. Evidence suggests that 70% to 80% of cases of cerebral palsy are due to prenatal factors,2 and that birth asphyxia plays a relatively minor role.3 Chorioamnionitis, or intrauterine infection, has been implicated as a potential cause of cerebral palsy.4- 6 Chorioamnionitis is common and often subclinical. Histologic signs of chorioamnionitis can be detected in more than 50% of women who deliver prematurely,7 and most patients have no clinical signs of infection.8 It is postulated that both subclinical and clinical chorioamnionitis can lead to a fetal inflammatory response, and that this inflammation contributes to neonatal brain injury and subsequent cerebral palsy.5,9- 10 Recent reports of elevated neonatal blood11 and amniotic fluid12 cytokine levels in children with cerebral palsy support the notion that cerebral palsy is preceded by a perinatal inflammatory condition. A number of studies have assessed the relationship between chorioamnionitis and cerebral palsy in premature infants,12- 20 but most have not reported a significant association. In full-term infants, the existing literature supports a relationship between chorioamnionitis and cerebral palsy,6,21 but few studies are available. We conducted a meta-analysis to evaluate the potential association between chorioamnionitis and cerebral palsy in both full-term and preterm infants. In addition to cerebral palsy, we were interested in the outcome of cystic periventricular leukomalacia (cPVL), a powerful predictor of cerebral palsy in preterm infants. An estimated 60% to 100% of patients with cPVL go on to develop cerebral palsy.22 We performed a systematic review of the existing literature addressing all forms of chorioamnionitis as a potential risk factor for cerebral palsy or cPVL.
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To evaluate the association between the presence of bacterial pathogens in the amniotic cavity at the time of preterm delivery and neuromotor outcome at two years adjusted age in preterm infants born at < or =33 weeks' gestation. The cohort included 114 preterm infants, born at 23-33 weeks' gestation to mothers with amniotic cavity cultures taken during cesarean delivery who were subsequently evaluated at 24.0+/-1.1 months corrected age with the Bayley Scales of Infant Development II and a standardized neurologic examination. A group of 67 infants with negative amniotic cavity cultures was compared to 47 infants with positive amniotic cavity cultures (Ureaplasma urealyticum (Uu) in 32 cases and other bacteria in 15 cases). Patients with positive amniotic cavity cultures had a significantly higher risk for an adverse psychomotor development index (PDI) score (OR 3.1, CI 1.3-7.1), an abnormal neurologic outcome (OR 4.8, CI 1.7-13.8), and a higher probability for diagnosis of cerebral palsy (OR 4.8, CI 1.4-16.4) at two years compared to patients with negative culture results. Isolation of Uu at birth was associated with a particular adverse outcome of preterm infants. Isolation of pathogens from the amniotic cavity at birth is significantly associated with abnormal PDI and adverse neuromotor outcome in preterm infants, irrespective of gestational age and birthweight.
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Previous studies have indicated that foetomaternal infection increases the risk of spastic cerebral palsy (CP) in term infants, whereas this association appears to be less evident in preterm infants. The aim of this study was to analyse infection-related risk factors for spastic CP in preterm infants. A population-based series of preterm infants with spastic CP, 91 very preterm (>32wk) and 57 moderately preterm (32–36 wk), born in 1983–90, were included and matched with a control group (n= 296). In total, 154 maternal, antenatal and intrapartal variables were retrieved from obstetric records. In the entire group, histological chorioamnionitis/pyelonephritis, long interval between rupture of membranes and birth, admission-delivery interval >4 h and Apgar scores of >7 at 1 min just significantly increased the risk of CP, and Apgar scores of >7 at 5 and 10 min were strongly associated with an increased risk. Abruptio placentae, Apgar scores >7 at 1 min and pathological non-stress test (reason for delivery) were significant risk factors of CP only in the moderately preterm and hemiplegic groups, whereas fever before delivery was a significant risk factor in the very preterm and spastic diplegic groups. Antibiotics during pregnancy was associated with CP only in the spastic diplegic CP group. Conclusion: Antenatal infections marginally increased the risk of CP. Low Apgar score and abruptio placentae were associated with CP, especially in moderately preterm infants with hemiplegic CP.
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Prematurity is the leading cause of perinatal morbidity and mortality worldwide. Intrauterine infection has emerged as a major cause of premature labor and delivery. It has been estimated that 25% of all preterm deliveries occur to mothers who have microbial invasion of the amniotic cavity, although these infections are mostly subclinical in nature. This article describes the pathways leading to intrauterine infection, microbiology, frequency and clinical consequences of infection. The pathophysiology of the fetal inflammatory response syndrome is reviewed, as is its relationship to long-term handicap, such as cerebral palsy and bronchopulmonary dysplasia. A possible role for two micronutrients, vitamins C and E, in the prevention of the preterm prelabor rupture of membranes and the consequences of fetal inflammation is considered. Research needs are listed.
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Half of all cases of cerebral palsy (CP) occur in term infants, for whom risk factors have not been clearly defined. Recent studies suggest a possible role of chorioamnionitis. To determine whether clinical chorioamnionitis increases the risk of CP in term and near-term infants. Case-control study nested within a cohort of 231 582 singleton infants born at 36 or more weeks' gestation between January 1, 1991, and December 31, 1998, in the Kaiser Permanente Medical Care Program, a managed care organization providing care for more than 3 million residents of northern California. Case patients were identified from electronic records and confirmed by chart review by a child neurologist, and comprised all children with moderate to severe spastic or dyskinetic CP not due to postnatal brain injury or developmental abnormalities (n = 109). Controls (n = 218) were randomly selected from the study population. Association between clinical chorioamnionitis and increased risk of CP in term and near-term infants. Most CP cases had hemiparesis (40%) or quadriparesis (38%); 87% had been diagnosed by a neurologist and 83% had undergone neuroimaging. Chorioamnionitis, considered present if a treating physician made a diagnosis of chorioamnionitis or endometritis clinically, was noted in 14% of cases and 4% of controls (odds ratio [OR], 3.8; 95% confidence interval [CI], 1.5-10.1; P =.001). Independent risk factors identified in multiple logistic regression included chorioamnionitis (OR, 4.1; 95% CI, 1.6-10.1), intrauterine growth restriction (OR, 4.0; 95% CI, 1.3-12.0), maternal black ethnicity (OR, 3.6; 95% CI, 1.4-9.3), maternal age older than 25 years (OR, 2.6; 95% CI, 1.3-5.2), and nulliparity (OR, 1.8; 95% CI, 1.0-3.0). The population-attributable fraction of chorioamnionitis for CP is 11%. Our data suggest that chorioamnionitis is an independent risk factor for CP among term and near-term infants.
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Background The association between cerebral palsy in very preterm infants and clinical, histopathologic and microbiological indicators of chorioamnionitis, including the identification of specific micro-organisms in the placenta, was evaluated in a case-cohort study. Methods Children with a diagnosis of cerebral palsy at five years of age were identified from amongst participants in a long-term follow-up program of preterm infants. The comparison group was a subcohort of infants randomly selected from all infants enrolled in the program. The placentas were examined histopathologically for chorioamnionitis and funisitis, and the chorioamnionic interface was aseptically swabbed and comprehensively cultured for aerobic and anaerobic bacteria, yeast and genital mycoplasmas. Associations between obstetric and demographic variables, indicators of chorioamnionitis and cerebral palsy status were examined by univariate analysis. Results Eighty-two infants with cerebral palsy were compared with the subcohort of 207 infants. Threatened preterm labor was nearly twice as common among the cases as in the subcohort (p < 0.01). Recorded clinical choroamnionitis was similar in the two groups and there was no difference in histopathologic evidence of infection between the two groups. E. coli was cultured from the placenta in 6/30 (20%) of cases as compared with 4/85 (5%) of subcohort (p = 0.01). Group B Streptococcus was more frequent among the cases, but the difference was not statistically significant. Conclusions The association between E. coli in the chorioamnion and cerebral palsy in preterm infants identified in this study requires confirmation in larger multicenter studies which include microbiological study of placentas.
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Inconsistent findings linking placental histologic chorioamnionitis (HCA) and preterm delivery may result from variations in HCA definition, population studied, and exclusion criteria. This analysis from the 1998-2004 Pregnancy Outcomes and Community Health Study (five Michigan communities) includes the first 1,053 subcohort women (239 preterm, 814 term) with completed placental assessments. Multiple HCA definitions were constructed by 1) varying polymorphonuclear leukocytes/high-powered field thresholds and placenta components included and 2) using polymorphonuclear leukocyte characteristics to assign low/high maternal, fetal inflammation stage and grade. In African Americans, HCA was associated with preterm delivery before 35 weeks. The effect size was modest for polymorphonuclear leukocytes/high-powered field thresholds of greater than 10 and greater than 30 (odds ratios (ORs) = 0.8 and 2.0); larger for greater than 100 (OR = 3.2, 95% confidence interval (CI): 1.4, 7.1); strengthened after excluding medically indicated preterm deliveries (OR = 4.9, 95% CI: 2.0, 11.8); and strongest for high maternal/high fetal HCA (OR = 5.6, 95% CI: 1.4, 22.1). These latter HCA criteria also produced the largest effect size in Whites/others (OR = 2.7, 95% CI: 0.3, 26.9). Among preterm deliveries before 35 weeks excluding those medically indicated, 12% of Whites/others and 55% of African Americans had high maternal HCA. The authors conclude that HCA definition, exclusion criteria, and race/ethnicity influence the HCA-preterm delivery association and that HCA contributes to preterm delivery-related ethnic disparity.
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It is well known that preterm birth increases the risk of cerebral palsy (CP), but more than half of affected children are born at term and the prevalence of CP in term infants has not declined in recent years. Because there is evidence that chorioamnionitis could substantially raise the risk of CP in term infants, a case-control study was done to clarify this relationship. The study population consisted of 231,582 singleton infants born alive at 36 or more weeks gestation in the years 1991-1998. The case group included 109 children having moderate to severe spastic or dyskinetic CP that could not be ascribed to postnatal brain injury or developmental abnormalities. Control subjects were 218 randomly selected women from the study population. CP was taken to mean a congenital nonprogressive motor dysfunction with spasticity, rigidity, or choreoathetosis. The prevalence of CP in this population was 0.9 per 1000 live births. More than 90% of children were followed up for 2 years or longer. Chorioamnionitis was diagnosed in 14% of the case group and 4% of control children, for an odds ratio (OR) of 3.8. On univariate analysis, CP also was associated with maternal fever, prolonged membrane rupture, nulliparity, and intrauterine growth retardation (IUGR). Intrapartum antibiotic treatment did not appear to have altered the OR of chorioamnionitis and CP. Chorioamnionitis was an independent risk factor for CP on multivariable analysis (OR, 4.1; 95% confidence interval, 1.6-10.1). Other risk factors were IUGR (OR, 4.0), a maternal age more than 25 years (OR, 2.6), being black (OR, 3.6), and nulliparity (OR, 1.8). These findings suggest that clinical chorioamnionitis is an independent risk factor for CP in term and near-term infants. Possible explanations include direct injury of the fetal brain by cytokines in the presence of maternal infection; inflammation of the placental membranes that interrupts gas exchange and blood flow, causing hypoxic-ischemic injury of the fetal brain; elevated core temperature in the fetus; and direct infection of the fetal brain or meninges secondary to maternal intrauterine infection.
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We tested the hypothesis that term and preterm infants exposed to maternal infection at the time of delivery are at increased risk of developing cerebral palsy (CP). A population-based case-control study was conducted using Washington State birth certificate data linked to hospital discharge data. Cases (688) were children <or=6 years old, singleton births, hospitalized during 1987 to 1999 with an ICD-9 diagnosis code for CP. Controls were 3,068 singleton birth infants randomly selected from birth records for the same years without CP-related hospitalizations. Infection information was available only for the birth hospitalization. Infants of women who had any infection during their hospitalization for delivery were at increased risk of CP (odds ratio (OR) 3.1, 95% confidence interval (CI) 2.3 to 4.2). This was observed for term deliveries (OR 1.8, 95% CI 1.1 to 2.8) and preterm deliveries (OR 2.3, 95% CI 1.3 to 4.2). Our results suggest that maternal infection is a risk factor for CP in both term and preterm infants.
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Injury to the cerebellum and brainstem is becoming increasingly recognized in prematurely born infants. The role of infection/inflammation in mediating damage to those structures in the preterm brain is largely unknown. Preterm fetal sheep (70% gestation) received either saline-vehicle (control group; n=11) or Escherichia coli lipopolysaccharide (100 ng intravenous [i.v.]; lipopolysaccharide [LPS] group; n=9), and were allowed to recover for 3 days before sacrifice. A diffuse pattern of cerebellar white matter damage was observed in all animals exposed to LPS, while focal cerebellar white matter lesions were observed in three out of nine animals, and an intragyral white matter hemorrhage in one animal. Cerebellar white matter injury was associated with a statistically significant loss of oligodendrocyte transcription factor-2-positive oligodendrocytes and increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cell counts. Ionized calcium binding adapter molecule 1 (Iba1)-positive cells which had the morphology of activated microglia were commonly observed in areas of injury. There was no obvious injury to the cerebellar cortex or to cerebellar Purkinje cells, and no obvious injury in any region of the brainstem. These data provide support for a role of infection/inflammation in selective white matter injury in the immature cerebellum, and demonstrate a differential vulnerability of the brainstem and cerebellar white matter to injury at this time.
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In determining the role inter-study variation should play in an overview analysis, it is important to consider three factors: which question one is trying to answer; the degree of similarity or dissimilarity of design, and the degree to which heterogeneity of outcomes can be explained. Three questions one might be interested in are: whether treatment can be effective in some circumstances; whether treatment is effective on average, and whether treatment was effective on average in the trials at hand. Under the assumption of no qualitative interaction, the answers to these questions coincide. The O-E analysis most directly answers the third question. Other analyses are suggested when the first question is of interest, using the aspirin post-MI studies as an example.
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The objective of this study was to determine the frequency and clinical significance of a systemic inflammatory response as defined by an elevated plasma interleukin-6 concentration in fetuses with preterm labor or preterm premature rupture of membranes. Amniocenteses and cordocenteses were performed in 157 patients with preterm labor and preterm premature rupture of membranes. Written informed consent and multi-institutional review board approvals were obtained. Amniotic fluid was cultured for aerobic and anaerobic bacteria, as well as mycoplasmas. Amniotic fluid and fetal plasma interleukin-6 concentrations were measured with a sensitive and specific immunoassay. Statistical analyses included contingency tables, receiver operating characteristic curve analysis, and multiple logistic regression. One hundred five patients with preterm labor and 52 patients with preterm premature rupture of membranes were included in this study. The overall prevalence of severe neonatal morbidity (defined as the presence of respiratory distress syndrome, suspected or proved neonatal sepsis, pneumonia, bronchopulmonary dysplasia. intraventricular hemorrhage, periventricular leukomalacia, or necrotizing enterocolitis) among survivors was 34.8% (54/155). Neonates in whom severe neonatal morbidity developed had higher concentrations of fetal plasma interleukin-6 than fetuses without development of severe neonatal morbidity (median 14.0 pg/mL, range 0.5 to 900 vs median 5.2 pg/mL, range 0.3 to 900, respectively; P < .005). Multivariate analysis was performed to explore the relationship between the presence of a systemic fetal inflammatory response and subsequent neonatal outcome. To preserve a meaningful temporal relationship between the results of fetal plasma interleukin-6 concentrations and the occurrence of severe neonatal morbidity, the analysis was restricted to 73 fetuses delivered within 7 days of cordocentesis who survived. The prevalence of severe neonatal morbidity in this subset of patients was 53.4% (39/73). A fetal plasma interleukin-6 cutoff value of 11 pg/mL was used to define the presence of a systemic inflammatory response. The prevalence of a fetal plasma interleukin-6 level > 11 pg/mL was 49.3% (36/73). Fetuses with fetal plasma interleukin-6 concentrations > 11 pg/mL had a higher rate of severe neonatal morbidity than did those with fetal plasma interleukin-6 levels < or = 11 pg/mL (77.8% [28/36] vs 29.7% [11/37], respectively; P < .001). Stepwise logistic regression analysis demonstrated that the fetal plasma interleukin-6 concentration was an independent predictor of the occurrence of severe neonatal morbidity (odds ratio 4.3, 95% confidence interval 1 to 18.5) when adjusted for gestational age at delivery, the cause of preterm delivery (preterm labor or preterm premature rupture of membranes), clinical chorioamnionitis, the cordocentesis-to-delivery interval, amniotic fluid culture, and amniotic fluid interleukin-6 results. A systemic fetal inflammatory response, as determined by an elevated fetal plasma interleukin-6 value, is an independent risk factor for the occurrence of severe neonatal morbidity.
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Periventricular white matter injury, specifically cystic periventricular leukomalacia (PVL) and ipsilateral hemorrhage into white matter associated with periventricular-intraventricular hemorrhage (PV-IVH), contribute significantly to neonatal mortality and long-term neurodevelopmental deficits in the premature infant. The first lesion PVL occurs in approximately 3-4% of infants of birth weight (BW) < 1500 grams. It manifests either as a focal or diffuse lesion within white matter. Although the pathogenesis of PVL is complex and likely multifactorial, principle contributors include vascular factors which markedly increase the risk for ischemia during periods of systemic hypotension and the intrinsic vulnerability of the oligodendrocyte to neurotoxic factors such as free radicals or cytokines. Clinical associations with PVL include a history of chorioamnionitis, prolonged rupture of membranes, asphyxia, sepsis, hypocarbia, etc. The vast majority of infants exhibit long-term neurodevelopmental deficits that affect motor, cognitive and visual function. The second lesion, the ipsilateral hemorrhage into white matter lesion associated with PV-IVH, occurs in approximately 10-15% of infants of BW < 1000 grams. The white matter injury appears to be a venous infarction with hemorrhage occurring as a secondary phenomenon. Prevention of this lesion has to include prevention of the associated PV-IVH. In this regard, the antenatal administration of glucocorticoids has been associated with a significant reduction in the sonographic incidence of severe IVH and the associated white matter involvement. The postnatal administration of indomethacin to high risk infants appears to hold the most promise at the current time in preventing this lesion. The neurodevelopmental outcome with extensive white matter injury is universally poor, affecting long-term motor and cognitive deficits; the long-term outcome is more favorable with lesser involvement. A clearer understanding of pathogenesis of both conditions is essential so as to provide targeted preventative strategies.
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The aim of this study was to determine whether fetal exposure to intra-amniotic inflammation and a systemic fetal inflammatory response (funisitis) are associated with the development of cerebral palsy at the age of 3 years. This cohort study included 123 preterm singleton newborns (gestational age at birth, </=35 weeks) born to mothers who underwent amniocentesis and were followed up for >/=3 years. The presence of intra-amniotic inflammation was determined by elevated amniotic fluid concentrations of proinflammatory cytokines such as interleukins 6 and 8 and by amniotic fluid white blood cell count. Cytokine concentrations were measured with sensitive and specific immunoassays. Funisitis was diagnosed in the presence of neutrophil infiltration into the umbilical vessel walls or Wharton jelly. Cerebral palsy was diagnosed by neurologic examination at the age of 3 years. Newborns with subsequent development of cerebral palsy had a higher rate of funisitis and were born to mothers with higher median concentrations of interleukins 6 and 8 and higher white blood cell counts in the amniotic fluid compared with newborns without subsequent development of cerebral palsy (funisitis: 75% [9/12] vs 23% [24/105]; interleukin 6: median, 18.9 ng/mL; range, 0. 02-92.5 ng/mL; vs median, 1.0 ng/mL; range, 0.01-115.2 ng/mL; interleukin 8: median, 13.0 ng/mL; range, 0.1-294.5 ng/mL; vs median, 1.2 ng/mL; range, 0.05-285.0 ng/mL; white blood cell count: median, 198 cells/mm(3); range, 0->1000 cells/mm(3); vs median, 3 cells/mm(3); range, 0-19,764 cells/mm(3); P <.01 for each). After adjustment for the gestational age at birth, the presence of funisitis and elevated concentrations of interleukins 6 and 8 in amniotic fluid significantly increased the odds of development of cerebral palsy (funisitis: odds ratio, 5.5; 95% confidence interval, 1.2-24.5; interleukin 6: odds ratio, 6.4; 95% confidence interval, 1. 3-33.0; interleukin 8: odds ratio, 5.9; 95% confidence interval, 1. 1-30.7; P <.05 for each). Antenatal exposure to intra-amniotic inflammation and evidence of a systemic fetal inflammatory response (funisitis) are strong and independent risk factors for the subsequent development of cerebral palsy at the age of 3 years.
Article
Placental abnormalities reflect antenatal disease processes that may interact with other perinatal risk factors to affect long-term outcome. We performed a nested case control analysis of placental and clinical risk factors associated with neurologic impairment (NI) at 20-mo corrected age (60 cases and 59 controls) using data collected in a prospective study of very low birth weight (less than 1500 g) infants born between 1983 and 1991. In a preliminary analysis we explored the relationship between clinical infection and histologic chorioamnionitis (CA). Only histologic CA with a fetal vascular response correlated with either clinical CA or early onset neonatal sepsis. We then assessed the relative contribution of the nine risk factors (four placental and five clinical) associated with NI at the univariate level by multiple logistic regression. Three risk factors were independent predictors of NI: severe cranial ultrasound abnormalities (odds ratio 13.6, 95% confidence intervals 4.5-66.7), multiple placental lesions (odds ratio 13.2, 95% confidence intervals 1.3-137.0), and oxygen dependence at 36 wk (odds ratio 4.2, 95% confidence intervals 1.2-14.6). Finally, a series of logistic regressions was conducted with the dependent variable changing as we moved back along the causal chain to explore the relationships between risk factors operating at different stages. This analysis suggested that antenatal variables that were not independent predictors of NI by multiple logistic regression exerted their effects through the following intermediate pathways: fetal grade 3 histologic CA via chorionic vessel thrombi, clinical CA via grade 3 villous edema, and grade 3 villous edema via severe cranial ultrasound abnormalities.
Article
To identify prenatal events associated with cerebral palsy (CP) in infants born between 26 and 30 weeks of gestation. Case (n=22)-control (n=170) study was performed using a logistic regression model. Significant association of intrauterine infection with increased risk of CP was found in a logistic regression model that controlled for abnormal FHR patterns, placental infection, fetal acidosis at birth (umbilical artery pH<7. 1), and low Apgar score (<7) (odds ratio (OR) 5.47, 95% confidence interval (CI) 1.46-20.4). Magnesium sulfate exposure was associated with decreased risk (OR 0.13, CI 0.03-0.66) after exclusion of premature rupture of the membranes and abruptio placentae. In the magnesium exposure group, cases were infants born less than 28 weeks of gestation (3/21 vs. 0/61, P=0.015). In this case-control study, both intrauterine infection and magnesium sulfate exposure were significant factors related to the occurrence of cerebral palsy.
Article
Infections in pregnancy, including the most common congenital infections (TORCH: toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus), are known causes of long-term neurodevelopmental disabilities, although the proportion of children with specific disabilities attributable to TORCH infections appears to be 5% to 10% or less. Intrauterine infection, especially subclinical infection of the kind associated with preterm birth, is under investigation as a cause of neurodevelopmental disability. These studies have focused almost exclusively on cerebral palsy. Summary estimates from a published meta-analysis suggest that chorioamnionitis is associated with a twofold increased risk of cerebral palsy in preterm and a fivefold increased risk in term children. In some studies, cytokine levels in amniotic fluid or newborn blood have also been found to be significantly elevated in preterm and term children with cerebral palsy compared to controls. These data suggest that factors related to the fetal inflammatory response, including cytokines, may be causal agents in brain damage and neurodevelopmental disability associated with intrauterine infection. We need to greatly improve both our understanding of and our ability to measure the relevant exposures related to infection and inflammation, to further understand differences in the association between intrauterine infection and cerebral palsy relative to gestational age, and to investigate a broad range of neurodevelopmental outcomes as potential adverse effects of intrauterine infection.
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The study aimed to identify significant antenatal risk factors for cerebral palsy (CP) among extremely preterm infants with a matched case-control design. Infants born between 1989 and 1996 at 24 to 27 weeks' gestation who survived to hospital discharge were evaluated: 30 with a proven diagnosis of CP at 2 years corrected for prematurity and 120 control children matched for gestational age without CP. Information on maternal obstetric risk factors and medication was obtained. Matched analyses were performed and odds ratios (OR) and 95% confidence intervals (CI) were calculated. An antenatal diagnosis of intrauterine growth restriction was associated with an increased risk of CP (OR 6.6; 95% CI 1.8 to 25.2), while maternal administration of corticosteroids was associated with a reduced risk of CP (OR 0.4; 95% CI 0.1 to 0.98). A high rate of placental histopathology was achieved but no relation between clinical or histological chorioamnionitis or funisitis and CP was demonstrated. Maternal preeclampsia was not associated with a statistically significant reduction in the risk of CP. It is concluded that a reduced risk of CP in extremely preterm infants is associated with the antenatal use of corticosteroids.
Article
White matter damage (WMD) in preterm neonates is strongly associated with adverse outcome. The etiology of white matter injury is not known but clinical data suggest that ischemia-reperfusion and/or infection-inflammation are important factors. Furthermore, antenatal infection seems to be an important risk factor for brain injury in term infants. In order to explore the pathophysiological mechanisms of WMD and to better understand how infectious agents may affect the vulnerability of the immature brain to injury, numerous novel animal models have been developed over the past decade. WMD can be induced by antenatal or postnatal administration of microbes (E. coli or Gardnerella vaginalis), virus (border disease virus) or bacterial products (lipopolysaccharide, LPS). Alternatively, various hypoperfusion paradigms or administration of excitatory amino acid receptor agonists (excitotoxicity models) can be used. Irrespective of which insult is utilized, the maturational age of the CNS and choice of species seem critical. Generally, lesions with similarity to human WMD, with respect to distribution and morphological characteristics, are easier to induce in gyrencephalic species (rabbits, dogs, cats and sheep) than in rodents. Recently, however, models have been developed in rats (PND 1-7), using either bilateral carotid occlusion or combined hypoxia-ischemia, that produce predominantly white matter lesions. LPS is the infectious agent most often used to produce WMD in immature dogs, cats, or fetal sheep. The mechanism whereby LPS induces brain injury is not completely understood but involves activation of toll-like receptor 4 on immune cells with initiation of a generalized inflammatory response resulting in systemic hypoglycemia, perturbation of coagulation, cerebral hypoperfusion, and activation of inflammatory cells in the CNS. LPS and umbilical cord occlusion both produce WMD with quite similar distribution in 65% gestational sheep. The morphological appearance is different, however, with a more pronounced infiltration of inflammatory cells into the brain and focal microglia/macrophage ("inflammatory WMD") in response to LPS compared to hypoperfusion evoking a more diffuse microglial response usually devoid of cellular infiltrates ("ischemic WMD"). Furthermore, low doses of LPS that by themselves have no adverse effects in 7-day-old rats (maturation corresponding to the near term human fetus), dramatically increase brain injury to a subsequent hypoxic-ischemic challenge, implicating that bacterial products can sensitize the immature CNS. Contrary to this finding, other bacterial agents like lipoteichoic acid were recently shown to induce tolerance of the immature brain suggesting that the innate immune system may respond differently to various ligands, which needs to be further explored.
Article
Intrauterine infection is a major cause of premature labor with and without intact membranes. Intrauterine infection is present in approximately 25% of all preterm births and the earlier the gestational age at delivery, the higher the frequency of intra-amniotic infection. Microorganisms may also gain access to the fetus before delivery. A fetal inflammatory response syndrome elicited in response to microbial products is associated with the impending onset of preterm labor and also with multi-systemic organ involvement in the human fetus and a higher rate of perinatal morbidity. The most common microorganisms involved in intrauterine infections are Ureaplasma urealyticum, Fusobacterium species and Mycoplasma hominis. The role of Chlamydia trachomatis and viruses in preterm labor remain to be determined. Use of molecular microbiology techniques to diagnose intrauterine infection may uncover the role of fastidious microorganisms that have not yet been discovered. Antibiotic administration to patients with asymptomatic bacteriuria is associated with a significant reduction in the rate of preterm birth. However, such benefit has not been demonstrated for patients with bacterial vaginosis, or women who carry Streptococcus agalactia, Ureaplasma urealyticum or Trichomonas vaginalis. Antibiotic administration to patients with preterm premature rupture of membranes is associated with prolongation of pregnancy and a reduction in the rate of clinical chorioamnionitis and neonatal sepsis. The benefit has not been demonstrated in patients with preterm labor and intact membranes. Major efforts are required to determine why some women develop an ascending intrauterine infection and others do not and also what interventions may reduce the deleterious effect of systemic fetal inflammation.
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Unlabelled: Cerebral palsy rates of 2 in every 1,000 births have varied little over the last 40 years, despite improvements in obstetric care. In the past, cerebral palsy was thought to be due to poor obstetric care and management; however, epidemiological studies have refuted this, suggesting that there is usually an antenatal timing to the neuropathology of cerebral palsy. There are many known risk factors for cerebral palsy, including multiple gestation, prematurity, and low birth weight. Recently, intrauterine infection, maternal pyrexia, and the presence of thrombophilic disorders (thrombophilia) have been identified as major risk factors for subsequent cerebral palsy. This review examines the links between intrauterine infection, the fetal inflammatory response, and thrombophilia as possible causes of cerebral palsy. The interactions of viral or bacterial infections during pregnancy, normal or abnormal fetal cytokine responses, and hereditary fetal thrombophilias as antenatal causes of the neuropathology of cerebral palsy are now areas of research priority. Target audience: Obstetricians & Gynecologists, Family Physicians Learning objectives: After completion of this article, the reader will be able to describe the condition cerebral palsy, list the risk factors for the development of cerebral palsy, outline the ultrasound findings associated with cerebral palsy, and point out other conditions associated with cerebral palsy.
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To examine the relationship of cytokines in blood of very preterm neonates with later diagnosis of spastic cerebral palsy (CP) compared with infants of similar gestational age without CP, we measured concentrations of inflammatory cytokines and other substances in archived neonatal blood by recycling immunoaffinity chromatography. Subjects were surviving children born before 32 wk gestational age (GA) to women without preeclampsia, 64 with later diagnoses of CP and 107 control children. The initial analyses were augmented by measurement of 11 cytokines by a bead-based flow analytic system (Luminex) in an additional 37 children with CP and 34 control children from the same cohort. Concentrations of examined substances did not differ by presence of indicators of infection in mother, infant, or placenta. On ANOVA, concentrations of a number of cytokines were significantly related to neonatal ultrasound abnormalities (periventricular leukomalacia, ventricular enlargement, or moderate or severe germinal matrix hemorrhage). None of the substances measured either by immunoaffinity chromatography or flow analytic methods, including IL-1, -6, and -8 and tumor necrosis factor-alpha, was related to later diagnosis of CP or its subtypes. Inflammatory cytokines in neonatal blood of very premature infants did not distinguish those with later diagnoses of CP from control children.
Article
Cerebral palsy is a serious motor disorder that appears in early life. The expectation that improved obstetrical and neonatal care would decrease the rate of this condition has not been realised. Recent evidence indicates that white matter brain lesions, often termed periventricular leukomalacia (PVL), are the most important identifiable risk factors for the development of cerebral palsy. The hypothesis under examination is that inflammatory cytokines released during the course of intrauterine infection play a central role in the genesis of preterm parturition, fetal PVL, and cerebral palsy. We examined the relationship between umbilical cord plasma concentrations of cytokines at birth and the occurrence of PVL in preterm gestation and demonstrated that umbilical cord plasma concentrations of interleukin (IL)-6 was a significant independent predictor of PVL-associated lesions. We also demonstrated that preterm neonates born to mothers with elevated amniotic fluid concentrations of pro-inflammatory cytokines were at increased risk for the subsequent development of PVL and cerebral palsy. Histological chorioamnionitis and congenital neonatal infection-related morbidity were more common in neonates with PVL than those without PVL in this study. We have also been able to induce PVL-like brain white matter lesions in the fetal rabbit after experimental ascending intrauterine infection. In support of this hypothesis, we were able to demonstrate overexpression of tumour necrosis factor-alpha and IL-6 in histological sections of neonatal brains with PVL. Moreover, the presence of funisitis, a histological counterpart of the fetal inflammatory response syndrome, and elevated concentrations of amniotic fluid IL-6 and IL-8 were strong and independent risk factors for the subsequent development of cerebral palsy at the age of 3 years in our recent study. Therefore, clinical and experimental data provide strong support for the hypothesis. There are significant implications of our findings. First, cytokine determinations in amniotic fluid provide information about the risk of PVL and cerebral palsy before birth. Second, the process responsible for some cases of PVL and cerebral palsy begins during intrauterine life, implying that effective strategies for the prevention of cerebral palsy associated with PVL must begin in utero.
Article
Chorioamnionitis is a risk factor for preterm delivery. Intrauterine infection leads to the fetal inflammatory response which is characterised by elevated cytokine levels. Chorioamnionitis is reported to cause accelerated but abnormal lung maturation, resulting in decreased incidence of respiratory distress syndrome (RDS) but increased chronic lung disease (CLD), and predisposes the infant to cerebral injury. To investigate the relation between chorioamnionitis and RDS, CLD, cerebral lesions, neurodevelopmental outcome and mortality in a cohort of extremely premature infants. Infants born between 1997 and 2001 with a gestational age of less than 28 weeks or a birth weight of less than 1000 g were divided into two groups: Group 1 with evidence of chorioamnionitis and Group 2 without. Outcomes of these two groups of infants were compared. A total of 388 infants were included (105 in Group 1 and 283 in Group 2). Chorioamnionitis was significantly associated with an increased risk of extreme preterm delivery. Group 1 showed a trend towards an increased incidence of CLD and mortality, while the incidence of periventricular leukomalacia, retinopathy of prematurity (ROP) and necrotising enterocolitis (NEC) were similar between the two groups. Subgroup analysis of 2-year neurodevelopmental outcome showed an increased trend towards cerebral palsy and visual impairment, while the incidence of developmental delay and hearing impairment are similar between the two groups. Extremely preterm infants with chorioamnionitis showed a trend towards an increased incidence of CLD, mortality, cerebral palsy and visual impairement, but a decreased risk of RDS.
Article
Although antenatal infection is thought to play an important role in the pathogenesis of preterm labor and neonatal diseases, the exact mechanisms are largely unknown. We sought to clarify the relationship between antenatal infection and intrauterine and neonatal inflammation. Samples were obtained from 41 preterm infants of <33 wk gestation delivered to 36 mothers and analyzed for the presence of 16s ribosomal RNA (16s rRNA) genes using PCR and for the proinflammatory cytokines IL-6 and IL-8. In 16 (44%) mother-baby pairings, at least one sample was found to be positive for the presence of 16s rRNA genes. All but one of the positive samples were from mothers presenting with preterm prelabor rupture of membranes (pPROM) or in spontaneous idiopathic preterm labor. A strong association was found between the presence of 16s rRNA genes and chorioamnionitis and with funisitis. A marked increase in IL-6 and IL-8 was noted in all tissues positive for 16s rRNA genes, including placenta, fetal membranes, cord blood serum, and, where samples were available, in bronchoalveolar lavage fluid (BAL) and in amniotic fluid. Interestingly, gastric fluid was always positive for 16s rRNA genes if any other intrauterine or BAL sample was positive, suggesting that this sample may provide an alternative to amniotic fluid to identify antenatal infection. In conclusion, we have found that microbial genes are particularly prevalent in pPROM and spontaneous preterm labor groups and that their presence is strongly associated with a marked intrauterine inflammatory response.
Article
To identify crucial factors that precipitate cerebral palsy by controlling confounding factors in logistic regression analyses. We retrospectively investigated a cohort of all 922 infants with gestational ages of less than 34 weeks (22-33 weeks), who were admitted to our neonatal intensive care unit between 1990 and 1998. Thirty (3.7%) were diagnosed to have cerebral palsy. We analyzed the prenatal and postnatal clinical variables of the cerebral palsy cases and compared them with 150 randomly selected controls. Risk factors for cerebral palsy identified in univariate analysis were: twin pregnancy, long-term ritodrine tocolysis, respiratory distress syndrome, air leak, surfactant administration, intermittent mandatory ventilation, high frequency oscillation, lowest PaCO2 levels, prolonged hypocarbia during the first 72 h of life, and postnatal steroid therapy. In a conditional multiple logistic model, long-term ritodrine tocolysis, prolonged hypocarbia and postnatal steroid therapy remained associated with an increased risk of cerebral palsy after adjustment for other antenatal and postnatal variables (OR [Odds Ratio] = 8.62, 95% CI [Confidence Interval], 2.18-33.97; OR = 7.81, 95% CI, 1.42-42.92; OR = 21.37, 95% CI, 2.01-227.29, respectively). Our results suggest that long-term ritodrine tocolysis underlines the development of cerebral palsy. Further assessments of the effect of ritodrine on fetal circulation and nervous system are required. Moreover, possible alternatives to systemic postnatal steroids are needed, and carbon dioxide levels should be more strictly controlled.
Article
In this article, the author reviews the etiology and biochemical links between infection and preterm birth, the problem of preterm birth, and the management of infection-related risks of preterm birth. The management section reviews current opinions regarding prophylactic antibiotic therapy in the prevention of preterm birth, adjunctive antibiotic therapy in the treatment of preterm labor with and without rupture of membranes, and antibiotic therapy of intra-amniotic infection (clinical chorioamnionitis, IAI). Finally, the article reviews the risk of neurodevelopmental handicap potentially associated with IAI.
Article
Intrauterine inflammation may relate to neurologic disability among preterm children. We investigated the relationship between chorioamnionitis, cord serum cytokines, and neurologic outcome. Sixty-one consecutively born very preterm extremely low birth weight (ELBW) infants were prospectively enrolled. Histologic inflammation in placenta and umbilical cord and vascular pathology were evaluated. Cord sera were analyzed for five proinflammatory cytokines. Serial brain ultrasound and magnetic resonance imaging were performed for evaluation of intraventricular hemorrhage (IVH grade I-III) and white matter damage (WMD: cystic periventricular leukomalacia or IVH grade IV). Neurologic and neurocognitive outcomes were assessed at the corrected age of 2 y. The incidences of HCA, WMD, and abnormal neurologic outcome were 48%, 13% and 19%, respectively. HCA or high IL-6 in cord serum predicted spontaneous preterm labor with high accuracy. HCA increased the risk of IVH grade II-III. In HCA, without either clinical chorioamnionitis or histologic placental perfusion defect, the children had a low risk of WMD (0%) and a low risk of abnormal neurologic outcome (6%). In HCA, the concentration of IL-6 in cord serum was lower in children with abnormal neurologic outcome than in children with normal neurologic outcome. In HCA and placental perfusion defect (compound defect) the risk of abnormal neurologic outcome was high. Compound placental defect and WMD additively predicted abnormal neurologic outcome. We propose that HCA together with other insults (placental perfusion defect or maternal systemic infection) increases the risk of poor neurologic outcome in very preterm ELBW infants.
Article
Premature delivery is still a significant problem in Obstetrics. It has multiple causes, with around 50% thought due to infection. Of note infection as a pathogenesis is more likely in those pre-term births occurring <30 weeks gestation and is largely sub-clinical. Potential pathogens largely arise from the ascending route and from the endogenous vaginal flora, causing chorioamnionitis. Resultant morbidity from the release of endo+/exotoxins from such pathogens, the stimulation and production of inflammatory cytokine pathways, prostaglandins, metalloproteinases includes maternal sepsis (chorioamnionitis, septicaemia, post-partum endometritis), pre-term delivery (infant pre-maturity and its consequences, increased susceptibility to cerebral palsy and neonatal sepsis). As well, infection increases mortality due to fetal loss (extreme pre-maturity) as well as severe neonatal sepsis.
Article
Infections of the mother, the intrauterine environment, the fetus, and the neonate can cause cerebral palsy through a variety of mechanisms. Each of these processes is reviewed. The recently proposed theory of cytokine-induced white matter brain injury and the systemic inflammatory response syndrome with multiple organ dysfunction syndrome is critically evaluated.