Hans Ulrich Bucher

Postnatal growth in VLBW infants: Significant association with neurodevelopmental outcome

OBJECTIVE To study the significance of growth status at birth and postnatal growth on neurodevelopmental outcome in very low birth weight (VLBW) infants. STUDY DESIGN Growth and neurodevelopment were examined in 219 VLBW (<1250 g) children, 94 small for gestational age (SGA) (<10th percentile) and 125 appropriate for gestational age (AGA) (>10th percentile). Outcome at age 2 was assessed with the Bayley Scales of Infant Development (Mental Developmental Index [MDI], Psychomotor Developmental Index [PDI]) and a standardized neurologic examination. RESULTS SGA status was not associated with poor neurodevelopmental outcome. However, after adjustment for covariables including cerebral palsy (CP), SGA children with weight <10th percentile at age 2 had lower mean PDI than SGA children with catch-up growth to weight >10th percentile (mean [SD], 89.9 [17.4] versus 101.8 [14.5]; P<.001). AGA children with catch-down growth (weight <10th percentile at age 2) were, independent of CP, more likely to have lower mean MDI (94.9 vs 101.7, P=.05) and PDI (81.9 vs 95.1; P<.001) than AGA children remaining >10th percentile at age 2. They also more frequently had severe CP (22.9% vs 1.2%; P=.008). CONCLUSIONS In VLBW children, the course of postnatal growth rather than the appropriateness of weight for gestational age at birth determines later neurodevelopmental outcome.

Population based trends in mortality, morbidity and treatment for very preterm- and very low birth weight infants over 12 years

BackgroundOver the last two decades, improvements in medical care have been associated with a significant increase and better outcome of very preterm (VP, < 32 completed gestational weeks) and very low birth weight (VLBW, < 1500 g) infants. Only a few publications analyse changes of their short-term outcome in a geographically defined area over more than 10 years. We therefore aimed to investigate the net change of VP- and VLBW infants leaving the hospital without major complications.MethodsOur population-based observational cohort study used the Minimal Neonatal Data Set, a database maintained by the Swiss Society of Neonatology including information of all VP- and VLBW infants. Perinatal characteristics, mortality and morbidity rates and the survival free of major complications were analysed and their temporal trends evaluated.ResultsIn 1996, 2000, 2004, and 2008, a total number of 3090 infants were enrolled in the Network Database. At the same time the rate of VP- and VLBW neonates increased significantly from 0.87% in 1996 to 1.10% in 2008 (p < 0.001). The overall mortality remained stable by 13%, but the survival free of major complications increased from 66.9% to 71.7% (p < 0.01). The percentage of infants getting a full course of antenatal corticosteroids increased from 67.7% in 1996 to 91.4% in 2008 (p < 0.001). Surfactant was given more frequently (24.8% in 1996 compared to 40.1% in 2008, p < 0.001) and the frequency of mechanical ventilation remained stable by about 43%. However, the use of CPAP therapy increased considerably from 43% to 73.2% (p < 0.001). Some of the typical neonatal pathologies like bronchopulmonary dysplasia, necrotising enterocolitis and intraventricular haemorrhage decreased significantly (p ≤ 0.02) whereas others like patent ductus arteriosus and respiratory distress syndrome increased (p < 0.001).ConclusionsOver the 12-year observation period, the number of VP- and VLBW infants increased significantly. An unchanged overall mortality rate and an increase of survivors free of major complication resulted in a considerable net gain in infants with potentially good outcome.

Association between early administration of high-dose erythropoietin in preterm infants and brain MRI abnormality at term-equivalent age.

IMPORTANCE Premature infants are at risk of developing encephalopathy of prematurity, which is associated with long-term neurodevelopmental delay. Erythropoietin was shown to be neuroprotective in experimental and retrospective clinical studies. OBJECTIVE To determine if there is an association between early high-dose recombinant human erythropoietin treatment in preterm infants and biomarkers of encephalopathy of prematurity on magnetic resonance imaging (MRI) at term-equivalent age. DESIGN, SETTING, AND PARTICIPANTS A total of 495 infants were included in a randomized, double-blind, placebo-controlled study conducted in Switzerland between 2005 and 2012. In a nonrandomized subset of 165 infants (n=77 erythropoietin; n=88 placebo), brain abnormalities were evaluated on MRI acquired at term-equivalent age. INTERVENTIONS Participants were randomly assigned to receive recombinant human erythropoietin (3000 IU/kg; n=256) or placebo (n=239) intravenously before 3 hours, at 12 to 18 hours, and at 36 to 42 hours after birth. MAIN OUTCOMES AND MEASURES The primary outcome of the trial, neurodevelopment at 24 months, has not yet been assessed. The secondary outcome, white matter disease of the preterm infant, was semiquantitatively assessed from MRI at term-equivalent age based on an established scoring method. The resulting white matter injury and gray matter injury scores were categorized as normal or abnormal according to thresholds established in the literature by correlation with neurodevelopmental outcome. RESULTS At term-equivalent age, compared with untreated controls, fewer infants treated with recombinant human erythropoietin had abnormal scores for white matter injury (22% [17/77] vs 36% [32/88]; adjusted risk ratio [RR], 0.58; 95% CI, 0.35-0.96), white matter signal intensity (3% [2/77] vs 11% [10/88]; adjusted RR, 0.20; 95% CI, 0.05-0.90), periventricular white matter loss (18% [14/77] vs 33% [29/88]; adjusted RR, 0.53; 95% CI, 0.30-0.92), and gray matter injury (7% [5/77] vs 19% [17/88]; adjusted RR, 0.34; 95% CI, 0.13-0.89). CONCLUSIONS AND RELEVANCE In an analysis of secondary outcomes of a randomized clinical trial of preterm infants, high-dose erythropoietin treatment within 42 hours after birth was associated with a reduced risk of brain injury on MRI. These findings require assessment in a randomized trial designed primarily to assess this outcome as well as investigation of the association with neurodevelopmental outcomes. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00413946.

Grief and Post-Traumatic Growth in Parents 2–6 Years after the Death of Their Extremely Premature Baby

Objective: To assess grief and post-traumatic growth in parents 2–6 years after the death of a premature baby (24–26 weeks’ gestation) and to evaluate Pictorial Representation of Illness and Self-Measure (PRISM) in the assessment of bereavement. Method: Fifty-four parents were assessed for their experiences during hospitalization and by questionnaires regarding grief (MTS), post-traumatic growth, affective symptoms and the visual representation of the baby and the self of the parents (PRISM). Results: Even 2–6 years after the loss of their extremely preterm infant the parents still suffer a lot from their bereavement, mothers more so than fathers (Mann-Whitney U test, U = 230.5, p < 0.05). Having another child reduced the level of grief (U = 119.0, p < 0.05). Mothers showed more post-traumatic growth than fathers (U = 140.5, p < 0.001). For all parents a shorter distance between the baby and the self (PRISM) correlated with greater grief (ρ = –0.62, p < 0.001); in multiple regression analysis MTS explained 38% of the SBS-variance. Conclusions: Clinicians should be aware that the death of an extremely premature infant triggers not only a painful long-term process of mourning but also of individual personal growth. Adaptation processes after the death differ depending on gender, with mothers experiencing more intense grief but also more growth than fathers. The modified PRISM test is recommended as a visual, non-verbal and easy-to-use instrument to assess bereavement.

Outcome at two years of age in a Swiss national cohort of extremely preterm infants born between 2000 and 2008

BackgroundWhile survival rates of extremely preterm infants have improved over the last decades, the incidence of neurodevelopmental disability (ND) in survivors remains high. Representative current data on the severity of disability and of risk factors associated with poor outcome in this growing population are necessary for clinical guidance and parent counselling.MethodsProspective longitudinal multicentre cohort study of preterm infants born in Switzerland between 240/7 and 276/7 weeks gestational age during 2000–2008. Mortality, adverse outcome (death or severe ND) at two years, and predictors for poor outcome were analysed using multilevel multivariate logistic regression. Neurodevelopment was assessed using Bayley Scales of Infant Development II. Cerebral palsy was graded after the Gross Motor Function Classification System.ResultsOf 1266 live born infants, 422 (33%) died. Follow-up information was available for 684 (81%) survivors: 440 (64%) showed favourable outcome, 166 (24%) moderate ND, and 78 (11%) severe ND. At birth, lower gestational age, intrauterine growth restriction and absence of antenatal corticosteroids were associated with mortality and adverse outcome (p < 0.001). At 360/7 weeks postmenstrual age, bronchopulmonary dysplasia, major brain injury and retinopathy of prematurity were the main predictors for adverse outcome (p < 0.05). Survival without moderate or severe ND increased from 27% to 39% during the observation period (p = 0.02).ConclusionsIn this recent Swiss national cohort study of extremely preterm infants, neonatal mortality was determined by gestational age, birth weight, and antenatal corticosteroids while neurodevelopmental outcome was determined by the major neonatal morbidities. We observed an increase of survival without moderate or severe disability.

Impaired motor performance and movement quality in very-low-birthweight children at 6 years of age

Motor performance and movement quality were quantitatively examined (Zurich Neuromotor Assessment: timed motor performances and associated movements) in 87 prospectively enrolled very-low-birthweight (VLBW; <1250g) children (38 males, 49 females; mean birthweight 1016.2g [SD 141.5]:, range 720-1240g; mean gestational age 28.7wks [SD 2], range 25.7-33.4wks) at 6 years of age. All motor tasks were below the reference population: pure motor (median z-score) -0.46; adaptive fine motor (pegboard) -0.99; adaptive gross motor -0.88; static balance -0.48; and associated movements -1.90. All tasks correlated with the degree of neurological abnormalities (p<or=0.004). VLBW children with no neurological abnormality also performed below the 10th centile and associated movements occurred more frequently than in the reference population (odds ratio 18, 95% confidence interval 6.7-47.9). Severity of periventricular leukomalacia and intraventricular haemorrhage assessed by ultrasound was associated with adaptive fine and gross motor tasks. We conclude that speed of motor performance and movement quality in particular were substantially impaired in VLBW children and are related to the degree of neurological abnormalities and neonatal cerebral injury.

Hemodynamic response to visual stimulation in newborn infants using functional near-infrared spectroscopy

Brain activity is associated with physiological changes, which alter the optical properties of tissue. These changes can be detected by near‐infrared spectroscopy (NIRS). Aim of the study was to determine changes in cerebral oxygenation in response to stimulation in the visual cortex in newborn infants during spontaneous sleep in the first days of life. We used an in‐house developed multichannel NIRS imaging instrument, the MCP‐II, to measure changes in concentration of oxyhemoglobin (O2Hb) and deoxyhemoglobin (HHb) in specific brain areas. In 10 out of 15 subjects, a significant increase in O2Hb and/or a significant decrease in HHb were found in one or more channels over the occipital cortex. During stimulation, O2Hb increased by a mean of 0.98 μmol/l, HHb decreased by a mean 0.17 μmol/l, and total‐Hb increased by a mean of 0.81 μmol/l. The hemodynamic response to visual stimulation in the occipital cortex in newborn infants is similar to adults. The increase in O2Hb and the simultaneous decrease in HHb during stimulation suggest an increase in cerebral blood flow (CBF) that overcompensates for the increased oxygen consumption (CMRO2) in the activated cortical area. Hum Brain Mapp, 2008.

Liver tissue oxygenation as measured by near-infrared spectroscopy in the critically ill child in correlation with central venous oxygen saturation

Objective: To evaluate the clinical usefulness of near-infrared spatially resolved spectroscopic quantitative assessment of liver tissue oxygenation for simple, non-invasive estimation of global tissue oxygenation in critically ill neonates and children. Design: Prospective observational clinical study. Setting: A tertiary multidisciplinary neonatal and paediatric intensive care unit (23 beds). Patients: One hundred neonates and children consecutively admitted to the paediatric intensive care unit. Measurements and results: Near-infrared spectroscopic single-point assessment of liver tissue oxygenation index (TOILiver) was compared with global tissue oxygenation as measured by central venous oxygen saturation (SvO2) and derived haemodynamic parameters. Data were compared using linear and multiple regression analysis. Overall correlation between TOILiver and SvO2 was good (r=0.72, p<0.0001). Multivariable regression revealed that SvO2 alone explained 51% of the observed variance of TOILiver. However, our data demonstrated large inter-individual differences between SvO2 and TOILiver values. Conclusion: Near-infrared spatially resolved spectroscopic quantitative measurement of liver tissue oxygenation correlates well with SvO2 in critically ill neonates and children. Large inter-individual SvO2 to TOILiver differences may prevent its use for non-invasive single-point estimation of global tissue oxygenation. Further clinical studies are required to validate the method with other regional and global haemodynamic parameters and to evaluate its clinical use for continuous non-invasive haemodynamic monitoring.

Near-Infrared Spectroscopy Measurements of Cerebral Oxygenation in Newborns during Immediate Postnatal Adaptation

OBJECTIVE In view of growing concerns regarding the optimal supplementation of oxygen at birth, we measured cerebral oxygenation during the first minutes of life. STUDY DESIGN Using near-infrared spectroscopy, changes in cerebral oxygenated hemoglobin (O(2)Hb), dexoxygenated hemoglobin (HHb), and tissue oxygenation index (TOI) were measured during the first 15 minutes of life in 20 healthy newborn infants delivered at term by elective cesarean section. RESULTS O(2)Hb and TOI increased rapidly within the first minutes of life (median slope for O(2)Hb, 3.4 micromol/L/min; range, 1.4 to 20.6 micromol/L/min; median slope for TOI, 4.2 %/min; range, -0.4 to 27.3%/min), and cerebral HHb decreased (median slope, -4.8 micromol/L/min; range, -0.2 to -20.6 micromol/L/min). O(2)Hb, TOI, and HHb all reached a plateau within 8 minutes. CONCLUSIONS A significant increase in cerebral O(2)Hb and TOI and a significant decrease in HHb occur during immediate adaptation in healthy term newborns, reaching a steady plateau at around 8 minutes after birth.

Finnegan neonatal abstinence scoring system: normal values for first 3 days and weeks 5-6 in non-addicted infants

OBJECTIVE The neonatal abstinence scoring system proposed by Finnegan is used widely in neonatal units to initiate and to guide therapy in babies of opiate-dependent mothers. The purpose of this study was to assess the variability of the scores in newborns and infants not exposed to opiates during the first 3 days of life and during 3 consecutive days in weeks 5 or 6. PATIENTS AND METHODS Healthy neonates born after 34 completed weeks of gestation, whose parents denied opiate consumption and gave informed consent, were included in this observational study. Infants with signs or symptoms of disease or with feeding problems were excluded. A modified scoring system was used every 8 hours during 72 hours by trained nurses; 102 neonates were observed for the first 3 days of life and 26 neonates in weeks 5-6. A meconium sample and a urine sample at weeks 5-6 were stored from all infants to be analysed for drugs when the baby scored high. Given a non-Gaussian distribution the scores were represented as percentiles. RESULTS During the first 3 days of life median scores remained stable at 2 but the variability increased, with the 95th percentile rising from 5.5 on day 1 to 7 on day 2. At weeks 5-6 median values were higher during daytime (50th percentile = 5, 95th percentile = 8) than night-time (50th percentile = 2, 95th percentile = 6, P = 0.02). CONCLUSION Scores increase from days 1-3 to weeks 5-6 and show day-night cycles with 5-6 weeks. Values above 8 can be considered pathological. This data may help to raise suspicion of narcotic withdrawal and to guide therapy.