Improving incidence trends of severe intraventricular haemorrhages in preterm infants <32 weeks gestation: a cohort study.

OBJECTIVE: To describe the trend and risk factors for severe intraventricular haemorrhage (IVH) among infants <32 weeks gestation. DESIGN: Population-based cohort study. SETTING: Australia and New Zealand. PATIENTS: All preterm infants <32 weeks gestation in the Australian and New Zealand Neonatal Network (ANZNN) from 1995 to 2012. INTERVENTIONS: Comparison of IVH incidence between 6-year epochs. MAIN OUTCOME MEASURES: Overall IVH and severe IVH incidence. RESULTS: A total of 60 068 infants were included, and overall survival to discharge increased from 89% to 93% over the three epochs. As the percentage of infants with IVH decreased from 23.6% to 21.3% and 21.4% (p<0.001) from epoch 1 to 3, respectively, fewer survivors had severe IVH (4.0%, 3.3% and 2.8%, respectively, p<0.001). Over time, there were fewer antenatal complications, higher antenatal steroid usage and more caesarean-section births. Fewer infants were intubated at birth, had low 5 min Apgar score, had sepsis or pneumothorax needing drainage. Adjusted for perinatal confounders, there was significant reduction in odds of severe IVH from epoch 1 to 3 (adjusted OR (AOR) 0.8, 95% CI 0.7 to 0.9). Factors associated with development of severe IVH include no antenatal steroids (AOR 1.7, 95% CI 1.5 to 1.9), male (AOR 1.3, 95% CI 1.2 to 1.4), 5 min Apgar score <7 (AOR 2.0, 95% CI 1.9 to 2.2), intubated at birth (AOR 2.0, 95% CI 1.8 to 2.2), extremely low gestational age (AOR 4.0, 95% CI 3.7 to 4.4), outborn (AOR 1.6, 95% CI 1.5 to 1.8) and vaginal delivery (AOR 1.4, 95% CI 1.3 to 1.6). CONCLUSIONS: Along with increased survival among infants born <32 weeks gestation, the incidence of severe IVH has decreased over the 18 years, especially in the most recent period. This coincided with reduction in rates of risk factors for severe IVH development.

Effect of Prophylactic Indomethacin in Extremely Low Birth Weight Infants Based on the Predicted Risk of Severe Intraventricular Hemorrhage.

BACKGROUND: Prophylactic indomethacin reduces the risk of severe intraventricular hemorrhage (IVH) but does not reduce death or neurodevelopmental impairment (NDI) among extremely low birth weight (ELBW) infants. Some investigators have suggested that prophylactic indomethacin may have a greater treatment effect on severe IVH among infants at high risk for severe IVH. OBJECTIVE: To determine whether the relative treatment effects of prophylactic indomethacin on severe IVH and the composite outcome of death or NDI vary based on the risk of severe IVH. METHODS: Post hoc analysis of the Trial of Indomethacin Prophylaxis in Preterms (TIPP). We generated a model to predict the risk for severe IVH based on gestational age, birth weight, antenatal steroids, delivery mode, outborn status, sex, and 5-min Apgar score, and we divided the TIPP participants into risk quartiles. We used logistic regression to determine the adjusted odds ratios (aOR) of severe IVH and death or NDI based on indomethacin treatment for each quartile. RESULTS: The relative treatment effects of prophylactic indomethacin on severe IVH did not vary based on the predicted risk of severe IVH: quartile 1: aOR 0.68 (95% confidence interval [CI] 0.19-2.37); quartile 2: aOR 0.61 (95% CI 0.27-1.42); quartile 3: aOR 0.63 (95% CI 0.31-1.31); quartile 4: aOR 0.58 (95% CI 0.32-1.05). The relative treatment effect of prophylactic indomethacin on death or NDI did not vary significantly between quartiles. CONCLUSIONS: These findings do not support selective prophylactic indomethacin treatment to improve long-term outcomes of ELBW infants at high risk for severe IVH.

Prediction of outcomes of extremely low gestational age newborns in Australia and New Zealand.

OBJECTIVE: To determine the accuracy of the National Institute of Child Health and Human Development (NICHD) calculator in predicting death and neurodevelopmental impairment in Australian and New Zealand infants. DESIGN: Population-based cohort study. SETTING: Australia and New Zealand. PATIENTS: Preterm infants 22-25 completed weeks gestation. INTERVENTIONS: Comparison of NICHD calculator predicted rates of death and death or neurodevelopmental impairment, with actual rates recorded in the Australian and New Zealand Neonatal Network cohort. MAIN OUTCOME MEASURES: Infant death and death or neurodevelopmental impairment rates. RESULTS: A total of 714 infants were included in the study. Of these infants, 100 (14.0%) were <24 weeks, 389 (54.5%) male, 529 (74.1%) were singletons, 42 (5.9%) had intrauterine growth restriction, 563 (78.9%) received antenatal steroids and 625 (87.5 %) were born in a tertiary hospital. There were 288 deaths (40.3%), 75 infants (10.5%) with neurodevelopment impairment and 363 (50.8%) with death or neurodevelopmental impairment. The area under the curve (AUC) for prediction of death and the composite death or neurodevelopmental impairment by the NICHD calculator in our population was 0.65(95% CI 0.61 to 0.69) and 0.65 (95% CI 0.61 to 0.69), respectively. When stratified and compared with gestational age outcomes, the AUC did not change substantially for the outcomes investigated. The calculator was less accurate with outcome predictions at the extreme categories of predicted outcomes-underestimation of outcomes for those predicted to have the lowest risk (<20%) and overestimation for those in the highest risk category (>80%). CONCLUSION: In our recent cohort of extremely preterm infants, the NICHD model does not accurately predict outcomes and is marginally better than gestational age based outcomes.

Mid-Childhood Outcomes of Repeat Antenatal Corticosteroids: A Randomized Controlled Trial.

OBJECTIVE: To assess if exposure to repeat dose(s) of antenatal corticosteroids has beneficial effects on neurodevelopment and general health in mid-childhood, at 6 to 8 years' corrected age. METHODS: Women at risk for very preterm birth, who had received a course of corticosteroids ≥7 days previously, were randomized to intramuscular betamethasone (11.4 mg Celestone Chronodose) or saline placebo, repeated weekly if risk of very preterm birth remained. Mid-childhood assessments included neurocognitive function, behavior, growth, lung function, blood pressure, health-related quality of life, and health service utilization. The primary outcome was survival free of neurosensory disability. RESULTS: Of the 1059 eligible long-term survivors, 963 (91%) were included in the primary outcome; 479 (91%) in the repeat corticosteroid group and 484 (91%) in the placebo group. The rate of survival free of neurosensory disability was similar in both groups (78.3% repeat versus 77.3% placebo; risk ratio 1.00, 95% confidence interval, 0.94-1.08). Neurodevelopment, including cognitive function, and behavior, body size, blood pressure, spirometry, and health-related quality of life were similar in both groups, as was the use of health services. CONCLUSIONS: Treatment with repeat dose(s) of antenatal corticosteroids was associated with neither benefit nor harm in mid-childhood. Our finding of long-term safety supports the use of repeat dose(s) of antenatal corticosteroids, in view of the related neonatal benefits. For women at risk for preterm birth before 32 weeks' gestation, ≥7 days after an initial course of antenatal corticosteroids, clinicians could consider using a single injection of betamethasone, repeated weekly if risk remains.

School-age outcomes of very preterm infants after antenatal treatment with magnesium sulfate vs placebo.

IMPORTANCE: Antenatal magnesium sulfate given to pregnant women at imminent risk of very preterm delivery reduces the risk of cerebral palsy in early childhood, although its effects into school age have not been reported from randomized trials. OBJECTIVE: To determine the association between exposure to antenatal magnesium sulfate and neurological, cognitive, academic, and behavioral outcomes at school age. DESIGN, SETTING, AND PARTICIPANTS: The ACTOMgSO4 was a randomized clinical trial conducted in 16 centers in Australia and New Zealand, comparing magnesium sulfate with placebo given to pregnant women (n = 535 magnesium; n = 527 placebo) for whom imminent birth was planned or expected before 30 weeks' gestation. Children who survived from the 14 centers who participated in the school-age follow-up (n = 443 magnesium; n = 424 placebo) were invited for an assessment at 6 to 11 years of age between 2005 and 2011. MAIN OUTCOMES AND MEASURES: Mortality, cerebral palsy, motor function, IQ, basic academic skills, attention and executive function, behavior, growth, and functional outcomes. Main analyses were imputed for missing data. RESULTS: Of the 1255 fetuses known to be alive at randomization, the mortality rate to school age was 14% (88/629) in the magnesium sulfate group and 18% (110/626) in the placebo group (risk ratio [RR], 0.80; 95% CI, 0.62-1.03, P = .08). Of 867 survivors available for follow-up, outcomes at school age (corrected age 6-11 years) were determined for 669 (77%). Comparing the magnesium sulfate and placebo groups revealed no statistically significant difference in proportions with cerebral palsy (23/295 [8%] and 21/314 [7%], respectively; odds ratio [OR], 1.26; 95% CI, 0.84-1.91; P = .27) or abnormal motor function (80/297 [27%] and 80/300 [27%], respectively; OR, 1.16; 95% CI, 0.88-1.52; P = .28). There was also little difference between groups on any of the cognitive, behavioral, growth, or functional outcomes. CONCLUSIONS AND RELEVANCE: Magnesium sulfate given to pregnant women at imminent risk of birth before 30 weeks' gestation was not associated with neurological, cognitive, behavioral, growth, or functional outcomes in their children at school age, although a mortality advantage cannot be excluded. The lack of long-term benefit requires confirmation in additional studies. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12606000252516.

The International Network for Evaluating Outcomes of very low birth weight, very preterm neonates (iNeo): a protocol for collaborative comparisons of international health services for quality improvement in neonatal care.

BACKGROUND: The International Network for Evaluating Outcomes in Neonates (iNeo) is a collaboration of population-based national neonatal networks including Australia and New Zealand, Canada, Israel, Japan, Spain, Sweden, Switzerland, and the UK. The aim of iNeo is to provide a platform for comparative evaluation of outcomes of very preterm and very low birth weight neonates at the national, site, and individual level to generate evidence for improvement of outcomes in these infants. METHODS/DESIGN: Individual-level data from each iNeo network will be used for comparative analysis of neonatal outcomes between networks. Variations in outcomes will be identified and disseminated to generate hypotheses regarding factors impacting outcome variation. Detailed information on physical and environmental factors, human and resource factors, and processes of care will be collected from network sites, and tested for association with neonatal outcomes. Subsequently, changes in identified practices that may influence the variations in outcomes will be implemented and evaluated using quality improvement methods. DISCUSSION: The evidence obtained using the iNeo platform will enable clinical teams from member networks to identify, implement, and evaluate practice and service provision changes aimed at improving the care and outcomes of very low birth weight and very preterm infants within their respective countries. The knowledge generated will be available worldwide with a likely global impact.

Body positioning and medical therapy for infantile gastroesophageal reflux symptoms.

OBJECTIVE: Proton-pump inhibitors (PPIs) reduce acid gastroesophageal reflux (GER) and esophageal acid exposure in infants; however, they do not reduce total GER or symptoms attributed to GER. Reflux is reduced in the left lateral position (LLP). We hypothesize that the effect of LLP in combination with acid suppression is most effective in reducing GER symptoms in infants. METHODS: In this prospective sham-controlled trial, infants (0-6 months) with symptoms suggestive of gastroesophageal reflux disease were studied using 8-hour pH-impedance, cardiorespiratory and video monitoring, direct nurse observation, and a validated questionnaire. Infants demonstrating a positive GER symptom association were randomized to 1 of 4 groups; PPI + LLP, PPI + head of cot elevation (HE), antacid (AA) + LLP, or AA + HE. HE and AA were considered "sham" therapies. After 2 weeks the 8-hour studies were repeated on-therapy. RESULTS: Fifty-one patients were included (aged 13.6 [2-26] weeks). PPI + LLP was most effective in reducing GER episodes (69 [13] to 46 [10], P < 0.001) and esophageal acid exposure (median [interquartile range] 8.9% [3.1%-18.1%] to 1.1% [0%-4.4%], P = 0.02). No treatment group showed improvement in crying/irritability, although vomiting was reduced in AA + LLP (from 7 [2] to 2 [0] episodes P = 0.042). LLP compared with HE produced greater reduction in total GER (-21 [4] vs -10 [4], P = 0.056), regardless of acid-suppressive therapy. Acid exposure was reduced on PPI compared with AA (-6.8 [2.1] vs -0.9 [1.4]%, pH < 4, P = 0.043) regardless of positional intervention. A post-hoc analysis using automated analysis software revealed a significant reduction in crying symptoms in the PPI + LLP group (99 [65-103] to 62 [32-96] episodes, P = 0.018). CONCLUSIONS: "Symptomatic gastroesophageal reflux disease" implies disease causation for distressing infant symptoms. In infants with symptoms attributed to GER, LLP produced a significant reduction in total GER, but did not result in a significant improvement in symptoms other than vomiting; however, automated analysis appeared to identify infants with GER-associated crying symptoms who responded to positioning therapy. This is an important new insight for future research.

Thyrotropin-releasing hormone added to corticosteroids for women at risk of preterm birth for preventing neonatal respiratory disease.

BACKGROUND: Thyrotropin-releasing hormones (TRH) added to prenatal corticosteroids has been suggested as a way to further reduce breathing problems and neonatal lung disease in infants born preterm. OBJECTIVES: To assess the effects of giving prenatal TRH in addition to corticosteroids to women at risk of preterm birth for the prevention of neonatal respiratory disease. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 June 2013) and reference lists of retrieved studies. We also contacted trial authors. SELECTION CRITERIA: Randomised controlled trials in women at sufficient risk of preterm birth to warrant the use of prenatal corticosteroids to promote lung maturity. TRH and corticosteroids were compared with corticosteroids, with or without placebo. DATA COLLECTION AND ANALYSIS: All assessments of trial eligibility, risk of bias and data extractions were independently carried out by at least two review authors. MAIN RESULTS: Over 4600 women were recruited into the 15 trials included in the review, however two trials did not contribute any outcome data to the review. The trials had a moderate risk of bias. Overall, prenatal TRH, in addition to corticosteroids, did not reduce the risk of death prior to hospital discharge (risk ratio (RR) 1.05, 95% confidence interval (CI) 0.86 to 1.27, six trials, 3694 infants), neonatal respiratory distress syndrome (average RR 1.05, 95% CI 0.91 to 1.22, nine trials, 3833 infants), or chronic lung disease (RR 1.01, 95% CI 0.85 to 1.19, five trials, 2511 infants), and did not improve any of the secondary fetal, neonatal or childhood outcomes assessed by intention-to-treat analyses.Indeed, the data showed prenatal TRH to have adverse effects for women and their infants. All side effects reported (nausea, vomiting, light headedness, urgency of micturition, facial flushing) were significantly more likely to occur in women receiving TRH. In the infants, prenatal TRH increased the risk of needing respiratory support (RR 1.16, 95% CI 1.03 to 1.29, three trials, 1969 infants), and of having a low Apgar score at five minutes (RR 1.48, 95% CI 1.14 to 1.92, three trials, 1969 infants). Only three trials provided data on childhood follow-up, and while one trial suggested poorer outcomes for infants who were exposed to prenatal TRH, the other two trials, that assessed infants using an established developmental instrument, showed no clear differences between groups in follow-up outcomes.Sensitivity analyses by trial quality, or subgroups with differing times from entry to birth, or different dose regimens of TRH, did not change these findings. AUTHORS' CONCLUSIONS: Prenatal TRH in addition to corticosteroids, given to women at risk of preterm birth, does not improve infant outcomes and can cause maternal side effects.

Magnesium sulphate at 30 to 34 weeks' gestational age: neuroprotection trial (MAGENTA)--study protocol.

BACKGROUND: Magnesium sulphate is currently recommended for neuroprotection of preterm infants for women at risk of preterm birth at less than 30 weeks' gestation, based on high quality evidence of benefit. However there remains uncertainty as to whether these benefits apply at higher gestational ages.The aim of this randomised controlled trial is to assess whether giving magnesium sulphate compared with placebo to women immediately prior to preterm birth between 30 and 34 weeks' gestation reduces the risk of death or cerebral palsy in their children at two years' corrected age. DESIGN: Randomised, multicentre, placebo controlled trial. INCLUSION CRITERIA: Women, giving informed consent, at risk of preterm birth between 30 to 34 weeks' gestation, where birth is planned or definitely expected within 24 hours, with a singleton or twin pregnancy and no contraindications to the use of magnesium sulphate.Trial entry & randomisation: Eligible women will be randomly allocated to receive either magnesium sulphate or placebo.Treatment groups: Women in the magnesium sulphate group will be administered 50 ml of a 100 ml infusion bag containing 8 g magnesium sulphate heptahydrate [16 mmol magnesium ions]. Women in the placebo group will be administered 50 ml of a 100 ml infusion bag containing isotonic sodium chloride solution (0.9%). Both treatments will be administered through a dedicated IV infusion line over 30 minutes.Primary study outcome: Death or cerebral palsy measured in children at two years' corrected age. SAMPLE SIZE: 1676 children are required to detect a decrease in the combined outcome of death or cerebral palsy, from 9.6% with placebo to 5.4% with magnesium sulphate (two-sided alpha 0.05, 80% power, 5% loss to follow up, design effect 1.2). DISCUSSION: Given the magnitude of the protective effect in the systematic review, the ongoing uncertainty about benefits at later gestational ages, the serious health and cost consequences of cerebral palsy for the child, family and society, a trial of magnesium sulphate for women at risk of preterm birth between 30 to 34 weeks' gestation is both important and relevant for clinical practice globally. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry - ACTRN12611000491965.

Reduced corticomotor excitability and motor skills development in children born preterm.

The mechanisms underlying the altered neurodevelopment commonly experienced by children born preterm, but without brain lesions, remain unknown. While individuals born the earliest are at most risk, late preterm children also experience significant motor, cognitive and behavioural dysfunction from school age, and reduced income and educational attainment in adulthood. We used transcranial magnetic stimulation and functional assessments to examine corticomotor development in 151 children without cerebral palsy, aged 10-13 years and born after gestations of 25-41 completed weeks. We hypothesized that motor cortex and corticospinal development are altered in preterm children, which underpins at least some of their motor dysfunction. We report for the first time that every week of reduced gestation is associated with a reduction in corticomotor excitability that remains evident in late childhood. This reduced excitability was associated with poorer motor skill development, particularly manual dexterity. However, child adiposity, sex and socio-economic factors regarding the child's home environment soon after birth were also powerful influences on development of motor skills. Preterm birth was also associated with reduced left hemisphere lateralization, but without increasing the likelihood of being left handed per se. These corticomotor findings have implications for normal motor development, but also raise questions regarding possible longer term consequences of preterm birth on motor function.

Planned vaginal birth or elective repeat caesarean: patient preference restricted cohort with nested randomised trial.

BACKGROUND: Uncertainty exists about benefits and harms of a planned vaginal birth after caesarean (VBAC) compared with elective repeat caesarean (ERC). We conducted a prospective restricted cohort study consisting of a patient preference cohort study, and a small nested randomised trial to compare benefits and risks of a planned ERC with planned VBAC. METHODS AND FINDINGS: 2,345 women with one prior caesarean, eligible for VBAC at term, were recruited from 14 Australian maternity hospitals. Women were assigned by patient preference (n = 2,323) or randomisation (n = 22) to planned VBAC (1,225 patient preference, 12 randomised) or planned ERC (1,098 patient preference, ten randomised). The primary outcome was risk of fetal death or death of liveborn infant before discharge or serious infant outcome. Data were analysed for the 2,345 women (100%) and infants enrolled. The risk of fetal death or liveborn infant death prior to discharge or serious infant outcome was significantly lower for infants born in the planned ERC group compared with infants in the planned VBAC group (0.9% versus 2.4%; relative risk [RR] 0.39; 95% CI 0.19-0.80; number needed to treat to benefit 66; 95% CI 40-200). Fewer women in the planned ERC group compared with women in the planned VBAC had a major haemorrhage (blood loss ≥ 1,500 ml and/or blood transfusion), (0.8% [9/1,108] versus 2.3% [29/1,237]; RR 0.37; 95% CI 0.17-0.80). CONCLUSIONS: Among women with one prior caesarean, planned ERC compared with planned VBAC was associated with a lower risk of fetal and infant death or serious infant outcome. The risk of major maternal haemorrhage was reduced with no increase in maternal or perinatal complications to time of hospital discharge. Women, clinicians, and policy makers can use this information to develop health advice and make decisions about care for women who have had a previous caesarean. TRIAL REGISTRATION: Current Controlled Trials ISRCTN53974531

Timing of birth for women with a twin pregnancy at term: a randomised controlled trial.

BACKGROUND: There is a well recognized risk of complications for both women and infants of a twin pregnancy, increasing beyond 37 weeks gestation. Preterm birth prior to 37 weeks gestation is a recognized complication of a twin pregnancy, however, up to 50% of twins will be born after this time. The aims of this randomised trial are to assess whether elective birth at 37 weeks gestation compared with standard care in women with a twin pregnancy affects the risk of perinatal death, and serious infant complications. DESIGN: Multicentred randomised trial. INCLUSION CRITERIA: women with a twin pregnancy at 366 weeks or more without contraindication to continuation of pregnancy. Trial Entry & Randomisation: Following written informed consent, eligible women will be randomised from 36+6 weeks gestation. The randomisation schedule uses balanced variable blocks, with stratification for centre of birth and planned mode of birth. Women will be randomised to either elective birth or standard care. Treatment Schedules: Women allocated to the elective birth group will be planned for elective birth from 37 weeks gestation. Where the plan is for vaginal birth, this will involve induction of labour. Where the plan is for caesarean birth, this will involve elective caesarean section. For women allocated to standard care, birth will be planned for 38 weeks gestation or later. Where the plan is for vaginal birth, this will involve either awaiting the spontaneous onset of labour, or induction of labour if required. Where the plan is for caesarean birth, this will involve elective caesarean section (after 38 and as close to 39 weeks as possible). Primary Study Outcome: A composite of perinatal mortality or serious neonatal morbidity. SAMPLE SIZE: 460 women with a twin pregnancy to show a reduction in the composite outcome from 16.3% to 6.7% with adjustment for the clustering of twin infants within mothers (p = 0.05, 80% power). DISCUSSION: This is a protocol for a randomised trial, the findings of which will contribute information about the optimal time of birth for women with an uncomplicated multiple pregnancy at and beyond 37 weeks gestation.

Small volumes of feed can trigger transient lower esophageal sphincter relaxation and gastroesophageal reflux in the right lateral position in infants.

OBJECTIVE: To investigate the threshold amount of constantly infused feed needed to trigger lower esophageal sphincter relaxation (TLESR) in the right lateral position (RLP) and left lateral position (LLP). STUDY DESIGN: Eight healthy infants (3 male; gestational age: 32.9 +/- 2.4 weeks; corrected age: 36.1 +/- 1.3 weeks) were studied using an esophageal impedance-manometry catheter incorporating an intragastric infusion port. After tube placement, infants were randomly positioned in RLP or LLP. They were then tube-fed their normal feed (62.5 [40 to 75] mL) at an infusion rate of 160 mL/h. Recordings were made during the feed and 15 minutes thereafter. The study was repeated with the infant in the opposite position. RESULTS: More TLESRs were triggered in the RLP compared with LLP (4.0 [3.0 to 6.0] vs 2.5 [1.0 to 3.0], P = .027). First TLESR occurred at a significantly lower infused volume in RLP compared with LLP (10.6 +/- 9.4 vs 21.0 +/- 4.9 mL, P = .006). The percentage of feed infused at time of first TLESR was significantly lower in RLP compared with LLP (17.6% +/- 15.5% vs 35.4% +/- 8.02%, P = .005). CONCLUSIONS: In the RLP, TLESRs and gastroesophageal reflux are triggered at volumes unlikely to induce gastric distension.

Caffeine for Apnea of Prematurity trial: benefits may vary in subgroups.

OBJECTIVE: To determine whether the benefits of caffeine vary in three subgroups of 2006 participants in the Caffeine for Apnea of Prematurity (CAP) trial. STUDY DESIGN: Post-hoc subgroup analyses were performed on the basis of: (1) indication for commencement of study drug: treat apnea, prevent apnea, or facilitate extubation; (2) positive pressure ventilation (PPV) at randomization: endotracheal tube (ETT), noninvasive ventilation, or none; and (3) timing of commencement of study drug: early or late (< or =3 versus >3 days). Outcomes assessed were those showing treatment effects in the original analyses. We investigated the consistency of caffeine effects by using regression models that incorporated treatment/subgroup factor interactions. RESULTS: There was little evidence of a differential treatment effect of caffeine in subgroups defined by the clinical indication for starting study drug. The size and direction of the caffeine effect on death or disability differed depending on PPV at randomization (P = .03). Odds ratios (95% CI) were: no support, 1.32 (0.81-2.14); noninvasive support, 0.73 (0.52-1.03); and ETT, 0.73 (0.57-0.94). Adjustment for baseline factors strengthened this effect (P = .02). Starting caffeine early resulted in larger reductions in days of respiratory support. Postmenstrual age at time of discontinuing PPV was shorter with earlier treatment (P = .01). Mean differences (95% CI) were: early, 1.35 weeks (0.90-1.81); and late 0.55 weeks (-0.11-0.99). Adjustment for baseline factors weakened this effect (P = .03). CONCLUSIONS: There is evidence of variable beneficial effects of caffeine. Infants receiving respiratory support appeared to derive more neurodevelopmental benefits from caffeine than infants not receiving support. Earlier initiation of caffeine may be associated with a greater reduction in time on ventilation.

Pharmacodynamics and systemic exposure of esomeprazole in preterm infants and term neonates with gastroesophageal reflux disease.

OBJECTIVE: To characterize the pharmacodynamics and systemic exposure of esomeprazole in 26 preterm infants and term neonates with symptoms of gastroesophageal reflux and pathologic acid exposure. STUDY DESIGN: Enrolled patients received oral esomeprazole 0.5 mg/kg once daily for 7 days. Twenty-four-hour esophagogastric pH-impedance monitoring was performed at baseline and on day 7. Pharmacokinetic analysis was performed on day 7. Symptoms occurring during the baseline and day 7 studies were recorded on a symptom chart. RESULTS: There were no significant differences from baseline to day 7 of therapy in the frequency of bolus reflux, consistency of bolus reflux (liquid, mixed, or gas), extent of bolus reflux, or bolus clearance time. Acid bolus reflux episodes were reduced on therapy (median 30 vs 8, P < .001), as was the reflux index (mean % time esophageal pH < 4, 15.7% vs 7.1%, P < .001). The estimated geometric mean of area under the plasma concentration time curve during the dosing interval and observed maximum plasma concentration was 2.5 micromol x h/L and 0.74 micromol/L, respectively. The number of gastroesophageal reflux symptoms recorded over 24 hours was lower on therapy (median 22 vs 12, P < .05). CONCLUSIONS: In preterm infants and term neonates esomeprazole produces no change in bolus reflux characteristics despite significant acid suppression.

Effect of body position changes on postprandial gastroesophageal reflux and gastric emptying in the healthy premature neonate.

OBJECTIVE: To identify a body-positioning regimen that promotes gastric emptying (GE) and reduces gastroesophageal reflux (GER) by changing body position 1 hour after feeding. STUDY DESIGN: Ten healthy preterm infants (7 male; mean postmenstrual age, 36 weeks [range, 33 to 38 weeks]) were monitored with combined esophageal impedance-manometry. Infants were positioned in the left lateral position (LLP) or right lateral position (RLP) and then gavage-fed. After 1 hour, the position was changed to the opposite side. Subsequently, all infants were restudied with the order of positioning reversed. RESULTS: There was more liquid GER in the RLP than in the LLP (median, 9.5 [range, 6.0 to 22.0] vs 2.0 [range, 0.0 to 5.0] episodes/hour; P = .002). In the RLP-first protocol, the number of liquid GER episodes per hour decreased significantly after position change (first postprandial hour [RLP], 5.5 [2.0 to 13.0] vs second postprandial hour [LLP], 0.0 [0.0 to 1.0]; P = .002). GE was faster in the RLP-first protocol than in the LLP-first protocol (37.0 +/- 21.1 vs 61.2 +/- 24.8 minutes; P = .006). CONCLUSIONS: A strategy of right lateral positioning for the first postprandial hour with a position change to the left thereafter promotes GE and reduces liquid GER in the late postprandial period and may prove to be a simple therapeutic approach for infants with GER disease.

Outcomes at 2 years of age after repeat doses of antenatal corticosteroids.

BACKGROUND: We previously reported the results of a randomized, controlled trial showing that repeat doses of antenatal corticosteroids reduced the risk of respiratory distress syndrome and serious neonatal morbidity. However, data have not been available regarding longer-term effects of this treatment. METHODS: Women who had received an initial course of corticosteroid treatment 7 or more days previously were randomly assigned to receive an intramuscular injection of corticosteroid (11.4 mg of betamethasone) or saline placebo; the dose was repeated weekly if the mother was still considered to be at risk for preterm delivery and the duration of gestation was less than 32 weeks. We assessed survival free of major neurosensory disability and body size of the children at 2 years of corrected age. RESULTS: Of the 1085 children who were alive at 2 years of age, 1047 (96.5%) were seen for assessment (521 exposed to repeat-corticosteroid treatment and 526 exposed to placebo). The rate of survival free of major disability was similar in the repeat-corticosteroid and placebo groups (84.4% and 81.0%, respectively; adjusted relative risk, 1.04, 95% confidence interval, 0.98 to 1.10; adjusted P=0.20). There were no significant differences between the groups in body size, blood pressure, use of health services, respiratory morbidity, or child behavior scores, although children exposed to repeat doses of corticosteroids were more likely than those exposed to placebo to warrant assessment for attention problems (P=0.04). CONCLUSIONS: Administration of repeat doses of antenatal corticosteroids reduces neonatal morbidity without changing either survival free of major neurosensory disability or body size at 2 years of age. (Current Controlled Trials number, ISRCTN48656428 [controlled-trials.com].).

Birth after caesarean study--planned vaginal birth or planned elective repeat caesarean for women at term with a single previous caesarean birth: protocol for a patient preference study and randomised trial.

BACKGROUND: For women who have a caesarean section in their preceding pregnancy, two care policies for birth are considered standard: planned vaginal birth and planned elective repeat caesarean. Currently available information about the benefits and harms of both forms of care are derived from retrospective and prospective cohort studies. There have been no randomised trials, and recognising the deficiencies in the literature, there have been calls for methodologically rigorous studies to assess maternal and infant health outcomes associated with both care policies. The aims of our study are to assess in women with a previous caesarean birth, who are eligible in the subsequent pregnancy for a vaginal birth, whether a policy of planned vaginal birth after caesarean compared with a policy of planned repeat caesarean affects the risk of serious complications for the woman and her infant. DESIGN: Multicentered patient preference study and a randomised clinical trial. INCLUSION CRITERIA: Women with a single prior caesarean presenting in their next pregnancy with a single, live fetus in cephalic presentation, who have reached 37 weeks gestation, and who do not have a contraindication to a planned VBAC. Trial Entry & Randomisation: Eligible women will be given an information sheet during pregnancy, and will be recruited to the study from 37 weeks gestation after an obstetrician has confirmed eligibility for a planned vaginal birth. Written informed consent will be obtained. Women who consent to the patient preference study will be allocated their preference for either planned VBAC or planned, elective repeat caesarean. Women who consent to the randomised trial will be randomly allocated to either the planned vaginal birth after caesarean or planned elective repeat caesarean group. Treatment Groups: Women in the planned vaginal birth group will await spontaneous onset of labour whilst appropriate. Women in the elective repeat caesarean group will have this scheduled for between 38 and 40 weeks. Primary Study Outcome: Serious adverse infant outcome (death or serious morbidity). SAMPLE SIZE: 2314 women in the patient preference study to show a difference in adverse neonatal outcome from 1.6% to 3.6% (p = 0.05, 80% power).

Effect of omeprazole on acid gastroesophageal reflux and gastric acidity in preterm infants with pathological acid reflux.

INTRODUCTION: Proton pump inhibitor (PPI) therapy is increasingly being used to treat premature infants with gastroesophageal reflux disease (GERD); however, the efficacy of PPI on acid production in this population has yet to be assessed in this patient group. The aim of this study was to determine the effect of 0.7 mg/kg/d omeprazole on gastric acidity and acid gastroesophageal reflux in preterm infants with reflux symptoms and pathological acid reflux on 24-h pH probe. METHODS: A randomized, double blind, placebo-controlled, crossover design trial of omeprazole therapy was performed in 10 preterm infants (34-40 weeks postmenstrual age). Infants were given omeprazole for 7 d and then placebo for 7 d in randomized order. Twenty-four-hour esophageal and gastric pH monitoring was performed on days 7 and 14 of the trial. RESULTS: Compared to placebo, omeprazole therapy significantly reduced gastric acidity (%time pH <4, 54% vs 14%, P < 0.0005), esophageal acid exposure (%time pH <4, 19% vs 5%, P < 0.01) and number of acid GER episodes (119 vs 60 episodes, P < 0.05). CONCLUSIONS: Omeprazole is effective in reducing esophageal acid exposure in premature infants with pathological acid reflux on 24-h pH probe; however, the far more complex issues of safety and efficacy have yet to be addressed.

Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial.

BACKGROUND: The efficacy and safety of repeat doses of prenatal corticosteroids remains uncertain. Our aim was to establish whether repeat prenatal corticosteroids given to women at risk of preterm birth can reduce neonatal morbidity without harm. METHODS: In this hospital-based study, 982 women who remained at risk of preterm birth at less than 32 weeks' gestation, 7 or more days after receiving a first course of prenatal corticosteroids, were randomly assigned to receive a repeat intramuscular dose of either 11.4 mg betamethasone (as Celestone Chronodose), or saline placebo. This was repeated every week the woman remained undelivered, at less than 32 weeks' gestation, and at risk of preterm birth. Primary outcomes were occurrence and severity of neonatal respiratory distress syndrome, use and duration of oxygen and mechanical ventilation, and weight, length, and head circumference at birth and hospital discharge. Statistical analyses were on an intention to treat basis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN48656428. FINDINGS: Fewer babies exposed to repeat corticosteroids had respiratory distress syndrome (33%vs 41%; relative risk 0.82, 95% CI 0.71-0.95, p=0.01) and fewer had severe lung disease (12%vs 20%; relative risk 0.60, 95% CI 0.46-0.79, p=0.0003) than those in the placebo group. In keeping with these benefits, babies exposed to repeat corticosteroids needed less oxygen therapy (p=0.03), and shorter duration of mechanical ventilation (p=0.01). Mean weight, length, and head circumference at birth and hospital discharge did not differ between treatment groups. Z-scores for weight (p=0.04) and head circumference (p=0.03) at birth were lower in the babies who received repeat corticosteroids although at the time of hospital discharge Z-scores did not differ between treatment groups (p=0.29 for weight, p=0.48 for head circumference). INTERPRETATION: Exposure to repeat doses of antenatal corticosteroids reduces neonatal morbidity. Pending long-term outcome results, the short-term benefits for the babies in our study support the use of repeat doses of corticosteroids in women who remain at risk of very preterm birth 7 or more days after an initial course.