Search

Background: Despite the use of intraoperative opioid analgesia, postoperative pain is often reported by patients undergoing craniotomies. Opioids also cause undesirable side effects in neurosurgical patients. Hence, the role of nonopioid analgesia has been explored for craniotomies in recent years., Methods: This systematic review evaluated evidence from randomized controlled trials (RCTs) comparing opioid and nonopioid analgesia during craniotomies regarding postoperative pain, recovery, and adverse events., Results: Of the 10,459 records obtained by searching MEDLINE, Embase, and Web of Science databases, 6 RCTs were included. No difference was observed in pain scores between opioid and nonopioid analgesia at 1 and 24 hours after surgery: mean difference (MD), 1.11 units; 95% confidence interval [CI], -0.16 to 2.38, P = 0.09 and MD, -0.06 units; 95% CI, -1.14 to 1.01, P = 0.91, respectively. The time for first postoperative analgesic requirement was shorter with opioids but was not statistically significant (MD, -84.77 minutes; 95% CI, -254.65 to 85.11; P = 0.33). Postoperative nausea and vomiting (relative risk = 1.60; 95% CI, 0.96-2.66; P = 0.07) was similar but shivering (relative risk = 2.01; 95% CI, 1.09-3.71; P = 0.03) was greater in the opioid group than nonopioid group., Conclusions: There were no important differences in clinical outcomes between the groups in our review. The GRADE certainty of evidence was rated low for most outcomes. Available evidence does not suggest superiority of intraoperative nonopioid over opioid analgesia for postoperative pain in patients undergoing craniotomy. More studies are needed to firmly establish the role of nonopioid intraoperative analgesics as an alternative to opioids in this population., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: With therapeutic hypothermia (HT) for neonatal encephalopathy, disability rates are reduced, but not all babies benefit. Pre-clinical rodent studies suggest mesenchymal stromal cells (MSCs) augment HT protection., Aims: The authors studied the efficacy of intravenous (IV) or intranasal (IN) human umbilical cord-derived MSCs (huMSCs) as adjunct therapy to HT in a piglet model., Methods: A total of 17 newborn piglets underwent transient cerebral hypoxia-ischemia (HI) and were then randomized to (i) HT at 33.5°C 1-13 h after HI (n = 7), (ii) HT+IV huMSCs (30 × 10 6 cells) at 24 h and 48 h after HI (n = 5) or (iii) HT+IN huMSCs (30 × 10 6 cells) at 24 h and 48 h after HI (n = 5). Phosphorus-31 and hydrogen-1 magnetic resonance spectroscopy (MRS) was performed at 30 h and 72 h and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells and oligodendrocytes quantified. In two further piglets, 30 × 10 6 IN PKH-labeled huMSCs were administered., Results: HI severity was similar between groups. Amplitude-integrated electroencephalogram (aEEG) recovery was more rapid for HT+IN huMSCs compared with HT from 25 h to 42 h and 49 h to 54 h (P ≤ 0.05). MRS phosphocreatine/inorganic phosphate was higher on day 2 in HT+IN huMSCs than HT (P = 0.035). Comparing HT+IN huMSCs with HT and HT+IV huMSCs, there were increased OLIG2 counts in hippocampus (P = 0.011 and 0.018, respectively), internal capsule (P = 0.013 and 0.037, respectively) and periventricular white matter (P = 0.15 for IN versus IV huMSCs). Reduced TUNEL-positive cells were seen in internal capsule with HT+IN huMSCs versus HT (P = 0.05). PKH-labeled huMSCs were detected in the brain 12 h after IN administration., Conclusions: After global HI, compared with HT alone, the authors saw beneficial effects of HT+IN huMSCs administered at 24 h and 48 h (30 × 10 6 cells/kg total dose) based on more rapid aEEG recovery, improved 31 P MRS brain energy metabolism and increased oligodendrocyte survival at 72 h., (Copyright © 2020 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

This study aimed to investigate the association of adenomyosis with fertility, pregnancy and neonatal outcomes. An electronic search was conducted using the MEDLINE, PubMed and Cochrane databases up to April 2020. Seventeen observational studies were included. Adenomyosis was significantly associated with a lower clinical pregnancy rate (odds ratio [OR] 0.69; 95% confidence interval [CI] 0.51-0.94) and higher miscarriage rate (OR 2.17; 95% CI 1.25-3.79) after treatment with assisted reproductive technology (ART). The lower clinical pregnancy rate was more significant in the subgroup of patients with short down-regulation protocols. Similar associations were recorded after age adjustment. Adenomyosis was also significantly associated with an increased risk of pre-eclampsia, preterm delivery, Caesarean section, fetal malpresentation, small for gestational age infancy and post-partum haemorrhage, which was confirmed after correction for age and mode of conception. In conclusion, adenomyosis is associated with negative effects on fertility after ART. The potentially protective role of the ultra-long down-regulation protocols needs further evaluation in randomized controlled studies. Adenomyosis is also associated (independently of the mode of conception) with adverse pregnancy and neonatal outcomes. Proper counselling prior to ART and close monitoring of pregnancy in patients with adenomyosis should be recommended., (Copyright © 2020 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Prenatal inflammation is a major risk for preterm birth and neonatal morbidity, but its effects on postnatal immunity and organ functions remain unclear. Using preterm pigs as a model for preterm infants, we investigated whether prenatal intra-amniotic (IA) inflammation modulates postnatal systemic immune status and organ functions. Preterm pigs exposed to IA lipopolysaccharide (LPS) for 3 days were compared with controls at birth and postnatal day 5 after formula feeding. IA LPS induced mild chorioamnionitis but extensive intra-amniotic inflammation. There were minor systemic effects at birth (increased blood neutrophil counts), but a few days later, prenatal LPS induced delayed neonatal arousal, systemic inflammation (increased blood leukocytes, plasma cytokines, and splenic bacterial counts), altered serum biochemistry (lower albumin and cholesterol and higher iron and glucose values), and increased urinary protein and sodium excretion. In the gut and lungs, IA LPS-induced inflammatory responses were observed mainly at birth (increased LPS, CXCL8, and IL-1β levels and myeloperoxidase-positive cell density, multiple increases in innate immune gene expressions, and reduced villus heights), but not on postnatal day 5 (except elevated lung CXCL8 and diarrhea symptoms). Finally, IA LPS did not affect postnatal gut brush-border enzymes, hexose absorption, permeability, or sensitivity to necrotizing enterocolitis on day 5. Short-term IA LPS exposure predisposes preterm pigs to postnatal systemic inflammation after acute fetal gut and lung inflammatory responses., (Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: The efficacy of antenatal steroids for fetal lung maturation in the periviable period is not fully understood., Objective: We sought to determine the lung maturational effects of antenatal steroids and inflammation in early gestation sheep fetuses, similar to the periviable period in human beings., Study Design: Date-mated ewes with singleton fetuses were randomly assigned to 1 of 4 treatment groups (n = 8/group): (1) maternal intramuscular injection of betamethasone; (2) intraamniotic lipopolysaccharide; (3) betamethasone + lipopolysaccharide; and (4) intraamniotic + intramuscular saline (controls). Fetuses were delivered surgically 48 hours later at 94 days' gestation (63% term gestation) for comprehensive evaluations of lung maturation, and lung and systemic inflammation., Results: Relative to controls, first, betamethasone increased the fetal lung air space to mesenchymal area ratio by 47% but did not increase the messenger RNAs for the surfactant proteins-B and -C that are important for surfactant function or increase the expression of pro-surfactant protein-C in the alveolar type II cells. Second, betamethasone increased expression of 1 of the 4 genes in surfactant lipid synthetic pathways. Third, betamethasone increased genes involved in epithelium sodium channel transport, but not sodium-potassium adenosine triphosphatase or Aquaporin 5. Fourth, lipopolysaccharide increased proinflammatory genes in the lung but did not effectively recruit activated inflammatory cells. Last, betamethasone incompletely suppressed lipopolysaccharide-induced lung inflammation. In the liver, betamethasone when given alone increased the expression of serum amyloid A3 and C-reactive protein messenger RNAs., Conclusion: Compared the more mature 125-day gestation sheep, antenatal steroids do not induce pulmonary surfactants during the periviable period, indicating a different response., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Antenatal steroids are standard of care for women who are at risk of preterm delivery; however, antenatal steroid dosing and formulation have not been evaluated adequately. The standard clinical 2-dose treatment with betamethasone-acetate+betamethasone-phosphate is more effective than 2 doses of betamethasone-phosphate for the induction of lung maturation in preterm fetal sheep. We hypothesized that the slowly released betamethasone-acetate component induces similar lung maturation to betamethasone-phosphate+betamethasone-acetate with decreased dose and fetal exposure., Objective: The purpose of this study was to investigate pharmacokinetics and fetal lung maturation of antenatal betamethasone-acetate in preterm fetal sheep., Study Design: Groups of 10 singleton-pregnant ewes received 1 or 2 intramuscular doses 24 hours apart of 0.25 mg/kg/dose of betamethasone-phosphate+betamethasone-acetate (the standard of care dose) or 1 intramuscular dose of 0.5 mg/kg, 0.25 mg/kg, or 0.125 mg/kg of betamethasone-acetate. Fetuses were delivered 48 hours after the first injection at 122 days of gestation (80% of term) and ventilated for 30 minutes, with ventilator settings, compliance, vital signs, and blood gas measurements recorded every 10 minutes. After ventilation, we measured static lung pressure-volume curves and sampled the lungs for messenger RNA measurements. Other groups of pregnant ewes and fetuses were catheterized and treated with intramuscular injections of betamethasone-phosphate 0.125 mg/kg, betamethasone-acetate 0.125 mg/kg, or betamethasone-acetate 0.5 mg/kg. Maternal and fetal betamethasone concentrations in plasma were measured for 24 hours., Results: All betamethasone-treated groups had increased messenger RNA expression of surfactant proteins A, B, and C, ATP-binding cassette subfamily A member 3, and aquaporin-5 compared with control animals. Treatment with 1 dose of intramuscular betamethasone-acetate 0.125mg/kg improved dynamic and static lung compliance, gas exchange, and ventilation efficiency similarly to the standard treatment of 2 doses of 0.25 m/kg of betamethasone-acetate+betamethasone-phosphate. Betamethasone-acetate 0.125 mg/kg resulted in lower maternal and fetal peak plasma concentrations and decreased fetal exposure to betamethasone compared with betamethasone-phosphate 0.125 mg/kg., Conclusion: A single dose of betamethasone-acetate results in similar fetal lung maturation as the 2-dose clinical formulation of betamethasone-phosphate+betamethasone-acetate with decreased fetal exposure to betamethasone. A lower dose of betamethasone-acetate may be an effective alternative to induce fetal lung maturation with less risk to the fetus., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Data on long-term consequences of neonatal pain is limited., Aim: To assess whether perinatal factors, later pain experience and pain coping strategies are associated with altered pain threshold, pain tolerance and pain intensity in adolescents born preterm., Study Design: Observational, longitudinal study (Project on Preterm and SGA-infants, POPS-19)., Subjects: We analyzed data of 412 adolescents at the age of 19years, who were born at a gestational age<32weeks or with a birth weight<1500g., Outcome Measures: Participants performed a standardized cold pressor test to assess pain threshold, tolerance and intensity. Furthermore, they completed a pain coping questionnaire (PCQ)., Results: In univariate analysis, female gender and necrotizing enterocolitis (NEC) were associated with lower pain tolerance, indicated by reaching the ceiling time of 180s in ice water (females 19% vs males 29%, NEC 7% vs no NEC 25%). Female gender was associated with higher pain intensity (mean difference 0.58; 95%CI 0.21; 0.95) and lower pain threshold (log rank test p 0.007). In a multivariate Cox regression analyses, emotion focused avoidance pain coping style was significantly associated with lower pain threshold (hazard ratio HR 1.38; 95%CI 1.02; 1.87) and pain tolerance (HR 1.72; 95%CI 1.21; 2.42). NEC was significantly associated with lower pain threshold (HR 1.47; 95%CI 1.01; 2.14) and pain tolerance (HR 1.63; 95%CI 1.09; 2.41)., Conclusion: In adolescence, maladaptive pain coping strategy was associated with lower pain threshold, pain tolerance and higher pain intensity. NEC was associated with altered pain response in adolescents born preterm., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Antenatal steroids are standard of care for cases of anticipated preterm labor to improve neonatal outcomes. However, steroids are potent drugs, and their use in pregnancy remains largely unoptimized., Objective: The objective of the study was to measure the maternofetal pharmacokinetics of constant, low-dose intravenous betamethasone phosphate infusions and correlate these data with the transcriptional effect exerted by subclinical betamethasone exposures on the ovine fetal lung., Study Design: Thirty-two ewes carrying a single fetus had surgery to catheterize fetal and maternal jugular veins at 116 days of gestation (term, 150 days). Animals were recovered for 2 days and then were randomized to receive 2 sequential maternal intravenous infusions of either (n = 4/group) of the following: 1) saline, 0.125, 0.04, or 0.0125 mg/kg betamethasone phosphate over 3 hours; or 2) saline, 0.25, 0.08, or 0.025 mg/kg betamethasone phosphate over 12 hours. Each infusion was separated by 2 days. Fetal lung tissue was collected for analysis using quantitative polymerase chain reaction and an ovine-specific microarray. Plasma betamethasone levels from time-course catheter samples were determined by mass spectrometry. Data were assessed for distribution, variance, and tested by an analysis of variance., Results: Betamethasone was detectable (>1 ng/mL) in fetal plasma only in animals randomized to 0.125 mg/kg 3 hour or 0.250 mg/kg 12 hour infusions. Fetal betamethasone half-lives were 1.7-2.8 times greater than maternal values. At maximum concentration, fetal plasma betamethasone levels were approximately 10% of maternal levels. Compared with saline control, all animals, other than those receiving 0.0125 mg/kg 3 hour betamethasone phosphate infusions, had evidence of dose-dependent glucocorticoid transcriptional responses in the fetal lung., Conclusion: Constant maternal betamethasone infusions delivering substantially lower fetal and maternal betamethasone maximal concentrations than those achieved with current clinical treatment protocols were associated with dose-dependent changes in glucocorticoid-response markers in the fetal lung. Further studies to determine the minimally efficacious dose of steroids for improving outcomes in preterm infants should be viewed as a priority., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Data on long-term consequences of preterm birth on pain coping later in life are limited., Aim: To assess whether gestational age, birth weight and neonatal disease severity have effect on pain coping style in adolescents born preterm or with low birth weight., Study Design: Observational, longitudinal study (Project On Preterm and SGA-infants, POPS-19)., Subjects: We analyzed data of 537 adolescents at the age of 19 years, who were born at a gestational age <32 weeks or with a birth weight <1500g., Outcome Measures: Participants completed the pain coping questionnaire (PCQ) that assesses pain coping strategies in three higher-order factors: approach ("to deal with pain"), problem-focused avoidance ("to disengage from pain") and emotion-focused avoidance ("expression of pain"). Furthermore, their pain coping effectiveness, pain controllability and emotional reactions to pain were assessed. All participants completed an IQ test., Results: Univariate analysis showed no significant correlation between length of stay, sepsis and necrotizing enterocolitis and any of the higher-order factors. Approach was only correlated with IQ. Problem-focused avoidance was, in the multiple regression analysis (including gestational age, IVH and IQ), only correlated with IQ. For emotion-focused avoidance (including birth weight, SGA, IVH, respiratory support and IQ) three independent predictors remained: IVH was positively correlated, while respiratory support and IQ were negatively correlated with emotion-focused avoidance., Conclusions: Early neonatal characteristics and neonatal disease severity have limited effect on pain coping style in adolescence. Higher IQ was associated with the use of adaptive coping strategies, while maladaptive strategies were used less., (Copyright © 2016. Published by Elsevier Ireland Ltd.)

Introduction: Perinatal asphyxia (PA) is a major cause of neonatal mortality and morbidity. Research has shown that in rats fetal asphyxia (FA) can provoke neuroprotection against a subsequent more severe perinatal asphyctic insult. This is called fetal asphyctic preconditioning (PC). Our objective was to investigate alterations in the placental inflammatory phenotype associated with PC., Methods: FA was induced in the rat at embryonic day 17 by reversibly clamping the uterine circulation and PA was induced at birth by submersion of the uterine horns in a saline bath for 19 min. The effect of PC was studied by inducing FA at E17, followed by PA at E21. Placental TNF-α, IL-1β, IL-6 and IL-10 mRNA and protein levels were measured by qPCR and ELISA., Results: IL-1β mRNA increased in the labouring FA group, but IL-1β protein decreased after both FA and PA. In the PC group, IL-1β mRNA and protein levels were similar to controls. IL-6 protein increased 6 h after FA, however decreased 24 h after FA. IL-6 mRNA was higher in the labouring PA group. IL-10 protein decreased 24 h after FA. At birth, IL-10 mRNA increased in the PA group; however, IL-10 protein decreased in both the PA and the FA group. In the PC group, IL-10 mRNA and protein were similar to control levels., Discussion: Depleted protein concentrations of IL-10 and IL-1β after one single asphyctic insult were reversed after fetal asphyctic PC. In addition, PC placentas showed less up-regulation of IL-6 mRNA compared to the PA ones. This modulated placental inflammatory phenotype might contribute to the improved neonatal outcome showed after fetal asphyctic PC., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In recent years, translational research with various animal models has been helpful to answer basic questions about the effect of antenatal inflammation on maturation and development of the fetal lung and immune system. The fetal lung and immune systems are very plastic and their development can be conditioned and influenced by both endogenous and/or exogenous factors. Antenatal inflammation can induce pulmonary inflammation, leading to lung injury and remodeling in the fetal lung. Exposure to antenatal inflammation can induce interleukin-1α production, which enhances surfactant protein and lipid synthesis thereby promoting lung maturation. Interleukin-1α is therefore a candidate for the link between lung inflammation and lung maturation, preventing respiratory distress syndrome in preterm infants. Antenatal inflammation can, however, cause structural changes in the fetal lung and affect the expression of growth factors, such as transforming growth factor-beta, connective tissue growth factor, fibroblast growth factor-10, or bone morphogenetic protein-4, which are essential for branching morphogenesis. These alterations cause alveolar and microvascular simplification resembling the histology of bronchopulmonary dysplasia. Antenatal inflammation may also affect neonatal outcome by modulating the responsiveness of the immune system. Lipopolysaccharide-tolerance (endotoxin hyporesponsiveness/immunoparalysis), induced by exposure to inflammation in utero, may prevent fetal lung damage, but increases susceptibility to postnatal infections. Moreover, prenatal exposure to inflammation appears to be a predisposition for the development of adverse neonatal outcomes, like bronchopulmonary dysplasia, if the preterm infant is exposed to a second postnatal hit, such as mechanical ventilation oxygen exposure, infections, or steroids., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Objective: Ureaplasma colonization in the setting of polymicrobial flora is common in women with chorioamnionitis, and is a risk factor for preterm delivery and neonatal morbidity. We hypothesized that Ureaplasma colonization of amniotic fluid would modulate chorioamnionitis induced by Escherichia coli lipopolysaccharide (LPS)., Study Design: Sheep received intraamniotic (IA) injections of media (control) or live Ureaplasma either 7 or 70 days before delivery. Another group received IA LPS 2 days before delivery. To test for interactions, U parvum-exposed animals were challenged with IA LPS, and delivered 2 days later. All animals were delivered preterm at 125 ± 1 day of gestation., Results: Both IA Ureaplasma and LPS induced leukocyte infiltration of chorioamnion. LPS greatly increased the expression of proinflammatory cytokines and myeloperoxidase in leukocytes, while Ureaplasma alone caused modest responses. Interestingly, 7-day but not 70-day Ureaplasma exposure significantly down-regulated LPS-induced proinflammatory cytokines and myeloperoxidase expression in the chorioamnion., Conclusion: Acute (7-day) U parvum exposure can suppress LPS-induced chorioamnionitis., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Chorioamnionitis and fetal sepsis can induce a fetal inflammatory response syndrome (FIRS) which is closely related to the development of white matter injury in the fetal brain. Large epidemiological studies support the link between FIRS and fetal brain injury with a clear association between the presence of in utero inflammation and neurodevelopmental complications such as cerebral palsy, autism and cognitive impairments later in life. Translational animal models of chorioamnionitis and fetal sepsis are essential in understanding the underlying pathophysiological mechanisms of fetal brain injury after exposure to intra-uterine inflammation. Concerning this aspect, ovine models have high translational value since neurodevelopment in sheep closely resembles the human situation. In this article, we will review clinical and experimental evidence for the link between FIRS and white matter injury in the fetal brain. With respect to experimental findings, we will particularly focus on the lessons learned from ovine models of chorioamnionitis and fetal sepsis. We also highlight two key players implied in the pathophysiology of white matter injury after in utero exposure to inflammation., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Aim: To analyze quantitatively multi-channel amplitude-integrated EEG (aEEG) characteristics and assess regional differences., Methods: We investigated 40 preterm infants (postmenstrual age, PMA: range 27-37 weeks) with normal follow-up at 24 months of age, at a median postnatal age of 8 days using 4-h EEG recordings according to the international 10-20 system reduced montage. Nine (3 transverse and 6 longitudinal) channels were selected and converted to aEEG registrations. For each aEEG registration, lower margin amplitude (LMA), upper margin amplitude (UMA) and bandwidth (UMA-LMA) were calculated., Results: In all channels PMA and LMA showed strong positive correlations. Below 32 weeks of PMA, LMA was ≤5μV. Linear regression analysis showed a maximum LMA difference between channels of approximately 2 and 1μV at 27 and 37 weeks of PMA, respectively. The lowest are LMA values in the occipital channel and the highest values are in centro-occipital channels. In the frontal, centro-temporal and centro-occipital channels, UMA and bandwidth changed with PMA. No differences in LMA, UMA and bandwidth were found between hemispheres. Skewness of LMA values strongly correlated with PMA, positive skewness indicating an immature brain (PMA≤32 weeks) and negative skewness a maturing (PMA>32 weeks) brain., Conclusions: We detected symmetric increase of aEEG characteristics, indicating symmetric brain maturation of the left and right hemispheres. Our findings demonstrate the clinical potential of computer-assisted analyses of aEEG recordings in detecting maturational features which are not readily identified visually. This may provide an objective and reproducible method for assessing brain maturation and long-term prognosis., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

We were able to demonstrate the presence of transforming growth factor β1 and transforming growth factor β2 (TGF-β1,2) in human as well as porcine pulmonary surfactants and SP-A purified from these surfactants. Human SP-A contained 480±74 pg TGF-β1 and 61±16 pg TGF-β2 per mg SP-A and human pulmonary surfactant contained 140±28 pg TGF-β1 and 67±13 TGF-β2 per mg protein. Porcine SP-A contained 306±46 pg TGF-β1 and 43±12 pg TGF-β2 per mg SP-A and porcine pulmonary surfactant contained 75±18 pg TGF-β1 and 22±13 TGF-β2 per mg protein. Size-exclusion chromatography indicated binding of TGF-β1,2 to SP-A. Deglycosylation of SP-A released TGF-β1,2 from SP-A indicating a role for the carbohydrate moieties of SP-A in binding of TGF-β1,2. TGF-β-free SP-A was obtained by incubating SP-A with 5 mM deoxycholate at pH 9.2 followed by size-exclusion chromatography, a protocol which can be used to study the biological activities of SP-A and TGF-β1,2 separately. In addition, we demonstrated that after incubation of SP-A with TGF-β1,2, only a part of the added TGF-β1,2 can be measured, whereas after acid treatment almost all added TGF-β1,2 was determined, suggesting that complex formation between SP-A and TGF-β1,2 influences the measurements of TGF-β1,2 in biological samples., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: We hypothesized that fetal innate immune responses to lipopolysaccharide-induced chorioamnionitis would alter postnatal systemic immune and airway responsiveness., Study Design: Ewes received intraamniotic injections with saline or lipopolysaccharide at 90, 100, and 110 days of gestation. Immune status and airway responsiveness were evaluated at term and at 7 weeks of age., Results: At term, lymphocytes, monocytes, and neutrophils were significantly increased (respectively, 24-fold, 127-fold, and 31,000-fold) in lungs and blood monocytes became Toll-like receptor 2 responsive after lipopolysaccharide exposures. Furthermore, CD4 and CD4/CD25 lymphocytes were increased in thymus and lymph nodes. At 7 weeks, airway reactivity decreased and concentrations of CD8 cytotoxic T lymphocytes changed in the lungs and thymus relative to controls., Conclusion: Early gestational lipopolysaccharide exposure increased leukocyte responsiveness at term. Decreased airway reactivity and changes in lymphocytes at 7 weeks postnatal demonstrate persistent effects of fetal exposure to LPS., (Copyright © 2011 Mosby, Inc. All rights reserved.)

Objective: Regulatory T lymphocytes mediate homeostasis of the immune system and differentiate under the control of the transcription factor FoxP3 in the fetal thymus. We asked whether fetal inflammation caused by chorioamnionitis would modulate thymus development., Study Design: Fetal sheep were exposed to an intraamniotic injection of 10 mg lipopolysaccharide at 5 hours, 1 day, 2 days, or 5 days before delivery at 123 gestation days. Cord blood lymphocytes, plasma cortisol, and thymus weight were measured. Glucocorticoid receptor-, activated caspase-3-, Ki-67-, proliferating cell nuclear antigen-, nuclear factor-kappaB-, and FoxP3-positive cells were immunohistochemically evaluated in thymus., Results: Intraamniotic lipopolysaccharide exposure decreased the number of circulating lymphocytes by 40% after 1 day. Thymus-to-body weight ratios were reduced in all lipopolysaccharide groups by a maximum of 40% at 5 days. Lipopolysaccharide exposure modestly increased plasma cortisol concentration, increased nuclear factor-kappaB immunostaining in fetal thymus and reduced the number of FoxP3-positive cells by 40% at 1 day., Conclusion: Intraamniotic exposure to lipopolysaccharide induced thymic changes and influenced thymic FoxP3 expression., (Copyright (c) 2010 Mosby, Inc. All rights reserved.)

Objective: We hypothesized that fetal lipopolysaccharide exposures to the chorioamnion, lung, or gut would induce distinct systemic inflammatory responses., Study Design: Groups of 5-7 time-mated ewes were used to surgically isolate the fetal respiratory and the gastrointestinal systems from the amniotic compartment. Outcomes were assessed at 124 days gestational age, 2 days and 7 days after lipopolysaccharide (10 mg, Escherichia coli 055:B5) or saline solution infusions into the fetal airways or amniotic fluid., Results: Lipopolysaccharide induced systemic inflammatory changes in all groups in the blood, lung, liver, and thymic lymphocytes. Changes in lymphocytes in the posterior mediastinal lymph node draining lung and gut, occurred only after direct contact of lipopolysaccharide with the fetal lung or gut., Conclusion: Fetal systemic inflammatory responses occurred after chorioamnion, lung, or gut exposures to lipopolysaccharide. The organ responses differed based on route of the fetal exposure., (2010. Published by Mosby, Inc.)

Objective: The objective of the study was to study the effects of histologic chorioamnionitis (HC) with or without fetal involvement and antenatal steroid (AS) exposure on neonatal outcome in a prospective cohort of preterm infants., Study Design: The clinical characteristics and placental histology were prospectively collected in 301 infants born at a gestational age 32.0 weeks or less in the Erasmus University Medical Center., Results: In univariable analyses, HC without fetal involvement (n=53) was associated with decreased severe respiratory distress syndrome (RDS) (11% vs 28%; P<.05), whereas HC with fetal involvement infants (n=68) had more necrotizing enterocolitis (9% vs 2%; P<.05), intraventricular hemorrhage (IVH) (25% vs 12%; P<.05), and neonatal mortality (19% vs 9%; P<.05). In HC without fetal involvement infants, AS reduced the incidences of RDS (43% vs 85%; P<.05) and IVH (5% vs 39%; P<.01). In multivariable analyses, HC without fetal involvement was associated with decreased severe RDS (odds ratio, 0.22; 95% confidence interval, 0.05-0.93; P<.05) and increased early-onset sepsis (odds ratio, 2.22; 95% confidence interval, 1.02-4.83; P<.05)., Conclusion: In a prospective cohort of preterm infants, multivariable analyses reveal only a modest association between histologic chorioamnionitis and neonatal outcome.

Objective: We quantified the impact of chorioamnionitis on both the white and gray matter structures of the preterm ovine central nervous system (CNS)., Study Design: The CNS was studied at 125 days of gestation, either 2 or 14 days after the intraamniotic administration of 10 mg of lipopolysaccharide (LPS) (Escherichia coli) or saline. Apoptotic cells and cell types were analyzed in the brain, cerebellum, and spinal cord using flow cytometry., Results: Apoptosis and microglial activation increased in all regions with prolonged exposure to LPS-induced chorioamnionitis. Astrocytes were increased in the brain and cerebellum of LPS-exposed fetuses but not in the spinal cord. Mature oligodendrocytes decreased in the cerebral and cerebellar white matter, the cerebral cortex, caudate putamen, and hippocampus 14 days after LPS. Neurons in the cerebral cortex, hippocampus, and substantia nigra were reduced 14 days after LPS., Conclusion: Fetal inflammation globally but differentially affected the CNS depending on the maturational stage of the brain region.

Prenatal exposure of very low birth weight infants to chronic indolent chorioamnionitis with organisms such as mycoplasma and ureaplasma is frequent. Chorioamnionitis is inconsistently associated with changed risks of respiratory distress syndrome (RDS) or bronchopulmonary dysplasia (BPD), probably because the diagnosis of chorioamnionitis does not quantify the extent or duration of the fetal exposures to infection and inflammation. The correlations between prenatal exposures and postnatal lung disease also are confounded by the imprecision of the diagnoses of RDS and BPD. In animal models, chorioamnionitis caused by pro-inflammatory mediators or live ureaplasma induces lung maturation, but also causes alveolar simplification and vascular injury. Intra-amniotic endotoxin administration also modulates the fetal innate immune system, resulting in maturation of monocytes to alveolar macrophages and the induction or paralysis of inflammatory responses depending on exposure history. Prenatal inflammation can have profound effects on the fetal lung and subsequent immune responses.

Background: Antenatal pulmonary inflammation is associated with reduced risk for respiratory distress syndrome but with an increased risk for bronchopulmonary dysplasia (BPD) with impaired alveogenesis., Objective: We hypothesized that fetal systemic inflammation induced by intravenous (IV) lipopolysaccharide (LPS) would affect lung development in utero., Study Design: Twenty-one fetal sheep were instrumented (107 days gestational age). Control fetuses received saline (N = 12) and 9 in the study group received 100 ng of LPS IV 3 days after surgery. Animals were assessed for lung maturation and structure after 3 (N = 5) and 7 (N = 4) days., Results: Interleukin-6 concentration increased in the bronchoalveolar lavage more than 40-fold 3 days after LPS IV. Processing of pro-surfactant protein (SP)-B to mature SP-B and increased SP-B concentrations were shown 7 days after LPS IV. Deposition of elastin fibers at sites of septation was disturbed within 3 days after LPS IV., Conclusion: Lung maturation and disturbed lung structure occurred after short-term exposure to fetal inflammation and suggests new targeted therapies for BPD.

Objective: Macrophage migration inhibitory factor is a proinflammatory mediator of innate immunity, enhances cell growth, and plays a role in preterm delivery. We speculated that funisitis, reflecting fetal systemic inflammation, would be associated with higher concentrations of macrophage migration inhibitory factor in airways of extremely premature infants., Study Design: We measured macrophage migration inhibitory factor by enzyme linked immunosorbent assay in tracheobronchial aspirate fluid of 35 ventilated infants less than 30 weeks' gestational age, throughout the first week of life. Three groups were distinguished histologically: chorioamnionitis, funisitis, and control., Results: Unexpectedly, funisitis was associated with significantly decreased macrophage migration inhibitory factor in tracheobronchial aspirate fluid on day 1 (P < .01) and levels remained lower than in the chorioamnionitis group thereafter. For the 35 patients in total, macrophage migration inhibitory factor steadily declined., Conclusion: Decreased macrophage migration inhibitory factor concentrations in airways of extremely premature infants with systemic fetal inflammation early in life might predispose them to pulmonary infection and interfere with maturation of the lung, contributing to adverse pulmonary outcome.

Objective: Fetal brain injury is associated with chorioamnionitis, which is often present without signs of overt infection or fetal compromise. We aimed to determine if prolonged exposure to intrauterine inflammation caused by intra-amniotic infusion of lipopolysaccharide (LPS) would affect the fetal brain., Methods: At 80 days of pregnancy ewes bearing singletons had osmotic pumps implanted intra-amniotically to infuse Escherichia coli LPS (055:B5; n = 8) or saline (n = 7) for 28 days. At delivery (110 days), umbilical arterial blood and chorioamnion were assessed for inflammation; cytokine concentrations (interleukin [IL]-6 and IL-8) in amniotic fluid and fetal and maternal plasma were measured. The fetal cerebral hemispheres were examined for gross anatomical changes and the number of activated microglia/macrophages, astrocytes, and oligodendrocytes estimated after immunohistochemical staining., Results: Intra-amniotic administration of LPS caused chorioamnionitis, fetal leucocytosis, and a moderate to extensive infiltration of activated microglia/macrophages in the subcortical white matter in six of eight fetuses; the remaining two fetuses were less affected. Within these focal regions of damage there was an attenuation of astrocytic processes, axonal injury, and a reduction in the number of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) immunoreactive oligodendrocytes in areas of extensive focal damage. In control fetuses there was mild (3/7) or no infiltration of activated microglia/macrophages in the subcortical white matter. Overall the infiltration of activated microglia/macrophages in the white matter was significantly greater in LPS-exposed fetuses compared to controls. In regions devoid of injury, the number of oligodendrocytes and astrocytes was not different between groups, nor was there a difference in the volume of cerebral white matter or density of blood vessels within the white matter. Amniotic fluid IL-6 and IL-8, and maternal plasma IL-8 concentrations were significantly increased by LPS infusion., Conclusions: An increase in inflammatory cells and axonal disruption in the subcortical white matter of the fetal brain can accompany chorioamnionitis induced by intra-amniotic administration of LPS, but cystic lesions do not occur. Thus, the effect on the fetal brain is milder than that reported from animal models of acute fetal/intrauterine infection.

Objective: Intra-amniotic administration of endotoxin in sheep is a model of subclinical chorioamnionitis. Intrauterine inflammation alters lung development to improve postnatal lung function and may predispose the infant to lung and brain injury. We describe the effects of intra-amniotic endotoxin on cytokines and white cell responses in the membranes and amniotic fluid and investigate the hypothesis that betamethasone treatment suppresses these responses., Study Design: Pregnant ewes were allocated at random to receive either intra-amniotic saline solution (control animals), maternal intramuscular betamethasone, intra-amniotic endotoxin by ultrasound guidance (10 mg Escherichia coli 055:B5), or a combination of the betamethasone and endotoxin treatments. Lambs were delivered abdominally at 110 to 125 days of gestation at time points that ranged from 2 hours to 15 days after treatment., Results: When compared with saline solution-injected control animals, the intra-amniotic injection of endotoxin increased white cell counts in amniotic fluid. Levels of interleukin-8, but not interleukin-6, were significantly increased in amniotic fluid from 5 hours to 15 days after intra-amniotic endotoxin injection, and interleukin-8 levels were not decreased by concurrent treatment with betamethasone. After endotoxin treatment, interleukin-1beta and interleukin-8 messenger RNA were expressed in chorion, and interleukin-6 messenger RNA expression was localized to chorionic blood vessel epithelium. The half-life of endotoxin in the amniotic fluid was 1.7 days, and levels remained measurable 15 days after injection., Conclusion: These findings confirm that the fetus can survive within amniotic fluid that contains endotoxin, white cells, and cytokines for periods of weeks or more. Betamethasone treatment can suppress the initial inflammation in the amnion-chorion, but interleukin-8 levels and inflammatory cells in amniotic fluid were not suppressed 5 and 15 days after betamethasone treatment, presumably because of the slow clearance of bioactive endotoxin from the amniotic fluid.

Objective: Our purpose was to determine whether improved preterm lung function caused by intraamniotic endotoxin treatment requires endotoxin entry into the respiratory tract., Study Design: We assessed lung inflammation 2 days after intra-amniotic endotoxin (10 mg, Escherichia coli 055:B5) or saline solution in preterm lambs (123 days' gestation) that had undergone surgery to isolate the gastrointestinal or respiratory systems from the amniotic sac. In other sheep longer-term effects were assessed 7 days after we isolated the fetal respiratory tract and gave endotoxin or saline solution directly to the lungs or into the amniotic sac. We measured pulmonary inflammation, lung function, and surfactant 1 week after treatment (approximately 125 days)., Results: Pulmonary inflammation was present after intra-amniotic endotoxin only if there was communication between the respiratory tract and the amniotic sac. Lung function was improved and surfactant was increased only in preterm lambs that received direct pulmonary endotoxin., Conclusion: Endotoxin causes functional improvement of the preterm lung by direct effects on the developing respiratory system.

Objectives: In clinical practice, chorioamnionitis has been observed to enhance fetal lung maturation in the short term but may predispose to chronic lung disease thereafter. Using the sheep model, we have previously shown that injection of endotoxin into the amniotic cavity results in inflammatory responses and profoundly enhances newborn lung function after preterm birth. The fetus tolerates intra-amniotic doses of endotoxin considerably greater than those that are lethal if given intramuscularly. This study aimed to explore the mechanisms by which endotoxin matures the lungs by determining whether the route of administration influenced the maturational responses of the fetus., Study Design: Date-mated ewes at 118 days of pregnancy were allocated at random to receive endotoxin (Escherichia coli lipopolysaccharide 055;B5) directly into the trachea (n = 7), stomach (n = 6), amniotic cavity (n = 7), or peritoneal cavity (n = 4) of the fetal lamb by surgical implantation of an osmotic pump delivering 1 mg of endotoxin over a 24-hour period. Results were compared with those obtained in saline solution-infused controls (n = 9). The lambs were delivered by cesarean section at 125 days' gestation (term is 150 days)., Results: Endotoxin infusion into the trachea, stomach, and amniotic cavity each resulted in inflammatory responses in lung fluid and improved postnatal lung function, and effects were similar for each route of administration. These effects occurred with minimal features of systemic inflammation. Intraperitoneal infusion resulted in severe fetal acidosis or death., Conclusion: These findings provide further evidence that the lung-maturing effects of intra-amniotic endotoxin are mediated by local factors in the respiratory system rather than by systemic inflammatory responses. Chorioamnionitis may alter lung function and possibly lead to chronic injury without clinical features of systemic inflammation or compromise.