Preterm birth: inflammation, fetal injury and treatment strategies
Ashley Boyle2016, Journal of Reproductive Immunology
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Abstract
Preterm birth (PTB) is the leading cause of childhood mortality in children under 5 and accounts for approximately 11% of births worldwide. Premature babies are at risk of a number of health complications, notably cerebral palsy, but also respiratory and gastrointestinal disorders. Preterm deliveries can be medically indicated/elective procedures or they can occur spontaneously. Spontaneous PTB is commonly associated with intrauterine infection/inflammation. The presence of inflammatory mediators in utero has been associated with fetal injury, particularly affecting the fetal lungs and brain. This review will outline (i) the role of inflammation in term and PTB, (ii) the effect infection/inflammation has on fetal development and (iii) recent strategies to target PTB. Further research is urgently required to develop effective methods for the prevention and treatment of PTB and above all, to reduce fetal injury.
Related papers
Inflammation and preterm birth
Journal of Leukocyte Biology, 2015
Preterm birth is the leading cause of neonatal morbidity and mortality. Although the underlying causes of pregnancy-associated complication are numerous, it is well established that infection and inflammation represent a highly significant risk factor in preterm birth. However, despite the clinical and public health significance, infectious agents, molecular trigger(s), and immune pathways underlying the pathogenesis of preterm birth remain underdefined and represent a major gap in knowledge. Here, we provide an overview of recent clinical and animal model data focused on the interplay between infection-driven inflammation and induction of preterm birth. Furthermore, here, we highlight the critical gaps in knowledge that warrant future investigations into the interplay between immune responses and induction of preterm birth.
Inflammation and Preterm Birth: A Systematic Review
Reproductive Medicine
Inflammatory mechanisms have a critical role in parturition, which results from a gathering of different stimuli that collectively initiate labour. In fact, a sophisticated interaction occurs between contractile and immuno-inflammatory pathways, whereby proinflammatory amplification is intensified by collaborative connections between cells, ligands, and tissues. Preterm birth (PTB) is one of the major challenges of modern obstetrics and still lacks an efficient treatment. Therefore, the scientific research of modern therapies is warranted. This systematic review aims to provide an overview of recent research into inflammation and PTB. The main inclusion criterion was articles concerning birth and inflammation, and searches were performed in the electronic databases MEDLINE, Embase, Scopus, Web of Science and Cochrane Library, from 2017 to 2021. A literature search from all databases yielded 1989 results which, applying the specified eligibility criteria, resulted in the 16 articles ...
Inflammation induced preterm labor and birth
Journal of reproductive immunology, 2018
Preterm birth which occurs before 37 weeks gestation is one of the most common obstetrical complication in humans. After many studies, it appears that "not one answer fits all" regarding the risk factors, causes and the treatments for this syndrome. However, it is becoming more evident that one of the major risk factors is inflammation and/or infection in the fetoplacental unit. In animal models (usually consisting of mice injected with lipopolysaccharide at 14 days of gestation), IL-22 and IL-6 have been identified as factors related to preterm birth. There are some clinical tests available to determine the risk for preterm labor and delivery, which can be identified before, during early, or at mid-gestation. However, treatment of preterm birth with antibiotics so far has not been "curable" and studies using anti-inflammatory treatments are not readily available. More studies regarding causes and treatments for preterm labor and delivery in humans are necessary ...
Interventions for Infection and Inflammation-Induced Preterm Birth: a Preclinical Systematic Review
Reproductive Sciences
Spontaneous preterm births (< 37 weeks gestation) are frequently associated with infection. Current treatment options are limited but new therapeutic interventions are being developed in animal models. In this PROSPERO-registered preclinical systematic review, we aimed to summarise promising interventions for infection/inflammation-induced preterm birth. Following PRISMA guidance, we searched PubMed, EMBASE, and Web of Science using the themes: "animal models", "preterm birth", "inflammation", and "therapeutics". We included original quantitative, peer-reviewed, and controlled studies applying prenatal interventions to prevent infection/inflammation-induced preterm birth in animal models. We employed two risk of bias tools. Of 4020 identified studies, 23 studies (24 interventions) met our inclusion criteria. All studies used mouse models. Preterm birth was most commonly induced by lipopolysaccharide (18 studies) or Escherichia coli (4 studies). Models varied according to infectious agent serotype, dose, and route of delivery. Gestational length was significantly prolonged in 20/24 interventions (83%) and markers of maternal inflammation were reduced in 20/23 interventions (87%). Interventions targeting interleukin-1, interleukin-6, and toll-like receptors show particular therapeutic potential. However, due to the heterogeneity of the methodology of the included studies, meta-analysis was impossible. All studies were assigned an unclear risk of bias using the SYRCLE risk of bias tool. Interventions targeting inflammation demonstrate therapeutic potential for the prevention of preterm birth. However, better standardisation of preterm birth models, including the dose, serotype, timing of administration and pathogenicity of infectious agent, and outcome reporting is urgently required to improve the reproducibility of preclinical studies, allow meaningful comparison of intervention efficacy, and aid clinical translation.
Inflammation in preterm and term labour and delivery
Seminars in Fetal and Neonatal Medicine, 2006
Modulation of pro- and anti-inflammatory cytokine production in very preterm infants
Cytokine, 2003
Background: In premature infants, outcome of infection-associated complications is heterogeneous despite advances in antibiotic treatment and diagnosis. Information on the immune response in preterm infants is limited. Immune modulatory strategies require detailed analysis of mediators and their kinetics. Objective: To determine the kinetics of IL-1b, TNFa, IL-6, IL-8, IL-10, cINF and G-CSF in preterm and term infants in an ex vivo cord blood culture (CBC) endotoxin model. Design and methods: Cord blood of 25 infants was obtained immediately after birth from the fetal side of the placenta and incubated in culture medium (RPMI 1640) in the presence or absence of 500 pg/ml lipopolysaccharide (LPS) for 48 h. TNFa, IL-1b, IL-6 and IL-8 were measured by sequential immunometric assay (IMMULITE Ò , DPC Biermann, Germany); IL-10 (Milenia Biotec, Bad Nauheim, Germany), cINF (Diaclone, Besancon, France) and G-CSF (R & D Systems, Wiesbaden, Germany) were determined by ELISA in supernatants at 0, 4, 8, 12, 24 and 48 h. Infants were stratified into three gestational age groups (32 weeks, 33-36 weeks, !37 weeks). Variations between the groups were first analyzed for significance by Kruskal-Wallis test and pairs were compared by Mann-Whitney-U test. Effects of gestational age, leucocyte count, hematocrit and frequency of antenatal steroid exposure were tested by linear regression analysis. To correct a possible impact of variable, WBC count, cytokine levels were adjusted according to individual leucocyte numbers. Results: LPS-stimulated maximum levels of IL-6, IL-1b,TNFa and G-CSF in CBC were significantly lower in very preterm infants compared to more advanced gestational age groups. After adjusting the cytokine levels for 10 5 leucocytes, a significant effect of gestational age on IL-6 and G-CSF production ðp , 0:05Þ was detected. A non-significant trend towards reduced cytokine levels was observed following multiple antenatal steroid exposures. IL-10 : TNFa ratio increased in very preterm neonates when compared with the advanced gestational age, although the increase was not significant. Conclusions: Pro-inflammatory cytokine activity in CBC correlates with gestational age, whereas IL-10 does not. Although ex vivo synthesis of IL-1b, TNFa, IL-6, G-CSF in CBC depends in part on leucocyte numbers, IL-6 and G-CSF synthesis appeared to be related to immaturity. Non-significant effects of multiple antenatal steroid exposure and increased IL-10 : TNFa ratio in preterm neonates, observed in a small sample size, warrant further investigation.
Infection and the role of inflammation in preterm premature rupture of the membranes
Best Practice & Research Clinical Obstetrics & Gynaecology, 2007
Spontaneous preterm birth, caused by preterm labor (contractions before 37 weeks' gestation) or preterm premature rupture of the membranes (pPROM) (membrane rupture before the onset of labor) or both account for w80% of preterm deliveries. pPROM is associated with 30-40% of preterm deliveries and the incidence of pPROM has increased in the past decade. The question we address here is why some women experience pPROM and some experience preterm labor with no rupture of membranes (ROM) when the etiologic factors associated with both these pathologic complications are the same. To date, studies had evaluated the markers that are commonly elevated in both preterm labor and pPROM. A better understanding of the similarities and differences between the biomolecular pathways leading to each of these conditions may open new avenues for research and intervention. In this chapter we review the role of inflammatory mediators (cytokines and matrix metalloproteinases), and programmed cell death (apoptosis) in preterm labor with no ROM and preterm labor with pPROM to delineate the differences in pathways between the two conditions.
Prevention of preterm labour via the modulation of inflammatory pathways
Pregnancy is characterized by a complex interplay of inflamma-tory events regulated by both the innate and acquired immune systems. Similarly, parturition can be viewed as the activation of " pro-labour " inflammatory pathways, which drive cervical ripening and myometrial activation. Premature activation of these pathways, for example, by infection, can lead to preterm labour and birth. Nuclear factor κβ is a key modulator of these pathways and functions by regulating the expression of prosta-glandins, chemokines and pro-inflammatory cytokines involved in both term and preterm labour. Future design of therapeutics that target key mediators of inflammation and immune activation would therefore be a rational approach for preventing preterm labour and immune-mediated neonatal brain damage.
Inflammation at Birth is Associated With Subnormal Development in Very Preterm Infants
Pediatric Research, 2008
Preterm birth carries a risk for impaired developmental outcome. We have previously described an association between increased levels of proinflammatory cytokines during the first 72 postnatal hours and cerebral damage as detected by ultrasound in a cohort of 74 very preterm infants. Sixty-seven of 71 surviving children with a mean gestational age of 27.1 (2.0) wk were examined at 2 y corrected age with a standardized neurologic examination and with Bayley Scales of Infant Development. We hypothesized that proinflammatory cytokine concentrations at or shortly after birth would be associated with an adverse developmental outcome. Increased concentrations of TNF-␣ in cord blood odds ratio (95% confidence interval) 3.3 (1.1-10.2), p ϭ 0.013 and at 6 h 7.8 (0.9 -71.8), p ϭ 0.015 and of IL-6 in cord blood 1.7 (1.0 -2.9), p ϭ 0.048 were associated with psychomotor developmental index Ͻ85. Increased concentrations of TNF-␣ in cord blood odds ratio (95% confidence interval) 3.6 (1.002-12.8), p ϭ 0.044 and of IL-8 in cord blood 3.5 (1.2-10.6), p ϭ 0.023 were associated with cerebral palsy. Associations of TNF-␣ and IL-8 in cord blood with the respective outcome measures remained significant after adjustment for other clinical variables. Proinflammation at birth is associated with impaired functional outcome at 2 y of corrected age in children with very preterm birth.
MEDIATORS OF FETAL INFLAMMATION IN EXTREMELY LOW GESTATIONAL AGE NEWBORNS
Cytokine, 2001
To establish levels of mediators of inflammation in cord blood and postnatal serum from extremely low gestational age newborns (ELGANs, c28 weeks), we measured sixteen markers of inflammation by recycling immunoaffinity chromatography in 15 ELGANs who had serum sampled at days 2-5. Median levels of IL-1, IL-6, IL-8, IL-11, IL-13, TNF-, G-CSF, M-CSF, GM-CSF, MIP-1 , and RANTES were considerably higher than published values of these inflammatory mediators from term newborns. In three of eight ELGANS who had serial measurements taken, levels of IL-1, IL-6, IL-8, IL-11, TNF-, G-CSF, and MIP-1 declined from initially very high levels to reach an apparent baseline towards the end of the first postnatal week. In these same three infants, GM-CSF and TGF-1 levels increased continuously during the first week. In the other five ELGANs, no consistent changes were observed. We speculate, that in some ELGANs, a fetal systemic inflammatory response is characterized by an antenatal wave of pro-inflammatory cytokines, followed by a second, postnatal wave of anti-inflammatory cytokines. Large epidemiologic studies are needed to clarify relationships among inflammation markers and their expression in the fetal and neonatal circulation over time. Such studies would also add to our understanding of the possible role of inflammatory mediators in the pathophysiology of the major complications of extreme prematurity.
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Reproductive Sciences
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JCI Insight, 2021
and Human Services, under contract HHSN275201300006C. We thank the physicians and nurses from the Center for Advanced Obstetrical Care and Research and the Intrapartum Unit at Detroit Medical Center for help in collecting tissue samples. We thank Yi Xu and Jose Galaz for help analyzing flow cytometry and clinical data, Derek Miller for critical reading of the manuscript, and David Sharkey for performing the imulus amebocyte lysate assay. RR contributed as an employee of the US federal government. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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Inflammation and Preterm Birth: A Systematic Review
Reproductive Medicine
Inflammatory mechanisms have a critical role in parturition, which results from a gathering of different stimuli that collectively initiate labour. In fact, a sophisticated interaction occurs between contractile and immuno-inflammatory pathways, whereby proinflammatory amplification is intensified by collaborative connections between cells, ligands, and tissues. Preterm birth (PTB) is one of the major challenges of modern obstetrics and still lacks an efficient treatment. Therefore, the scientific research of modern therapies is warranted. This systematic review aims to provide an overview of recent research into inflammation and PTB. The main inclusion criterion was articles concerning birth and inflammation, and searches were performed in the electronic databases MEDLINE, Embase, Scopus, Web of Science and Cochrane Library, from 2017 to 2021. A literature search from all databases yielded 1989 results which, applying the specified eligibility criteria, resulted in the 16 articles ...
Inflammatory Molecules Responsible for Length Shortening and Preterm Birth
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It is estimated that inflammation at the placental–maternal interface is directly responsible for or contributes to the development of 50% of all premature deliveries. Chorioamnionitis, also known as the premature rupture of the amniotic membrane in the mother, is the root cause of persistent inflammation that preterm newborns experience. Beyond contributing to the onset of early labor, inflammation is a critical element in advancing several conditions in neonates, including necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia, intraventricular hemorrhage, retinopathy of prematurity and periventricular leukomalacia. Notably, the immune systems of preterm infants are not fully developed; immune defense mechanisms and immunosuppression (tolerance) have a delicate balance that is easily upset in this patient category. As a result, premature infants are exposed to different antigens from elements such as hospital-specific microbes, artificial devices, medica...
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There is a clear association between antenatal infection/inflammation and preterm labour, with intrauterine infection complicating up to one third of preterm deliveries. In addition to this, there is now accumulating evidence that intrauterine infection and inflammation can lead to the development of a systemic inflammatory response in the fetus and subsequent tissue injury. The fetal inflammatory response is characterized by funisitis, high levels of pro-inflammatory cytokines in the amniotic fluid and cord blood, and systemic immune activation. This review discusses the evidence for this process and focuses on the clinical and experimental data supporting the hypothesis that these inflammatory processes contribute to brain and lung injury in the newborn.
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Journal of Reproductive Immunology, 2011
The major cause of spontaneous preterm birth (sPTB) at less than 32 weeks of gestation is intrauterine inflammation as a consequence of colonisation of the gestational membranes by pathogenic microorganisms which trigger activation of the local innate immune system. This results in release of inflammatory mediators, leukocytosis (chorioamnionitis), apoptosis, membrane rupture, cervical ripening and onset of uterine contractions. Recent PCR evidence suggests that in the majority of cases of inflammation-driven preterm birth, microorganisms are present in the amniotic fluid, but these are not always cultured by standard techniques. The nature of the organism and its cell wall constituents, residence time in utero, microbial load, route of infection and extent of tissue penetration are all factors which can modulate the timing and magnitude of the inflammatory response and likelihood of progression to sPTB. Administration of anti-inflammatory drugs could be a viable therapeutic option to prevent sPTB and improve fetal outcomes in women at risk of intrauterine inflammation. Preventing fetal inflammation via administration of placentapermeable drugs could also have significant perinatal benefits in addition to those related to extension of gestational age, as a fetal inflammatory response is associated with a range of significant morbidities. A number of potential drugs are available, effective against different aspects of the inflammatory process, although the pathways actually activated in spontaneous preterm labour have yet to be confirmed. Several pharmacological candidates are discussed, together with clinical and toxicological considerations associated with administration of anti-inflammatory agents in pregnancy.
Role of cytokines in preterm labour and brain injury
BJOG: An International Journal of Obstetrics & Gynaecology, 2005
Intrauterine infection induces an intra-amniotic inflammatory response involving the activation of a number of cytokines and chemokines which, in turn, may trigger preterm contractions, cervical ripening and rupture of the membranes. Infection and cytokine-mediated inflammation appear to play a prominent role in preterm birth at early gestations (<30 weeks). The role of infection/inflammation in preterm birth in Europe has been incompletely characterised. The rate of preterm birth in Sweden is lower, and the rate of chorioamnionitis, bacterial vaginosis (BV), neonatal sepsis, and urinary tract infections during pregnancy is lower compared with the USA. In a Swedish population of women with preterm labour or preterm premature rupture of the membranes (PPROM) <34 weeks of gestation, microorganisms were detected in the amniotic fluid in 25% of women with PPROM and in 16% of those in preterm labour. Nearly half of these women had intra-amniotic inflammation defined as elevated interleukin-6 (IL-6) and IL-8, and there was a high degree of correlation between cytokine levels and preterm birth or the presence of microbial colonisation. These data do not support the hypothesis that infection-related preterm birth is less frequent in northern Europe than elsewhere. The intra-amniotic inflammatory response has also been associated with white matter injury and cerebral palsy. We find that in experimental models, induction of a systemic inflammatory response using lipopolysaccharide activates toll-like receptors (TLRs), which produce either white matter lesions or increase brain susceptibility to secondary insults. Recently, IL-18 in umbilical blood was shown to correlate with brain injury in preterm infants and IL-18 deficiency in mice decreases CNS vulnerability.
Fetal Inflammatory Response and Brain Injury in the Preterm Newborn
Journal of Child Neurology, 2009
Preterm birth can be caused by intrauterine infection and maternal/fetal inflammatory responses. Maternal inflammation (chorioamnionitis) is often followed by a systemic fetal inflammatory response characterized by elevated levels of pro-inflammatory cytokines in the fetal circulation. The inflammation signal is likely transmitted across the blood-brain barrier, and initiates a neuroinflammatory response. Microglial activation has a central role in this process, and triggers excitotoxic, inflammatory, and oxidative damage in the developing brain. Neuroinflammation can persist over a period of time and sensitize the brain to subinjurious insults in early and chronic phases, but may offer relative tolerance in the intermediate period through activation of endogenous anti-inflammatory, protective, and repair mechanisms. Neuroinflammatory injury not only destroys what exists, but also changes what develops.
Brain damage of the preterm infant: new insights into the role of inflammation
Biochemical Society Transactions, 2014
Epidemiological studies have shown a strong association between perinatal infection/inflammation and brain damage in preterm infants and/or neurological handicap in survivors. Experimental studies have shown a causal effect of infection/inflammation on perinatal brain damage. Infection including inflammatory factors can disrupt programmes of brain development and, in particular, induce death and/or blockade of oligodendrocyte maturation, leading to myelin defects. Alternatively, in the so-called multiple-hit hypothesis, infection/inflammation can act as predisposing factors, making the brain more susceptible to a second stress (sensitization process), such as hypoxic-ischaemic or excitotoxic insults. Epidemiological data also suggest that perinatal exposure to inflammatory factors could predispose to long-term diseases including psychiatric disorders.
Inflammatory Molecules Responsible for Length Shortening and Preterm Birth
Cells
It is estimated that inflammation at the placental–maternal interface is directly responsible for or contributes to the development of 50% of all premature deliveries. Chorioamnionitis, also known as the premature rupture of the amniotic membrane in the mother, is the root cause of persistent inflammation that preterm newborns experience. Beyond contributing to the onset of early labor, inflammation is a critical element in advancing several conditions in neonates, including necrotizing enterocolitis, retinopathy of prematurity, bronchopulmonary dysplasia, intraventricular hemorrhage, retinopathy of prematurity and periventricular leukomalacia. Notably, the immune systems of preterm infants are not fully developed; immune defense mechanisms and immunosuppression (tolerance) have a delicate balance that is easily upset in this patient category. As a result, premature infants are exposed to different antigens from elements such as hospital-specific microbes, artificial devices, medica...
Both antenatal and postnatal inflammation contribute information about the risk of brain damage in extremely preterm newborns
Carolina Digital Repository (University of North Carolina at Chapel Hill), 2017
Background-Preterm newborns exposed to intrauterine inflammation are at increased risk of neurodevelopmental disorders. We hypothesized that adverse outcomes are more strongly associated with a combination of antenatal and postnatal inflammation than with either of them alone. Methods-We defined antenatal inflammation as histologic inflammation in the placenta. We measured the concentrations of seven inflammation-related proteins in blood obtained on postnatal days 1, 7, and 14 from 763 infants born before 28 weeks of gestation. We defined postnatal inflammation as a protein concentration in the highest quartile on at least 2 days. We used logistic regression models to evaluate the contribution of antenatal and postnatal inflammation to the risk of neurodevelopmental disorders. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
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