Cerebral ultrasound abnormalities in preterm infants caused by late-onset sepsis

RESEARCH ARTICLE Cerebral ultrasound abnormalities in preterm infants caused by late-onset sepsis L. C. Claessens1☯, I. A. Zonnenberg1☯*, F. A. M. van den Dungen1, R. J. Vermeulen2¤, M. M. van Weissenbruch1 1 Department of Neonatology, VU University Medical Center, Amsterdam, The Netherlands, 2 Department of Child Neurology, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 ☯ These authors contributed equally to this work. ¤ Current address: Department of Child Neurology, MUMC+, Maastricht, The Netherlands * Abstract Introduction OPEN ACCESS Citation: Claessens LC, Zonnenberg IA, van den Dungen FAM, Vermeulen RJ, van Weissenbruch MM (2017) Cerebral ultrasound abnormalities in preterm infants caused by late-onset sepsis. PLoS ONE 12(3): e0173227. https://doi.org/10.1371/ journal.pone.0173227 Editor: Umberto Simeoni, Centre Hospitalier Universitaire Vaudois, FRANCE Received: December 5, 2016 Accepted: February 19, 2017 Published: March 16, 2017 Copyright: © 2017 Claessens et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper. Funding: This work was supported by grants from Fonds Nuts Ohra (grant numbers 0901-042 and 1101-093), http://www.fondsnutsohra.nl/. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. This study describes cerebral ultrasound abnormalities caused by late-onset sepsis (LOS) in very preterm infants with a gestational age of < 32 weeks and/or birthweight < 1500 grams. Methods The prospective study (“INFANT study”) included 117 preterm infants with suspected LOS. Proven LOS was defined as a positive blood culture after 72 hours of life. In case of coagulase-negative staphylococci an elevated C-reactive protein was additionally required to establish proven LOS. Patients were identified as proven LOS and patients with only clinical symptoms of LOS. Cerebral ultrasound images were obtained in the first week after birth, during/after LOS and before discharge. Cerebral findings were divided in no/minor and major abnormalities. Results Eighty-six preterm infants had proven LOS and 31 preterm infants had only clinical signs of LOS. Four infants were excluded because pre-existing major brain abnormalities. No significant differences (p = 0.624) for incidence of major brain abnormalities on cerebral ultrasound were found. Conclusion No differences were revealed in prevalence of major brain abnormalities between the groups with proven LOS and with clinical signs of LOS. Both infants with a gram negative sepsis developed major brain abnormalities, whereas only two of 66 preterm infants coagulase-negative staphylococci sepsis developed major brain abnormalities. PLOS ONE | https://doi.org/10.1371/journal.pone.0173227 March 16, 2017 1 / 10 Cerebral ultrasound abnormalities in preterm infants caused by late-onset sepsis Abbreviations: CoNS, Coagulase-negative Staphylococci; CRIB, Clinical Risk Index for Babies; CRP, C-Reactive Protein; HELLP, Hemolysis Elevated Liver Enzymes and Low Platelets; HSPDA, Hemodynamic Significant Patent Ductus Arteriosus; IVH, Germinal/Intra Ventricular Hemorrhage; LOS, Late-Onset Sepsis; MRI, Magnetic Resonance Imaging; NEC, Necrotizing Enterocolitis; NICU, Neonatal Intensive Care Unit; PCR, Polymerase Chain Reaction; PVL, Periventricular Leukomalacia. Introduction Late-onset sepsis (LOS) has a large impact on the neurodevelopment of very preterm infants (gestational age < 32 weeks) and/or very low birth weight infants (birth weight < 1500 gram) characterized by an increased risk for developing cognitive impairments, cerebral palsy and other neurodevelopmental disabilities compared to preterm infants without a sepsis.[1–5] Earlier studies have shown that up to 40% of the very preterm infants (born < 32 weeks gestational age) had at least one episode of LOS during their Neonatal Intensive Care Unit (NICU) stay.[6–9] Moreover, infants with a birth weight < 1000 grams were more likely to develop an infection.[9] Overall, half of the preterm infants with clinical symptoms of LOS showed a positive blood culture, in most cases coagulase-negative staphylococci (CoNS).[2;7;10] Several studies have revealed that preterm infants with a proven infection were more likely to develop periventricular leukomalacia (PVL).[1;3] PVL grade II and III (cystic form), associated with the worst neurodevelopmental outcome, occurs in up to 1.3% of the preterm infants and is a strong predictor of cerebral palsy.[1;11] A more common brain injury is the germinal/ intra ventricular hemorrhage (IVH) that affects 30% of the preterm infants.[12] IVH can be complicated by post-hemorrhagic ventricular dilation or periventricular venous infarction. These complications are related to cerebral palsy and cognitive impairment.[13;14] Transient abnormalities and changes of the preterm brain during an infection episode have not been fully described yet. Moreover, it is important to know how different bacterial agents causing LOS may act on the developing preterm brain. Short-term abnormalities can be diagnosed using ultrasonography or MRI. MRI as a neuroimaging technique is preferred because of its high sensitivity and specificity, but has also disadvantages for a preterm infant. MRI cannot be performed bedside and the use of sedatives is frequently necessary. Ultrasound as a neuroimaging technique, however, has the advantage it can easily be performed longitudinally and bedside. The aim of this study was to investigate the abnormalities seen on cerebral ultrasound during and after LOS. Methods Study population Preterm infants with a gestational age of < 32 weeks and/or birth weight < 1500 gram admitted to the level III NICU of the VU University Medical Center between March 2008 and December 2014. Parents were asked for informed consent to participate in the “INFANT” study, a prospective study investigating immunogenetic, pharmacological and neurodevelopmental aspects of LOS and meningitis in preterm infants. All preterm infants with a suspected LOS were prospectively included. Infants with syndromal or chromosomal abnormalities and congenital metabolic disorders were excluded. Informed parental written consent was obtained and approval was given by the medical ethical committee of the VU University Medical Center. An observational study was performed, due to a lack of information on the outcome parameter in this age group it was not possible to perform a power calculation to calculate sample size. Late-onset sepsis LOS was suspected when one of the following (...truncated)