Antenatal magnesium sulphate for the prevention of cerebral palsy in infants born preterm: a double-blind, randomised, placebo-controlled, multi-centre trial.

OBJECTIVE: To study the effect of antenatal magnesium sulphate (MgSO4 ) on cerebral palsy (CP) in a manner that also provides adequate power for a linked trial sequential analysis. DESIGN: Double-blind, randomised, placebo-controlled, multi-centre trial. SETTING: Fourteen Danish obstetric departments. POPULATION: In total, 560 pregnant women at risk for preterm delivery before 32 weeks of gestation were randomised from December 2011 to January 2018. Those women gave birth to 680 children. METHODS: Women were randomised to receive either a loading dose of 5 g MgSO4 followed by 1 g/hour or a placebo in identical volumes. The children were followed up at a corrected age of 18 months or older with a review of their medical charts and with the Ages and Stages Questionnaire. MAIN OUTCOME MEASURE: The primary outcome measure was moderate to severe CP. Secondary outcomes included mortality, neonatal morbidity, blindness and mild CP. RESULTS: The crude rates of moderate to severe CP in the MgSO4 group and the placebo group were 2.0% and 3.3%, respectively. The adjusted odds of moderate to severe CP were lower in the MgSO4 group than in the placebo group (odds ratio 0.61; 95% CI 0.23-1.65). CONCLUSIONS: Antenatal MgSO4 before 32 weeks of gestation decreases the likelihood of moderate to severe CP; these results are entirely consistent with other randomised evidence summarised in the linked trial sequential analysis. TWEETABLE ABSTRACT: Antenatal magnesium sulphate may decrease the risk of moderate to severe cerebral palsy in children born before 32 weeks of gestation.

Bacillus Calmette-Guérin vaccination at birth and in vitro cytokine responses to non-specific stimulation. A randomized clinical trial.

Several studies have shown increased in vitro cytokine responses to non-related pathogens after Bacillus Calmette-Guérin (BCG) vaccination. A total of 158 infants (80 BCG administered within 7 days of birth; 78 controls) were bled 4 days post-randomization, and at age 3 and 13 months. Geometric mean concentrations of IL-1ß, TNF-α, IL-6 (24 h stimulation) and IFN-γ, IL-10, IL-17, IL-22 (96 h stimulation) in response to in vitro stimulation with RPMI, LPS, PHA, Escherichia coli, Streptococcus pneumoniae, Candida albicans and BCG were compared among BCG vaccinated children and controls. BCG vaccination did not affect in vitro cytokine production, except IFN-γ and IL-22 response to BCG. Stratifying for 'age at randomization' we found a potentiating effect of BCG on cytokine production (TNF-α, IL-6, IL-10) in the 4 days post randomization stimulations, among children who were vaccinated at age 2-7 days versus age 0-1 days. BCG vaccination did not potentiate cytokine production to non-BCG antigens. At 4 days post randomization, BCG was associated with higher cytokine production in the later randomized children.

Newborn regional body composition is influenced by maternal obesity, gestational weight gain and the birthweight standard score.

AIM: This study investigated whether newborn body composition is influenced by prepregnancy obesity and gestational weight gain (GWG) and explored any associations between body composition and birthweight standard score (z-score), categorised by size for gestational age. METHODS: We recruited 231 obese and 80 normal weight mothers and their newborn infants and assessed the babies' body composition using dual-energy X-ray absorptiometry. RESULTS: The total and abdominal fat masses of infants born to mother who were obese before pregnancy were 135 g (p < 0.001) and 18 g (p < 0.001) higher than the offspring of normal weight mothers. The infants' fat mass increased by 11 g (p < 0.001) for every kilogram of GWG. There were no associations between prepregnancy obesity and fat-free mass. The fat percentage was significantly higher in infants who were large for gestational age (15.3%) than small for gestational age (5.2%) and appropriate for gestational age (9.8%) (p < 0.001). Lower birthweight z-score was associated with a higher proportion of abdominal fat mass (p = 0.009). CONCLUSION: Infants born to obese mothers had higher fat mass at birth, with abdominal fat accumulation. Low birthweight was associated with a lower crude abdominal fat mass, but a higher proportion of total fat mass placed abdominally.

Intramuscular adrenaline does not reduce the incidence of respiratory distress and hypoglycaemia in neonates delivered by elective caesarean section at term.

AIM: To test whether intramuscular injection of 30 microg adrenaline decreased the incidence of respiratory distress and hypoglycaemia in term infants delivered by elective caesarean section before active labour. METHOD: The study was randomised and double-blinded. A total of 270 neonates were assigned to intramuscular treatment with saline (0.30 ml) or 30 microg adrenaline (0.30 ml) immediately after birth. The primary endpoint was referral to the neonatal ward because of respiratory distress or a blood glucose level <1.8 mmol/l measured 2 h after birth. The first 50 infants were monitored with pulse oximetry to disclose potential side effects. RESULTS: Pulse-oximetry recordings revealed a modest systemic effect by intramuscular adrenaline as the heart rate and the haemoglobin oxygen saturation were significantly higher in infants who received adrenaline. In contrast, the incidence of respiratory distress and hypoglycaemia was 14% among infants treated with adrenaline compared with 7% in those who received saline injection (p = 0.048). CONCLUSION: Intramuscular injection of 30 microg adrenaline does not reduce the incidence of respiratory distress or hypoglycaemia after elective caesarean section.

Perinatal risk factors of adverse outcome in very preterm children: a role of initial treatment of respiratory insufficiency?

AIM: To investigate risk factors of adverse outcome in a cohort of very preterm children treated mainly with nasal continuous positive airway pressure (CPAP) during the neonatal course. METHODS: In Denmark, preterm children are treated with nasal CPAP as a first approach to respiratory support. A national prospective study of all infants with a birthweight below 1000 g or a gestational age below 28 wk born in 1994-1995 was initiated to evaluate this approach. Of the 269 surviving children 164 (61%) were not treated with mechanical ventilation in the neonatal period. A follow-up of the children at 5 y of age was conducted. Data from the neonatal period and the 5-y follow-up were analysed. RESULTS: In multivariate analyses including 250 children, a severely abnormal neonatal brain ultrasound scan was predictive of cerebral palsy (OR = 19.9, CI 95%: 6.1-64.8) and intellectual disability (OR = 6.2, CI 95%: 2.3-16.5). A high Clinical Risk Index for Babies (CRIB) score (OR = 2.4, CI 95%: 1.1-5.5) and chronic lung disease (OR = 2.8, CI 95%: 1.2-6.9) were predictive of intellectual disability. In univariate analyses mechanical ventilation was associated with cerebral palsy (OR=4.3, CI 95%: 1.7-10.8) and intellectual disability (OR = 2.2, CI 95%: 1.2-4.2), but the associations became insignificant in multivariate analyses including chronic lung disease and a severely abnormal ultrasound scan. CONCLUSION: The associations between neonatal risk factors and adverse outcome in our cohort were very similar to those found in other cohorts with another initial treatment of respiratory insufficiency. We found no significant adverse effects of mechanical ventilation beyond what could be explained by associations with chronic lung disease and IVH 3-4/PVL.

The Danish national study in infants with extremely low gestational age and birthweight (the ETFOL study): respiratory morbidity and outcome.

AIM: To describe and analyse neonatal care, short and long-term morbidity with special reference to ventilatory support and chronic lung disease (CLD) in a population-based study. METHODS: During 1994 and 1995 a prospective, nation-wide, multicentre study was conducted, comprising 477 liveborn infants with gestational age (GA) < 28 wk and/or birthweight < 1000 g. Of these, 407 infants received active treatment. The ventilatory treatment was based on the principle of permissive hypercapnia and early nasal continuous positive airway pressure (NCPAP) supplemented with surfactant and ventilator therapy in case of CPAP failure. RESULTS: Among actively treated infants 85% received CPAP and 23% mechanical ventilation from the first day of life. A total of 269 infants (56%) survived to discharge. Of these, 195 had a GA < 28 wk. One-hundred and five survivors with GA < 28 wk survived with NCPAP as sole respiratory support. In surviving infants, periventricular leucomalacia/intraventricular haemorrhage grade 3-4 was found in 10%, retinopathy of prematurity grade > 2 in 4%, and oxygen requirement at 36 and 40 wk of postmenstrual age (CLD) in 16 and 5%, respectively. Three infants either died of CLD (n = 1) or required oxygen therapy beyond 43 wk of postmenstrual age. Logistic regression analysis showed significant associations between oxygen requirement at 40 wk and GA, septicaemia, mechanical ventilation, symptomatic patent ductus arteriosus and Clinical Risk Index for Babies score. Only the two last-mentioned factors proved significant in infants with GA < 28 wk. No infant died after discharge and 253 (94%) were followed up at 2 y of corrected age; one or more moderate to severe impairments were found in 66 (26%) of the examined children. CONCLUSION: Ventilatory treatment in extremely premature and extremely low-birthweight infants based on early NCPAP and permissive hypercapnia may result in comparable survival rates and sensorineural outcome; however, the incidence of CLD seems lower than that reported on conventional treatment.

The haemodynamic effects of dopamine and volume expansion in sick preterm infants.

AIM: To determine the haemodynamic effects of dopamine and volume expansion in preterm neonates. Effect parameters were mean arterial blood pressure (MABP), left ventricular output (LVO) and global cerebral blood flow (CBF). METHODS: In a randomised, clinical control trial 36 preterm neonates were randomised to receive either dopamine 5 microg/kg per min, volume expansion with albumin 20% 15 ml/kg or no treatment. Parameters were measured before and 2 h after initiation of treatment. RESULTS: Dopamine was effective in increasing MABP; both treatments increased LVO, whereas no significant difference between the treatment groups and the control group could be demonstrated with regard to CBF. CONCLUSION: No effect on global cerebral blood flow could be demonstrated in this study, despite significant effects on systemic circulatory parameters. However, the variance on the measurement of cerebral blood flow indicates that a small but clinically significant effect may have been overlooked.

Brain lesions in preterms: origin, consequences and compensation.

Twenty-nine high-risk preterm born children, from a cohort with cerebral blood flow (CBF) measurements in the first 2 d of life, were examined prospectively at the age of 5.5-7 y neurologically, neuropsychologically and by magnetic resonance imaging (MRI). They were compared to 57 control children in terms of neurology and neuropsychology. Abnormal MRI was found in 19 children. Low oxygen delivery to the brain was found in 63% of them, in contrast to 12.5% in those with normal MRI, indicating neonatal hypoxia-ischemia as an important factor. The MRI abnormalities were mainly periventricular lesions (n = 19), especially periventricular leucomalacia (PVL, n = 17). Three of the very preterm children had severe cerebellar atrophy in addition to relatively mild periventricular abnormalities. MRI showed specific morphological correlates for the major disabilities, e.g. spastic CP (involvement of motor tracts), mental retardation (bilateral extensive white matter reduction or cerebellar atrophy) and severe visual impairment (severe optic radiation involvement). A morphological correlate for minor disabilities, i.e. functional variations in motor performance or intelligence, was not found, with the exception that symptoms of attention deficit hyperactivity disorder were related to mild MRI abnormalities. This could mean that with respect to cognitive functions, mild or unilateral periventricular MRI lesions could be compensated. However, as among preterms without mental retardation (n = 19), IQ was generally and significantly lower than in the control group; other, more chronic pathogenetic factors, not detectable by MRI alone, may play a role.

[The first Danish experiences with neonatal extracorporeal membrane oxygenation]. / De første danske erfaringer med neonatal ekstrakorporal membranoxygenering.

In 1995, neonatal extra-corporeal membrane oxygenation (ECMO) was established at the Department of Neonatology, Rigshospitalet, Copenhagen. The indication for ECMO is circulatory or respiratory failure with arterial oxygen tension below 8 kPa despite maximal conventional treatment. During the first two and a half years 17 newborn infants and one child of 21 months have been treated with ECMO at the Rigshospital. Fifteen survived, of 12 followed at least nine months, 11 have normal development and one has cerebral palsy. There were problems including surgical placement of the cannula, technical difficulties or bleeding in 12 patients. During the same two years at least eight newborns in Denmark fulfilled the ECMO indication, but were not treated, half were not transferred to the Rigshospital. Seven of these eight infants died. The need for ECMO treatment in newborn infants is documented but small. We have succeeded in establishing this complicated treatment due to teamwork between different specialities with a good result.

Regional cerebral blood flow during seizures in neonates.

With the use of 99mTc-D, L,-hexamethylpropylenamine oxime and single photon emission computed tomography, regional cerebral blood flow was measured ictally in 12 mature infants with recurrent seizures and compared with a reference group of nine interictal studies. The study indicates that both clinical and electrical seizures in neonates are associated with a focal cerebral hyperperfusion of the same amount as seen in adults.

[Intrauterine growth retardation and premature delivery. The effect of smoking and psychosocial factors]. / Intrauterin vaeksthaemning og praematur fødsel. Effekten af rygning og psykosociale faktorer.

The purpose of the study is to investigate the influence of psychosocial stress, maternal schooling, social support, psychological well-being, alcohol and smoking on intrauterine growth retardation and premature delivery. At a Copenhagen university hospital 2432 consecutive Danish-speaking women in 20th week of pregnancy completed a questionnaire including the General Health Questionnaire and Severity of Psychosocial Stressor Scale and questions about social network, education, smoking and drinking habits. In 212 cases (8.7%) the women delivered before day 259 of gestation. In a multiple logistic regression model, pre-term delivery proved to be associated with psychosocial stress and poor school education. In 152 cases (6.3%) infants had a birth weight below the defined 10th percentile. In a multiple logistic regression model, IUGR was associated with smoking. In preventive programmes, such as anti-smoking campaigns, it should be kept in mind that women who smoke are also the least educated and have the poorest support from a social network.

[Oxygen during delivery and cerebral vasoconstriction in preterm infants]. / Ilttilskud ved fødslen og konstriktion af hjernens kar hos for tidligt fødte børn.

To determine if the use of oxygen in the delivery room influences subsequent global cerebral blood flow (CBF), 70 infants of gestational age of less than 33 completed weeks were randomly assigned to receive room air (group I) or 80% oxygen (group II) during the initial stabilisation at birth. In group I supplemental oxygen was administered on clinical indications, when required. After being admitted to the neonatal intensive care unit all infants were treated according to our normal practice. At a postnatal age of two hours CBF was measured by xenon clearance. Seventy four per cent of the infants in group I were successfully established without the need for supplemental oxygen. CBF was significantly higher in group I than in group II (CBF median (interquartile range): 15.9 (13.6-21.9) vs 12.2 (10.7-13.8) ml/100 g/minute). Differences in oxygen exposure seemed to be the only explanation for the differences in CBF. No differences in short term outcome were found between the groups.

Limited role for nitric oxide in mediating cerebrovascular control of newborn piglets.

AIMS: To investigate the effects of the nitric oxide (NO) synthase inhibitor L-nitro-arginine methyl ester (L-NAME) on cerebral blood flow, and its response to alterations in arterial carbon dioxide tension (CBF-CO2 reactivity). METHODS: Cerebral blood flow was measured six times at varying arterial carbon dioxide tension (PaCO2) using the intravenous 133Xenon clearance technique in eight mechanically ventilated piglets of less than 24 hours postnatal age. After the third measurement L-NAME was administered as a bolus (20 mg/kg) and subsequently infused (10 mg/kg/hour). RESULTS: PaCO2 ranged between 2.7-8.9 kPa. Cerebral blood flow decreased by 14.0% (95% confidence interval 1.9-27.4) after L-NAME. CBF-CO2 reactivity was 18.4% per kPa (95% CI 14.1-22.2) before L-NAME and 15.2%/kPa (95% CI 11.1-19.3) afterwards; the difference between the CBF-CO2 reactivities was 3.2%/kPa (95% CI -0.4-6.8): these were not significantly different. CONCLUSIONS: Inhibition of nitric oxide synthesis reduces cerebral blood flow no more than a 0.5-1.0 kPa fall in PaCO2. Nitric oxide is not an important mediator of CBF-CO2 reactivity.

[The significance of psychosocial stress for pregnancy course and fetal development]. / Betydningen af psykosocialt stress for graviditetsforløb og fosterudvikling.

In a population-based study, 3021 women in a central Copenhagen district received a questionnaire on environmental and psychological factors during mid-gestation. Of these, 70 women were selected consecutively on the basis of moderate to severe stressful life-events (DSM-III-R categories 3 to 5), in combination with an inadequate social network. They were compared with 50 non-stressed women with an intact social network. Stress and smoking significantly affected birthweight and head circumference. When birthweight was corrected, stress remained a significant determinant of small head circumference, indicating a specific effect on brain development. Stress also led to a suboptimal Prechtl neonatal neurological score. These findings suggest the existence of a fetal stress syndrome with adverse effects on fetal development, including deficient brain development.

Intrauterine growth retardation and premature delivery: the influence of maternal smoking and psychosocial factors.

OBJECTIVES: This study investigated the influence of psychosocial stress, maternal schooling, social support, psychological well-being, alcohol, and smoking on intrauterine growth retardation and premature delivery. METHODS: At a Copenhagen university hospital, 2432 pregnant women completed a questionnaire on general health, psychosocial stressors, and sociodemographic characteristics. RESULTS: In 212 cases (8.7%) the women delivered prematurely. Preterm delivery as associated with psychosocial stress (adjusted odds ratio [OR]=1.14 for each 1-point increase on the psychosocial stressor 5-point scale and 1.92 for the whole scale) and poor school education (adjusted OR=2.62 for 7-9 years of schooling, 1.91 for 10 years, and 1.0 for 11-13 years). In 152 cases (6.3%), infants had a birthweight below the 10th percentile. Intrauterine growth retardation was associated with smoking, daily drinking, school education, and social network variables. In a multiple logistic regression model, intrauterine growth retardation was associated with smoking habits (adjusted OR=2.40 for 0-9 cigarettes daily, 2.68 for 10-15 daily, and 2.88 for more than 15 daily). CONCLUSIONS: Psychosocial stressors and limited duration of schooling appeared to influence preterm delivery. Smoking habits influenced intrauterine growth retardation.

Cerebral blood flow in the newborn infant.

Studies of CBF have provided some insight into cerebrovascular physiology and pharmacology. However, the precise relation between CBF and cerebral damage remains elusive, and there is no definition of a threshold CBF below which ischaemic brain damage always occurs. Measurement of CBF thus does not currently provide a secure guide in the clinical management of sick infants. Further work, particularly using techniques like magnetic resonance imaging and NIRS, which provide data in addition to CBF measurements, may yet disclose strategies which manipulate CBF to reduce cerebral ischaemia. While cerebral injury remains a substantial problem in neonatal intensive care, such research is urgently needed.

Oxygen at birth and prolonged cerebral vasoconstriction in preterm infants.

To determine if the use of oxygen in the delivery room influences subsequent global cerebral blood flow (CBF), 70 infants of gestational age of less than 33 completed weeks were randomly assigned to receive room air (group I) or 80% oxygen (group II) during the initial stabilisation at birth. In group I supplemental oxygen was administered on clinical indications, when required. After being admitted to the neonatal intensive care unit all infants were treated according to our normal practice. At a postnatal age of 2 hours CBF was measured by xenon clearance. Seventy four per cent of the infants in group I were successfully stabilised without the need for supplemental oxygen. CBF was significantly higher in group I than in group II (CBF median (interquartile range): 15.9 (13.6-21.9) v 12.2 (10.7-13.8) ml/100 g/minute). Differences in oxygen exposure seemed to be the only explanation for the differences in CBF. No differences in short term outcome were found between the groups.

[Neonatal hypoglycemia--new limits for treatment?]. / Neonatal hypoglykaemi--nye groenser for behandling?

Neonatal hypoglycaemia is the commonest clinical manifestation af disordered energy metabolism and is important because sustained hypoglycaemia may cause neuronal damage. Infants at high risk of developing low brain energy levels are those who have increased metabolic demands, low glycogen reserves, insufficient counter-regulatory responses or hyperinsuliaemia, and there is accumulating evidence that blood glucose should be maintained above 2.5 mM in this group. If possible, early and regular feeding at a volume of 120 ml/kg/dag should be established, but supplementation with intravenous glucose may be necessary.

Brain lactate in preterm and growth-retarded neonates.

Glucose is the predominant cerebral energy source under physiological conditions, although other substrates may support cerebral metabolism. The present study was undertaken to determine if lactate is present in the immature human brain, and if so, whether or not concentrations of lactate differ between small-for-gestational-age and appropriate-for-gestational-age infants. Thirty stable, healthy infants with normal brains were investigated. As the only nutrient, all received milk enterally prior to the investigation, which was carried out without sedation. Mean gestational age was 35 completed weeks (range 28-41 weeks) and mean birth weight was 2170 g (range 855-4100 g). Proton nuclear magnetic resonance spectra from the striatal region were obtained while the infants were sleeping quietly. Lactate was present in all 10 preterm small-for-gestational-age and 10 of 13 preterm appropriate-for-gestational-age infants, and the concentration was inversely related to postmenstrual age (p < 0.002). In addition, lactate increased with the degree of growth retardation (p < 0.01). At present the significance of lactate is unclear. Lactate may be produced locally or in peripheral tissues, and may support brain metabolism.