Kenneth J. Poskitt

Procedural pain and brain development in premature newborns.

Preterm infants are exposed to multiple painful procedures in the neonatal intensive care unit (NICU) during a period of rapid brain development. Our aim was to examine relationships between procedural pain in the NICU and early brain development in very preterm infants.

Effect of chorioamnionitis on brain development and injury in premature newborns

The association of chorioamnionitis and noncystic white matter injury, a common brain injury in premature newborns, remains controversial. Our objectives were to determine the association of chorioamnionitis and postnatal risk factors with white matter injury, and the effects of chorioamnionitis on early brain development, using advanced magnetic resonance imaging.

Recurrent Postnatal Infections Are Associated With Progressive White Matter Injury in Premature Infants

OBJECTIVE. Our objective was to identify clinical predictors of progressive white matter injury. METHODS. We evaluated 133 infants of <34 weeks of gestation at birth from 2 university hospitals. Infants underwent MRI twice, initially when in stable condition for transport and again at term-equivalent age or before transfer or discharge. Two neuroradiologists who were blinded to the clinical course graded MRI white matter injury severity by using a validated scale. Potential risk factors were extracted from medical charts. RESULTS. Twelve neonates (9.0%) had progressive white matter injury. In the unadjusted analysis of 10 newborns without Candida meningoencephalitis, recurrent culture-positive postnatal infection and chronic lung disease were associated with progressive white matter injury. Exposure to multiple episodes of culture-positive infection significantly increased the risk of progressive white matter injury. Of the 11 neonates with >1 infection, 36.4% (4 infants) had progressive injury, compared with 5.0% (6 infants) of those with ≤1 infection. Of the 35 infants with chronic lung disease, 17.1% (6 infants) had progressive injury, compared with 4.3% (4 infants) of those without chronic lung disease. After adjustment for gestational age at birth, the association between infection and white matter injury persisted, whereas chronic lung disease was no longer a statistically significant risk factor. CONCLUSIONS. Recurrent postnatal infection is an important risk factor for progressive white matter injury in premature infants. This is consistent with emerging evidence that white matter injury is attributable to oligodendrocyte precursor susceptibility to inflammation, hypoxia, and ischemia.

Slower Postnatal Growth Is Associated with Delayed Cerebral Cortical Maturation in Preterm Newborns

Impaired growth during neonatal intensive care is associated with delayed microstructural development of the cortical gray matter after accounting for prenatal growth, neonatal illness, and brain injury in infants born very preterm. Early Start for Better Brains Despite all of the recent advances in medical care for premature newborns, these infants still often experience complications. In particular, cognitive problems and developmental delays are common in this patient population and can be difficult to predict. Now, two sets of authors have obtained new data that approach this problem from different angles using diffusion tensor magnetic resonance imaging (MRI) in human infants and newborn lambs. Vinall and coauthors examined 95 premature newborn babies who were born at 24 to 32 weeks of gestation. The authors performed two sets of MRI scans on these infants: one scan was done about 2 months before their due dates and the other scan when they reached full term. The authors also tracked the infants’ growth parameters—weight, length, and head size—as well as data on other factors that could affect brain growth, including the presence of infections or other serious illnesses. A detailed analysis of the MRI scans showed that the development of normal brain structure correlated with postnatal growth (and presumably nutrition) even after accounting for any other illnesses the infants may have experienced early in life. Dean et al. took a different approach to studying premature brain development: they analyzed the brain structures of fetal lambs that had experienced ischemia in utero at a time that corresponded to about two-thirds of full gestation time. The lambs were analyzed both by MRI and by histological analysis of the brain at 1, 2, or 4 weeks after an in utero ischemic event, and these data were compared to those of age-matched animals that did not undergo ischemic episodes. Here, the authors also saw abnormalities in brain development by MRI and correlated them with histological and structural aberrations. The growth impairment seen in the animals’ brains by MRI corresponded to disturbances in the branching of neuronal dendrites and abnormal formation of synapse connections with other neurons. More studies are needed to understand how postnatal growth, nutrition, illness, and prenatal ischemia affect the developing brain to develop methods for preventing any resulting injury. In addition, long-term studies should help to determine how differences in brain anatomy and MRI data translate into developmental and cognitive outcomes. Slower postnatal growth is an important predictor of adverse neurodevelopmental outcomes in infants born preterm. However, the relationship between postnatal growth and cortical development remains largely unknown. Therefore, we examined the association between neonatal growth and diffusion tensor imaging measures of microstructural cortical development in infants born very preterm. Participants were 95 neonates born between 24 and 32 weeks gestational age studied twice with diffusion tensor imaging: scan 1 at a median of 32.1 weeks (interquartile range, 30.4 to 33.6) and scan 2 at a median of 40.3 weeks (interquartile range, 38.7 to 42.7). Fractional anisotropy and eigenvalues were recorded from 15 anatomically defined cortical regions. Weight, head circumference, and length were recorded at birth and at the time of each scan. Growth between scans was examined in relation to diffusion tensor imaging measures at scans 1 and 2, accounting for gestational age, birth weight, sex, postmenstrual age, known brain injury (white matter injury, intraventricular hemorrhage, and cerebellar hemorrhage), and neonatal illness (patent ductus arteriosus, days intubated, infection, and necrotizing enterocolitis). Impaired weight, length, and head growth were associated with delayed microstructural development of the cortical gray matter (fractional anisotropy: P < 0.001), but not white matter (fractional anisotropy: P = 0.529), after accounting for prenatal growth, neonatal illness, and brain injury. Avoiding growth impairment during neonatal care may allow cortical development to proceed optimally and, ultimately, may provide an opportunity to reduce neurological disabilities related to preterm birth.

Postnatal infection is associated with widespread abnormalities of brain development in premature newborns.

Introduction:Infection is a risk factor for adverse neurodevelopmental outcome in preterm newborns. Our objective was to characterize the association of postnatal infection with adverse microstructural and metabolic brain development in premature newborns.Results:In 34/117 newborns studied, clinical signs were accompanied by positive cultures whereas 17 had clinical signs of sepsis alone. White matter injury (WMI) was identified in 34 newborns. In multivariate regression models, infected newborns had brain imaging measures indicative of delayed brain development: lower N-acetylaspartate/choline, elevated average diffusivity (DAV), and decreased white matter fractional anisotropy. These widespread brain abnormalities were found in both newborns with positive-culture infection and in those with clinical infection.Discussion:These findings suggest that postnatal infection, even without a positive culture, is an important risk factor for widespread abnormalities in brain development. These abnormalities extend beyond brain injuries apparent with conventional magnetic resonance injury (MRI).Methods:117 preterm newborns (24–32 wk gestation) were studied prospectively at a median of 32.0 and 40.3 wk ostmenstrual age with MRI (WMI, hemorrhage), magnetic resonance (MR) spectroscopy (metabolism), and diffusion tensor imaging (microstructure). Newborns were categorized as having “no infection,” “clinical infection,” or “positive-culture infection.” We compared brain injuries as well as metabolic and microstructural development across these infection groups.

Abnormal brain maturation in preterm neonates associated with adverse developmental outcomes

Objective: Our objective was to determine the association of early brain maturation with neurodevelopmental outcome in premature neonates. Methods: Neonates born between 24 and 32 weeks’ gestation (April 2006 to August 2010) were prospectively studied with MRI early in life and again at term-equivalent age. Using diffusion tensor imaging and magnetic resonance spectroscopic imaging, fractional anisotropy (FA) (microstructure) and N-acetylaspartate (NAA)/choline (metabolism) were measured from the basal nuclei, white matter tracts, and superior white matter. Brain maturation is characterized by increasing FA and NAA/choline from early in life to term-equivalent age. In premature neonates, systemic illness and critical care therapies have been linked to abnormalities of these measures. Of the 177 neonates in this cohort, 5 died and 157 (91% of survivors) were assessed at 18 months’ corrected age (adjusted for prematurity) using the Bayley Scales of Infant and Toddler Development III motor, cognitive, and language composite scores (mean = 100, SD = 15). Results: Among these 157 infants, white matter injury was seen in 48 (30%). Severe white matter injury, in 10 neonates (6%), was associated with a decrease in motor (−18 points; p < 0.001) and cognitive (−8 points; p = 0.085) scores. With greater severity of adverse neurodevelopmental outcomes, slower increases in FA and NAA/choline were observed in the basal nuclei and brain white matter regions as neonates matured to term-equivalent age, independent of the presence of white matter injury. Conclusions: In the preterm neonate, abnormal brain maturation evolves through the period of neonatal intensive care and is associated with adverse neurodevelopmental outcomes.

Preterm Cerebellar Growth Impairment After Postnatal Exposure to Glucocorticoids

Glucocorticoid exposure in preterm newborns is associated with impaired cerebellar development, pointing to a modifiable risk factor for improving motor and cognitive outcomes after premature birth. Dangers at the Time of Preterm Birth Sometimes, it is bad to show up early for an appointment. Babies born before the usual 40-week term of pregnancy are at risk for many problems, including impaired brain development. Despite advances in neonatology, these children experience developmental problems at the same frequency that they did 10 years ago. To pinpoint the causes of these lifelong issues, Tam et al. carefully assessed 172 newborn babies. The researchers documented a long list of clinical factors that the babies experienced and measured the volume of their brains after birth, and then many weeks later, a sensitive index of whether the brain is developing normally. As shown previously in animals, treatment of neonates with the glucocorticoids dexamethasone and hydrocortisone—often given to babies to promote lung development or treat hypotension—is associated with significant decreases in the rate of growth of the cerebellum, suggesting that these steroids should be used with caution. The authors showed that other things experienced by the babies were also associated with decreased cerebellar volumes: intubation, hypotension, and heart abnormalities—although these effects did not account for the effects of the glucocorticoids, which caused a significant 8 to 10% smaller cerebellum. Brain hemorrhage also affected cerebellar development, as the authors have previously reported. One bit of good news was that treatment of the babies (before birth) with another glucocorticoid, betamethasone, to encourage lung development and prevent hemorrhage had no effect on brain volumes. The American Academy of Pediatrics presently recommends that high-dose dexamethasone treatment in neonates be avoided, although they have no recommendation against hydrocortisone (the babies treated with dexamethasone in this study were from the University of British Columbia). The authors suggest that clinicians weigh the risks and benefits of glucocorticoid treatment for neonates, taking into account the association with impaired brain development. Other approaches to this problem may be possible, including adjuvant drug treatment given along with the glucocorticoids that could inhibit the detrimental effects of glucocorticoids, while preserving their ability to promote lung development, as reported in the accompanying paper by Heine et al. As survival rates of preterm newborns improve as a result of better medical management, these children increasingly show impaired cognition. These adverse cognitive outcomes are associated with decreases in the volume of the cerebellum. Because animals exhibit reduced preterm cerebellar growth after perinatal exposure to glucocorticoids, we sought to determine whether glucocorticoid exposure and other modifiable factors increased the risk for these adverse outcomes in human neonates. We studied 172 preterm neonatal infants from two medical centers, the University of British Columbia and the University of California, San Francisco, by performing serial magnetic resonance imaging examinations near birth and again near term-equivalent age. After we adjusted for associated clinical factors, antenatal betamethasone was not associated with changes in cerebellar volume. Postnatal exposure to clinically routine doses of hydrocortisone or dexamethasone was associated with impaired cerebellar, but not cerebral, growth. Alterations in treatment after preterm birth, particularly glucocorticoid exposure, may help to decrease risk for adverse neurological outcome after preterm birth.

Differential effects of intraventricular hemorrhage and white matter injury on preterm cerebellar growth

OBJECTIVE To hypothesize that detailed examination of early cerebellar volumes in time would distinguish differences in cerebellar growth associated with intraventricular hemorrhage (IVH) and white matter injury in preterm infants. STUDY DESIGN Preterm newborns at the University of California San Francisco (n = 57) and the University of British Columbia (n = 115) were studied with serial magnetic resonance imaging scans near birth and again at near term-equivalent age. Interactive semi-automated tools were used to determine volumes of the cerebellar hemispheres. RESULTS Adjusting for supratentorial brain injury, cerebellar hemorrhage, and study site, cerebellar volume increased 1.7 cm(3)/week postmenstrual age (95% CI, 1.6-1.7; P < .001). More severe supratentorial IVH was associated with slower growth of cerebellar volumes (P < .001). Volumes by 40 weeks were 1.4 cm(3) lower in premature infants with grade 1 to 2 IVH and 5.4 cm(3) lower in infants with grade 3 to 4 IVH. The same magnitude of decrease was found between ipsilateral and contralateral IVH. No association was found with severity of white matter injury (P = .3). CONCLUSIONS Early effects of decreased cerebellar volume associated with supratentorial IVH in either hemisphere may be a result of concurrent cerebellar injury or direct effects of subarachnoid blood on cerebellar development.

Neonatal Pain-Related Stress Predicts Cortical Thickness at Age 7 Years in Children Born Very Preterm

Background Altered brain development is evident in children born very preterm (24–32 weeks gestational age), including reduction in gray and white matter volumes, and thinner cortex, from infancy to adolescence compared to term-born peers. However, many questions remain regarding the etiology. Infants born very preterm are exposed to repeated procedural pain-related stress during a period of very rapid brain development. In this vulnerable population, we have previously found that neonatal pain-related stress is associated with atypical brain development from birth to term-equivalent age. Our present aim was to evaluate whether neonatal pain-related stress (adjusted for clinical confounders of prematurity) is associated with altered cortical thickness in very preterm children at school age. Methods 42 right-handed children born very preterm (24–32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children with severe brain injury and major motor/sensory/cognitive impairment were excluded. Regional cortical thickness was calculated using custom developed software utilizing FreeSurfer segmentation data. The association between neonatal pain-related stress (defined as the number of skin-breaking procedures) accounting for clinical confounders (gestational age, illness severity, infection, mechanical ventilation, surgeries, and morphine exposure), was examined in relation to cortical thickness using constrained principal component analysis followed by generalized linear modeling. Results After correcting for multiple comparisons and adjusting for neonatal clinical factors, greater neonatal pain-related stress was associated with significantly thinner cortex in 21/66 cerebral regions (p-values ranged from 0.00001 to 0.014), predominately in the frontal and parietal lobes. Conclusions In very preterm children without major sensory, motor or cognitive impairments, neonatal pain-related stress appears to be associated with thinner cortex in multiple regions at school age, independent of other neonatal risk factors.

Clinically silent preoperative brain injuries do not worsen with surgery in neonates with congenital heart disease.

OBJECTIVE Preoperative brain injury, particularly stroke and white matter injury, is common in neonates with congenital heart disease. The objective of this study was to determine the risk of hemorrhage or extension of preoperative brain injury with cardiac surgery. METHODS This dual-center prospective cohort study recruited 92 term neonates, 62 with transposition of the great arteries and 30 with single ventricle physiology, from 2 tertiary referral centers. Neonates underwent brain magnetic resonance imaging scans before and after cardiac surgery. RESULTS Brain injury was identified in 40 (43%) neonates on the preoperative magnetic resonance imaging scan (median 5 days after birth): stroke in 23, white matter injury in 21, and intraventricular hemorrhage in 7. None of the brain lesions presented clinically with overt signs or seizures. Preoperative brain injury was associated with balloon atrial septostomy (P = .003) and lowest arterial oxygen saturation (P = .007); in a multivariable model, only the effect of balloon atrial septostomy remained significant when adjusting for lowest arterial oxygen saturation. On postoperative magnetic resonance imaging in 78 neonates (median 21 days after birth), none of the preoperative lesions showed evidence of extension or hemorrhagic transformation (0/40 [95% confidence interval: 0%-7%]). The presence of preoperative brain injury was not a significant risk factor for acquiring new injury on postoperative magnetic resonance imaging (P = .8). CONCLUSIONS Clinically silent brain injuries identified preoperatively in neonates with congenital heart disease, including stroke, have a low risk of progression with surgery and cardiopulmonary bypass and should therefore not delay clinically indicated cardiac surgery. In this multicenter cohort, balloon atrial septostomy remains an important risk factor for preoperative brain injury, particularly stroke.