Anne Synnes

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.

Neonatal pain, parenting stress and interaction, in relation to cognitive and motor development at 8 and 18 months in preterm infants

ABSTRACT Procedural pain in the neonatal intensive care unit triggers a cascade of physiological, behavioral and hormonal disruptions which may contribute to altered neurodevelopment in infants born very preterm, who undergo prolonged hospitalization at a time of physiological immaturity and rapid brain development. The aim of this study was to examine relationships between cumulative procedural pain (number of skin‐breaking procedures from birth to term, adjusted for early illness severity and overall intravenous morphine exposure), and later cognitive, motor abilities and behavior in very preterm infants at 8 and 18 months corrected chronological age (CCA), and further, to evaluate the extent to which parenting factors modulate these relationships over time. Participants were N = 211 infants (n = 137 born preterm ⩽32 weeks gestational age [GA] and n = 74 full‐term controls) followed prospectively since birth. Infants with significant neonatal brain injury (periventricular leucomalacia, grade 3 or 4 intraventricular hemorrhage) and/or major sensori‐neural impairments, were excluded. Poorer cognition and motor function were associated with higher number of skin‐breaking procedures, independent of early illness severity, overall intravenous morphine, and exposure to postnatal steroids. The number of skin‐breaking procedures as a marker of neonatal pain was closely related to days on mechanical ventilation. In general, greater overall exposure to intravenous morphine was associated with poorer motor development at 8 months, but not at 18 months CCA, however, specific protocols for morphine administration were not evaluated. Lower parenting stress modulated effects of neonatal pain, only on cognitive outcome at 18 months.

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.

Perinatal outcomes of a large cohort of extremely low gestational age infants (twenty-three to twenty-eight completed weeks of gestation)

OBJECTIVES To determine gestational age (GA)-specific mortality rates; the effects of GA, birth weight, sex, and multiple gestation on mortality rates; short-term morbidity for infants born at 23 to 28 weeks GA; and impairment rates at a corrected chronologic age of 18 months for those born at 23 to 25 weeks GA. METHODS A data base analysis was performed with a linked obstetric and a neonatal database. GA was determined by obstetric data and confirmed by early ultrasonography (available in 88%) on all births < 30 weeks GA at British Columbias tertiary perinatal center from 1983 to 1989. RESULTS Of 1024 births occurring between 23 and 28 weeks GA, 911 were live born. The mortality rate decreased with increasing GA: 84% at 23 weeks; 57% at 24 weeks; 45% at 25 weeks; 37% at 26 weeks; 23% at 27 weeks; and 13% at 28 weeks GA. For each GA, mortality rate versus birth weight plots showed a decreasing mortality rate with increasing birth weight, except for infants who were large for GA. Male infants had a higher mortality rate than female infants (odds ratio, 1.8; confidence interval, 1.4 to 2.5). Twins fared worse than singletons with a decreasing effect from 24 weeks GA (odds ratio, 10.3) to no effect at 28 weeks GA. The median number of days supported by mechanical ventilation and the length of stay in the neonatal intensive care unit decreased markedly with increasing GA. Eighteen-month outcome of survivors between 23 and 25 weeks GA with 93% follow-up rate revealed an overall impairment rate of 36%, but 6 of the 9 surviving 23-week infants had major impairments. CONCLUSIONS The GA-specific perinatal outcome results of this large cohort provide information to assist in perinatal management decision making and for counseling parents prenatally.

Handwriting: Current Trends in Occupational Therapy Practice

The objective of this survey was to describe assessment and treatment approaches commonly used by occupational therapists for children exhibiting handwriting and related fine motor difficulties. Secondarily, the application of weights as a treatment modality was also explored. Fifty experienced paediatric occupational therapists from Ontario (46%), Quebec (22%) and six other Canadian provinces, were surveyed by telephone. The majority of therapists indicated that they evaluated gross/fine motor and perceptual skills, motor planning, quality of movement and sensory functioning for this population, while psychosocial and environmental factors were often not formally evaluated. Evaluations most commonly utilized included the Beery, Bruininks-Oseretsky and Gardner Tests. Standardized handwriting assessments were rarely employed. All used an eclectic treatment approach with sensorimotor most frequently selected (90%). Work setting and years of experience did not influence the treatment approach favoured.

Neurodevelopmental Outcomes After Cardiac Surgery in Infancy

BACKGROUND: Neurodevelopmental disability is the most common complication for survivors of surgery for congenital heart disease (CHD). METHODS: We analyzed individual participant data from studies of children evaluated with the Bayley Scales of Infant Development, second edition, after cardiac surgery between 1996 and 2009. The primary outcome was Psychomotor Development Index (PDI), and the secondary outcome was Mental Development Index (MDI). RESULTS: Among 1770 subjects from 22 institutions, assessed at age 14.5 ± 3.7 months, PDIs and MDIs (77.6 ± 18.8 and 88.2 ± 16.7, respectively) were lower than normative means (each P < .001). Later calendar year of birth was associated with an increased proportion of high-risk infants (complexity of CHD and prevalence of genetic/extracardiac anomalies). After adjustment for center and type of CHD, later year of birth was not significantly associated with better PDI or MDI. Risk factors for lower PDI were lower birth weight, white race, and presence of a genetic/extracardiac anomaly (all P ≤ .01). After adjustment for these factors, PDIs improved over time (0.39 points/year, 95% confidence interval 0.01 to 0.78; P = .045). Risk factors for lower MDI were lower birth weight, male gender, less maternal education, and presence of a genetic/extracardiac anomaly (all P < .001). After adjustment for these factors, MDIs improved over time (0.38 points/year, 95% confidence interval 0.05 to 0.71; P = .02). CONCLUSIONS: Early neurodevelopmental outcomes for survivors of cardiac surgery in infancy have improved modestly over time, but only after adjustment for innate patient risk factors. As more high-risk CHD infants undergo cardiac surgery and survive, a growing population will require significant societal resources.

Disease-modifying drugs for multiple sclerosis in pregnancy A systematic review

Objective: To systematically review the literature regarding safety of disease-modifying drug (DMD) use during pregnancy on perinatal and developmental outcomes in offspring of patients with multiple sclerosis (MS). Methods: A PubMed and EMBASE search up to February 2012 was conducted with a manual search of references from relevant articles. Selected studies were evaluated using internationally accepted criteria. Results: Fifteen studies identified 761 interferon β-, 97 glatiramer acetate-, and 35 natalizumab-exposed pregnancies. Study quality ranged from poor to good; no study was rated excellent. Small sample sizes limited most studies. Compared with data for unexposed pregnancies, fair- to good-quality prospective cohort studies reported that interferon β exposure was associated with lower mean birth weight, shorter mean birth length, and preterm birth (<37 weeks), but not low birth weight (<2,500 g), cesarean delivery, congenital anomaly (including malformation), or spontaneous abortion. Fewer studies of fair quality were available for glatiramer acetate and natalizumab. Glatiramer acetate exposure was not associated with lower mean birth weight, congenital anomaly, preterm birth, or spontaneous abortion. Natalizumab exposure did not appear to be associated with shorter mean birth length, lower mean birth weight, or lower mean gestational age. No studies examined mitoxantrone or fingolimod exposure. One study of paternal DMD use during conception found no effect on gestational age or birth weight. Few studies examined longer-term developmental outcomes. Conclusion: Further studies are needed to determine the potential risks associated with preconceptional and in utero DMD exposure in patients with MS. Discontinuation of DMDs before conception is still recommended.

Neonatal pain-related stress, functional cortical activity and visual-perceptual abilities in school-age children born at extremely low gestational age

Summary Neonatal pain‐related stress is associated with altered brain activity and visual‐perceptual abilities in school‐age children born at extremely low gestational age. Abstract Children born very prematurely (≤32 weeks) often exhibit visual‐perceptual difficulties at school‐age, even in the absence of major neurological impairment. The alterations in functional brain activity that give rise to such problems, as well as the relationship between adverse neonatal experience and neurodevelopment, remain poorly understood. Repeated procedural pain‐related stress during neonatal intensive care has been proposed to contribute to altered neurocognitive development in these children. Due to critical periods in the development of thalamocortical systems, the immature brain of infants born at extremely low gestational age (ELGA; ≤28 weeks) may have heightened vulnerability to neonatal pain. In a cohort of school‐age children followed since birth we assessed relations between functional brain activity measured using magnetoencephalogragy (MEG), visual‐perceptual abilities and cumulative neonatal pain. We demonstrated alterations in the spectral structure of spontaneous cortical oscillatory activity in ELGA children at school‐age. Cumulative neonatal pain‐related stress was associated with changes in background cortical rhythmicity in these children, and these alterations in spontaneous brain oscillations were negatively correlated with visual‐perceptual abilities at school‐age, and were not driven by potentially confounding neonatal variables. These findings provide the first evidence linking neonatal pain‐related stress, the development of functional brain activity, and school‐age cognitive outcome in these vulnerable children.

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.