Stuart R Dalziel

Cardiovascular risk factors after antenatal exposure to betamethasone : 30-year follow-up of a randomised controlled trial

BACKGROUND Antenatal betamethasone treatment is widely used for the prevention of neonatal respiratory distress syndrome in preterm infants and substantially reduces neonatal mortality and morbidity. Fetal exposure to excess glucocorticoids has been proposed as one of the core mechanisms of the fetal origins of adult disease hypothesis. We assessed whether antenatal exposure to betamethasone for the prevention of neonatal respiratory distress syndrome affects cardiovascular risk factors at 30 years of age. METHODS We followed up at age 30 years 534 individuals whose mothers participated in a double-blind, placebo-controlled, randomised trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome. Mothers received two doses of betamethasone or placebo given by intramuscular injection 24 h apart. Follow-up assessments included anthropometry; measurement of blood pressure, blood lipids (after overnight fasting), and early morning cortisol levels; and a 75 g oral glucose tolerance test. FINDINGS There were no differences between those exposed to betamethasone and to placebo in body size, blood lipids, blood pressure, plasma cortisol, prevalence of diabetes, or history of cardiovascular disease. After a 75 g oral glucose tolerance test, participants exposed to betamethasone had higher plasma insulin concentrations at 30 min (60.5 vs 52.0 mIU/L; ratio of geometric means 1.16 [95% CI 1.03 to 1.31], p=0.02) and lower glucose concentrations at 120 min (4.8 vs 5.1 mmol/L; difference -0.26 mmol/L [-0.53 to 0.00], p=0.05) than did those exposed to placebo. INTERPRETATION Antenatal exposure to betamethasone might result in insulin resistance in adult offspring, but has no clinical effect on cardiovascular risk factors at 30 years of age. Thus, obstetricians should continue to use a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome.

Antenatal exposure to betamethasone: psychological functioning and health related quality of life 31 years after inclusion in randomised controlled trial

Abstract Objectives To determine if antenatal exposure to betamethasone for the prevention of neonatal respiratory distress syndrome alters psychological functioning and health related quality of life in adulthood. Design Follow-up of the first and largest double blind, placebo controlled, randomised trial of a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome. Setting Tertiary obstetric hospital in Auckland, New Zealand. Participants 192 adult offspring, mean age 31 years, of mothers who took part in a randomised controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (87 exposed to betamethasone and 105 exposed to placebo). Interventions Mothers received two doses of betamethasone or placebo 24 hours apart. Main outcome measures Cognitive functioning assessed with Wechsler abbreviated scale of intelligence; working memory and attention assessed with Benton visual retention test, paced auditory serial addition test, and Brown attention deficit disorder scale; psychiatric morbidity assessed with Beck depression inventory II, state-trait anxiety inventory, and schizotypy traits questionnaire; handedness assessed with Edinburgh handedness inventory; health related quality of life assessed with short form 36 health survey. Results No differences were found between groups exposed to betamethasone and placebo in cognitive functioning, working memory and attention, psychiatric morbidity, handedness, or health related quality of life. Conclusions Prenatal exposure to a single course of betamethasone does not alter cognitive functioning, working memory and attention, psychiatric morbidity, handedness, or health related quality of life in adulthood. Obstetricians should continue to use a single course of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome.

Psychological functioning and health-related quality of life in adulthood after preterm birth.

The aim of this study was to determine if preterm birth is associated with socioeconomic status (SES), psychological functioning, and health‐related quality of life (HRQoL) in adulthood. We used prospective follow‐up of 192 adult offspring of mothers who took part in a randomized controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (66 born at term [33 males, 33 females] 126 born preterm [66 males, 60 females]). Cognitive functioning was assessed using the Wechsler Abbreviated Scale of Intelligence. Working memory and attention was assessed using the Benton Visual Retention Test, the Paced Auditory Serial Addition Test, and the Brown Attention Deficit Disorder Scale. Psychiatric morbidity was assessed using the Beck Depression Inventory II, the State‐Trait Anxiety Inventory, and the Schizotypy Traits Questionnaire. Handedness was assessed using the Edinburgh Handedness Inventory. HRQoL was assessed using the Short Form‐36 Health Survey. Moderately preterm birth (median gestation 34wks, mean birthweight 1946g [SD 463g]) was not related to later marital status, educational attainment, SES, cognitive functioning, working memory, attention, or symptoms of anxiety or schizotypy at 31 years of age. Preterm birth was associated with fewer symptoms of depression and higher levels of satisfaction in three of the eight HRQoL domains measured (bodily pain, general health perception, and social functioning). Adults who were born moderately preterm have SES, psychological functioning, and HRQoL consistent with those who were born at term. This good long‐term outcome cannot be extrapolated to those with early childhood disability or very low birthweights.

Predictors of severe H1N1 infection in children presenting within Pediatric Emergency Research Networks (PERN): retrospective case-control study.

Objective To identify historical and clinical findings at emergency department presentation associated with severe H1N1 outcome in children presenting with influenza-like illness. Design Multicentre retrospective case-control study. Setting 79 emergency departments of hospitals associated with the Pediatric Emergency Research Networks in 12 countries. Participants 265 children (<16 years), presenting between 16 April and 31 December 2009, who fulfilled Centers for Disease Control and Prevention criteria for influenza-like illness and developed severe outcomes from laboratory confirmed H1N1 infection. For each case, two controls presenting with influenza-like illness but without severe outcomes were included: one random control and one age matched control. Main outcome measures Severe outcomes included death or admission to intensive care for assisted ventilation, inotropic support, or both. Multivariable conditional logistic regression was used to compare cases and controls, with effect sizes measured as adjusted odds ratios. Results 151 (57%) of the 265 cases were male, the median age was 6 (interquartile range 2.3-10.0) years, and 27 (10%) died. Six factors were associated with severe outcomes in children presenting with influenza-like illness: history of chronic lung disease (odds ratio 10.3, 95% confidence interval 1.5 to 69.8), history of cerebral palsy/developmental delay (10.2, 2.0 to 51.4), signs of chest retractions (9.6, 3.2 to 29.0), signs of dehydration (8.8, 1.6 to 49.3), requirement for oxygen (5.8, 2.0 to 16.2), and tachycardia relative to age). Conclusion These independent risk factors may alert clinicians to children at risk of severe outcomes when presenting with influenza-like illness during future pandemics.

Increased Adiposity in Adults Born Preterm and Their Children

Background Preterm birth is associated with abnormalities in growth, body composition, and metabolism during childhood, but adult data are scarce and none exist for their offspring. We therefore aimed to examine body composition and cardiovascular risk factors in adults born preterm and their children. Methods A cohort of 52 adults (aged 35.7 years, 54% female, 31 born preterm) and their term-born children (n=61, aged 8.0 years, 54% female, 60% from a preterm parent) were studied. Auxology and body composition (whole-body dual-energy X-ray absorptiometry) were measured, and fasting blood samples taken for metabolic and hormonal assessments. Results Adults born preterm had greater abdominal adiposity, displaying more truncal fat (p=0.006) and higher android to gynoid fat ratio (p=0.004). Although women born preterm and at term were of similar weight and BMI, men born preterm (n=8) were on average 20 kg heavier (p=0.010) and of greater BMI (34.2 vs 28.4 kg/m2; p=0.021) than men born at term (n=16). Adults born preterm also displayed a less favourable lipid profile, including lower HDL-C concentrations (p=0.007) and greater total cholesterol to HDL-C ratio (p=0.047). Children of parents born preterm tended to have more body fat than the children of parents born at term (21.3 vs 17.6%; p=0.055). Even after adjustment for mean parental BMI, children of parents born preterm had altered fat distribution, with more truncal fat (p=0.048) and greater android to gynoid fat ratio (p=0.009). Conclusions Adults born preterm, particularly men, have markedly increased fat mass and altered fat distribution. A similar increase in abdominal adiposity was observed in the term born offspring of parents born preterm, indicating that adverse outcomes associated with preterm birth may extend to the next generation.

Long-term effects of antenatal betamethasone on lung function: 30 year follow-up of a randomised controlled trial

Background: Antenatal betamethasone is routinely used for the prevention of neonatal respiratory distress syndrome in preterm infants. However, little is known of the long term effects of exposure to antenatal betamethasone on lung function in adulthood. Methods: Five hundred and thirty four 30 year olds whose mothers had participated in the first and largest randomised controlled trial of antenatal betamethasone were followed. Lung function was assessed by portable spirometric testing. The prevalence of asthma symptoms was assessed using the European Community Respiratory Health Survey questionnaire. Results: Fifty (20%) betamethasone exposed and 53 (19%) placebo exposed participants met the criteria for current asthma (relative risk 0.98 (95% CI 0.74 to 1.30), p = 0.89). 181 betamethasone exposed and 202 placebo exposed participants had acceptable spirometric data. There were no differences in lung function between betamethasone and placebo exposed groups (mean (SD) forced vital capacity in the betamethasone and placebo groups 105.9 (12.0) v 106.6 (12.6)% predicted, difference = −0.7 (95% CI −3.2 to 1.8), p = 0.59; mean (SD) forced expiratory volume in 1 second in the betamethasone and placebo groups 98.9 (13.4) v 98.5 (13.6)% predicted, difference = 0.3 (95% CI −2.4 to 3.1, p = 0.80)). Conclusions: Antenatal exposure to a single course of betamethasone does not alter lung function or the prevalence of wheeze and asthma at age 30.

Peak bone mass after exposure to antenatal betamethasone and prematurity: follow-up of a randomized controlled trial.

Small birth size is associated with reduced adult bone mass. We determined if antenatal betamethasone exposure, birth weight, or prematurity affects peak bone mass in 174 adults. Antenatal betamethasone exposure did not. Lower birth weight and prematurity predicted reduced adult height. Slower fetal growth rather than prematurity predicted lower bone mass, but this lower bone mass was appropriate for reduced adult height.

Nasogastric hydration versus intravenous hydration for infants with bronchiolitis: a randomised trial.

BACKGROUND Bronchiolitis is the most common lower respiratory tract infection in infants and the leading cause of hospital admission. Hydration is a mainstay of treatment, but insufficient evidence exists to guide clinical practice. We aimed to assess whether intravenous hydration or nasogastric hydration is better for treatment of infants. METHODS In this multicentre, open, randomised trial, we enrolled infants aged 2-12 months admitted to hospitals in Australia and New Zealand with a clinical diagnosis of bronchiolitis during three bronchiolitis seasons (April 1-Oct 31, in 2009, 2010, and 2011). We randomly allocated infants to nasogastric hydration or intravenous hydration by use of a computer-generated sequence and opaque sealed envelopes, with three randomly assigned block sizes and stratified by hospital site and age group (2-<6 months vs 6-12 months). The primary outcome was length of hospital stay, assessed in all randomly assigned infants. Secondary outcomes included rates of intensive-care unit admission, adverse events, and success of insertion. This trial is registered with the Australian and New Zealand clinical trials registry, ACTRN12605000033640. FINDINGS Mean length of stay for 381 infants assigned nasogastric hydration was 86·6 h (SD 58·9) compared with 82·2 h (58·8) for 378 infants assigned intravenous hydration (absolute difference 4·5 h [95% CI -3·9 to 12·9]; p=0·30). Rates of admission to intensive-care units, need for ventilatory support, and adverse events did not differ between groups. At randomisation, seven infants assigned nasogastric hydration were switched to intravenous hydration and 56 infants assigned intravenous hydration were switched to nasogastric hydration because the study-assigned method was unable to be inserted. For those infants who had data available for successful insertion, 275 (85%) of 323 infants in the nasogastric hydration group and 165 (56%) of 294 infants in the intravenous hydration group required only one attempt for successful insertion. INTERPRETATION Intravenous hydration and nasogastric hydration are appropriate means to hydrate infants with bronchiolitis. Nasogastric insertion might require fewer attempts and have a higher success rate of insertion than intravenous hydration. FUNDING Australian National Health and Medical Research Council, Samuel Nissen Charitable Foundation (Perpetual), Murdoch Childrens Research Institute, Victorian Government.

Blood Pressure at 6 Years of Age After Prenatal Exposure to Betamethasone: Follow-up Results of a Randomized, Controlled Trial

Objective. To determine whether prenatal exposure to betamethasone for the prevention of neonatal respiratory distress syndrome (RDS) alters blood pressure in childhood. Design. Prospective follow-up study of a randomized, double-blind, placebo-controlled trial. Setting. National Womens Hospital (Auckland, New Zealand). Participants. Two hundred twenty-three 6-year-old children of mothers who presented with unplanned premature labor and took part in a randomized, controlled trial of prenatal betamethasone therapy for the prevention of neonatal RDS. Intervention. Mothers received 2 doses of betamethasone (12 mg) or placebo, administered through intramuscular injection, 24 hours apart. Main Outcome Measures. Systolic and diastolic blood pressure at 6 years of age. Results. Children exposed prenatally to betamethasone (n = 121) did not differ in systolic or diastolic blood pressure from children exposed to placebo (n = 102) (mean difference: systolic: −1.6 mm Hg; 95% confidence interval: −4.1 to 0.8 mm Hg; diastolic: −0.3 mm Hg; 95% confidence interval: −2.5 to 1.8 mm Hg). Conclusion. Prenatal exposure to betamethasone for prevention of neonatal RDS does not alter blood pressure at 6 years of age.

Accuracy of PECARN, CATCH, and CHALICE head injury decision rules in children: a prospective cohort study

BACKGROUND Clinical decision rules can help to determine the need for CT imaging in children with head injuries. We aimed to validate three clinical decision rules (PECARN, CATCH, and CHALICE) in a large sample of children. METHODS In this prospective observational study, we included children and adolescents (aged <18 years) with head injuries of any severity who presented to the emergency departments of ten Australian and New Zealand hospitals. We assessed the diagnostic accuracy of PECARN (stratified into children aged <2 years and ≥2 years), CATCH, and CHALICE in predicting each rule-specific outcome measure (clinically important traumatic brain injury [TBI], need for neurological intervention, and clinically significant intracranial injury, respectively). For each calculation we used rule-specific predictor variables in populations that satisfied inclusion and exclusion criteria for each rule (validation cohort). In a secondary analysis, we compiled a comparison cohort of patients with mild head injuries (Glasgow Coma Scale score 13-15) and calculated accuracy using rule-specific predictor variables for the standardised outcome of clinically important TBI. This study is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12614000463673. FINDINGS Between April 11, 2011, and Nov 30, 2014, we analysed 20 137 children and adolescents attending with head injuries. CTs were obtained for 2106 (10%) patients, 4544 (23%) were admitted, 83 (<1%) underwent neurosurgery, and 15 (<1%) died. PECARN was applicable for 4011 (75%) of 5374 patients younger than 2 years and 11 152 (76%) of 14 763 patients aged 2 years and older. CATCH was applicable for 4957 (25%) patients and CHALICE for 20 029 (99%). The highest point validation sensitivities were shown for PECARN in children younger than 2 years (100·0%, 95% CI 90·7-100·0; 38 patients identified of 38 with outcome [38/38]) and PECARN in children 2 years and older (99·0%, 94·4-100·0; 97/98), followed by CATCH (high-risk predictors only; 95·2%; 76·2-99·9; 20/21; medium-risk and high-risk predictors 88·7%; 82·2-93·4; 125/141) and CHALICE (92·3%, 89·2-94·7; 370/401). In the comparison cohort of 18 913 patients with mild injuries, sensitivities for clinically important TBI were similar. Negative predictive values in both analyses were higher than 99% for all rules. INTERPRETATION The sensitivities of three clinical decision rules for head injuries in children were high when used as designed. The findings are an important starting point for clinicians considering the introduction of one of the rules. FUNDING National Health and Medical Research Council, Emergency Medicine Foundation, Perpetual Philanthropic Services, WA Health Targeted Research Funds, Townsville Hospital Private Practice Fund, Auckland Medical Research Foundation, A + Trust.