Elective high-frequency oscillatory versus conventional ventilation in preterm infants: a systematic review and meta-analysis of individual patients' data.

BACKGROUND: Population and study design heterogeneity has confounded previous meta-analyses, leading to uncertainty about effectiveness and safety of elective high-frequency oscillatory ventilation (HFOV) in preterm infants. We assessed effectiveness of elective HFOV versus conventional ventilation in this group. METHODS: We did a systematic review and meta-analysis of individual patients' data from 3229 participants in ten randomised controlled trials, with the primary outcomes of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age, death or severe adverse neurological event, or any of these outcomes. FINDINGS: For infants ventilated with HFOV, the relative risk of death or bronchopulmonary dysplasia at 36 weeks' postmenstrual age was 0.95 (95% CI 0.88-1.03), of death or severe adverse neurological event 1.00 (0.88-1.13), or any of these outcomes 0.98 (0.91-1.05). No subgroup of infants (eg, gestational age, birthweight for gestation, initial lung disease severity, or exposure to antenatal corticosteroids) benefited more or less from HFOV. Ventilator type or ventilation strategy did not change the overall treatment effect. INTERPRETATION: HFOV seems equally effective to conventional ventilation in preterm infants. Our results do not support selection of preterm infants for HFOV on the basis of gestational age, birthweight for gestation, initial lung disease severity, or exposure to antenatal corticosteroids. FUNDING: Nestlé Belgium, Belgian Red Cross, and Dräger International.

Building capacity for evidence generation, synthesis and implementation to improve the care of mothers and babies in South East Asia: methods and design of the SEA-ORCHID Project using a logical framework approach.

BACKGROUND: Rates of maternal and perinatal mortality remain high in developing countries despite the existence of effective interventions. Efforts to strengthen evidence-based approaches to improve health in these settings are partly hindered by restricted access to the best available evidence, limited training in evidence-based practice and concerns about the relevance of existing evidence. South East Asia--Optimising Reproductive and Child Health in Developing Countries (SEA-ORCHID) was a five-year project that aimed to determine whether a multifaceted intervention designed to strengthen the capacity for research synthesis, evidence-based care and knowledge implementation improved clinical practice and led to better health outcomes for mothers and babies. This paper describes the development and design of the SEA-ORCHID intervention plan using a logical framework approach. METHODS: SEA-ORCHID used a before-and-after design to evaluate the impact of a multifaceted tailored intervention at nine sites across Thailand, Malaysia, Philippines and Indonesia, supported by three centres in Australia. We used a logical framework approach to systematically prepare and summarise the project plan in a clear and logical way. The development and design of the SEA-ORCHID project was based around the three components of a logical framework (problem analysis, project plan and evaluation strategy). RESULTS: The SEA-ORCHID logical framework defined the project's goal and purpose (To improve the health of mothers and babies in South East Asia and To improve clinical practice in reproductive health in South East Asia), and outlined a series of project objectives and activities designed to achieve these. The logical framework also established outcome and process measures appropriate to each level of the project plan, and guided project work in each of the participating countries and hospitals. CONCLUSIONS: Development of a logical framework in the SEA-ORCHID project enabled a reasoned, logical approach to the project design that ensured the project activities would achieve the desired outcomes and that the evaluation plan would assess both the process and outcome of the project. The logical framework was also valuable over the course of the project to facilitate communication, assess progress and build a shared understanding of the project activities, purpose and goal.

Prophylactic methylxanthines for endotracheal extubation in preterm infants.

BACKGROUND: Weaning and extubating preterm infants on intermittent positive pressure ventilation (IPPV) for respiratory failure may be difficult. A significant contributing factor is thought to be the relatively poor respiratory drive and tendency to develop hypercarbia and apnoea, particularly in very preterm infants. Methylxanthine treatment started before extubation might stimulate breathing and increase the chances of successful weaning from IPPV. OBJECTIVES: To determine the effects of prophylactic methylxanthine treatment on the use of intubation and IPPV and other clinically important side effects in preterm infants being weaned from IPPV and in whom endotracheal extubation is planned. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2010), the Oxford Database of Perinatal Trials, MEDLINE (1966 to July 2010), CINAHL (1982 to July 2010) and EMBASE (1988 to July 2010). SELECTION CRITERIA: All published trials utilising random or quasi-random patient allocation in which treatment with methylxanthines (theophylline or caffeine) was compared with placebo or no treatment to improve the chances of successful extubation of preterm or low birth weight infants were included. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. MAIN RESULTS: Seven studies were identified for inclusion. Methylxanthine treatment results in a reduction in failure of extubation within one week (summary RR 0.48, 95%CI 0.32 to 0.71; summary RD -0.27, 95%CI -0.39 to -0.15; NNT 4, 95%CI 3 to 7; six trials, 172 infants). There is significant heterogeneity in the RD meta-analysis perhaps related to the large variation in baseline rate in the control groups (range 20 to 100%).The CAP trial enrolled the largest number of infants, but did not report extubation rates. In the caffeine group, there were lower rates of bronchopulmonary dysplasia, PDA ligation, cerebral palsy and death or major disability at 18 to 21 months. Infants receiving caffeine had reduced postmenstrual ages at time of discontinuing oxygen therapy, positive pressure ventilation and endotracheal intubation. AUTHORS' CONCLUSIONS: Methylxanthines increase the chances of successful extubation of preterm infants within one week of age. Important neurodevelopmental outcomes are improved by methylxanthine therapy. In any future trials, there is a need to stratify infants by gestational age (a better indicator of immaturity than birth weight). Caffeine, with its wider therapeutic margin, would be the better treatment to evaluate against placebo.

Methylxanthine treatment for apnoea in preterm infants.

BACKGROUND: Recurrent apnoea is common in preterm infants, particularly at very early gestational ages. These episodes of ineffective breathing can lead to hypoxaemia and bradycardia that may be severe enough to require the use of positive pressure ventilation. Methylxanthines (such as caffeine, theophylline or aminophylline) have been used to stimulate breathing and reduce apnoea and its consequences. OBJECTIVES: To determine the effects of methylxanthine treatment on the incidence of apnoea and the use of intermittent positive pressure ventilation (IPPV) and other clinically important outcomes in preterm infants with recurrent apnoea. SEARCH STRATEGY: Searches were made of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2010), the Oxford Database of Perinatal Trials, MEDLINE (1966 to June 2010), EMBASE (1982 to June 2010), previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching mainly in the English language. SELECTION CRITERIA: All trials utilizing random or quasi-random patient allocation in which methylxanthine (theophylline, caffeine or aminophylline) as treatment for apnoea was compared with placebo or no treatment for apnoea in preterm infants were included. DATA COLLECTION AND ANALYSIS: Methodological quality was assessed independently by the review authors. Data were extracted independently by the review authors. Analysis was done in accordance with the recommendations of the Cochrane Neonatal Review Group. MAIN RESULTS: Six trials reported on the effect of methylxanthine in the treatment of apnoea (three trials of theophylline and three trials of caffeine). Five trials that enrolled a total of 192 preterm infants with apnoea evaluated short term outcomes; in these studies, methylxanthine therapy led to a reduction in apnoea and use of IPPV in the first two to seven days. The post-hoc analysis of the large CAP Trial comparing caffeine to control in a subgroup of infants being treated for apnoea reported significantly reduced rates of PDA ligation; postmenstrual age at last oxygen treatment, last endotracheal tube use, last positive pressure ventilation; and reduced chronic lung disease at 36 weeks. AUTHORS' CONCLUSIONS: Methylxanthine is effective in reducing the number of apnoeic attacks and the use of mechanical ventilation in the two to seven days after starting treatment. Caffeine is also associated with better longer term outcomes. In view of its lower toxicity, caffeine would be the preferred drug for the treatment of apnoea.

Prophylactic methylxanthine for prevention of apnoea in preterm infants.

BACKGROUND: Recurrent apnoea is common in preterm infants. These episodes can lead to hypoxaemia and bradycardia, which may be severe enough to require the use of positive pressure ventilation. In infants with apnoea, methylxanthine treatment has been used successfully to prevent further episodes. It is possible that prophylactic therapy given to all very preterm infants soon after birth might prevent apnoea and the need for additional ventilator support. OBJECTIVES: To determine the effect of prophylactic treatment with methylxanthine on apnoea, bradycardia, episodes of hypoxaemia, use of mechanical ventilation, and morbidity in preterm infants at risk for apnoea of prematurity SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was updated in August 2010. This included searches of the Cochrane Central Register of Controlled Trials, Oxford Database of Perinatal Trials, MEDLINE, CINAHL and EMBASE. SELECTION CRITERIA: All trials using random or quasi-random patient allocation in which prophylactic methylxanthine (caffeine or theophylline) was compared with placebo or no treatment in preterm infants were eligible. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. MAIN RESULTS: Three studies were eligible for inclusion in the review. Two small studies (randomising a total of 104 infants) evaluated the effect of prophylactic caffeine on short term outcomes. There were no meaningful differences between the caffeine and placebo groups in the number of infants with apnoea, bradycardia, hypoxaemic episodes, use of IPPV or side effects in either of the studies. Only two outcomes (use of IPPV and tachycardia) were common to the two studies and meta-analysis showed no substantive differences between the groups. One large trial of caffeine therapy (CAP 2006) in a heterogeneous group of infants at risk for and having apnoea of prematurity demonstrated an improved rate of survival without developmental disability at 18 to 21 months corrected age. The reports of the subgroup of infants treated with prophylactic caffeine did not demonstrate any significant differences in clinical outcomes except for a decrease in the risk of PDA ligation. AUTHORS' CONCLUSIONS: The results of this review do not support the use of prophylactic caffeine for preterm infants at risk of apnoea.Any future studies need to examine the effects of prophylactic methylxanthines in preterm infants at higher risk of apnoea. This should include examination of important clinical outcomes such as need for IPPV, neonatal morbidity, length of hospital stay and long term development.

Magnesium sulphate versus phenytoin for eclampsia.

BACKGROUND: Eclampsia, the occurrence of a seizure in association with pre-eclampsia, remains a rare but serious complication of pregnancy. A number of different anticonvulsants have been used to control eclamptic fits and to prevent further seizures. OBJECTIVES: The objective of this review was to assess the effects of magnesium sulphate compared with phenytoin when used for the care of women with eclampsia. Magnesium sulphate is compared with diazepam and with lytic cocktail in other Cochrane reviews. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2010). SELECTION CRITERIA: Randomised trials comparing magnesium sulphate (intravenous or intramuscular administration) with phenytoin for women with a clinical diagnosis of eclampsia. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial quality and extracted data. MAIN RESULTS: We have included data from seven trials, involving 972 women. One large trial (775 women) was of good quality. Magnesium sulphate was associated with a substantial reduction in the recurrence of seizures, when compared to phenytoin (six trials, 972 women; risk ratio (RR) 0.34, 95% confidence interval (CI) 0.24 to 0.49). The trend in maternal mortality favours magnesium sulphate, but the difference does not reach statistical significance (three trials, 847 women; RR 0.50, 95% CI 0.24 to 1.05). There were reductions in the risk of pneumonia (one trial, RR 0.44, 95% CI 0.24 to 0.79), ventilation (one trial, RR 0.68, 95% CI 0.50 to 0.91) and admission to an intensive care unit (one trial, RR 0.67, 95% CI 0.50 to 0.89) associated with the use of magnesium sulphate rather than phenytoin.For the baby, magnesium sulphate was associated with fewer admissions to a special care baby unit (SCBU) (one trial, 518 babies; RR 0.73, 95% CI 0.58 to 0.91) and fewer babies who died or were in SCBU for more than seven days (one trial, 643 babies; RR 0.77, 95% CI 0.63 to 0.95) than phenytoin. There was no clear difference in perinatal deaths (two trials, 665 babies; (RR 0.85, 95% CI 0.67 to 1.09). AUTHORS' CONCLUSIONS: Magnesium sulphate, rather than phenytoin, for women with eclampsia reduces the risk ratio of recurrence of seizures, probably reduces the risk of maternal death, and improves outcome for the baby. Magnesium sulphate is the drug of choice for women with eclampsia. The use of phenytoin should be abandoned.

Caffeine versus theophylline for apnea in preterm infants.

BACKGROUND: Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia, which may be severe enough to require resuscitation including use of positive pressure ventilation. Two forms of methylxanthine (caffeine and theophylline) have been used to stimulate breathing in order to prevent apnea and its consequences. OBJECTIVES: To evaluate the effect of caffeine compared with theophylline treatment on the risk of apnea and use of mechanical ventilation in preterm infants with recurrent apnea. SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of electronic databases in August 2009: Oxford Database of Perinatal Trials; Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2009); MEDLINE (1966 to April 2009); and EMBASE Drugs and Pharmacology (1990 to April 2009), previous reviews including cross references. SELECTION CRITERIA: Randomized and quasi-randomized trials comparing caffeine to theophylline for treating apnea in preterm infants and reporting effects on apnea event rates. DATA COLLECTION AND ANALYSIS: Each author assessed eligibility and trial quality, extracted data separately and compared and resolved differences. Study authors were contacted for additional information. MAIN RESULTS: Five trials involving a total of 108 infants were included. The quality of most of these small trials was fair to good. No difference in treatment failure rate (less than 50% reduction in apnea/bradycardia) was found between caffeine and theophylline after one to three days treatment (based on two studies) or five to seven days treatment (based on one study). There was no difference in mean apnea rate between caffeine and theophylline groups after one to three days treatment (based on five trials) and five to seven days treatment (based on four trials).Adverse effects, indicated by tachycardia or feed intolerance leading to change in dosing, were lower in the caffeine group (summary relative risk 0.17, 95% CI 0.04 to 0.72). This was reported and consistent in three studies.No trial reported the use of ventilation and no data were available to assess effects on growth and development. AUTHORS' CONCLUSIONS: Caffeine appears to have similar short-term effects on apnea/bradycardia as does theophylline although caffeine has certain therapeutic advantages over theophylline. Theophylline is associated with higher rates of toxicity. The possibility that higher doses of caffeine might be more effective in extremely preterm infants needs further evaluation in randomized clinical trials.

Phenobarbital prior to preterm birth for preventing neonatal periventricular haemorrhage.

BACKGROUND: Preterm infants are at risk of periventricular haemorrhage. Phenobarbital might prevent ischaemic injury or reduce fluctuations in blood pressure and blood flow in the brain. OBJECTIVES: To assess the benefits and harms of giving phenobarbital to women at risk of imminent very preterm birth with the primary aim of preventing periventricular haemorrhage in the infant. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2008). SELECTION CRITERIA: Randomised trials with reported data that compared neonatal and maternal outcomes following prenatal exposure to phenobarbital, with outcomes in controls with or without placebo. DATA COLLECTION AND ANALYSIS: We independently assessed trial eligibility and quality and extracted data. We included eligible trials in the initial analysis and prespecified sensitivity analyses to evaluate the effect of trial quality. MAIN RESULTS: Nine trials (1752 women) were included. Analyses of all included trials showed a significant reduction in the rates of all grades of periventricular haemorrhage (PVH) (risk ratio (RR) 0.65, 95% confidence interval (CI) 0.50 to 0.83; nine trials; 1591 women) and severe grades PVH (3 and 4) (RR 0.41, 95% CI 0.20 to 0.85; eight trials; 1527 women) in infants whose mothers had been given prenatal phenobarbital. These results were influenced by trials of poor quality which contributed excessive weight in the analysis due to their higher rates of severe PVH. When only the two higher quality trials were included, these beneficial effects disappeared for all grades of PVH (RR 0.90, 95% CI 0.75 to 1.08; two trials; 945 women), and severe grades of PVH (RR 1.05, 95% CI 0.60 to 1.83; two trials; 945 women).No difference was found in the incidence of neurodevelopmental abnormalities at paediatric follow up at 18 to 24 months or seven years of age between children born to mothers given prenatal phenobarbital and children not so exposed. Maternal sedation was more likely in women receiving phenobarbital (RR 2.06, 95% CI 1.79 to 2.37; one trial; 576 women). AUTHORS' CONCLUSIONS: The evidence in this review does not support the use of prophylactic maternal phenobarbital administration to prevent periventricular haemorrhage in preterm infants or to protect them from neurological disability in childhood. Phenobarbital administration may lead to maternal sedation. If any future trials are carried out, they should measure neurodevelopmental status at follow up.

Vitamin K prior to preterm birth for preventing neonatal periventricular haemorrhage.

BACKGROUND: Preterm infants are at risk of periventricular haemorrhage. This can be a sign of brain damage that might lead to neurodevelopmental abnormalities, including cerebral palsy. It has been suggested that vitamin K might improve coagulation in preterm infants and thereby decrease the risk of periventricular haemorrhage. OBJECTIVES: The objective of this review was to assess the effects of vitamin K administered to women at risk of imminent very preterm birth to prevent periventricular haemorrhage and associated neurological injury in the infant. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 March 2008). SELECTION CRITERIA: Randomised or quasi-randomised trials of vitamin K administered parenterally or orally to women at risk of imminent preterm birth. The primary outcomes were neonatal mortality, neonatal neurological morbidity, as measured by the presence of periventricular haemorrhage (PVH) on ultrasound during the first week of life, and long-term neurodevelopment. Secondary outcomes included other neonatal morbidity and any maternal side effects. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility, trial quality and extracted data. MAIN RESULTS: Seven trials were included, involving 607 women. The trials were of variable quality. Antenatal vitamin K was associated with a non-significant reduction in all grades of periventricular haemorrhage (risk ratio (RR) 0.76; 95% confidence interval (CI) 0.54 to 1.06) and a significant reduction in severe PVH (grades 3 and 4) (RR 0.58; 95% CI 0.37 to 0.91) for babies receiving prenatal vitamin K compared with control babies. When the two quasi-randomised trials were excluded, antenatal vitamin K was associated with a non-significant reduction in all grades of PVH (RR 0.87; 95% CI 0.60 to 1.26) and a non-significant reduction in severe PVH (RR 0.82; 95% CI 0.49 to 1.36).There was an unfavourable effect of vitamin K on development as measured by the Bayley Mental Development Index at two years of age, however these results are derived from one trial with many participants lost to follow up. No difference was found in the incidence of other neurodevelopmental abnormalities at paediatric follow up at 18 to 24 months or seven years of age between children born to mothers given vitamin K and children not so exposed. AUTHORS' CONCLUSIONS: Vitamin K administered to women prior to very preterm birth has not been shown to significantly prevent periventricular haemorrhages in preterm infants or improve neurodevelopmental outcomes in childhood.

Magnesium sulphate versus diazepam for eclampsia.

BACKGROUND: Eclampsia, the occurrence of a seizure in association with pre-eclampsia, remains a rare but serious complication of pregnancy. A number of different anticonvulsants are used to control eclamptic fits and to prevent further fits. OBJECTIVES: The objective of this review was to assess the effects of magnesium sulphate compared with diazepam when used for the care of women with eclampsia. Magnesium sulphate is compared with phenytoin and with lytic cocktail in other Cochrane reviews. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2010) and CENTRAL (2010, Issue 3). SELECTION CRITERIA: Randomised trials comparing magnesium sulphate (intravenous or intramuscular administration) with diazepam for women with a clinical diagnosis of eclampsia. DATA COLLECTION AND ANALYSIS: Two authors assessed and extracted data independently. MAIN RESULTS: We have included seven trials, involving 1396 women. Three trials (1030 women) were good quality. Magnesium sulphate was associated with a reduction in maternal death (seven trials;1396 women; risk ratio (RR) 0.59, 95% confidence interval (CI) 0.38 to 0.92) and recurrence of seizures (seven trials;1390 women; RR 0.43, 95% CI 0.33 to 0.55) compared to diazepam. There were no clear differences in other measures of maternal morbidity.There was no clear difference in perinatal mortality (four trials; 788 infants; RR 1.04, 95% CI 0.81 to 1.34) or neonatal mortality (four trials; 759 infants; RR 1.18, 95% CI 0.75 to 1.84). In the magnesium sulphate group, fewer liveborn babies had an Apgar score less than seven at one minute (two trials; 597 babies; RR 0.75, 95% CI 0.65 to 0.87) or at five minutes (RR 0.70, 95% CI 0.54 to 0.90), and fewer appeared to need intubation at the place of birth (two trials; 591 infants; RR 0.67, 95% CI 0.45 to 1.00). There was no difference in admission to a special care nursery (four trials; 834 infants; RR 0.91, 95% CI 0.79 to 1.05), but fewer babies in the magnesium sulphate group had a length of stay more than seven days (three trials 631 babies; RR 0.66, 95% CI 0.46 to 0.96). AUTHORS' CONCLUSIONS: Magnesium sulphate for women with eclampsia reduces the risk ratio of maternal death and of recurrence of seizures, compared with diazepam.

Magnesium sulphate and other anticonvulsants for women with pre-eclampsia.

BACKGROUND: Eclampsia, the occurrence of a seizure (fit) in association with pre-eclampsia, is rare but potentially life-threatening. Magnesium sulphate is the drug of choice for treating eclampsia. This review assesses its use for preventing eclampsia. OBJECTIVES: To assess the effects of magnesium sulphate, and other anticonvulsants, for prevention of eclampsia. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (4 June 2010), and the Cochrane Central Register of Controlled Trials Register (The Cochrane Library 2010, Issue 3). SELECTION CRITERIA: Randomised trials comparing anticonvulsants with placebo or no anticonvulsant, or comparisons of different drugs, for pre-eclampsia. DATA COLLECTION AND ANALYSIS: Two authors assessed trial quality and extracted data independently. MAIN RESULTS: We included 15 trials. Six (11,444 women) compared magnesium sulphate with placebo or no anticonvulsant: magnesium sulphate more than a halved the risk of eclampsia (risk ratio (RR) 0.41, 95% confidence interval (CI) 0.29 to 0.58; number needed to treat for an additional beneficial outcome (NNTB) 100, 95% CI 50 to 100), with a non-significant reduction in maternal death (RR 0.54, 95% CI 0.26 to 1.10) but no clear difference in serious maternal morbidity (RR 1.08, 95% CI 0.89 to 1.32). It reduced the risk of placental abruption (RR 0.64, 95% CI 0.50 to 0.83; NNTB 100, 95% CI 50 to 1000), and increased caesarean section (RR 1.05, 95% CI 1.01 to 1.10). There was no clear difference in stillbirth or neonatal death (RR 1.04, 95% CI 0.93 to 1.15). Side effects, primarily flushing, were more common with magnesium sulphate (24% versus 5%; RR 5.26, 95% CI 4.59 to 6.03; number need to treat for an additional harmful outcome (NNTH) 6, 95% CI 5 to 6).Follow-up was reported by one trial comparing magnesium sulphate with placebo: for 3375 women there was no clear difference in death (RR 1.79, 95% CI 0.71 to 4.53) or morbidity potentially related to pre-eclampsia (RR 0.84, 95% CI 0.55 to 1.26) (median follow-up 26 months); for 3283 children exposed in utero there was no clear difference in death (RR 1.02, 95% CI 0.57 to 1.84) or neurosensory disability (RR 0.77, 95% CI 0.38 to 1.58) at age 18 months.Magnesium sulphate reduced eclampsia compared to phenytoin (three trials, 2291 women; RR 0.08, 95% CI 0.01 to 0.60) and nimodipine (one trial, 1650 women; RR 0.33, 95% CI 0.14 to 0.77). AUTHORS' CONCLUSIONS: Magnesium sulphate more than halves the risk of eclampsia, and probably reduces maternal death. There is no clear effect on outcome after discharge from hospital. A quarter of women report side effects with magnesium sulphate.

Restricted versus liberal oxygen exposure for preventing morbidity and mortality in preterm or low birth weight infants.

BACKGROUND: While the use of supplemental oxygen has a long history in neonatal care, resulting in both significant health care benefits and harms, uncertainty remains as to the most appropriate range to target blood oxygen levels in preterm and low birth weight infants. Potential benefits of higher oxygen targeting may include more stable sleep patterns and improved long-term growth and development. However, there may be significant deleterious pulmonary effects and health service use implications resulting from such a policy. OBJECTIVES: To determine whether targeting ambient oxygen concentration to achieve a lower vs. higher blood oxygen range, or administering restricted vs. liberal supplemental oxygen, effects mortality, retinopathy of prematurity, lung function, growth or development in preterm or low birth weight infants. SEARCH STRATEGY: The standard search strategy of the Neonatal Review Group was used. An additional literature search was conducted of the MEDLINE and CINAHL databases in order to locate any trials in addition to those provided by the Cochrane Controlled Trials Register (CENTRAL/CCTR). Search updated to week two July 2008. SELECTION CRITERIA: All trials in preterm or low birth weight infants utilising random or quasi-random patient allocation in which ambient oxygen concentrations were targeted to achieve a lower vs. higher blood oxygen range, or restricted vs. liberal oxygen was administered were eligible for inclusion. DATA COLLECTION AND ANALYSIS: The methodological quality of the eligible trials was assessed independently by each review author for the degree of selection, performance, attrition and detection bias. Data were extracted and reviewed independently by the each author. Data analysis was conducted according to the standards of the Cochrane Neonatal Review Group. MAIN RESULTS: In the meta-analysis of the five trials included in this review, the restriction of oxygen significantly reduced the incidence and severity of retinopathy of prematurity without unduly increasing death rates The one prospective, multicenter, double-blind, randomized trial investigating lower vs. higher blood oxygen levels from 32 weeks postmenstrual age showed no significant differences in the rates of ROP, mortality or growth and development between the two groups. However, this study did show increased rates of chronic lung disease and home oxygen use. AUTHORS' CONCLUSIONS: The results of this systematic review confirm that (the now historical) policy of unrestricted, unmonitored oxygen therapy has potential harms without clear benefits. However, the question of what is the optimal target range for maintaining blood oxygen levels in preterm/LBW infants was not answered by the data available for inclusion in this review.

Elective high frequency oscillatory ventilation versus conventional ventilation for acute pulmonary dysfunction in preterm infants.

BACKGROUND: Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although the use of intermittent positive pressure ventilation (IPPV) in neonates with respiratory failure saves lives, its use is associated with lung injury and chronic lung disease (CLD). A newer form of ventilation called high frequency oscillatory ventilation (HFOV) has been shown to result in less lung injury in experimental studies. OBJECTIVES: The objective of this review is to determine the effect of the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation (CV) on the incidence of chronic lung disease, mortality and other complications associated with prematurity and assisted ventilation in preterm infants who are mechanically ventilated for respiratory distress syndrome (RDS). SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, journal hand searching by the Cochrane Collaboration, mainly in the English language. The search was updated in January 2009. SELECTION CRITERIA: Randomised controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who required assisted ventilation. Randomisation and commencement of treatment needed to be as soon as possible after the start of CV and usually in the first 12 hours of life. DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was independently reviewed by the various authors. The standard effect measures are relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) to produce one outcome were calculated. For all measures of effect, 95% confidence intervals were used. In subgroup analyses the 99% CIs are also given for summary RRs in the text. Meta-analysis was performed using a fixed effects model. Where heterogeneity was over 50%, the random effects RR is also given. MAIN RESULTS: Seventeen eligible studies of 3,652 infants were included. Meta-analysis comparing HFOV with CV revealed no evidence of effect on mortality at 28 - 30 days of age or at approximately term equivalent age. These results were consistent across studies and in subgroup analyses. The effect of HFOV on CLD in survivors at term equivalent gestational age was inconsistent across studies and the reduction was of borderline significance overall. The effect was similar in trials with a high lung volume strategy for HFOV targeting at very low FiO(2) and trials with a high lung volume strategy with somewhat higher or unspecified target FiO(2). Subgroups of trials showed a significant reduction in CLD with HFOV when no surfactant was used, when piston oscillators were used for HFOV, when lung protective strategies for CV were not used, when randomisation occurred at two to six hours of age, and when inspiratory:expiratory ratio of 1:2 was used for HFOV. In the meta-analysis of all trials, pulmonary air leaks occurred more frequently in the HFOV group.In some studies, short-term neurological morbidity with HFOV was found, but this effect was not statistically significant overall. The subgroup of two trials not using a high volume strategy with HFOV found increased rates of Grade 3 or 4 intraventricular haemorrhage and of periventricular leukomalacia. An adverse effect of HFOV on long-term neurodevelopment was found in one large trial but not in the five other trials that reported this outcome. The rate of retinopathy of prematurity is reduced overall in the HFOV group. AUTHORS' CONCLUSIONS: There is no clear evidence that elective HFOV offers important advantages over CV when used as the initial ventilation strategy to treat preterm infants with acute pulmonary dysfunction. There may be a small reduction in the rate of CLD with HFOV use, but the evidence is weakened by the inconsistency of this effect across trials and the overall borderline significance. Future trials on elective HFOV should target those infants who are at most risk of CLD (extremely preterm infants), compare different strategies for generating HFOV and CV, and report important long-term neurodevelopmental outcomes.

High frequency oscillatory ventilation versus conventional ventilation for infants with severe pulmonary dysfunction born at or near term.

BACKGROUND: Pulmonary disease is a major cause of mortality and morbidity in term and near term infants. Conventional ventilation (CV) has been used for many years but may lead to lung injury, require the subsequent use of more invasive treatment such as extracorporeal membrane oxygenation (ECMO), or result in death. There are some observational studies indicating that high frequency oscillatory ventilation (HFOV) may be more effective in these infants as compared to CV. OBJECTIVES: To determine the effect of HFOV as compared with CV on mortality and morbidity in infants born at 35 weeks gestational age or more with severe respiratory failure requiring mechanical ventilation. SEARCH STRATEGY: Standard search methods of the Cochrane Neonatal Review group were used. These included searches in January 2009 of The Cochrane Library, MEDLINE, EMBASE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants, and journal hand searching by the Cochrane Collaboration. SELECTION CRITERIA: Randomized or quasi-randomized trials comparing HFOV and CV in term or near term infants with intractable respiratory failure were included in this review. DATA COLLECTION AND ANALYSIS: The standard methods of the Cochrane Neonatal Review Group were used. The investigators separately extracted, assessed and coded all data for each study. Any disagreement was resolved by discussion. Data were synthesized using risk ratio [RR with (95% confidence intervals, CI)] and mean difference (with standard deviation, SD). MAIN RESULTS: Two trials met the inclusion criteria. One trial involving the "elective" use of HFOV randomized 118 infants at the start of CV. The other trial of "rescue" HFOV randomized 81 infants with later respiratory failure on CV. Neither trial showed evidence of a reduction in mortality at 28 days or in failed therapy on the assigned mode of ventilation requiring cross-over to the other mode. Neither study reported significant differences in the risk of pulmonary air leak, chronic lung disease (28 days or more in oxygen) or intracranial injury. In the study of elective HFOV, there was no difference noted in days on a ventilator or days in hospital. In the one rescue study, there was no difference in the risk of needing extracorporeal membrane oxygenation. AUTHORS' CONCLUSIONS: There are no data from randomized controlled trials supporting the use of rescue HFOV in term or near term infants with severe pulmonary dysfunction. The area is complicated by diverse pathology in such infants and by the occurrence of other interventions (surfactant, inhaled nitric oxide, inotropes). Randomized controlled trials are needed to establish the role of elective or rescue HFOV in near term and term infants with pulmonary dysfunction before widespread use of this mode of ventilation in such infants.

Caesarean section in four South East Asian countries: reasons for, rates, associated care practices and health outcomes.

BACKGROUND: Caesarean section is a commonly performed operation on women that is globally increasing in prevalence each year. There is a large variation in the rates of caesarean, both in high and low income countries, as well as between different institutions within these countries. This audit aimed to report rates and reasons for caesarean and associated clinical care practices amongst nine hospitals in the four South East Asian countries participating in the South East Asia-Optimising Reproductive and Child Health in Developing countries (SEA-ORCHID) project. METHODS: Data on caesarean rates, care practices and health outcomes were collected from the medical records of the 9550 women and their 9665 infants admitted to the nine participating hospitals across South East Asia between January and December 2005. RESULTS: Overall 27% of women had a caesarean section, with rates varying from 19% to 35% between countries and 12% to 39% between hospitals within countries. The most common indications for caesarean were previous caesarean (7.0%), cephalopelvic disproportion (6.3%), malpresentation (4.7%) and fetal distress (3.3%). Neonatal resuscitation rates ranged from 7% to 60% between countries. Prophylactic antibiotics were almost universally given but variations in timing occurred between countries and between hospitals within countries. CONCLUSION: Rates and reasons for caesarean section and associated clinical care practices and health outcomes varied widely between the four South East Asian countries.

The establishment of the Australian and New Zealand Neonatal Network.

The Australian and New Zealand Neonatal Network was established in 1994 to monitor high-risk newborns admitted for care. Uniquely, all units in both countries have participated since inception, making it integral to the care of babies. The network's objectives include auditing care, publishing aggregated results annually, providing feedback to units, monitoring technologies and developing clinical indicators. Networking provides a forum for clinicians and a consortium of knowledge and advice. It facilitates collaborative research and clinical groups, producing projects from observational studies to randomised controlled trials. Members take a major role in reviewing the evidence for care and ensuring its effective use in clinical practice.

Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data.

BACKGROUND: Pre-eclampsia is a major cause of mortality and morbidity during pregnancy and childbirth. Antiplatelet agents, especially low-dose aspirin, might prevent or delay pre-eclampsia, and thereby improve outcome. Our aim was to assess the use of antiplatelet agents for the primary prevention of pre-eclampsia, and to explore which women are likely to benefit most. METHODS: We did a meta-analysis of individual patient data from 32,217 women, and their 32,819 babies, recruited to 31 randomised trials of pre-eclampsia primary prevention. FINDINGS: For women assigned to receive antiplatelet agents rather than control, the relative risk of developing pre-eclampsia was 0.90 (95% CI 0.84-0.97), of delivering before 34 weeks was 0.90 (0.83-0.98), and of having a pregnancy with a serious adverse outcome was 0.90 (0.85-0.96). Antiplatelet agents had no significant effect on the risk of death of the fetus or baby, having a small for gestational age infant, or bleeding events for either the women or their babies. No particular subgroup of women was substantially more or less likely to benefit from antiplatelet agents than any other. INTERPRETATION: Antiplatelet agents during pregnancy are associated with moderate but consistent reductions in the relative risk of pre-eclampsia, of birth before 34 weeks' gestation, and of having a pregnancy with a serious adverse outcome.

Does observer bias contribute to variations in the rate of retinopathy of prematurity between centres?

PURPOSE: We aimed to indirectly assess the contribution from observer bias to between centre variability in the incidence of acute retinopathy of prematurity (ROP). METHODS: The Australian and New Zealand Neonatal Network (ANZNN) collected data on the highest stage of acute ROP in either eye in 2286 infants born at less than 29 weeks in 1998-1999 and cared for in one of 25 neonatal intensive care units (NICUs). Chi-squared analysis was used to detect differences in the proportion of stages of ROP for each neonatal intensive care unit. These proportions were compared with those reported in two large studies of treatment for ROP. RESULTS: The incidence of acute ROP in the ANZNN cohort was 42% and the ratio of stage 1:2:3 ROP was 1.5:1.9:1. There was considerable variation in both the incidence of acute ROP and the proportions with stage 1:2:3 ROP between centres. A chi-squared test determined that the assignment of stages 1, 2 and 3/4 ROP was not independent of centre (chi(2)(48) = 165.2; P < 0.0001). Treatment of stage 3 ROP varied between 15% and 120%, indicating some eyes were treated at less than stage 3. CONCLUSION: The data are highly suggestive of observer bias contributing to the observed between centre variation in the incidence of acute ROP. In neonatal intervention studies where acute ROP is an outcome it would seem important to have an accreditation process for examining ophthalmologists, and there are similar arguments for neonatal networks which collect these data.

Optimising reproductive and child health outcomes by building evidence-based research and practice in South East Asia (SEA-ORCHID): study protocol.

BACKGROUND: Disorders related to pregnancy and childbirth are a major health issue in South East Asia. They represent one of the biggest health risk differentials between the developed and developing world. Our broad research question is: Can the health of mothers and babies in Thailand, Indonesia, the Philippines and Malaysia be improved by increasing the local capacity for the synthesis of research, implementation of effective interventions, and identification of gaps in knowledge needing further research? METHODS/DESIGN: The project is a before-after study which planned to benefit from and extend existing regional and international networks. Over five years the project was designed to comprise five phases; pre-study, pre-intervention, intervention, outcome assessment and reporting/dissemination. The study was proposed to be conducted across seven project nodes: four in South East Asia and three in Australia. Each South East Asian study node was planned to be established within an existing department of obstetrics and gynaecology or neonatology and was intended to form the project coordinating centre and focus for evidence-based practice activities within that region. Nine hospitals in South East Asia planned to participate, representing a range of clinical settings. The three project nodes in Australia were intended to provide project support. The intervention was planned to consist of capacity-strengthening activities targeted at three groups: generators of evidence, users of evidence and teachers of evidence. The primary outcome was established as changes in adherence to recommended clinical practices from baseline to completion of the project and impact on health outcomes. DISCUSSION: The SEA-ORCHID project was intended to improve care during pregnancy and the perinatal period of mothers and their babies in South East Asia. The possible benefits extend beyond this however, as at the end of this project there is hoped to be an existing network of South East Asian researchers and health care providers with the capacity to generalise this model to other health priority areas. It is anticipated that this project facilitate ongoing development of evidence-based practice and policy in South East Asia through attracting long-term funding, expansion into other hospitals and community-based care and the establishment of nodes in other countries.

Using hospital discharge data for determining neonatal morbidity and mortality: a validation study.

BACKGROUND: Despite widespread use of neonatal hospital discharge data, there are few published reports on the accuracy of population health data with neonatal diagnostic or procedure codes. The aim of this study was to assess the accuracy of using routinely collected hospital discharge data in identifying neonatal morbidity during the birth admission compared with data from a statewide audit of selected neonatal intensive care (NICU) admissions. METHODS: Validation study of population-based linked hospital discharge/birth data against neonatal intensive care audit data from New South Wales, Australia for 2,432 babies admitted to NICUs, 1994-1996. Sensitivity, specificity and positive predictive values (PPV) with exact binomial confidence intervals were calculated for 12 diagnoses and 6 procedures. RESULTS: Sensitivities ranged from 37.0% for drainage of an air leak to 97.7% for very low birthweight, specificities all exceeded 85% and PPVs ranged from 70.9% to 100%. In-hospital mortality, low birthweight (< or =1500 g), retinopathy of prematurity, respiratory distress syndrome, meconium aspiration, pneumonia, pulmonary hypertension, selected major anomalies, any mechanical ventilation (including CPAP), major surgery and surgery for patent ductus arteriosus or necrotizing enterocolitis were accurately identified with PPVs over 92%. Transient tachypnea of the newborn and drainage of an air leak had the lowest PPVs, 70.9% and 83.6% respectively. CONCLUSION: Although under-ascertained, routinely collected hospital discharge data had high PPVs for most validated items and would be suitable for risk factor analyses of neonatal morbidity. Procedures tended to be more accurately recorded than diagnoses.