Is sequential cranial ultrasound reliable for detection of white matter injury in very preterm infants?

Cranial ultrasound (cUS) may not be reliable for detection of diffuse white matter (WM) injury. Our aim was to assess in very preterm infants the reliability of a classification system for WM injury on sequential cUS throughout the neonatal period, using magnetic resonance imaging (MRI) as reference standard. In 110 very preterm infants (gestational age < 32 weeks), serial cUS during admission (median 8, range 4-22) and again around term equivalent age (TEA) and a single MRI around TEA were performed. cUS during admission were assessed for presence of WM changes, and contemporaneous cUS and MRI around TEA additionally for abnormality of lateral ventricles. Sequential cUS (from birth up to TEA) and MRI were classified as normal/mildly abnormal, moderately abnormal, or severely abnormal, based on a combination of findings of the WM and lateral ventricles. Predictive values of the cUS classification were calculated. Sequential cUS were classified as normal/mildly abnormal, moderately abnormal, and severely abnormal in, respectively, 22%, 65%, and 13% of infants and MRI in, respectively, 30%, 52%, and 18%. The positive predictive value of the cUS classification for the MRI classification was high for severely abnormal WM (0.79) but lower for normal/mildly abnormal (0.67) and moderately abnormal (0.64) WM. Sequential cUS during the neonatal period detects severely abnormal WM in very preterm infants but is less reliable for mildly and moderately abnormal WM. MRI around TEA seems needed to reliably detect WM injury in very preterm infants.Epidemiology in Pediatrics and Child Healt

Targeting human milk fortification to improve very preterm infant growth and brain development: study protocol for Nourish, a single-center randomized, controlled clinical trial.

Human milk is recommended for very preterm infants, but its variable macronutrient content may contribute to undernutrition during a critical period in development. We hypothesize that individually targeted human milk fortification is more effective in meeting macronutrient requirements than the current standard of care.MethodsWe designed a single-center randomized, controlled trial enrolling 130 infants born DiscussionWe expect this trial to provide important data regarding the effectiveness of individually targeted human milk fortification in the neonatal intensive care unit (NICU).Trial registrationNCT03977259 , registered 6 June, 2019

Gray matter injury associated with periventricular leukomalacia in the premature infant

Neuroimaging studies indicate reduced volumes of certain gray matter regions in survivors of prematurity with periventricular leukomalacia (PVL). We hypothesized that subacute and/or chronic gray matter lesions are increased in incidence and severity in PVL cases compared to non-PVL cases at autopsy. Forty-one cases of premature infants were divided based on cerebral white matter histology: PVL (n = 17) with cerebral white matter gliosis and focal periventricular necrosis; diffuse white matter gliosis (DWMG) (n = 17) without necrosis; and

Improving the outcome of infants born at <30 weeks' gestation - a randomized controlled trial of preventative care at home

Background: Early developmental interventions to prevent the high rate of neurodevelopmental problems in very preterm children, including cognitive, motor and behavioral impairments, are urgently needed. These interventions should be multi-faceted and include modules for caregivers given their high rates of mental health problems

TIPIT: A randomised controlled trial of thyroxine in preterm infants under 28 weeks' gestation

<p>Abstract</p> <p>Background</p> <p>Infants born at extreme prematurity (below 28 weeks' gestation) are at high risk of developmental disability. A major risk factor for disability is having a low level of thyroid hormone which is recognised to be a frequent phenomenon in these infants. At present it is unclear whether low levels of thyroid hormone are a cause of disability, or a consequence of concurrent adversity.</p> <p>Methods</p> <p>We propose an explanatory multi-centre double blind randomised controlled trial of thyroid hormone supplementation in babies born below 28 weeks' gestation. All infants will receive either levothyroxine or placebo until 32 weeks' corrected gestational age. The primary outcome will be brain growth. This will be assessed by the width of the sub-arachnoid space measured using cranial ultrasound and head circumference at 36 weeks' corrected gestational. The secondary outcomes will be (a) thyroid hormone concentrations measured at increasing postnatal age, (b) status of the hypothalamic pituitary axis, (c) auxological data between birth and 36 weeks' corrected gestational age, (d) thyroid gland volume, (e) volumes of brain structures (measured by magnetic resonance imaging), (f) determination of the extent of myelination and white matter integrity (measured by diffusion weighted MRI) and brain vessel morphology (measured by magnetic resonance angiography) at expected date of delivery and (g) markers of morbidity including duration of mechanical ventilation and chronic lung disease.</p> <p>We will also examine how activity of the hypothalamic-pituitary-adrenal axis modulates the effects of thyroid supplementation. This will contribute to decisions about which confounding variables to assess in large-scale studies.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN89493983</p

TIPIT: A randomised controlled trial of thyroxine in preterm infants under 28 weeks gestation: Magnetic Resonance Imaging and Magnetic Resonance Angiography protocol

<p>Abstract </p> <p>Background</p> <p>Infants born at extreme prematurity are at high risk of developmental disability. A major risk factor for disability is having a low level of thyroid hormone described as hypothyroxinaemia, which is recognised to be a frequent phenomenon in these infants. Derangements of critical thyroid function during the sensitive window in prematurity when early development occurs, may have a range of long term effects for brain development. Further research in preterm infants using neuroimaging techniques will increase our understanding of the specificity of the effects of hypothyroxinaemia on the developing foetal brain. This is an explanatory double blinded randomised controlled trial which is aimed to assess the effect of thyroid hormone supplementation on brain size, key brain structures, extent of myelination, white matter integrity and vessel morphology, somatic growth and the hypothalamic-pituitary-adrenal axis.</p> <p>Methods</p> <p>The study is a multi-centred double blinded randomised controlled trial of thyroid hormone supplementation in babies born below 28 weeks' gestation. All infants will receive either levothyroxine or placebo until 32 weeks corrected gestational age. The primary outcomes will be width of the sub-arachnoid space measured using cranial ultrasound and head circumference at 36 weeks corrected gestational age. The secondary outcomes will be thyroid hormone concentrations, the hypothalamic pituitary axis status and auxological data between birth and expected date of delivery; thyroid gland volume, brain size, volumes of key brain structures, extent of myelination and brain vessel morphology at expected date of delivery and markers of morbidity which include duration of mechanical ventilation and/or oxygen requirement and chronic lung disease.</p> <p><b>Trial registration</b></p> <p>Current Controlled Trials ISRCTN89493983</p

Modulation of EEG spectral edge frequency during patterned pneumatic oral stimulation in preterm infants

Background—Stimulation of the nervous system plays a central role in brain development and neurodevelopmental outcome. Thalamocortical and corticocortical development is diminished in premature infants and correlated to electroencephalography (EEG) progression. The purpose of this study was to determine the effects of orocutaneous stimulation on the modulation of spectral edge frequency, fc=90% (SEF-90) derived from EEG recordings in preterm infants. Methods—Twenty two preterm infants were randomized to experimental and control conditions. Pulsed orocutaneous stimulation was presented during gavage feedings begun at around 32 weeks postmenstrual age (PMA). The SEF-90 was derived from 2-channel EEG recordings. Results—Compared to the control condition, the pulsed orocutaneous stimulation produced a significant reorganization of SEF-90 in the left (p = 0.005) and right (p \u3c 0.0001) hemispheres. Notably, the left and right hemisphere showed a reversal in the polarity of frequency shift, demonstrating hemispheric asymmetry in the frequency domain. Pulsed orocutaneous stimulation also produced a significant pattern of short term cortical adaptation and a long term neural adaptation manifest as a 0.5 Hz elevation in SEF-90 after repeated stimulation sessions. Conclusion—This is the first study to demonstrate the modulating effects of a servo-controlled oral somatosensory input on the spectral features of EEG activity in preterm infants

Systemic Stimulation of TLR2 Impairs Neonatal Mouse Brain Development

Background: Inflammation is associated with perinatal brain injury but the underlying mechanisms are not completely characterized. Stimulation of Toll-like receptors (TLRs) through specific agonists induces inflammatory responses that trigger both innate and adaptive immune responses. The impact of engagement of TLR2 signaling pathways on the neonatal brain is still unclear. The aim of this study was to investigate the potential effect of a TLR2 agonist on neonatal brain development. Methodology/Principal Findings: Mice were injected intraperitoneally (i.p.) once a day from postnatal day (PND) 3 to PND11 with endotoxin-free saline, a TLR2 agonist Pam$_{3}$CSK$_{4}$ (5 mg/kg) or Lipopolysaccharide (LPS, 0.3 mg/kg). Pups were sacrificed at PND12 or PND53 and brain, spleen and liver were collected and weighed. Brain sections were stained for brain injury markers. Long-term effects on memory function were assessed using the Trace Fear Conditioning test at PND50. After 9 days of Pam$_{3}$CSK$_{4}$ administration, we found a decreased volume of cerebral gray matter, white matter in the forebrain and cerebellar molecular layer that was accompanied by an increase in spleen and liver weight at PND12. Such effects were not observed in Pam$_{3}$CSK$_{4}$-treated TLR 2-deficient mice. Pam$_{3}$CSK$_{4}$-treated mice also displayed decreased hippocampus neuronal density, and increased cerebral microglia density, while there was no effect on caspase-3 or general cell proliferation at PND12. Significantly elevated levels of IL-1β, IL-6, KC, and MCP-1 were detected after the first Pam$_{3}$CSK$_{4}$ injection in brain homogenates of PND3 mice. Pam$_{3}$CSK$_{4}$administration did not affect long-term memory function nor the volume of gray or white matter. Conclusions/Significance: Repeated systemic exposure to the TLR2 agonist Pam$_{3}$CSK$_{4}$ can have a short-term negative impact on the neonatal mouse brain