Mats Blennow

One-year survival of extremely preterm infants after active perinatal care in sweden

CONTEXT Up-to-date information on infant survival after extremely preterm birth is needed for assessing perinatal care services, clinical guidelines, and parental counseling. OBJECTIVE To determine the 1-year survival in all infants born before 27 gestational weeks in Sweden during 2004-2007. DESIGN, SETTING, AND PATIENTS Population-based prospective observational study of extremely preterm infants (707 live-born and 304 stillbirths) born to 887 mothers in 904 deliveries (102 multiple births) in all obstetric and neonatal units in Sweden from April 1, 2004, to March 31, 2007. MAIN OUTCOME MEASURES Infant survival to 365 days and survival without major neonatal morbidity (intraventricular hemorrhage grade >2, retinopathy of prematurity stage >2, periventricular leukomalacia, necrotizing enterocolitis, severe bronchopulmonary dysplasia). Associations between perinatal interventions and survival. RESULTS The incidence of extreme prematurity was 3.3 per 1000 infants. Overall perinatal mortality was 45% (from 93% at 22 weeks to 24% at 26 weeks), with 30% stillbirths, including 6.5% intrapartum deaths. Of live-born infants, 91% were admitted to neonatal intensive care and 70% survived to 1 year of age (95% confidence interval [CI], 67%-73%). The Kaplan-Meier survival estimates for 22, 23, 24, 25, and 26 weeks were 9.8% (95% CI, 4%-23%), 53% (95% CI, 44%-63%), 67% (95% CI, 59%-75%), 82% (95% CI, 76%-87%), and 85% (95% CI, 81%-90%), respectively. Lower risk of infant death was associated with tocolytic treatment (adjusted for gestational age odds ratio [OR], 0.43; 95% CI, 0.36-0.52), antenatal corticosteroids (OR, 0.44; 95% CI, 0.24-0.81), surfactant treatment within 2 hours after birth (OR, 0.47; 95% CI, 0.32-0.71), and birth at a level III hospital (OR, 0.49; 95% CI, 0.32-0.75). Among 1-year survivors, 45% had no major neonatal morbidity. CONCLUSION During 2004 to 2007, 1-year survival of infants born alive at 22 to 26 weeks of gestation in Sweden was 70% and ranged from 9.8% at 22 weeks to 85% at 26 weeks.

Resting-state networks in the infant brain

In the absence of any overt task performance, it has been shown that spontaneous, intrinsic brain activity is expressed as systemwide, resting-state networks in the adult brain. However, the route to adult patterns of resting-state activity through neuronal development in the human brain is currently unknown. Therefore, we used functional MRI to map patterns of resting-state activity in infants during sleep. We found five unique resting-states networks in the infant brain that encompassed the primary visual cortex, bilateral sensorimotor areas, bilateral auditory cortex, a network including the precuneus area, lateral parietal cortex, and the cerebellum as well as an anterior network that incorporated the medial and dorsolateral prefrontal cortex. These results suggest that resting-state networks driven by spontaneous signal fluctuations are present already in the infant brain. The potential link between the emergence of behavior and patterns of resting-state activity in the infant brain is discussed.

The Functional Architecture of the Infant Brain as Revealed by Resting-State fMRI

The functional network topology of the adult human brain has recently begun to be noninvasively mapped using resting-state functional connectivity magnetic resonance imaging and described using mathematical tools originating from graph theory. Previous studies have revealed the existence of disproportionally connected brain regions, so called cortical hubs, which act as information convergence zones and supposedly capture key aspects of how the brains architecture supports human behavior and how it is affected by disease. In this study, we present results showing that cortical hubs and their associated cortical networks are largely confined to primary sensory and motor brain regions in the infant brain. Our findings in infants stand in stark contrast to the situation found in adults where the majority of cortical hubs and hub-related networks are located in heteromodal association cortex. Our findings suggest that the functional network architecture in infants is linked to support tasks that are of a perception-action nature.

Enhanced Expression of Interleukin (IL)-1 and IL-6 Messenger RNA and Bioactive Protein after Hypoxia-Ischemia in Neonatal Rats

The effect of hypoxia-ischemia (HI) on IL-1, and IL-6 bioactivity in relation to expression of IL-1α, IL-1β, and IL-6 mRNA was studied, and the neuroprotective efficacy of IL-1 receptor antagonist (IL-1ra) was evaluated in neonatal rats. HI was induced in 7-d-old rats by unilateral carotid artery ligation and hypoxia for 70-100 min. Animals were killed at different time points up to 14 d after HI, and brains were analyzed for IL-1 and IL-6 bioactivity using bioassays and for mRNA for IL-1α, IL-1β, and IL-6 with reverse transcription followed by a polymerase chain reaction. In separate animals, IL-1ra was administered intracerebrally before or after HI, and the extent of brain injury was assessed 14 d after HI. A transient increase of IL-1 bioactivity occurred after HI, reaching a peak at 6 h of recovery. IL-1β mRNA followed a similar time course but attained maximum expression at 3 h. IL-6 bioactivity and mRNA were also stimulated by HI and followed a similar time course as IL-1. Pretreatment with IL-1ra reduced HI brain damage from 54.5 ± 9.3 to 41.4 ± 10.0% (p ≤ 0.01), and IL-1ra posttreatment increased the proportion of animals devoid of brain injury (40%) compared with vehicle-treated controls (13%) (p≤ 0.05). In conclusion, a transient activation of IL-1 and IL-6 occurred after HI, and IL-1ra reduced HI brain injury to a moderate degree.

Incidence of and risk factors for neonatal morbidity after active perinatal care : extremely preterm infants study in Sweden (EXPRESS)

Aims:  The aim of this study was to determine the incidence of neonatal morbidity in extremely preterm infants and to identify associated risk factors.

Spontaneous brain activity in the newborn brain during natural sleep--an fMRI study in infants born at full term.

Recent progress in functional neuroimaging research has provided the opportunity to probe at the brains intrinsic functional architecture. Synchronized spontaneous neuronal activity is present in the form of resting-state networks in the brain even in the absence of external stimuli. The objective of this study was to investigate the presence of resting-state networks in the unsedated infant brain born at full term. Using functional MRI, we investigated spontaneous low-frequency signal fluctuations in 19 healthy full-term infants. Resting-state functional MRI data acquired during natural sleep was analyzed using independent component analysis. We found five resting-state networks in the unsedated infant brain born at full term, encompassing sensory cortices, parietal and temporal areas, and the prefrontal cortex. In addition, we found evidence for a resting-state network that enclosed the bilateral basal ganglia.

Cytokine response in cerebrospinal fluid after birth asphyxia

Experimental studies suggest that cytokine-mediated inflammatory reactions are important in the cascade leading to hypoxicischemic brain injury. The purpose was to study the content of pro- and antiinflammatory cytokines in cerebrospinal fluid (CSF) of asphyxiated and control infants. Samples of CSF were obtained from 20 infants who fulfilled the criteria of birth asphyxia and from seven newborn control subjects. The concentrations of IL-1β, IL-8, IL-10, tumor necrosis factor (TNF)-α, and granulocyte/monocyte colony-stimulating factor (GM-CSF) were determined with ELISA and of IL-6 using a bioassay. The concentration of IL-6 (pg/mL) was higher in asphyxiated(250, 35-543; median, interquartile range) than in control (0, 0-18) infants(p = 0.001). There was also a significant relationship between IL-6 and the degree of HIE, and between IL-6 and outcome. In addition, the content of IL-8 (pg/mL) was higher (p = 0.009) in the asphyxia group (170, 70-1440), than in the the control group (10, 0-30) and there was an association between IL-8 and degree of HIE. The levels of IL-10, TNF-α, GM-CSF, and IL-1β did not differ between groups. In conclusion, the proinflammatory cytokines IL-6 and IL-8 were markedly elevated in CSF of asphyxiated infants, and the intrathecal levels of these cytokines corresponded to the degree of HIE.

Predictive value of fetal scalp blood lactate concentration and pH as markers of neurologic disability

OBJECTIVES We aimed to analyze the predictive value of the fetal scalp blood lactate concentration and pH, especially in regard to outcome variables that are strong predictors of impaired long-term outcome. An additional aim was to establish cutoff lactate levels in fetal scalp blood. STUDY DESIGN We conducted a retrospective study of all patients who had fetal scalp blood sampling performed because of an ominous fetal heart rate pattern at Huddinge University Hospital from October 1993 to October 1998. Fetal scalp blood sampling was performed in 1709 patients. The pH and the lactate concentration were determined in fetal scalp blood of 1221 and 814 of these patients, respectively. Outcome variables included pH <7.0 in umbilical artery blood; base deficit >16.0 mmol/L in umbilical artery blood; Apgar scores <7 at 1 minute, <7 at 5 minutes, and <4 at 5 minutes; and hypoxic-ischemic encephalopathy. RESULTS Sensitivity and specificity were generally higher in the lactate group than in the pH group, particularly in relation to an Apgar score <4 at 5 minutes and moderate to severe hypoxic-ischemic encephalopathy. In 326 patients the scalp blood lactate concentration and pH value had been obtained at the same time, thus allowing a comparison between these methods. The areas under the receiver operating characteristic curves were significantly higher for the lactate concentration than for the pH value with 2 outcome variables: Apgar score <4 at 5 minutes (P =.033) and moderate to severe hypoxic-ischemic encephalopathy (P =.015). CONCLUSIONS Our findings suggest that determination of the lactate concentration in fetal scalp blood is a more sensitive diagnostic tool than is determination of the pH value for predicting either an Apgar score <4 at 5 minutes or moderate to severe hypoxic-ischemic encephalopathy. In previous studies we also showed lactate measurements to be more often successful than pH analysis. Therefore we consider the measurement of lactate in fetal scalp blood to be an attractive alternative to pH analysis, and determination of the lactate concentration in fetal scalp blood seems to be a useful tool for monitoring the condition of the fetus. A suitable cutoff limit for fetal scalp blood lactate concentration as an indicator of fetal asphyxia could be 4.8 mmol/L.

Excitatory amino acids in the cerebrospinal fluid of asphyxiated infants: relationship to hypoxic‐ischemic encephalopathy

Asphyxiated (n = 27) and control infants (n = 25) were subjected to spinal taps. Amino acids were measured with liquid chromatography and the degree of hypoxic‐ischemic cncephalopathy was determined in each case. In asphyxiated infants, the concentrations of aspartate and glutamate were 286% and 387% (p0.01 and p 0.05) of the control values. respectively. The Cerebrospinal fluid aspartate levels were significantly (p 0.05) higher in the group with severe (3.4 μmol/l) compared with the group with mild hypoxic‐ischemic encephalopathy (1.0 μmol/l). Glutamate was also higher in the group with severe (12.3 μmol/l) than in the groups with mild (2.7 μmol/l) or moderate (3.2 μmol/l) hypoxic‐ischemic enccphalopathy (p 0.05). High concentrations of excitatory amino acids were present in the CSF of asphyxiated infants which may exert excitotoxic effects.

Transport of Methylmercury and Inorganic Mercury to the Fetus and Breast-Fed Infant

It is well established that methylmercury (MeHg) and mercury vapor pass the placenta, but little is known about infant exposure via breast milk. We measured MeHg and inorganic mercury (I-Hg) in blood of Swedish mothers (n = 20) and their infants, as well as total mercury (T-Hg) in breast milk up to 13 weeks postpartum. Infant blood MeHg was highly associated with maternal blood MeHg at delivery, although more than twice as high. Infant MeHg decreased markedly until 13 weeks of age. Infant blood I-Hg was associated with, and about as high as, maternal blood I-Hg at delivery. Infant I-Hg decreased until 13 weeks. In breast milk, T-Hg decreased significantly from day 4 to 6 weeks after delivery but remained unchanged thereafter. At 13 weeks, T-Hg in breast milk was associated with infant MeHg but not with maternal MeHg. Conversely, T-Hg in breast milk was associated with maternal I-Hg but not with infant I-Hg. From the findings of the present study in which the exposure to both MeHg and I-Hg was low, we conclude that the exposure to both forms of mercury is higher before birth than during the breast-feeding period, and that MeHg seems to contribute more than I-Hg to infant exposure postnatally via breast milk.