Neurodevelopmental Outcomes following Intrauterine Growth Restriction and Very Preterm Birth.

OBJECTIVES: To evaluate whether intrauterine growth restriction (IUGR) adds further neurodevelopmental risk to that posed by very preterm birth alone in terms of alterations in brain growth and poorer toddlerhood outcomes. STUDY DESIGN: Participants were 314 infants of very preterm birth enrolled in the Evaluation of Preterm Imaging Study (e-Prime) who were subsequently followed up in toddlerhood. IUGR was identified postnatally from discharge records (n = 49) and defined according to prenatal evaluation of growth restriction confirmed by birth weight <10th percentile for gestational age and/or alterations in fetal Doppler. Appropriate for gestational age (AGA; n = 265) was defined as birth weight >10th percentile for gestational age at delivery. Infants underwent magnetic resonance imaging at term-equivalent age (median = 42 weeks); T2-weighted images were obtained for voxelwise gray matter volumes. Follow-up assessments were conducted at corrected median age of 22 months using the Bayley Scales of Infant and Toddler Development III and the Modified-Checklist for Autism in Toddlers. RESULTS: Infants of very preterm birth with IUGR displayed a relative volumetric decrease in gray matter in limbic regions and a relative increase in frontoinsular, temporal-parietal, and frontal areas compared with peers of very preterm birth who were AGA. At follow-up, toddlers born very preterm with IUGR had significantly lower cognitive (effect size = 0.42) and motor (effect size = 0.41) scores and were more likely to have a positive Modified-Checklist for Autism in Toddlers screening for autism (OR = 2.12) compared with peers of very preterm birth who were AGA. CONCLUSIONS: IUGR might confer a neurodevelopmental risk that is greater than that posed by very preterm alone, in terms of both alterations in brain growth and poorer toddlerhood outcomes.

Multimodal image analysis of clinical influences on preterm brain development.

OBJECTIVE: Premature birth is associated with numerous complex abnormalities of white and gray matter and a high incidence of long-term neurocognitive impairment. An integrated understanding of these abnormalities and their association with clinical events is lacking. The aim of this study was to identify specific patterns of abnormal cerebral development and their antenatal and postnatal antecedents. METHODS: In a prospective cohort of 449 infants (226 male), we performed a multivariate and data-driven analysis combining multiple imaging modalities. Using canonical correlation analysis, we sought separable multimodal imaging markers associated with specific clinical and environmental factors and correlated to neurodevelopmental outcome at 2 years. RESULTS: We found five independent patterns of neuroanatomical variation that related to clinical factors including age, prematurity, sex, intrauterine complications, and postnatal adversity. We also confirmed the association between imaging markers of neuroanatomical abnormality and poor cognitive and motor outcomes at 2 years. INTERPRETATION: This data-driven approach defined novel and clinically relevant imaging markers of cerebral maldevelopment, which offer new insights into the nature of preterm brain injury. Ann Neurol 2017;82:233-246.

Specialization and integration of functional thalamocortical connectivity in the human infant.

Connections between the thalamus and cortex develop rapidly before birth, and aberrant cerebral maturation during this period may underlie a number of neurodevelopmental disorders. To define functional thalamocortical connectivity at the normal time of birth, we used functional MRI (fMRI) to measure blood oxygen level-dependent (BOLD) signals in 66 infants, 47 of whom were at high risk of neurocognitive impairment because of birth before 33 wk of gestation and 19 of whom were term infants. We segmented the thalamus based on correlation with functionally defined cortical components using independent component analysis (ICA) and seed-based correlations. After parcellating the cortex using ICA and segmenting the thalamus based on dominant connections with cortical parcellations, we observed a near-facsimile of the adult functional parcellation. Additional analysis revealed that BOLD signal in heteromodal association cortex typically had more widespread and overlapping thalamic representations than primary sensory cortex. Notably, more extreme prematurity was associated with increased functional connectivity between thalamus and lateral primary sensory cortex but reduced connectivity between thalamus and cortex in the prefrontal, insular and anterior cingulate regions. This work suggests that, in early infancy, functional integration through thalamocortical connections depends on significant functional overlap in the topographic organization of the thalamus and that the experience of premature extrauterine life modulates network development, altering the maturation of networks thought to support salience, executive, integrative, and cognitive functions.

Language ability in preterm children is associated with arcuate fasciculi microstructure at term.

In the mature human brain, the arcuate fasciculus mediates verbal working memory, word learning, and sublexical speech repetition. However, its contribution to early language acquisition remains unclear. In this work, we aimed to evaluate the role of the direct segments of the arcuate fasciculi in the early acquisition of linguistic function. We imaged a cohort of 43 preterm born infants (median age at birth of 30 gestational weeks; median age at scan of 42 postmenstrual weeks) using high b value high-angular resolution diffusion-weighted neuroimaging and assessed their linguistic performance at 2 years of age. Using constrained spherical deconvolution tractography, we virtually dissected the arcuate fasciculi and measured fractional anisotropy (FA) as a metric of white matter development. We found that term equivalent FA of the left and right arcuate fasciculi was significantly associated with individual differences in linguistic and cognitive abilities in early childhood, independent of the degree of prematurity. These findings suggest that differences in arcuate fasciculi microstructure at the time of normal birth have a significant impact on language development and modulate the first stages of language learning. Hum Brain Mapp 38:3836-3847, 2017. © 2017 Wiley Periodicals, Inc.

Coagulation Gene Expression Profiling in Infants With Necrotizing Enterocolitis.

OBJECTIVES: Coagulopathy and mesenteric thrombosis are common in premature neonates with necrotizing enterocolitis (NEC). This pilot study aimed to investigate the hypothesis that there are changes in the gene expression related to the coagulation and anticoagulation systems in NEC. METHODS: Consecutive neonates (n = 11) with NEC (Bell stages 2-3) were recruited. Two comparison groups, matched for birth weight and corrected gestational age, were selected based on the absence of inflammation and coagulopathy (healthy control, n = 10), or the presence of a confirmed blood infection (sepsis control, n = 12). A pathway-specific quantitative polymerase chain reaction array was used to determine the expression of 94 genes involved in human blood coagulation and anticoagulation cascade. RESULTS: Twelve genes of the coagulation and anticoagulation systems were significantly altered in the patients with NEC compared with healthy controls. In particular, neutrophil elastase, CD63, PROS1, HGF, and F12 were significantly upregulated (mean fold changes [FCs] +2.74, P < 0.05) with an overall procoagulant effect; MFGE8, factor II (thrombin) receptor-like 1 (F2RL1), FGL2, PLAT, PROCR, SERPIND1, and HNF4A were significantly downregulated (mean FCs -2.45, P < 0.05) with a reduction in fibrinolysis and endothelial regeneration. In the comparison between NEC and sepsis, we did observe a significant difference in expression of F2RL1 (FC -2.50, P = 0.01). CONCLUSIONS: We have identified potential biomarkers associated with coagulopathy and disease progression in NEC. In particular, the overall procoagulant status, at the transcriptional level, should be further investigated to unveil molecular mechanisms leading to intestinal necrosis, multiorgan failure, and death.

Early Childhood Temperamental Trajectories following Very Preterm Birth and Their Association with Parenting Style.

Childhood temperament is an early characteristic shaping later life adjustment. However, little is currently known about the stability of early temperament and its susceptibility to the environment in children born very preterm (VPT; <33 weeks' gestation). Here, we investigated infant-to-childhood temperamental trajectories, and their interaction with parental practices, in VPT children. Maternal reports of infant temperament were collected in 190 infants (mean age: 11.27 months; range 9−18 months) enrolled in the longitudinal Evaluation of Preterm Imaging (ePrime; Eudra: CT 2009-011602-42) study, using the ePrime questionnaire on infant temperament. At 4−7 years of age, further assessments of child temperament (Children's Behavior Questionnaire­Very Short Form) and parenting style (Arnold's Parenting Scale) were conducted. Results showed that more difficult temperament in infancy was associated with increased Negative Affectivity in childhood, regardless of parenting practices. This lends support to the stability of early temperamental traits reflecting negative emotionality. In contrast, a lax parenting style moderated the relationship between easy infant temperament and Negative Affectivity at 4−7 years, such that an easier infant temperament was increasingly associated with higher childhood Negative Affectivity scores as parental laxness increased. These results highlight a potential vulnerability of VPT infants considered by their mothers to be easy to handle, as they may be more susceptible to the effects of suboptimal parenting in childhood.

Deaths in people from Black, Asian and minority ethnic communities from both COVID-19 and non-COVID causes in the first weeks of the pandemic in London: a hospital case note review.

OBJECTIVE: To undertake a case review of deaths in a 6-week period during the COVID-19 pandemic commencing with the first death in the hospital from COVID-19 on 12th of March 2020 and contrast this with the same period in 2019. SETTING: A large London teaching hospital. PARTICIPANTS: Three groups were compared: group 1-COVID-19-associated deaths in the 6-week period (n=243), group 2-non-COVID deaths in the same period (n=136) and group 3-all deaths in a comparison period of the same 6 weeks in 2019 (n=194). PRIMARY AND SECONDARY OUTCOME MEASURES: This was a descriptive analysis of death case series review and as such no primary or secondary outcomes were pre-stipulated. RESULTS: Deaths in patients from the Black, Asian and minority ethnic (BAME) communities in the pandemic period significantly increased both in the COVID-19 group (OR=2.43, 95% CI=1.60-3.68, p<0.001) and the non-COVID group (OR=1.76, 95% CI=1.09-2.83, p=0.02) during this time period and the increase was independent of differences in comorbidities, sex, age or deprivation. While the absolute number of deaths increased in 2020 compared with 2019, across all three groups the distribution of deaths by age was very similar. Our analyses confirm major risk factors for COVID-19 mortality including male sex, diabetes, having multiple comorbidities and background from the BAME communities. CONCLUSIONS: There was no evidence of COVID-19 deaths occurring disproportionately in the elderly compared with non-COVID deaths in this period in 2020 and 2019. Deaths in the BAME communities were over-represented in both COVID-19 and non-COVID groups, highlighting the need for detailed research in order to fully understand the influence of ethnicity on susceptibility to illness, mortality and health-seeking behaviour during the pandemic.

Methemoglobinemia during the Use of Glyceryl Trinitrate Patches in Neonates: Two Case Reports.

Methemoglobinemia can result in severe hypoxia. It has been frequently reported during the use of inhaled nitric oxide, but can occur where nitrate containing medications are used. Glyceryl trinitrate (GTN) patches have been used in the treatment of digital and limb ischemia in prematurely born infants. Little is known about the pharmacokinetics of GTN when incorporated into patches. Studies of other topical forms of nitroglycerine have shown a wide range of absorption. It is likely that the increased permeability of the prematurely born infant's skin would facilitate absorption. We describe the use of GTN patches in two very prematurely born infants used to treat limb/digit ischemia. This resulted in methemoglobinemia and resultant increase in their supplementary oxygen requirements. Removal of the patches was associated with a reduction in their methemoglobin levels and the supplementary oxygen requirements back to baseline levels. In conclusion, routine monitoring of methemoglobin levels should be undertaken when GTN patches are used in very prematurely born infants.

Epidemiology of UK neonatal infections: the neonIN infection surveillance network.

OBJECTIVE: To describe the epidemiology of neonatal infection over the past decade in UK neonatal units. DESIGN: Retrospective analysis of prospectively collected infection surveillance network data from 2005 to 2014. SETTING: 30 neonatal units in the UK. PATIENTS: Newborns on participating neonatal units who had a positive blood, cerebrospinal fluid or urine culture and were treated with at least 5 days of appropriate antibiotics. RESULTS: 2171 episodes of neonatal infection in 1922 infants were recorded. The incidence of infection was 6.1/1000 live births and 48.8/1000 neonatal admissions (2.9 and 23.5 respectively if coagulase-negative staphylococci (CoNS) cultures excluded). The incidence of infection showed a statistically significant reduction over time with reductions in the rates of both early-onset sepsis (EOS) and late-onset sepsis (LOS).The majority of episodes (76%) represented LOS (diagnosed > 48 hours after birth), and infection was more common in premature (<37 weeks gestation) and low birth weight (<2500 g) neonates (84% and 81%, respectively). Commonly identified pathogens included group B streptococci (43%) and Escherichia coli (18%) for EOS, while E. coli (15%), Staphylococcus aureus (14%) and CoNS were prominent causes of LOS. CONCLUSIONS: This paper describes the epidemiology of neonatal infection in the UK over the past decade. These data enable benchmarking of practice and inform areas of future research and guideline development. The results support the hypothesis that the introduction of infection prevention care bundles and antibiotic stewardship programmes in the UK has reduced the burden of LOS.

Antimicrobial resistance in UK neonatal units: neonIN infection surveillance network.

OBJECTIVE: To define the susceptibilities of the common causative pathogens of neonatal sepsis in the UK. DESIGN: Retrospective analysis of the prospectively collected neonIN infection surveillance network data between 2005 and 2014. SETTING: 30 neonatal units in the UK. PATIENTS: Newborns admitted to participating neonatal units who return a positive blood, cerebrospinal fluid or urine culture and are treated with at least 5 days of appropriate antibiotics. RESULTS: 1568 isolates with recorded antimicrobial data were collected including 328 early-onset sepsis (EOS) isolates and 1240 late-onset sepsis (LOS) isolates. The majority of EOS pathogens (>92%) were susceptible to the four empirical commonly used antimicrobial combinations (eg, 93% for benzylpenicillin/gentamicin), while LOS pathogens demonstrated higher levels of resistance (eg, 89% for flucloxacillin/gentamicin). Among infants<1500 g and <32 weeks gestation, an amoxicillin/gentamicin combination demonstrated a trend towards improved coverage of EOS isolates than benzylpenicillin/gentamicin (93% vs 86%, p=0.211). CONCLUSIONS: This analysis provides insights into the patterns of antimicrobial resistance among UK neonatal pathogens. These data will inform areas of future research and can be used to update national evidence-based guidelines on antimicrobial usage.

Exploring the multiple-hit hypothesis of preterm white matter damage using diffusion MRI.

BACKGROUND: Preterm infants are at high risk of diffuse white matter injury and adverse neurodevelopmental outcome. The multiple hit hypothesis suggests that the risk of white matter injury increases with cumulative exposure to multiple perinatal risk factors. Our aim was to test this hypothesis in a large cohort of preterm infants using diffusion weighted magnetic resonance imaging (dMRI). METHODS: We studied 491 infants (52% male) without focal destructive brain lesions born at < 34 weeks, who underwent structural and dMRI at a specialist Neonatal Imaging Centre. The median (range) gestational age (GA) at birth was 30+ 1 (23+ 2-33+ 5) weeks and median postmenstrual age at scan was 42+ 1 (38-45) weeks. dMRI data were analyzed using tract based spatial statistics and the relationship between dMRI measures in white matter and individual perinatal risk factors was assessed. We tested the hypothesis that increased exposure to perinatal risk factors was associated with lower fractional anisotropy (FA), and higher radial, axial and mean diffusivity (RD, AD, MD) in white matter. Neurodevelopmental performance was investigated using the Bayley Scales of Infant and Toddler Development, Third Edition (BSITD-III) in a subset of 381 infants at 20 months corrected age. We tested the hypothesis that lower FA and higher RD, AD and MD in white matter were associated with poorer neurodevelopmental performance. RESULTS: Identified risk factors for diffuse white matter injury were lower GA at birth, fetal growth restriction, increased number of days requiring ventilation and parenteral nutrition, necrotizing enterocolitis and male sex. Clinical chorioamnionitis and patent ductus arteriosus were not associated with white matter injury. Multivariate analysis demonstrated that fetal growth restriction, increased number of days requiring ventilation and parenteral nutrition were independently associated with lower FA values. Exposure to cumulative risk factors was associated with reduced white matter FA and FA values at term equivalent age were associated with subsequent neurodevelopmental performance. CONCLUSION: This study suggests multiple perinatal risk factors have an independent association with diffuse white matter injury at term equivalent age and exposure to multiple perinatal risk factors exacerbates dMRI defined, clinically significant white matter injury. Our findings support the multiple hit hypothesis for preterm white matter injury.

Effect of MRI on preterm infants and their families: a randomised trial with nested diagnostic and economic evaluation.

BACKGROUND: We tested the hypothesis that routine MRI would improve the care and well-being of preterm infants and their families. DESIGN: Parallel-group randomised trial (1.1 allocation; intention-to-treat) with nested diagnostic and cost evaluations (EudraCT 2009-011602-42). SETTING: Participants from 14 London hospitals, imaged at a single centre. PATIENTS: 511 infants born before 33 weeks gestation underwent both MRI and ultrasound around term. 255 were randomly allocated (siblings together) to receive only MRI results and 255 only ultrasound from a paediatrician unaware of unallocated results; one withdrew before allocation. MAIN OUTCOME MEASURES: Maternal anxiety, measured by the State-Trait Anxiety inventory (STAI) assessed in 206/214 mothers receiving MRI and 217/220 receiving ultrasound. Secondary outcomes included: prediction of neurodevelopment, health-related costs and quality of life. RESULTS: After MRI, STAI fell from 36.81 (95% CI 35.18 to 38.44) to 32.77 (95% CI 31.54 to 34.01), 31.87 (95% CI 30.63 to 33.12) and 31.82 (95% CI 30.65 to 33.00) at 14 days, 12 and 20 months, respectively. STAI fell less after ultrasound: from 37.59 (95% CI 36.00 to 39.18) to 33.97 (95% CI 32.78 to 35.17), 33.43 (95% CI 32.22 to 34.63) and 33.63 (95% CI 32.49 to 34.77), p=0.02. There were no differences in health-related quality of life. MRI predicted moderate or severe functional motor impairment at 20 months slightly better than ultrasound (area under the receiver operator characteristic curve (CI) 0.74; 0.66 to 0.83 vs 0.64; 0.56 to 0.72, p=0.01) but cost £315 (CI £295-£336) more per infant. CONCLUSIONS: MRI increased costs and provided only modest benefits. TRIAL REGISTRATION: ClinicalTrials.gov NCT01049594 https://clinicaltrials.gov/ct2/show/NCT01049594. EudraCT: EudraCT: 2009-011602-42 (https://www.clinicaltrialsregister.eu/).

Antenatal infection/inflammation and fetal tissue injury.

There is a clear association between antenatal infection/inflammation and preterm labour, with intrauterine infection complicating up to one third of preterm deliveries. In addition to this, there is now accumulating evidence that intrauterine infection and inflammation can lead to the development of a systemic inflammatory response in the fetus and subsequent tissue injury. The fetal inflammatory response is characterized by funisitis, high levels of pro-inflammatory cytokines in the amniotic fluid and cord blood, and systemic immune activation. This review discusses the evidence for this process and focuses on the clinical and experimental data supporting the hypothesis that these inflammatory processes contribute to brain and lung injury in the newborn.

Punctate White Matter Lesions Associated With Altered Brain Development And Adverse Motor Outcome In Preterm Infants.

Preterm infants who develop neurodevelopmental impairment do not always have recognized abnormalities on cerebral ultrasound, a modality routinely used to assess prognosis. In a high proportion of infants, MRI detects punctate white matter lesions that are not seen on ultrasonography. To determine the relation of punctate lesions to brain development and early neurodevelopmental outcome we used multimodal brain MRI to study a large cohort of preterm infants. Punctate lesions without other focal cerebral or cerebellar lesions were detected at term equivalent age in 123 (24.3%) (59 male) of the 506 infants, predominantly in the centrum semiovale and corona radiata. Infants with lesions had higher gestational age, birth weight, and less chronic lung disease. Punctate lesions showed a dose dependent relation to abnormalities in white matter microstructure, assessed with tract-based spatial statistics, and reduced thalamic volume (p < 0.0001), and predicted unfavourable motor outcome at a median (range) corrected age of 20.2 (18.4-26.3) months with sensitivity (95% confidence intervals) 71 (43-88) and specificity 72 (69-77). Punctate white matter lesions without associated cerebral lesions are common in preterm infants currently not regarded as at highest risk for cerebral injury, and are associated with widespread neuroanatomical abnormalities and adverse early neurodevelopmental outcome.

Abnormal cortical development after premature birth shown by altered allometric scaling of brain growth.

BACKGROUND: We postulated that during ontogenesis cortical surface area and cerebral volume are related by a scaling law whose exponent gives a quantitative measure of cortical development. We used this approach to investigate the hypothesis that premature termination of the intrauterine environment by preterm birth reduces cortical development in a dose-dependent manner, providing a neural substrate for functional impairment. METHODS AND FINDINGS: We analyzed 274 magnetic resonance images that recorded brain growth from 23 to 48 wk of gestation in 113 extremely preterm infants born at 22 to 29 wk of gestation, 63 of whom underwent neurodevelopmental assessment at a median age of 2 y. Cortical surface area was related to cerebral volume by a scaling law with an exponent of 1.29 (95% confidence interval, 1.25-1.33), which was proportional to later neurodevelopmental impairment. Increasing prematurity and male gender were associated with a lower scaling exponent (p < 0.0001) independent of intrauterine or postnatal somatic growth. CONCLUSIONS: Human brain growth obeys an allometric scaling relation that is disrupted by preterm birth in a dose-dependent, sexually dimorphic fashion that directly parallels the incidence of neurodevelopmental impairments in preterm infants. This result focuses attention on brain growth and cortical development during the weeks following preterm delivery as a neural substrate for neurodevelopmental impairment after premature delivery.

Microchimerism in female bone marrow and bone decades after fetal mesenchymal stem-cell trafficking in pregnancy.

Fetal cells enter maternal blood during pregnancy and persist in women with autoimmune disease. The frequency of subsequent fetomaternal microchimerism in healthy women and its cell type is unknown. To test the hypothesis that fetal mesenchymal stem cells persist in maternal organs, we studied female bone marrow and ribs. Male cells were identified by XY fluorescence in-situ hybridisation in marrow-derived mesenchymal stem cells and in rib sections from all women with male pregnancies, but not in controls (9/9 vs 0/5, p=0.0005). We conclude that fetal stem cells transferred into maternal blood engraft in marrow, where they remain throughout life. This finding has implications for normal pregnancy, for obstetric complications that increase fetomaternal trafficking, and for graft survival after transplantation.

NICE neonatal early onset sepsis guidance: greater consistency, but more investigations, and greater length of stay.

BACKGROUND: In August 2012, new national guidance (National Institute of Health and Care Excellence (NICE) CG149) for management of early onset sepsis (EOS) was introduced in the UK. The guidance outlined a consistent approach for septic screens in newborn infants based on risk factors, and suggested biochemical and clinical parameters to guide management. In particular, it advised a second C-reactive protein level (CRP) 18-24 h into treatment to help determine length of antibiotic course, need for lumbar puncture (LP), and suggested review of blood culture at 36 h. OBJECTIVE: We evaluated impact of this guidance in our neonatal unit. METHODS: We compared two time periods, before and following the guidance. We evaluated length of stay, second CRP 18-24 h into treatment, percentage of babies having LP and duration of antibiotics. RESULTS: Before NICE guidance, 38.1% of screened babies stayed <72 h. This reduced to 18.4% following guidance. Before guidance, 20.9% babies stayed >5 days, which increased to 27.7% following NICE recommendations. Repeat CRP measurements increased from 45% to 97%. In 58% of these babies, repeat CRPs influenced management and hospital stay. An increase in LPs performed from 14% to 23% was noted. There were no positive blood cultures or LP results. CONCLUSIONS: We envisaged shorter hospital stays with new NICE standards, particularly, with the aim of 36 h blood culture reporting. However, repeat CRP led to further investigations, increased LPs and longer durations of treatment and stay. This, in turn, impacted on workload and cost, and influenced parental experience in the first few days of life.

T2 relaxation values in the developing preterm brain.

BACKGROUND AND PURPOSE: MR imaging is increasingly used to assess maturation and disease in the preterm brain. Knowledge of the changes in T2 values with increasing postmenstrual age (PMA) will aid image interpretation and help in the objective assessment of maturation and disease of the brain in infants. The aim of this study was to obtain T2 values in the preterm brain from 25 weeks' gestational age (GA) until term-equivalent age in infants who had normal neurodevelopmental findings at a minimum corrected age of 1 year. METHODS: The study group consisted of 18 preterm infants, born at 33 weeks' GA or sooner. The median GA of the infants at birth was 27 weeks (range, 23-33 weeks), and the median PMA at imaging was 31 weeks (range, 25-41 weeks). T2 measurements were obtained using a 1.0-T MR system and a four-echo pulse sequence (TR/TE, 2500/ 30, 60, 110, and 600). T2 values were measured in the thalami, lentiform nuclei, frontal white matter, occipital white matter, and central white matter at the level of the centrum semiovale. RESULTS: A significant negative linear correlation between T2 values and PMA was demonstrated in the lentiform nuclei (P =.003), frontal white matter (P <.0001), occipital white matter (P <.0001), and central white matter at the level of the centrum semiovale (P <.0001). T2 values were not significantly reduced with increasing PMA in the thalami (P =.06). CONCLUSION: T2 values decrease with increasing PMA in the preterm brain.

Perinatal applications of neural stem cells.

The brain, unlike many tissues, has a limited capacity for self-repair and so there has been great interest in the possibility of transplanting neural cells to replace those lost through injury or disease. Encouraging research in humans is already underway examining the possibility of neural cell replacement in adult neurodegenerative conditions such as Parkinson's disease and Huntington disease. In addition, experiments exploring neural stem cell replacement in rodent models of acute stroke, demyelination and spinal cord injury have demonstrated functional improvements in treated animals. When considering perinatal neural stem cell therapy, it should not be overlooked that the immature, developing brain might provide a more favourable environment for stem cell integration. However, considerable advances need to be made both in understanding the basic biology of neural stem cells, including the instructive signals that determine their proliferation and differentiation, and in characterising their responses when transplanted in a damaged or diseased area of the brain.