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Objective Very preterm-born neonates (24–32 weeks of gestation) are exposed to stressful and painful procedures during neonatal intensive care. Analgesic and sedation therapies are essential, and opiates and benzodiazepines are commonly used. These medications may negatively impact brain development. The hippocampus may be especially vulnerable to the effects of pain and analgesic and/or sedative therapies and contribute to adverse outcomes. The effect of invasive procedures and analgesic–sedative exposure on hippocampal growth was assessed, as was that of hippocampal growth on neurodevelopmental outcome. Methods A total of 138 neonates (51% male, median gestational age = 27.7 weeks) underwent magnetic resonance imaging and diffusion tensor imaging (DTI) scans, early in life (postmenstrual age [PMA] = 32.3 weeks) and at term-equivalent age (PMA = 40.2 weeks). Volumes and DTI measures of axial diffusivity, radial diffusivity, and mean diffusivity (MD) were obtained from the hippocampus. Cognitive, language, and motor abilities were assessed using the Bayley Scales of Infant Development–III at 18.7 months median corrected age. Models testing the association of invasive procedures with hippocampal volumes and DTI measures accounted for birth gestational age, sex, PMA, dose of analgesics/sedatives (fentanyl, morphine, midazolam), mechanical ventilation, hypotension, and surgeries. Results Total midazolam dose predicted decreased hippocampal volumes (β = −1.8, p 0.5 each). Lower cognitive scores were associated with hippocampal growth (β = −0.31, p = 0.003), midazolam dose (β = −0.27, p = 0.03), and surgery (β = −8.32, p = 0.04). Interpretation Midazolam exposure was associated with macro- and microstructural alterations in hippocampal development and poorer outcomes consistent with hippocampal dysmaturation. Use of midazolam in preterm neonates, particularly those not undergoing surgery, is cautioned. Ann Neurol 2016;79:548–559

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.Infants born very preterm (N=86; 24-32 weeks gestational age) were followed prospectively from birth, and studied with magnetic resonance imaging, 3-dimensional magnetic resonance spectroscopic imaging, and diffusion tensor imaging: scan 1 early in life (median, 32.1 weeks) and scan 2 at term-equivalent age (median, 40 weeks). We calculated N-acetylaspartate to choline ratios (NAA/choline), lactate to choline ratios, average diffusivity, and white matter fractional anisotropy (FA) from up to 7 white and 4 subcortical gray matter regions of interest. Procedural pain was quantified as the number of skin-breaking events from birth to term or scan 2. Data were analyzed using generalized estimating equation modeling adjusting for clinical confounders such as illness severity, morphine exposure, brain injury, and surgery.After comprehensively adjusting for multiple clinical factors, greater neonatal procedural pain was associated with reduced white matter FA (β=-0.0002, p=0.028) and reduced subcortical gray matter NAA/choline (β=-0.0006, p=0.004). Reduced FA was predicted by early pain (before scan 1), whereas lower NAA/choline was predicted by pain exposure throughout the neonatal course, suggesting a primary and early effect on subcortical structures with secondary white matter changes.Early procedural pain in very preterm infants may contribute to impaired brain development.

Objective To determine (1) whether the risk of adverse neonatal and delivery outcomes differs between mothers with and without multiple sclerosis (MS) and (2) whether risk is differentially associated with clinical factors of MS. Methods This retrospective cohort study analyzed data from the British Columbia (BC) MS Clinics' database and the BC Perinatal Database Registry. Comparisons were made between births to women with MS (n = 432) and to a frequency-matched sample of women without MS (n = 2,975) from 1998 to 2009. Outcomes included gestational age, birth weight, assisted vaginal delivery, and Caesarean section. Clinical factors examined included age at MS onset, disease duration, and disability. Multivariate regression models adjusting for confounding factors were built for each outcome. Results Babies born to MS mothers did not have a significantly different mean gestational age or birth weight compared to babies born to mothers without MS. MS was not significantly associated with assisted vaginal delivery (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.50–1.16; p = 0.20) or Caesarean section (OR, 0.94; 95% CI, 0.69–1.28; p = 0.69). There was a slightly elevated risk of adverse delivery outcomes among MS mothers with greater levels of disability, although findings were not statistically significant. Disease duration and age at MS onset were not significantly associated with adverse outcomes. Interpretation This study provides reassurance to MS patients that maternal MS is generally not associated with adverse neonatal and delivery outcomes. However, the suggestion of an increased risk with greater disability warrants further investigation; these women may require closer monitoring during pregnancy. ANN NEUROL 2011

Objective [ ] The association of chorioamnionitis and non-cystic 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 MR imaging. Methods [ ] Ninety-two preterm newborns (24-32 weeks gestation) were studied at a median age of 31.9 weeks and again at 40.3 weeks gestation. Histopathological chorioamnionitis and white matter injury were scored using validated systems. Measures of brain metabolism (N-acetylaspartate/choline and lactate/choline) on magnetic resonance spectroscopy, and microstructure (average diffusivity and fractional anisotropy) on diffusion tensor imaging were calculated from predefined brain regions. Results [ ] Thirty-one newborns (34%) were exposed to histopathological chorioamnionitis, and 26 (28%) had white matter injury. Histopathological chorioamnionitis was not associated with an increased risk of white matter injury (relative risk: 1.2; P=0.6). Newborns with postnatal infections and hypotension requiring therapy were at higher risk of white matter injury (P0.1). In contrast, white matter injury was associated with lower N-acetylaspartate/choline (–8.9%; P=0.009) and lower white matter fractional anisotropy (–11.9%; P=0.01). Interpretation [ ] Histopathological chorioamnionitis does not appear to be associated with an increased risk of white matter injury on magnetic resonance imaging or with abnormalities of brain development. In contrast, postnatal infections and hypotension are associated with an increased risk of white matter injury in the premature newborn. Final published version [ ] Ann Neurol. 2009 Aug;66(2):155-64. URL: http://www3.interscience.wiley.com/journal/76507645/home

Very preterm-born neonates (24-32 weeks of gestation) are exposed to stressful and painful procedures during neonatal intensive care. Analgesic and sedation therapies are essential, and opiates and benzodiazepines are commonly used. These medications may negatively impact brain development. The hippocampus may be especially vulnerable to the effects of pain and analgesic and/or sedative therapies and contribute to adverse outcomes. The effect of invasive procedures and analgesic-sedative exposure on hippocampal growth was assessed, as was that of hippocampal growth on neurodevelopmental outcome.A total of 138 neonates (51% male, median gestational age = 27.7 weeks) underwent magnetic resonance imaging and diffusion tensor imaging (DTI) scans, early in life (postmenstrual age [PMA] = 32.3 weeks) and at term-equivalent age (PMA = 40.2 weeks). Volumes and DTI measures of axial diffusivity, radial diffusivity, and mean diffusivity (MD) were obtained from the hippocampus. Cognitive, language, and motor abilities were assessed using the Bayley Scales of Infant Development-III at 18.7 months median corrected age. Models testing the association of invasive procedures with hippocampal volumes and DTI measures accounted for birth gestational age, sex, PMA, dose of analgesics/sedatives (fentanyl, morphine, midazolam), mechanical ventilation, hypotension, and surgeries.Total midazolam dose predicted decreased hippocampal volumes (β = -1.8, p0.001) and increased MD (β = 0.002, p = 0.02), whereas invasive procedures did not (β = 0, p0.5 each). Lower cognitive scores were associated with hippocampal growth (β = -0.31, p = 0.003), midazolam dose (β = -0.27, p = 0.03), and surgery (β = -8.32, p = 0.04).Midazolam exposure was associated with macro- and microstructural alterations in hippocampal development and poorer outcomes consistent with hippocampal dysmaturation. Use of midazolam in preterm neonates, particularly those not undergoing surgery, is cautioned.