Intrauterine Growth Restriction and the Innate Immune System in Preterm Infants of ≤32 Weeks Gestation

Tröger, Birte; Müller, Thomas S.; Faust, Kirstin; Bendiks, Meike; Bohlmann, Michael K.; Thonnissen, Susanne; Herting, Egbert; Göpel, Wolfgang; Härtel, Christoph

doi:10.1159/000343260

Cited by 52 publications

(42 citation statements)

References 47 publications

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“…However, no substantial effect was detectable in preterm neonates in our study (data not shown). Severe growth restrictions may also affect innate immune responsiveness in a subset of preterm neonates beyond the attenuation already resulting from prematurity [30]. …”

Section: Discussionmentioning

confidence: 99%

Hierarchical Maturation of Innate Immune Defences in Very Preterm Neonates

Sharma

Jen

Brant³

et al. 2014

Neonatology

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Background: Preterm neonates are highly vulnerable to infection. Objectives: To investigate the developmental contribution of prematurity, chorioamnionitis and antenatal corticosteroids (ANS) on the maturation of neonatal microbial pathogen recognition responses. Methods: Using standardized protocols, we assayed multiple inflammatory cytokine responses (IL-1β, IL-6, TNF-α and IL-12/23p40) to three prototypic Toll-like receptor (TLR) agonists, i.e. TLR4 (lipopolysaccharide), TLR5 (flagellin) and TLR7/8 (R848), and to the non-TLR retinoic acid-inducible gene I (RIG-I)-like receptor agonist, in cord blood mononuclear cells from neonates born before 33 weeks of gestation and at term. Results: TLR responses develop asynchronously in preterm neonates, whereby responses to TLR7/8 were more mature and were followed by the development of TLR4 responses, which were also heterogeneous. Responses to TLR5 were weakest and most immature. Maturity in TLR responses was not influenced by sex. Overall, we detected no significant contribution of ANS and chorioamnionitis to the developmental attenuation of either TLR or RIG-I responses. Conclusions: The maturation of anti-microbial responses in neonates born early in gestation follows an asynchronous developmental hierarchy independently of an exposure to chorioamnionitis and ANS. Our data provide an immunological basis for the predominance of specific microbial infections in this age group.

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Section: Discussionmentioning

confidence: 99%

Hierarchical Maturation of Innate Immune Defences in Very Preterm Neonates

Sharma

Jen

Brant³

et al. 2014

Neonatology

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“… b Premature infants who are small for gestational age may have leukocyte concentrations that are up to 50% lower than those who are appropriate for gestational age …”

Section: Methodsmentioning

confidence: 99%

Integration of Ontogeny Into a Physiologically Based Pharmacokinetic Model for Monoclonal Antibodies in Premature Infants

Malik

Edginton

2019

The Journal of Clinical Pharma

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An understanding of pediatric pharmacokinetics (PK) is essential for first‐in‐pediatric dose selection and clinical trial design. At present, there is no reliable way to scale the PK of monoclonal antibodies and immunoglobulin G drug products from adults to young children or to premature infants—a vulnerable population with a rapidly growing drug development pipeline. In this work, pediatric physiologically based PK models are constructed in PK‐Sim and Mobi to explore the PK of pagibaximab, palivizumab, MEDI8897, and intravenous immunoglobulin in preterm infants. In addition to considering ontogeny in pediatric organ volumes, organ composition, blood flow rates, and hematocrit, advanced ontogeny is applied for 3 key parameters: capillary surface area, hematopoietic cell concentration, and lymph flow rate. The role and importance of each parameter for determining pediatric clearance (CL) and volume of distribution at steady state (VSS) are quantitatively assessed with a local sensitivity analysis. In addition, the uncertainty around parameters with limited information in pediatrics is addressed (eg, free neonatal Fc receptor concentration). The full ontogeny parameterization yields pediatric PK predictions that are within 1.5‐fold prediction error >90% of the time for preterm infants, with an absolute average fold error of 1.05. This result suggests that many of the key factors related to ontogeny are appropriately addressed. Overall, this study makes a first step toward developing a platform pediatric physiologically based PK model for monoclonal antibodies and immunoglobulin G drug products by solidifying existing parameterizations, integrating new concepts, and drawing attention to unmet needs for physiologic knowledge in children.

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“…Both observations may indicate that intrauterine growth restriction (IUGR) finally results in exhaustion of erythropoietic activity. If counted under the microscope, NRBC count tended to be higher in SGA infants compared to AGA [22]. This may indicate a compromise not only in erythropoiesis but also in megakaryopoiesis and granulocytopoiesis of VLBW infants with IUGR.…”

Section: Discussionmentioning

confidence: 94%