Perinatal Trials Research Articles

Cochrane reviews in pregnancy: The role of perinatal randomized trials and systematic reviews in establishing evidence

Evidence from randomized trials and systematic reviews provides the highest level of evidence from which to make clinical decisions. There are over 340 Cochrane reviews and protocols in pregnancy and childbirth; these provide the best single source of evidence for care of pregnant women and their babies, and highlight further research priorities. The challenges to health professionals are to ensure that the Cochrane reviews are prepared, kept up to date, and used in clinical care, and where relevant reliable evidence is not available to ensure that high-quality randomized trials are promptly conducted.

“It was a snap decision”: Parental and professional perspectives on the speed of decisions about participation in perinatal randomised controlled trials

For some perinatal trials, parents can be asked to make important decisions about trial participation within limited timeframes in highly stressful circumstances. This qualitative study explores the pace of decision-making for 78 parents associated with one or more of four such trials in the UK. The themes associated with rapid decisions were concern for their baby, reactions to staff, and perceptions of the benefits and risks associated with the trial. Those who took longer to decide whether or not to participate often described similar emotions to those who made rapid decisions, but their slower decisions were because more time was available, they wanted further discussion or they found the decision particularly difficult. The majority of those who made rapid decisions felt that there were no risks associated with the trial in question, in contrast to the majority of those who made slower decisions who felt there were risks. The parents did not appear to view rapid decisions as problematic. Although there was evidence of parental vulnerability in each trial context, they largely felt that they acted swiftly and responsibly in the best interests of their child in accordance with the timeframes that were set for them.

Fluid restriction for term infants with hypoxic-ischaemic encephalopathy following perinatal asphyxia

Current recommendations to control the consequences of hypoxic-ischaemic encephalopathy following perinatal asphyxia include the careful management of fluids, with avoidance of fluid overload and thus avoidance of cerebral oedema. Recommendations for fluid restriction in a neonate are based on the experience of restricting fluid intake in adults or older children. The extrapolation from studies in adults, older children and animals to the human neonate is fraught with hazard due to the different physiology and mechanisms of injury. The objective of this review was to determine the effects of fluid restriction on short-term (mortality within the first 28 days of life, grade of hypoxic ischaemic encephalopathy, electrolyte disturbances, renal function, seizure activity) and long-term outcomes (death during the first year of life, CT or MRI changes, or severe neurodevelopmental disability at or equal to 12 months of age or more) in term infants following perinatal asphyxia. Subgroup analyses were planned on the basis of the severity of the resulting hypoxic-ischaemic encephalopathy, degree of fluid restriction, and length of fluid restriction. Searches were undertaken of MEDLINE October 2004 back to 1966, CINAHL back to 1966, the Oxford Database of Perinatal Trials and the Cochrane Central Register of Controlled Trial (CENTRAL, The Cochrane Library, Issue 3, 2004). Searches were made of previous reviews including cross-references and abstracts. The search was not limited to the English language; reports in foreign languages were translated. Randomised or quasi-randomised trials of fluid restriction in term newborn infants with perinatal asphyxia. No studies were found meeting the criteria for inclusion in this review. No studies were found meeting the criteria for inclusion in this review. Given that fluid restriction for the treatment of hypoxic ischaemic encephalopathy following perinatal asphyxia is recommended in standard textbooks, there is a need for randomised, controlled trials to establish if this practice affects mortality and morbidity. As it may not be ethical to include neonates with acute renal failure in a randomised trial, these babies will have to be excluded from the trial. These studies should investigate the effects of fluid management on outcomes such as mortality, seizure activity, evidence of cerebral damage on histology, and effects on renal function and electrolytes.

Early introduction of lipids to parenterally-fed preterm infants

Lipids are essential components of parenteral nutrition for preterm infants. Parenteral lipids can be administered through a peripheral vein, and their early introduction offers the potential advantages of increasing energy intake and providing essential fatty acids and fat soluble vitamins. Concerns have been raised about potential adverse effects including chronic lung disease (CLD), increase in pulmonary vascular resistance, impaired pulmonary gas diffusion, bilirubin toxicity, sepsis and free radical stress. To determine the safety and efficacy of 'early' (</= 5 days after birth) introduction of lipids to parenterally fed preterm infants. Eligible studies were identified by searching MEDLINE (December 2004), EMBASE 1980 - 2004, Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 4, 2004) and CINAHL (December 1982 - December 2004). Abstracts of the Society for Pediatric Research were hand searched from 1980 to 2004 inclusive. No language restrictions were applied. All randomised or quasi randomised controlled trials comparing 'early' versus 'no early' introduction of lipids to preterm infants. Data were sought regarding effects on growth and risk of CLD or death, other respiratory morbidities including duration of respiratory support, duration of supplemental oxygen, the need for home oxygen, pneumothorax (PTX), pulmonary haemorrhage and pulmonary interstitial emphysema (PIE), >/= stage 2 necrotizing enterocolitis (NEC), retinopathy of prematurity (ROP), patent ductus arteriosus (PDA), sepsis, intraventricular haemorrhage (IVH), clinically significant thrombocytopenia and significant jaundice. Methodological quality of eligible studies was assessed according to allocation concealment, blinding of intervention, blinding of outcome assessment and completeness of follow up. When appropriate, meta-analysis was conducted to provide a pooled estimate of effect. For categorical data the Typical relative risk (RR), Typical risk difference (RD) and number needed to treat (NNT) with 95% confidence intervals (CI) were calculated. Continuous data were analysed using weighted mean difference (WMD). Five studies (n = 397) were included in the review. All studies compared the effectiveness and safety of 'early' introduction versus 'no early' introduction of lipids in preterm infants. The timing of introduction of 'early lipids' ranged from < 12 hours after birth to day five of life. The timing of introduction of lipids in the 'no early' lipid group ranged from day six after birth to day 14 after birth. The initial dose ranged from 0.5 - 1 g/kg/day with gradual daily increments up to a maximum of 2.5 - 3.5 g/kg/day. For the primary outcomes (growth, death and CLD), there was no statistically significant difference between the 'early' lipid and 'no early' lipid groups. Days to regain birth weight: [WMD 0.59 (95% CI -2.41, 3.58); two trials; N = 71]. Rate of weight gain (g/day) during period of hospital stay: [MD -2.40 (95% CI -5.30, 0.50); one trial; N = 129]Death (irrespective of time): [Typical RR 1.04 (95% CI 0.69, 1.56); Typical RD 0.01 (95% CI -0.07, 0.08); five trials; N = 397]Neonatal deaths: [Typical RR 1.35 (95% CI 0.78, 2.34); Typical RD 0.05 (95% CI -0.04, 0.13); four trials; N = 268].CLD: [Typical RR 1.10 (95% CI 0.81, 1.49); Typical RD 0.04 (95% CI -0.09, 0.17); two trials; N = 193]. For the secondary outcomes of other respiratory morbidities including duration of respiratory support, duration of supplemental oxygen, PTX, pulmonary haemorrhage, PIE, NEC, ROP, PDA, sepsis, IVH and significant jaundice, there were no statistically significant differences between 'early' and 'no early' lipid groups. No statistically significant effects of 'early introduction' of lipids on short term nutritional or other clinical outcomes, either benefits or adverse effects, were demonstrated in the studies reviewed. Based on the currently available evidence, 'early' initiation of lipids (</= 5 days after birth) can not be recommended for short term growth or to prevent morbidity and mortality in preterm infants.

Audio recordings of consultations with doctors for parents of critically sick babies

Family centred care is an important part of neonatal intensive care. Ensuring effective communication in the neonatal intensive care unit (NICU) is a challenge but is crucial to the implementation of family centred care. Providing parents in NICU with audiotape recordings of their conversations with neonatologists could promote effective communication. The objective of this review was to assess the usefulness of providing parents of sick babies with audiotape recordings of their consultations with neonatologists. The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of electronic databases: Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue 3, 2004), and MEDLINE (1966 - February 2004); and previous reviews including cross references and expert informants. There were no language restrictions applied to the electronic searches. Hand searching of conference and symposia proceedings was restricted to the English language. Randomised or quasi-randomised trials of any form of providing parents of babies in NICU with audiotape recordings of their conversation with doctors in the NICU. Four reviewers independently assessed the eligibility of the trials. Our searches did not identify any trials which met the eligibility criteria. There is no information available from randomised or quasi-randomised trials to demonstrate any benefits from providing parents in NICU with audiotape recordings of their conversations with neonatologists.

Doxapram treatment for apnea in preterm infants.

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. Doxapram has been used to stimulate breathing and so prevent apnea and its consequences. In preterm infants with recurrent apnea, does treatment with Doxapram lead to a clinically important reduction in apnea and use of intermittent positive airways pressure (IPPV), without clinically important side effects? Searches were made of the Oxford Database of Perinatal trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 3, 2004), MEDLINE from 1966 - June 2004, EMBASE from 1980 - June 2001, CINAHL from 1982- June 2004. Text words 'doxapram', 'apnea or apnoea' and the MeSH term 'infant, premature' were used. Previous reviews including cross references, abstracts from conferences and symposia proceedings were also examined. Abstracts of the Society for Pediatric Research were searched from 1996 - 2004 inclusive. All trials utilising random or quasi-random patient allocation, in which doxapram was used for the treatment of apnea in preterm infants were included. Each author evaluated the papers for quality and inclusion criteria. Independent data extraction was carried out. Only one trial, which randomized 11 infants to intravenous doxapram and 10 infants to placebo, was found. There were fewer treatment failures after 48 hours in the group of preterm infants treated with doxapram (4/11) compared with the group treated with placebo (8/10). The wide confidence intervals made this result non-significant [RR 0.45 (0.20, 1.05)]. Only one infant, who was from the placebo group, was given IPPV. Of the seven responders by 48 hours in the group of 11 who received doxapram, five failed to respond between 48 hours and seven days after commencement of therapy. This gives a late failure rate of 9/11, similar to the short term failure rate in the placebo group of 8/10. It is not possible to evaluate the late responses of all those in the placebo group since they crossed over to a treatment arm. Although intravenous Doxapram might reduce apnea within the first 48 hours of treatment, there are insufficient data to evaluate the precision of this result or to assess potential adverse effects. No long term outcomes have been measured. Further studies are needed to determine the role of this treatment in clinical practice.

Replacement of estrogens and progestins to prevent morbidity and mortality in preterm infants

A potential therapeutic effect of sex steroids on premature infants has been proposed from animal data and observational studies in humans. Purported benefits include reduction in chronic lung disease, improved bone density and improved neurodevelopmental outcome. To determine if estrogens or progestins, either alone or in combination, when compared to placebo or no treatment, reduce morbidity and/or mortality in preterm infants. The standard search strategy of the Cochrane Neonatal Review Group as outlined in the Cochrane Library (Issue 2, 2004) was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2004), MEDLINE 1966 to July 2004 inclusive, previous reviews including cross references, abstracts, conferences and symposia proceedings (Perinatal Society of Australia and New Zealand 1998-2004 and Pediatric Academic Societies meetings 1998-2004). Randomised controlled trials comparing the use of estrogens and/or progestins with placebo or no treatment in preterm infants born less than 30 weeks gestation were included in this review. The primary outcome measures were neonatal mortality and medium-term neurodevelopmental outcome. Other outcomes included length of hospital stay, incidence of chronic lung disease, osteopaenia causing fractures and adverse effects of sex steroid administration. Two reviewers independently selected, assessed the quality of and extracted data from the included studies. Meta-analyses were performed using relative risk and risk difference for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals. Two randomised controlled trials were identified by the search strategy and one was included in this review, comprising 30 preterm infants. There was no significant effect of replacement of estradiol and progesterone on the outcomes of mortality or neurodevelopmental disability in survivors followed. No adverse effects of sex steroid replacement on short or longer term outcomes were detected. The one small randomised controlled trial demonstrated neither evidence of benefit or harm related to the replacement of estradiol and progesterone in preterm infants less than 30 weeks gestation. A properly powered randomised controlled trial is required to determine whether or not administration of estradiol or progesterone, either alone or in combination, and at varying doses, confers any clinically significant benefits, or poses any risk, to the preterm infant.

Early surfactant administration with brief ventilation vs selective surfactant and continued mechanical ventilation for preterm infants with or at risk for respiratory distress syndrome.

Both prophylactic and early surfactant replacement therapy, compared with later selective surfactant administration, reduce mortality and pulmonary complications in ventilated infants with respiratory distress syndrome (RDS). However, continued post-surfactant intubation and ventilation are risk factors for chronic lung disease. Whether prophylactic or early surfactant administration followed by prompt extubation, compared with later, selective use of surfactant followed by continued mechanical ventilation reduces the need for mechanical ventilation and the incidence of chronic lung disease is unknown. To compare two treatment strategies in preterm infants with, or at risk for, RDS: early surfactant administration with brief mechanical ventilation (less than one hour) followed by extubation, vs later, selective surfactant administration, continued mechanical ventilation and extubation from low respiratory support. Two populations of infants receiving early surfactant were considered: spontaneously breathing infants with signs of RDS (surfactant administration during evolution of RDS prior to requiring intubation for respiratory failure) and infants at high risk for RDS (prophylactic surfactant administration within 15 minutes after birth). Searches were made of the Oxford Database of Perinatal trials, MEDLINE (1966-December 2003), CINAHL (1982-December 2003), EMBASE (1980-December 2003), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2004), Pediatric Research (1990-2003), abstracts, expert informants and hand searching. No language restrictions were applied. Randomized or quasi-randomized controlled clinical trials comparing early surfactant administration with planned brief mechanical ventilation (less than one hour) followed by extubation, vs selective surfactant administration, continued mechanical ventilation and extubation from low respiratory support. Data were sought regarding effects on incidence of mechanical ventilation (ventilation continued or initiated beyond one hour after surfactant administration), incidence of bronchopulmonary dysplasia (BPD), chronic lung disease (CLD), mortality, duration of mechanical ventilation, duration of hospitalization, time in oxygen, duration of respiratory support (including CPAP and nasal cannula), number of patients receiving surfactant, number of surfactant doses administered per patient, incidence of air leak syndromes (pulmonary interstitial emphysema, pneumothorax), patent ductus arteriosus requiring treatment, pulmonary hemorrhage, and other complications of prematurity. Treatment effect was expressed as relative risk (RR) and risk difference (RD) for categorical variables, and weighted mean difference (WMD) for continuous variables. Four randomized controlled clinical trials met selection criteria and were included in this review. In these studies of infants with signs of RDS, intubation and early surfactant therapy followed by extubation to nasal CPAP (NCPAP) compared with later selective surfactant administration was associated with a lower incidence of mechanical ventilation [typical RR 0.70, 95% CI 0.59, 0.84]. None of the trials reported a significant difference in the incidence of BPD or CLD; however, meta-analysis for this outcome cannot yet be performed because the primary data from three of the trials have not yet been published in full. A larger proportion of infants in the early surfactant group received surfactant than in the selective surfactant group [typical RR 1.59, 95% CI 1.35, 1.88]. The number of surfactant doses per patient was significantly greater among patients randomized to the early surfactant group [WMD 0.51 doses per patient, 95% CI 0.36, 0.65]. Trends towards a decreased incidence of air leak syndromes (two studies) and a higher incidence of patent ductus arteriosus requiring treatment (one study) were seen in the early surfactant group. There was no evidence of effect on time in oxygen or duration of mechanical ventilation. Early surfactant replacement therapy with extubation to NCPAP compared with later, selective surfactant replacement and continued mechanical ventilation with extubation from low ventilator support is associated with a reduced need for mechanical ventilation and increased utilization of exogenous surfactant therapy. There is insufficient evidence at present to reliably evaluate effect on BPD or CLD.

Thyroid hormone supplementation for the prevention of morbidity and mortality in infants undergoing cardiac surgery.

Paediatric studies have demonstrated that cardiopulmonary bypass is associated with a decline in thyroid hormone levels. Adult patients who undergo open heart surgery and receive triiodothyronine supplementation have demonstrated a dose-dependent increase in cardiac output which has been associated with an improved clinical outcome. Thyroid hormone supplementation in infants may also reduce post-operative morbidity and mortality. To determine if peri-operative thyroid hormone supplementation or replacement in infants undergoing cardiac surgery on cardiopulmonary bypass improves post-operative and longer term morbidity and mortality. The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of The Oxford Database of Perinatal Trials, MEDLINE (1966 - December 2003), EMBASE (1980 - December 2003), CINAHL (1982 - December 2003), The Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2003), previous reviews including cross references, abstracts, conferences, symposia proceedings, expert informants and journal handsearching in the English language. All trials using random allocation to peri-operative thyroid hormone therapy (supplementation or replacement) compared to control (placebo or no therapy) in infants (birth to one year of age) undergoing cardiac surgery requiring cardiopulmonary bypass. Thyroid hormone therapy must be tri-iodothyronine. Primary clinical outcomes included measures of post-operative morbidity and mortality. The standard methods of the Cochrane Neonatal Review Group were used in the assessment of trial quality. Treatment effects were expressed using relative risk (RR) and mean difference (MD). Two very small studies were identified that tested peri-operative thyroid hormone supplementation or replacement in infants aged less than one year undergoing cardiac surgery (Chowdhury 2001; Portman 2000). In the Chowdhury 2001 study, a subgroup of nine neonates was eligible for this review. No deaths occurred during either study. Chowdhury 2001 found no significant effect of peri-operative thyroid hormone supplementation in neonates on either length of hospital stay or duration of mechanical ventilation. Portman 2000 found no significant difference in dopamine requirements for the treatment versus control groups for the first 24 hours post operatively, while in the Chowdhury neonatal subgroup, inotrope requirements were significantly lower in the treatment group. Portman 2000 reported significant differences between the two groups at 1 and 24 hours post operatively for free T3 and at 1 hour post operatively for total T3 levels. Total T4 levels showed no significant difference between groups, either pre-cardiopulmonary bypass or up to 72 hours post operatively. At present, there is a lack of evidence concerning the effects of tri-iodothyronine supplementation in infants undergoing cardiac surgery. Further randomised controlled trials which include sufficiently large subject numbers in a variety of different age strata (neonates, infants and older children) need to be undertaken.

Air versus oxygen for resuscitation of infants at birth.

100% oxygen is the commonly recommended gas for the resuscitation of infants at birth. There is growing evidence from both animal and human studies that room air is as effective as 100% oxygen and that 100% oxygen may have adverse effects on breathing physiology and cerebral circulation. There is also the theoretical risk of tissue damage due to free oxygen radicals when 100% oxygen is given. The use of room air has, therefore, been suggested as a safer and possibly more effective alternative. In newborn infants requiring resuscitation, does the use of room air reduce the incidence of death, neurological disability and short term morbidity when compared with the use of 100% oxygen? This included searches of the Oxford Database of Perinatal Trials, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2004) and MEDLINE PubMed 1966 to December 2003, and handsearches of reference lists of relevant articles and conference proceedings. All randomised and quasi-randomised studies comparing the use of room air or any other concentration of oxygen versus 100% oxygen in the resuscitation of infants at birth. Three authors assessed the methodological quality of eligible trials and extracted data independently. When appropriate, meta-analysis was conducted to provide a pooled estimate of effect. For categorical data the relative risk (RR), risk difference (RD) and number needed to treat (NNT) with 95% confidence intervals (CI) were calculated. Continuous data were analysed using weighted mean difference (WMD). Five studies were identified which enrolled a total of 1302 infants. In two studies allocation was randomised and the caregivers were blinded to intervention group. In the other three studies, allocation was quasi-randomised and the caregivers were not blinded. Pooled analysis of the four trials reporting effect on death showed a significant reduction in the rate of death in the group resuscitated with room air [typical RR 0.71 (0.54, 0.94), typical RD -0.05 (-0.08, -0.01), NNT 20 (12, 100)]. There were no significant differences between the groups with respect to rates of grade 2 or 3 hypoxic ischaemic encephalopathy. One of the four trials reported a statistically significant difference in median 5 minute Apgar scores, favouring the group allocated to room air. However, the absolute difference between the medians was small and there were no significant differences in the median 10 minute Apgar scores in the three trials reporting this outcome. One trial followed up a selected subgroup of survivors to 18-24 months. There were no significant differences in rates of adverse neurodevelopmental outcomes including cerebral palsy and failure to achieve various milestones; however, the proportion of eligible patients seen was less than 70%. Analyses that were planned for this review, but not able to be carried out because of lack of published data, included a sub-analysis stratified by gestational age and assessments of the effect on bronchopulmonary dysplasia and retinopathy of prematurity. There is insufficient evidence at present on which to recommend a policy of using room air over 100% oxygen, or vice versa, for newborn resuscitation. A reduction in mortality has been seen in infants resuscitated with room air, and no evidence of harm has been demonstrated. However, the small number of identified studies and their methodologic limitations dictate caution in interpreting and applying these results. We note the use of back-up 100% oxygen in more than a quarter of infants randomised to room air. Therefore, on the basis of currently available evidence, if one chooses room air as the initial gas for resuscitation, supplementary oxygen should continue to be made available.

Cooling for newborns with hypoxic ischaemic encephalopathy.

Newborn animal and human pilot studies suggest that mild hypothermia following peripartum hypoxia-ischaemia in newborn infants may reduce neurological sequelae, without adverse effects. To determine whether therapeutic hypothermia in encephalopathic asphyxiated newborn infants reduces mortality and long-term neurodevelopmental disability, without clinically important side effects. The standard search strategy of the Neonatal Review Group as outlined in the Cochrane Library (Issue 2, 2003) was used. Randomised controlled trials evaluating therapeutic hypothermia in term newborns with hypoxic ischaemic encephalopathy were identified by searching the Oxford Database of Perinatal Trials, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library Issue Issue 2, 2003), MEDLINE (1966 to July 2003), previous reviews including cross-references, abstracts, conferences, symposia proceedings, expert informants and journal hand searching. Randomised controlled trials comparing the use of therapeutic hypothermia with normothermia in encephalopathic newborn infants with evidence of peripartum asphyxia and without recognisable major congenital anomalies were included. The primary outcome measure was death or long-term major neurodevelopmental disability. Other outcomes included adverse effects of cooling and 'early' indicators of neurodevelopmental outcome. Three reviewers independently selected, assessed the quality of and extracted data from the included studies. Authors were contacted for further information. Meta-analyses were performed using relative risk and risk difference for dichotomous data, and weighted mean difference for continuous data with 95% confidence intervals. Two randomised controlled trials were included in this review, comprising 50 term infants with moderate/ severe encephalopathy and evidence of intrapartum asphyxia. There was no significant effect of therapeutic hypothermia on the combined outcome of death or major neurodevelopmental disability in survivors followed. No adverse effects of hypothermia on short term medical outcomes or on some 'early' indicators of neurodevelopmental outcome were detected. Although two small randomised controlled trials demonstrated neither evidence of benefit or harm, current evidence is inadequate to assess either safety or efficacy of therapeutic hypothermia in newborn infants with hypoxic ischaemic encephalopathy. Therapeutic hypothermia for encephalopathic asphyxiated newborn infants should be further evaluated in well designed randomised controlled trials.

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

Respiratory failure due to lung immaturity is a major cause of mortality in preterm infants. Although intermittent positive pressure ventilation (IPPV) saves lives, lung distortion during its use is associated with lung injury and chronic lung disease (CLD). Conventional IPPV is provided at 30-80 breaths per minute while a newer form of ventilation called high frequency oscillatory ventilation (HFOV) provides 'breaths' at 10-15 seconds. This has been shown to result in less lung injury in experimental studies. The objective of this review is to determine whether the elective use of high frequency oscillatory ventilation (HFOV) as compared to conventional ventilation in preterm infants who are mechanically ventilated for the respiratory distress syndrome decreases the incidence of chronic lung disease (CLD) without adverse effects. 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 handsearching by the Cochrane Collaboration, mainly in the English language. Expert informant's search in the Japanese language was made by Prof. Y. Ogawa. Randomized controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who are to be given IPPV. Randomization and commencement of treatment should have been as soon as possible after the start of IPPV and usually in the first 12 hours of life. The methodological quality of each trial was independently reviewed by the various authors. Each author extracted data separately; they were compared and differences were resolved. The standard method of the Cochrane Neonatal Review Group was used to synthesize the data using relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) for benefits, and number needed to harm (NNH) for adverse effects, were calculated. Meta-analysis of the six eligible studies comparing HFOV with CV revealed that there is no difference in mortality. There are trends toward decreases in CLD in survivors at 28-30 days, 'death or CLD at 28-30 days' and CLD in survivors at 36-37 weeks postmenstrual age or discharge in the HFOV group. However, there are trends towards increases in severe (grades 3 & 4) intraventricular hemorrhage (IVH) and in periventricular leukomalacia (PVL) in the HFOV group. HFOV results in a small increase in any air leak syndrome (ALS), [summary RR 1.20 (1.03, 1.39)]. Only 2 trials have included neurodevelopmental follow up and more survivors in the HFOV group are abnormal [summary RR 1.26 (1.01, 1.58)]. In the subgroup of four trials where a high volume strategy (HVS) was used, HFOV results in more favourable pulmonary outcomes. There are significantly lower rates of CLD in survivors at 28-30 days [summary RR 0.53 (0.36, 0.76)] and of 'death or CLD at 28-30 days' [summary RR 0.56 (0.40, 0.77) with a non-significant trend towards a reduction in oxygen use at 36-37 weeks postmenstrual age or discharge [summary RR 0.74 (0.55, 1.01)]. There were no differences in the rates of IVH or PVL. Of the four trials in the subgroup using surfactant routinely, three also used the HVS. The trends in results were similar with surfactant to those for the HVS subgroup analysis. One trial suggests that HFOV may reduce the cost of in-hospital care. In the subgroup of two trials (HIFI 1989, Rettwitz-Volk 1998) not using a HVS there is no effect of HFOV on the rate of CLD; however, there is an increase in the rate of PVL [summary RR 1.64 (1.02, 2.64). The overall meta-analyses is dominated by the large HIFI study which did not use the HVS recommended on the basis of animal studies, and in which surfactant was not available. Studies which used HVS have shown some benefits in short term measures of CLD without an in

Radiant warmers versus incubators for regulating body temperature in newborn infants.

This section is under preparation and will be included in the next issue. To assess the effects of radiant warmers versus incubators (in the neonatal period) on fluid and electrolyte balance, neonatal morbidity and mortality. The standard strategy of the Cochrane Neonatal Review Group was used. This includes searches of the Oxford Database of Perinatal Trials, Medline, previous reviews including cross references, abstracts, conference and symposia proceedings, expert informants, journal handsearching mainly in the English language. All randomised or quasi-randomised trials in which radiant warmers are compared to incubators in a neonatal population. Methods used to collect data from the included studies: Each author extracted data separately, then compared and resolved differences. A referee was sought for unresolved differences. Methods used to synthesise the data : Standard method of Neonatal Review Group with the use of weighted mean difference for outcome data measured on a continuous scale. A statistically significant increase in insensible water loss (IWL) was shown in neonates nursed under radiant warmers (WMD 0.94g/Kg/day, 95% CI 0.48, 1.41). A trend towards increased oxygen consumption which was not statistically significant was shown for the radiant warmer group (WMD 0. 27mL/kg/min, 95% CI -0.10, 0.63). A comparison of the radiant warmers with heat shields vs incubator without heat shields showed a similar trend for increased IWL in the radiant warmer group which was not statistically significant (WMD 1.00g/kg/day, 95% CI -0.10, 2. 10). No difference was shown in the rate of oxygen consumption when radiant warmers with heat shields were compared to incubators (WMD -0.05, 95% CI -0.84, 0.74). Radiant warmers result in increased IWL compared to incubators which needs to be taken into account when calculating daily fluid requirements.The results of this review do not provide sufficient evidence on important outcomes with the use of radiant warmers vs incubators to guide clinical practice. Further randomised controlled trials are required to assess the role of radiant warmers in neonatal care with particular attention to the extremely low birthweight population.

Steroid therapy for meconium aspiration syndrome in newborn infants.

Meconium aspiration syndrome may cause severe respiratory distress in the newborn infant, with an associated high morbidity and mortality. A chemical pneumonitis is believed to occur secondary to bile, bile acids and pancreatic secretions contained in meconium. It has therefore been hypothesised that corticosteroids may be of benefit in the management of this condition through their anti-inflammatory properties. The objective of this review was to determine whether steroid therapy for meconium aspiration syndrome decreases the morbidity and mortality associated with this condition without adverse effects. Searches were made of PREMEDLINE and MEDLINE from 1966 to April 2003, CINAHL back to 1982, Current Contents back to 1998, The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2003) and Oxford Database of Perinatal Trials. The search included cross-referencing of previous reviews, and a review of abstracts, conference and symposia proceedings published in Pediatric Research from 1993 to 2003. Randomised controlled trials and quasi-randomised trials comparing steroid treatment to no steroid treatment for neonates with meconium aspiration syndrome were considered for this review. The methodological quality of each trial was assessed independently by each author. Data were extracted, analysed and results reviewed independently by each author. Meta-analysis was performed with RevMan 4.2, using the fixed effects model. Mean difference (MD) and weighted mean differences (WMD) with 95% confidence intervals in brackets for continuous variables and Relative Risk (RR) with 95% confidence intervals for categorical data were reported. Three randomised controlled trials were identified. Two trials, by Wu 1999 (50 participants) and Yeh 1977 (35 participants), were included in the review. The trial by Davey 1995, as yet unpublished, was excluded from this review as insufficient information about methodology and results were available. On meta-analysis, there was no significant reduction in mortality [typical RR 0.95 (0.20, 4.58)]. A small but significant increase in duration of oxygen therapy was seen with the use of steroids [WMD 30.0 hours (8.4, 51.6)]. There was no significant difference in duration of hospital stay in the study by Wu 1999 [MD 0.00 days (-3.09, 3.09)]. Duration of mechanical ventilation was reported by Wu 1999 with no significant difference seen [MD -1.10 days (-2.79, 0.59)]. Incidence of air leak was reported by Yeh 1977 with no significant difference detected [RR 0.64 (0.18, 2.26)]. Long-term outcome was not reported in either of the two studies. At present, there is insufficient evidence to assess the effects of steroid therapy in the management of meconium aspiration syndrome. A further large randomised controlled trial assessing potential benefits and harm would be required to determine its role.

Deep versus shallow suction of endotracheal tubes in ventilated neonates and young infants.

Mechanical ventilation is commonly used in Neonatal Intensive Care Units to assist breathing in a variety of conditions. Mechanical ventilation is achieved through the placement of an endotracheal tube (ETT) which is left in-situ. The ETT is suctioned to prevent a build-up of secretions and therefore blockage of the airway. Methods of suctioning the endotracheal tube vary according to institutional practice and the individual clinician performing the task. The depth of suctioning is one of these variables. The catheter may be passed to the tip of the ETT or beyond the tip into the trachea or bronchi to facilitate removal of secretions. However, trauma to the lower airways may result from the suction catheter being passed into the airway beyond the tip of the endotracheal tube. To compare the effectiveness and complications of deep (catheter passed beyond the tip of the ETT) versus shallow (catheter passed to length of ETT only) suctioning of the endotracheal tube in ventilated infants. Using text words and subject headings relevant to endotracheal suctioning, searches were made of the Oxford Database of Perinatal Trials, Cochrane Register of Controlled Trials (The Cochrane Library, Issue 3, 2002), MEDLINE (from January 1966 to December 2002, all languages), CINAHL (from 1982 to 2002). In addition, a call was placed on the list servers, NICU-NET and Neonatal-Talk for unpublished trials, conference presentations and current trials. Controlled trials using random or quasi-random allocation of neonates receiving ventilatory support via an endotracheal tube to either deep or shallow endotracheal suctioning. No studies were found meeting the criteria for inclusion in this review No studies were found meeting the criteria for inclusion in this review There is no evidence from randomised controlled trials concerning the benefits or risks of deep versus shallow suctioning of endo-tracheal tubes in ventilated neonates and infants. Further high quality research would be required to conclusively establish whether there are any benefits to deep or shallow suctioning. However, as it may be considered unethical to conduct a trial of deep suctioning given anecdotal evidence regarding possible damage to the airway, it is proposed that a randomised controlled trial comparing deep with shallow suctioning may be considered in a NICU where the standard practice includes a deep suctioning technique.

Supplemental oxygen for the treatment of prethreshold retinopathy of prematurity.

Oxygen has long been implicated in the pathogenesis of retinopathy of prematurity (ROP) and is rigorously monitored in today's neonatal intensive care units. Recent research using a feline model has shown an improvement in ROP outcome of kittens treated with supplemental oxygen. Current treatment for ROP by retinal ablation is not without complications so a non-invasive method of treatment is preferred. The possible effects of long term oxygen supplementation on chronic lung disease, length of hospital stay and growth and development are, however, unknown. To determine whether, in preterm or low birth weight infants with prethreshold ROP, targeting higher as compared to normal transcutaneous oxygen levels or pulse oximetry levels when using supplemental oxygen reduces the progression of ROP to threshold disease and improves visual outcome without any adverse effects. The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Oxford Database of Perinatal Trials, MEDLINE, previous reviews including cross references, abstracts, conferences and symposia proceedings, expert informants and journal handsearching. An additional literature search of the MEDLINE (1966-June 2002), EMBASE (1980-April 2002), and CINAHL (1982-April 2002) databases was conducted in order to locate any trials in addition to those provided by the Cochrane Controlled Trials Register (CENTRAL/CCTR, The Cochrane Library Issue 2, 2002). All randomised or quasi randomised studies comparing higher versus normal target oxygen levels in preterm or low birthweight infants with prethreshold ROP were eligible for inclusion. The methodological quality of the one eligible trial was assessed independently by two authors for the degree of selection, performance, attrition and detection bias. Data regarding clinical outcomes including progression to threshold ROP, blindness or severe visual impairment, mortality, respiratory morbidities and long term growth were extracted and reviewed independently by two authors. Results were compared and differences resolved as required. Data analysis was conducted according to the standards of the Cochrane Neonatal Review Group. The one trial included in this review enrolled 649 infants. There was a trend for supplemental oxygen to reduce the progression to threshold ROP, however this did not reach statistical significance (RR 0.84, 95% CI 0.70, 1.02). A subgroup analysis of those infants without plus disease showed significantly fewer infants progressing to threshold ROP in infants treated with supplemental oxygen. However this analysis was not pre-specified so these results should be interpreted with caution. No significant effects were detected on blindness or severe visual function at three months corrected age, mortality, pneumonia, chronic lung disease or weight gain. Adverse pulmonary events were more common in the higher oxygen saturation group and these infants were in hospital and on supplemental oxygen for longer. Longer term visual outcomes were not reported. The results of this systematic review do not show a statistically significant reduction in the rate of progression to threshold ROP with supplemental oxygen treatment, but reveal increased adverse pulmonary sequelae with higher oxygen targeting in this group of preterm infants. Future research needs to be directed towards the question of whether infants without plus disease are more likely to respond to supplemental oxygen therapy than those with plus disease.

Infant position in neonates receiving mechanical ventilation.

Several body positions other than standard supine position have been used in patients undergoing intensive care for reducing the incidence of pressure ulcers of the skin, contractures or ankylosis and for improving the patient's well being. In patients from different age groups undergoing mechanical ventilation (MV), it has been observed that particular positions such as prone position may improve some respiratory parameters. Benefits from these positions have not been clearly defined in Neonatology, a field where it is common that patients require mechanical ventilation sometimes during extended time periods. To assess the effects on both short and long-term outcomes of different positioning of newborn infants receiving MV. Databases searched (up to January 2002) were the Oxford Database of Perinatal Trials, CINAHL, MEDLINE, EMBASE and Cochrane Controlled Trials Register (The Cochrane Library, Issue 1, 2002). Hand searches of proceedings of the Society for Pediatric Research from 1990 to January 2002 were used to identify unpublished studies. Randomised or quasi randomised clinical trials comparing different positions in newborns receiving mechanical ventilation. Three independent and unblinded reviewers assessed the trials for inclusion in the review and extracted the data. Data were double-checked and entered into the Review Manager software. Ten trials involving 164 infants were included in this review. Several positions were compared: prone vs. supine, prone vs. lateral right, lateral right vs. supine, lateral left vs. supine, lateral right vs. lateral left and good lung dependent vs. good lung uppermost. Apart from one of the two studies that compared lateral right vs. lateral left positions, all the included studies had a crossover design. Comparing prone vs. supine position, an increase in arterial P02 in the prone position of between 2.75 and 9.72 mm Hg (95%CI) was observed (one trial). When % hemoglobin oxygen saturation was measured with pulse oximetry, improvement in the prone position was from 1.17 to 4.36% (typical effect based on four trials). It was not possible to establish whether this effect remained once the intervention was stopped. Negative effects from the interventions were not described, although this issue was not studied enough. Effects of position on other outcomes were not statistically significant; however, these cannot be excluded considering the small numbers that were studied. The prone position was found to slightly improve the oxygenation in neonates undergoing mechanical ventilation. However, we found no evidence concerning whether particular body positions during mechanical ventilation of the neonate are effective in producing sustained and clinically relevant improvements.

Early postnatal (

Chronic lung disease (CLD) remains a major problem in neonatal intensive care units. Persistent inflammation in the lungs is the most likely underlying pathogenesis. Corticosteroids have been used to either prevent or treat CLD because of their potent anti-inflammatory effects. To determine if postnatal corticosteroid treatment is of benefit in the prevention of chronic lung disease (CLD) in the preterm infant. This review examines the outcome of trials where preterm infants at risk of CLD were given postnatal steroids within 96 hours after birth. Randomised controlled trials of postnatal corticosteroid therapy were sought from the Oxford Database of Perinatal Trials, the Cochrane Controlled Trials Register, MEDLINE (1966 - October 2002), hand searching paediatric and perinatal journals, examining previous review articles and information received from practising neonatologists. Authors of all studies were contacted, where possible, to confirm details of reported follow-up studies, or to obtain any information about long-term follow-up where none had been reported. Randomised controlled trials of postnatal corticosteroid treatment within 96 hours of birth (early) in high risk preterm infants were selected for this review. Data regarding clinical outcomes including mortality, CLD (including late rescue with corticosteroids, and need for home oxygen therapy), death or CLD, failure to extubate, complications during the primary hospitalisation (including infection, hyperglycaemia, hypertension, pulmonary air leak, patent ductus arteriosus (PDA), severe intraventricular haemorrhage (IVH), periventricular leucomalacia (PVL), necrotising enterocolitis (NEC), gastrointestinal bleeding, intestinal perforation, severe retinopathy of prematurity (ROP), and long-term outcome (including blindness, deafness, cerebral palsy and major neurosensory disability) were abstracted and analysed using RevMan 4.1. Twenty-one randomised controlled trials enrolling a total of 3072 participants were eligible for inclusion in this review. A meta-analysis of these trials demonstrated significant benefits as regards earlier extubation and decreased risks of CLD at both 28 days and 36 weeks, death or CLD at 28 days and 36 weeks, PDA and severe ROP. There were no significant differences in the rates of neonatal or subsequent mortality, infection, severe IVH, PVL, NEC or pulmonary haemorrhage. Gastrointestinal bleeding and intestinal perforation were important adverse effects and the risks of hyperglycaemia and hypertension were also increased. In the nine trials which have reported late outcomes, several adverse neurological effects were found at follow-up examinations of survivors treated with early steroids: developmental delay (not defined), cerebral palsy and abnormal neurological exam. However, major neurosensory disability was not significantly increased, either overall in the 4 studies where this outcome could be determined, or in the 2 individual studies where the rate of cerebral palsy and abnormal neurological exam were significantly increased. Moreover, the rate of the combined outcome of death or major neurosensory disability was not significantly increased. The benefits of early postnatal corticosteroid treatment (< 96 hours) may not outweigh the known or potential adverse effects of this treatment. Although early steroid treatment facilitates extubation and reduces the risk of chronic lung disease, it causes short-term adverse effects including gastrointestinal bleeding, intestinal perforation, hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure. Long-term follow-up studies report an increased risk of abnormal neurological exam and cerebral palsy. However, the methodological quality of the studies determining the long-term outcome is limited in some cases, the children have been assessed predominantly before school age, and no study has been sufficiently powered to detect important adverse long-term neurosensory outcomes. There is a compelling need for the long term follow-up and reporting of late outcomes, especially neurological and developmental outcomes, among surviving infants who participated in all randomised trials of early postnatal corticosteroid treatment. The role of inhaled steroids remains to be elucidated.

Indomethacin for asymptomatic patent ductus arteriosus in preterm infants.

Patent Ductus Arteriosus (PDA remains a significant cause of mortality and morbidity in premature infants. Indomethacin is an effective treatment to close a PDA, and has been used for many years with several treatment regimes, including prophylactic use in all at risk premature infants. There are however concerns regarding adverse side effects of indomethacin. By targeting a group of infants with an asymptomatic PDA, rather than treating all VLBW infants prophylactically, indomethacin use would be restricted, limiting the possibility of significant side effects to those with greater chance of benefit. To assess whether in premature neonates with asymptomatic PDA, treatment with indomethacin improves short and long term outcomes; in particular: incidence of symptomatic PDA, mortality, chronic neonatal lung disease (CLD), intraventricular haemorrhage (IVH), retinopathy of prematurity (ROP), neurodevelopmental outcome, length of ventilation. Standard strategies of the Cochrane Neonatal Review Group were used. Searches were made of the Oxford Database of Perinatal Trials, MEDLINE and EMBASE from 1966 to September 2002, CINAHL from 1982 to September 2002, and the Cochrane Controlled Trials Register (CENTRAL/CCTR) in The Cochrane Library, Issue 3, 2002. Searches were also made of previous reviews including cross-referencing, abstracts, and conference and symposia proceedings published in Pediatric Research. All randomised controlled trials of indomethacin compared with placebo or no intervention for the treatment of asymptomatic PDA in premature infants were eligible. Standard methods of the Cochrane Neonatal Review Group were used. Trials identified by the search strategy were independently reviewed by each author and assessed for eligibility and trial quality. Data were then extracted independently by each author and compared, with any differences resolved following discussion. Any additional information required was requested from trial authors. Only published data was available for review. Results are expressed as typical relative risk and typical risk difference for dichotomous outcomes, and weighted mean difference for continuous variables. Three small trials involving a total of 97 infants were included. Meta analysis of combined data was possible for seven outcomes. Treatment of an asymptomatic PDA with indomethacin significantly reduced the incidence of symptomatic PDA (RR 0.36, 95% CI 0.19, 0.68) and duration of supplemental oxygen (WMD -12.5, 95% CI -23.8, -1.26). There was no evidence of effect on mortality (RR 1.32, 95% CI 0.45, 3.86), CLD (RR 0.91, 95% CI 0.62, 1.35), IVH (RR 1.21, 95% CI 0.62, 2.37), ROP (RR 0.68, 95% CI 0.26, 1.78), or length of ventilation (WMD -7.00 days, 95%CI -17.33, 3.34). Long term neurodevelopmental outcomes were not reported. One trial reported a significant reduction in the duration of supplemental oxygen following treatment with indomethacin in the subgroup of infants with birth weight less than 1000g. This review demonstrates a significant decrease in the incidence of symptomatic PDA following treatment of an asymptomatic PDA with indomethacin. There is also a small but statistically significant decrease in the duration of requirement for supplemental oxygen. There are no reported long term outcomes in the included trials, and so it is not possible to comment on possible long term effects. Further studies are required to determine the long term benefits or harms of closing a PDA prior to the onset of symptoms.

Moderately early (7-14 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants.

Corticosteroids have been used late in the neonatal period to treat chronic lung disease (CLD) in preterm babies, and early to try to prevent it. CLD is likely to be the result of persisting inflammation in the lung and the use of powerful anti-inflammatory drugs like dexamethasone has some rationale. Early use tends to be associated with increased adverse effects so that studies of moderately early treatment (7-14 days postnatal) might have the dual benefits of fewer side effects and onset of action before chronic inflammation is established. To determine if moderately early (7-14 days) postnatal corticosteroid treatment vs control (placebo or nothing) is of benefit in the prevention and/or treatment of early chronic lung disease in the preterm infant. Randomised controlled trials of postnatal corticosteroid therapy were sought from the Oxford Database of Perinatal Trials, Cochrane Database of Controlled Trials, MEDLINE (1966 - October 2002), hand searching paediatric and perinatal journals, examining previous review articles and information received from practicing neonatologists. Authors of all studies were contacted, where possible, to confirm details of reported follow-up studies, or to obtain any information about long-term follow-up where none had been reported. Randomised controlled trials of postnatal corticosteroid treatment from 7-14 days of birth in high risk preterm infants were selected for this review. Data regarding clinical outcomes including mortality, CLD (including late rescue with corticosteroids, or need for home oxygen therapy), death or CLD, failure to extubate, complications during the primary hospitalisation (including infection, hyperglycaemia, hypertension, hypertrophic cardiomyopathy, pneumothorax, severe intraventricular haemorrhage (IVH), necrotizing enterocolitis (NEC), gastrointestinal bleeding, and severe retinopathy of prematurity (ROP)), and long term outcome (including blindness, deafness, cerebral palsy and major neurosensory disability), were abstracted and analysed using RevMan 4.1. Seven studies enrolling a total of 669 participants were eligible for inclusion in this review. Moderately early steroid treatment (vs placebo or nothing) reduced mortality by 28 days, chronic lung disease at 28 days and 36 weeks, and death or chronic lung disease at 28 days or 36 weeks. Earlier extubation was facilitated. There was no significant effect on the rates of pneumothorax, severe ROP, or NEC. Adverse effects included hypertension, hyperglycaemia, gastrointestinal bleeding, hypertrophic cardiomyopathy and infection. Steroid-treated infants were less likely to need late rescue with dexamethasone. There were limited data from four studies of long term follow-up; these did not show evidence of an increase in adverse neurological outcomes. Moderately early corticosteroid therapy (started at 7-14 days) reduces neonatal mortality and CLD, but at the cost of important short term adverse effects. Limited evidence concerning long term effects is provided by the trials included in this review. The methodological quality of the studies determining the long-term outcome is limited in some cases, the children have been assessed predominantly before school age, and no study has been sufficiently powered to detect important adverse long-term neurosensory outcomes. Therefore, given the risk:benefit ratio of short-term effects and the limited long-term follow-up data, it seems appropriate to reserve moderately early corticosteroid treatment to infants who cannot be weaned from mechanical ventilation and to minimise the dose and duration of any course of therapy. More research is urgently needed, including long term follow-up of survivors included in previous and any future trials, before the benefits and risks of postnatal steroid treatment, including initiation at 7-14 days, can be reliably assessed (See DART study; Doyle 2000a).