Use of evidence-based practices in pregnancy and childbirth: South East Asia Optimising Reproductive and Child Health in Developing Countries project.

BACKGROUND: The burden of mortality and morbidity related to pregnancy and childbirth remains concentrated in developing countries. SEA-ORCHID (South East Asia Optimising Reproductive and Child Health In Developing countries) is evaluating whether a multifaceted intervention to strengthen capacity for research synthesis, evidence-based care and knowledge implementation improves adoption of best clinical practice recommendations leading to better health for mothers and babies. In this study we assessed current practices in perinatal health care in four South East Asian countries and determined whether they were aligned with best practice recommendations. METHODOLOGY/PRINCIPAL FINDINGS: We completed an audit of 9550 medical records of women and their 9665 infants at nine hospitals; two in each of Indonesia, Malaysia and The Philippines, and three in Thailand between January-December 2005. We compared actual clinical practices with best practice recommendations selected from the Cochrane Library and the World Health Organization Reproductive Health Library. Evidence-based components of the active management of the third stage of labour and appropriately treating eclampsia with magnesium sulphate were universally practiced in all hospitals. Appropriate antibiotic prophylaxis for caesarean section, a beneficial form of care, was practiced in less than 5% of cases in most hospitals. Use of the unnecessary practices of enema in labour ranged from 1% to 61% and rates of episiotomy for vaginal birth ranged from 31% to 95%. Other appropriate practices were commonly performed to varying degrees between countries and also between hospitals within the same country. CONCLUSIONS/SIGNIFICANCE: Whilst some perinatal health care practices audited were consistent with best available evidence, several were not. We conclude that recording of clinical practices should be an essential step to improve quality of care. Based on these findings, the SEA-ORCHID project team has been developing and implementing interventions aimed at increasing compliance with evidence-based clinical practice recommendations to improve perinatal practice in South East Asia.

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). 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 cycles per second. This 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) in preterm infants who are mechanically ventilated for respiratory distress syndrome (RDS), on the incidence of chronic lung disease, mortality and other complications associated with prematurity and assisted ventilation. 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 April 2007. SELECTION CRITERIA: Randomised controlled trials comparing HFOV and CV in preterm or low birth weight infants with pulmonary dysfunction, mainly due to RDS, who were given IPPV. Randomisation and commencement of treatment needed to be as soon as possible after the start of IPPV 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: Fifteen eligible studies of 3,585 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. Subgroups of trials showed a significant reduction in CLD with HFOV when high volume strategy for HFOV 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.

WITHDRAWN: Antiplatelet agents for preventing and treating pre-eclampsia.

BACKGROUND: Pre-eclampsia is associated with deficient intravascular production of prostacyclin, a vasodilator, and excessive production of thromboxane, a platelet-derived vasoconstrictor and stimulant of platelet aggregation. These observations led to the hypotheses that antiplatelet agents, and low dose aspirin in particular, might prevent or delay the development of pre-eclampsia. OBJECTIVES: To assess the effectiveness and safety of antiplatelet agents when given to women at risk of developing pre-eclampsia, and to those with established pre-eclampsia. SEARCH STRATEGY: This review drew on the search strategy developed for the Pregnancy and Childbirth Group as a whole. The Cochrane Controlled Trials Register was also searched, The Cochrane Library 1999 Issue 1, Embase was searched from 1994-1999 and hand searches were performed of the congress proceedings of the International and European Societies for the Study of Hypertension in Pregnancy. SELECTION CRITERIA: All randomised trials comparing antiplatelet agents with either placebo or no antiplatelet agent during pregnancy. Quasi random study designs were excluded. Participants were pregnant women considered to be at risk of developing pre-eclampsia, and those with pre-eclampsia before delivery. Women treated postpartum were excluded. Interventions were any comparisons of an antiplatelet agent (such as low dose aspirin or dipyridamole) with either placebo or no antiplatelet agent. DATA COLLECTION AND ANALYSIS: Assessment of trials for inclusion in the review and extraction of data was performed independently and unblinded by two reviewers. Data were entered into the Review Manager software and double checked. MAIN RESULTS: Forty two trials involving over 32,000 women were included in this review, with 30,563 women in the prevention trials. There is a 15% reduction in the risk of pre-eclampsia associated with the use of antiplatelet agents [32 trials with 29,331 women; relative risk (RR) 0.85, 95% confidence interval (0.78, 0.92); Number needed to treat (NNT) 89, (59, 167)]. This reduction is regardless of risk status at trial entry or whether a placebo was used, and irrespective of the dose of aspirin or gestation at randomisation.Twenty three trials (28,268 women) reported preterm delivery. There is a small (8%) reduction in the risk of delivery before 37 completed weeks [RR 0.92, (0.88, 0.97); NNT 72 (44, 200)]. Baby deaths were reported in 30 trials (30,093 women). Overall there is a 14% reduction in baby deaths in the antiplatelet group [RR 0.86, (0.75, 0.98); NNT 250 (125, >10000)]. Small for gestational age babies were reported in 25 trials (20,349 women), with no overall difference between the groups, RR 0.92, (0.84, 1.01). There were no significant differences between treatment and control groups in any other measures of outcome. Five trials compared antiplatelet agents with placebo or no antiplatelet agent for the treatment of pre-eclampsia. There are insufficient data for any firm conclusions about the possible effects of these agents when used for treatment of pre-eclampsia. AUTHORS' CONCLUSIONS: Antiplatelet agents, in this review largely low dose aspirin, have small-moderate benefits when used for prevention of pre-eclampsia. Further information is required to assess which women are most likely to benefit, when treatment should be started, and at what dose.

Antiplatelet agents for preventing pre-eclampsia and its complications.

BACKGROUND: Pre-eclampsia is associated with deficient intravascular production of prostacyclin, a vasodilator, and excessive production of thromboxane, a vasoconstrictor and stimulant of platelet aggregation. These observations led to the hypotheses that antiplatelet agents, low-dose aspirin in particular, might prevent or delay development of pre-eclampsia. OBJECTIVES: To assess the effectiveness and safety of antiplatelet agents for women at risk of developing pre-eclampsia. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (July 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2005, Issue 1), EMBASE (1994 to November 2005) and handsearched congress proceedings of the International and European Societies for the Study of Hypertension in Pregnancy. SELECTION CRITERIA: All randomised trials comparing antiplatelet agents with either placebo or no antiplatelet agent were included. Quasi-random studies were excluded. Participants were pregnant women at risk of developing pre-eclampsia. Interventions were any comparisons of an antiplatelet agent (such as low-dose aspirin or dipyridamole) with either placebo or no antiplatelet. DATA COLLECTION AND ANALYSIS: Two authors assessed trials for inclusion and extracted data independently. MAIN RESULTS: Fifty-nine trials (37,560 women) are included. There is a 17% reduction in the risk of pre-eclampsia associated with the use of antiplatelet agents ((46 trials, 32,891 women, relative risk (RR) 0.83, 95% confidence interval (CI) 0.77 to 0.89), number needed to treat (NNT) 72 (52, 119)). Although there is no statistical difference in RR based on maternal risk, there is a significant increase in the absolute risk reduction of pre-eclampsia for high risk (risk difference (RD) -5.2% (-7.5, -2.9), NNT 19 (13, 34)) compared with moderate risk women (RD -0.84 (-1.37, -0.3), NNT 119 (73, 333)). Antiplatelets were associated with an 8% reduction in the relative risk of preterm birth (29 trials, 31,151 women, RR 0.92, 95% CI 0.88 to 0.97); NNT 72 (52, 119)), a 14% reduction in fetal or neonatal deaths (40 trials, 33,098 women, RR 0.86, 95% CI 0.76 to 0.98); NNT 243 (131, 1,666) and a 10% reduction in small-for-gestational age babies (36 trials, 23,638 women, RR 0.90, 95% CI0.83 to 0.98). There were no statistically significant differences between treatment and control groups for any other outcomes. AUTHORS' CONCLUSIONS: Antiplatelet agents, largely low-dose aspirin, have moderate benefits when used for prevention of pre-eclampsia and its consequences. Further information is required to assess which women are most likely to benefit, when treatment is best started, and at what dose.

Antihypertensive drug therapy for mild to moderate hypertension during pregnancy.

BACKGROUND: Mild to moderate hypertension during pregnancy is common. Antihypertensive drugs are often used in the belief that lowering blood pressure will prevent progression to more severe disease, and thereby improve outcome. OBJECTIVES: To assess the effects of antihypertensive drug treatments for women with mild to moderate hypertension during pregnancy. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (March 2006), the Cochrane Central Register of Controlled Trials (The Cochrane Library 2005, Issue 3), MEDLINE (1966 to November 2005), LILACS (1984 to November 2005) and EMBASE (1974 to November 2005). SELECTION CRITERIA: All randomised trials evaluating any antihypertensive drug treatment for mild to moderate hypertension during pregnancy defined, whenever possible, as systolic blood pressure 140 to 169 mmHg and diastolic blood pressure 90 to 109 mmHg. Comparisons were of one or more antihypertensive drug(s) with placebo, with no antihypertensive drug, or with another antihypertensive drug, and where treatment was planned to continue for at least seven days. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. MAIN RESULTS: Forty-six trials (4282 women) were included. Twenty-eight trials compared an antihypertensive drug with placebo/no antihypertensive drug (3200 women). There is a halving in the risk of developing severe hypertension associated with the use of antihypertensive drug(s) (19 trials, 2409 women; relative risk (RR) 0.50; 95% confidence interval (CI) 0.41 to 0.61; risk difference (RD) -0.10 (-0.12 to -0.07); number needed to treat (NNT) 10 (8 to 13)) but little evidence of a difference in the risk of pre-eclampsia (22 trials, 2702 women; RR 0.97; 95% CI 0.83 to 1.13). Similarly, there is no clear effect on the risk of the baby dying (26 trials, 3081 women; RR 0.73; 95% CI 0.50 to 1.08), preterm birth (14 trials, 1992 women; RR 1.02; 95 % CI 0.89 to 1.16), or small-for-gestational-age babies (19 trials, 2437 women; RR 1.04; 95 % CI 0.84 to 1.27). There were no clear differences in any other outcomes. Nineteen trials (1282 women) compared one antihypertensive drug with another. Beta blockers seem better than methyldopa for reducing the risk of severe hypertension (10 trials, 539 women, RR 0.75 (95 % CI 0.59 to 0.94); RD -0.08 (-0.14 to 0.02); NNT 12 (6 to 275)). There is no clear difference between any of the alternative drugs in the risk of developing proteinuria/pre-eclampsia. Other outcomes were only reported by a small proportion of studies, and there were no clear differences. AUTHORS' CONCLUSIONS: It remains unclear whether antihypertensive drug therapy for mild to moderate hypertension during pregnancy is worthwhile.

Drugs for treatment of very high blood pressure during pregnancy.

BACKGROUND: Very high blood pressure during pregnancy poses a serious threat to women and their babies. Antihypertensive drugs lower blood pressure. Their comparative effects on other substantive outcomes, however, is uncertain. OBJECTIVES: To compare different antihypertensive drugs for very high blood pressure during pregnancy. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group Trials Register (28 February 2006) and CENTRAL (The Cochrane Library 2006, Issue 2). SELECTION CRITERIA: Studies were randomised trials. Participants were women with severe hypertension during pregnancy. Interventions were comparisons of one antihypertensive drug with another. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data. MAIN RESULTS: Twenty-four trials (2949 women) with 12 comparisons were included. Women allocated calcium channel blockers rather than hydralazine were less likely to have persistent high blood (five trials, 263 women; 6% versus 18%; relative risk (RR) 0.33, 95% confidence interval (CI) 0.15 to 0.70). Ketanserin was associated with more persistent high blood pressure than hydralazine (four trials, 200 women; 27% versus 6%; RR 4.79, 95% CI 1.95 to 11.73), but fewer side-effects (three trials, 120 women; RR 0.32, 95% CI 0.19 to 0.53) and a lower risk of HELLP (Haemolysis, Elevated Liver enzymes and Lowered Platelets) syndrome (one trial, 44 women, RR 0.20, 95% CI 0.05 to 0.81). Labetalol was associated with a higher risk of hypotension (one trial 90 women; RR 0.06, 95% CI 0.00 to 0.99) and caesarean section (RR 0.43, 95% CI 0.18 to 1.02) than diazoxide. Data were insufficient for reliable conclusions about other outcomes. The risk of persistent high blood pressure was greater for nimodipine compared to magnesium sulphate (two trials 1683 women; 47% versus 65%; RR 0.84, 95% CI 0.76 to 0.93). Nimodipine was also associated with a higher risk of eclampsia (RR 2.24, 95% CI 1.06 to 4.73) and respiratory difficulties (RR 0.28, 95% CI 0.08 to 0.99), but fewer side-effects (RR 0.68, 95% CI 0.54 to 0.86) and less postpartum haemorrhage (RR 0.41, 95% CI 0.18 to 0.92) than magnesium sulphate. Stillbirths and neonatal deaths were not reported. There are insufficient data for reliable conclusions about the comparative effects of any other drugs. AUTHORS' CONCLUSIONS: Until better evidence is available, the choice of antihypertensive should depend on the clinician's experience and familiarity with a particular drug, and on what is known about adverse effects. Exceptions are diazoxide, ketanserin, nimodipine and magnesium sulphate, which are probably best avoided.

Prenatal predictors of chronic lung disease in very preterm infants.

OBJECTIVE: To identify prenatal risk factors for chronic lung disease (CLD) at 36 weeks postmenstrual age in very preterm infants. POPULATION: Data were collected prospectively as part of the ongoing audit of the Australian and New Zealand Neonatal Network (ANZNN) of all infants born at less than 32 weeks gestation admitted to all tertiary neonatal intensive care units in Australia and New Zealand. METHODS: Prenatal factors up to 1 minute of age were examined in the subset of infants born at gestational ages 22-31 weeks during 1998-2001, and who survived to 36 weeks postmenstrual age (n = 11 453). Factors that were significantly associated with CLD at 36 weeks were entered into a multivariate logistic regression model. RESULTS: After adjustment, low gestational age was the dominant risk factor, with an approximate doubling of the odds with each week of decreasing gestational age from 31 to less than 25 weeks (trend p<0.0001). Birth weight for gestational age also had a dose-response effect: the lower the birth weight for gestational age, the greater the risk, with infants below the third centile having 5.67 times greater odds of CLD than those between the 25th and 75th centile (trend p<0.0001). There was also a significantly increased risk for male infants (odds ratio 1.51 (95% confidence interval 1.36 to 1.68), p<0.0001). CONCLUSIONS: These population based data show that the prenatal factors low gestational age, low birth weight for gestational age, and male sex significantly predict the development of chronic respiratory insufficiency in very preterm infants and may assist clinical decision about delivery.

Variation in rates of severe retinopathy of prematurity among neonatal intensive care units in the Australian and New Zealand Neonatal Network.

AIM: To analyse variations in rates of severe retinopathy of prematurity (ROP) among neonatal intensive care units (NICUs) in the Australian and New Zealand Neonatal Network (ANZNN), adjusting for sampling variability and for case mix. METHODS: 25 NICUs were included in the study of 2105 infants born at less than 29 weeks in 1998 and 1999, who survived to 36 weeks post-menstrual age and were examined for ROP. The observed NICU rates of severe ROP were adjusted for case mix using logistic regression on gestation, weight for gestational age and sex, and for sampling variability using shrinkage estimates. The corrected rate in the best 20% of NICUs was identified and NICU variations in rates were compared with those in 2000-1. RESULTS: The overall (unadjusted) rate of severe ROP in the NICUs was 9.6% (interquartile range 5.4-12.8%). After adjusting for both case mix and sampling variability there remained significant variation among the NICUs. 20% of NICUs had a rate of severe ROP

Prophylactic nasal continuous positive airways pressure for preventing morbidity and mortality in very preterm infants.

BACKGROUND: Cohort studies (Avery 1987; Jonsson 1997) have suggested that early post-natal nasal continuous positive airways pressure (CPAP) may be beneficial in reducing the need for intubation and intermittent positive pressure ventilation, and in preventing chronic lung disease in preterm or low birth weight infants. OBJECTIVES: To determine if prophylactic nasal CPAP commenced soon after birth regardless of respiratory status in the very preterm or very low birth weight infant reduces the use of IPPV and the incidence of chronic lung disease (CLD) without adverse effects. SEARCH STRATEGY: The search was updated in April 2005. The standard search strategy of the Neonatal Review Group was used. This included searches of the Oxford Database of Perinatal Trials, Cochrane Library Issue 1 2005, MEDLINE 1966-April 2005, previous reviews including cross references, abstracts, conferences, symposia, proceedings, expert informants, journal hand searching mainly in the English language. SELECTION CRITERIA: All trials using random or quasi-random patient allocation of very preterm infants < 32 weeks gestation and / or < 1500 gms at birth were eligible. Comparison had to be between prophylactic nasal CPAP commencing soon after birth regardless of the respiratory status of the infant compared with "standard" methods of treatment where CPAP or IPPV is used for a defined respiratory condition. DATA COLLECTION AND ANALYSIS: Standard methods of the Cochrane Collaboration and its Neonatal Review Group, including independent assessment of trial quality and extraction of data by each author, were used. Data were analysed using relative risk (RR). Meta-analysis was performed using a fixed effects model. MAIN RESULTS: There are no statistically significant differences in any of the outcomes studied in either of the eligible trials (Han 1987; Sandri 2004) reporting on 82 and 230 infants respectively. In Han 1987 there are trends towards increases in the incidence of BPD at 28 days [RR 2.27 (0.77, 6.65)], death [RR 3.63 (0.42, 31.08)] and any IVH [RR 2.18 (0.84, 5.62)] in the CPAP group. In Sandri 2004 there is a trend towards an increase in IVH grade 3 or 4 [RR 3.0 (0.96, 28.42)] in the CPAP group. No outcome was significantly different in any of the meta-analyses. AUTHORS' CONCLUSIONS: There is currently insufficient information to evaluate the effectiveness of prophylactic nasal CPAP in very preterm infants. Neither of the included studies reviewed showed evidence of benefit in reducing the use of IPPV. The tendency for some adverse outcomes to be increased is of concern and further multicentre randomized controlled trials are needed to clarify this.

Trends in place of birth for preterm infants in New South Wales, 1992-2001.

OBJECTIVE: To examine trends in preterm births, especially those less than 33 weeks gestation, occurring in perinatal centres in New South Wales (NSW) from 1992 to 2001. METHODS: Population data were obtained from the NSW Midwives' Data Collection. Trends in the proportion of births in perinatal centres by gestation and by type of preterm birth (spontaneous or elective), and in Apgar scores and neonatal mortality were determined. RESULTS: The preterm birth rate increased from 6.1% in 1992 to 6.7% in 2001. Factors contributing to the increase in preterm births were multiple births and elective preterm deliveries. Births less than 33 weeks gestation in perinatal centres increased from 76% to 83% and for multiple births from 77% to 87%. This coincided with a decrease in 1-minute Apgar scores less than 4 but no significant change in 5-minute Apgar scores or neonatal mortality. CONCLUSIONS: Progress has been made towards the National Health and Medical Research Council guideline that births less than 33 weeks gestation occur in perinatal centres. Preterm births are increasing, creating greater demands for neonatal intensive care unit care and ventilation services.

Antiplatelet agents for preventing pre-eclampsia and its complications.

BACKGROUND: Pre-eclampsia is associated with deficient intravascular production of prostacyclin, a vasodilator, and excessive production of thromboxane, a platelet-derived vasoconstrictor and stimulant of platelet aggregation. These observations led to the hypotheses that antiplatelet agents, low-dose aspirin in particular, might prevent or delay the development of pre-eclampsia. OBJECTIVES: To assess the effectiveness and safety of antiplatelet agents when given to women at risk of developing pre-eclampsia. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register (September 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 2, 2003), EMBASE (1994 to 2003) and we handsearched the congress proceedings of the International and European Societies for the Study of Hypertension in Pregnancy. SELECTION CRITERIA: All randomised trials comparing antiplatelet agents with either placebo or no antiplatelet agent during pregnancy. Quasi-random study designs were excluded. Participants were pregnant women considered to be at risk of developing pre-eclampsia. Interventions were any comparisons of an antiplatelet agent (such as low-dose aspirin or dipyridamole) with either placebo or no antiplatelet agent. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trials for inclusion in the review and extracted data. We entered data into the Review Manager software and double checked. MAIN RESULTS: Fifty-one trials involving 36,500 women are included in this review. There is a 19% reduction in the risk of pre-eclampsia associated with the use of antiplatelet agents ((43 trials, 33,439 women; relative risk (RR) 0.81, 95% confidence interval (CI) 0.75 to 0.88); number needed to treat (NNT) 69 (51, 109)).Twenty-eight trials (31,845 women) reported preterm birth. There is a small (7%) reduction in the risk of delivery before 37 completed weeks ((RR 0.93, 95% CI 0.89 to 0.98); NNT 83 (50, 238)). Fetal or neonatal deaths were reported in 38 trials (34,010 women). Overall there is a 16% reduction in baby deaths in the antiplatelet group (RR 0.84, 95% CI 0.74 to 0.96); NNT 227 (128, 909)). Small-for-gestational age babies were reported in 32 trials (24,310 women), with an 8% reduction in risk (RR 0.92, 95% CI 0.85 to 1.00). There were no significant differences between treatment and control groups in any other measures of outcome. REVIEWER'S CONCLUSIONS: Antiplatelet agents, in this review largely low-dose aspirin, have small-moderate benefits when used for prevention of pre-eclampsia. Further information is required to assess which women are most likely to benefit, when treatment is best started, and at what dose.

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 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 cycles per second. This has been shown to result in less lung injury in experimental studies. OBJECTIVES: The objective of this review is to determine whether the elective use of high frequency oscillatory ventilation as compared to conventional ventilation (CV) in preterm infants who are mechanically ventilated for the respiratory distress syndrome decreases the incidence of chronic lung disease, without adverse effects. 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 May 2003. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: 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. Treatment effects were expressed using relative risk (RR) and risk difference (RD). From 1/RD the number needed to treat (NNT) to produce one outcome were calculated. Ninety five percent confidence intervals were used for all measures of effect. MAIN RESULTS: Eleven eligible studies on 3,275 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. The effect of HFOV on CLD in survivors at term equivalent GA was inconsistent across studies and not significant overall. Pre-specified subgroup analyses according to use of a high volume strategy, or use of surfactant, did not identify subgroups in which there was evidence of effect on death, or in which the size of effect on CLD was substantially increased, or in which heterogeneity of treatment effect on CLD was removed. Short term neurological morbidity caused by HFOV was found in some studies, 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 IVH and of periventricular leukomalacia. An adverse effect of HFOV on longer term neurodevelopment was found in one large trial but not in two other small trials which reported this outcome. REVIEWER'S CONCLUSIONS: There is no clear evidence from this systematic review that elective HFOV, as compared with CV, offers important advantages when used as the initial ventilation strategy to treat preterm babies with acute pulmonary dysfunction. There is no evidence of a reduction in death rate. 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 is not significant overall. Adverse effects on short term neurological outcomes have been observed in some studies but these effects are not significant overall. Information about effects on long term outcome is not adequate overall. Any future trials on elective HFOV should target those infants who are at most risk of CLD (extremely preterm), compare different strategies for generating HFOV and CV, and report important long term pulmonary and neurodevelopmental outcomes. Economic analysis should also be incorporated.

Analysing differences in clinical outcomes between hospitals.

OBJECTIVE: To examine the variation between hospitals in rates of severe intraventricular haemorrhage (IVH) in preterm babies adjusting for case mix and sampling variability. DESIGN: Cross sectional study of pooled data from 1995 to 1997. SETTING: 24 neonatal intensive care units (NICUs) in the Australian and New Zealand Neonatal Network. PARTICIPANTS: 5413 infants of gestational age 24-30 weeks. MAIN OUTCOME MEASURES: Crude rates of severe (grades 3 and 4) IVH and rates adjusted for case mix using logistic regression, and for sampling variability using shrinkage estimators. RESULTS: The overall rate of severe IVH was 6.8%, but crude rates for individual units ranged from 2.9 to 21.4%, with interquartile range (IQR) 5.7-8.1%. Adjusting for the five significant predictor variables--gestational age at birth, 1 minute Apgar score, antenatal corticosteroids, transfer after birth, and sex--actually increased the variability in rates (IQR 5.9-9.7%). Shrinkage estimators, which adjust for differences in unit sizes and outcome rates, reduced the variation in rates (IQR 6.3-7.5%). Adjusting for case mix and using shrinkage estimators showed that one unit had a significantly higher adjusted rate than expected, while another was significantly lower. If all units could achieve an average rate equal to the 20th centile (5.74%), then 60 cases of severe IVH could be prevented in a 3 year period. CONCLUSIONS: The use of shrinkage estimators may have a greater impact on the variation in outcomes between hospitals than adjusting for case mix. Greater reductions in morbidity may be achieved by concentrating on the best rather than the worst performing hospitals.

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 trials register (18 October 2002), the Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 1, 2003) and bibliographies. SELECTION CRITERIA: Randomised trials with reported data that compare outcomes, such as neonatal mortality, neonatal neurological and other morbidity, long-term neurodevelopment and maternal morbidity, 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. Results are expressed as relative risk (RR) and 95% confidence intervals (CI). MAIN RESULTS: Over 1750 women were entered into the nine trials included. Analyses of all included trials showed a significant reduction in the rates of all grades of periventricular haemorrhage (PVH) (RR 0.65, 95% CI 0.50 to 0.83, 9 trials, 1591 women) and severe grades PVH (3 and 4) (RR 0.41, 95% CI 0.20 to 0.85, 8 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, 2 trials, 945 women), and severe grades of PVH (RR 1.05, 95% CI 0.60 to 1.83, 2 trials, 945 women). No difference was found in the incidence of neurodevelopmental abnormalities at paediatric follow up assessed between 18 to 36 months of age. Maternal sedation was more likely in women receiving phenobarbital (RR 2.06, 95% CI 1.79 to 2.37, 1 trial, 576 women). REVIEWER'S CONCLUSIONS: The evidence in this review does not support the use of prophylactic maternal phenobarbital administration to prevent periventricular haemorrhage or to protect from neurological disability in preterm infants. Phenobarbital administration leads to maternal sedation. If any future trials are carried out, they should measure neurodevelopmental status at follow up.

Regional (spinal, epidural, caudal) versus general anaesthesia in preterm infants undergoing inguinal herniorrhaphy in early infancy.

BACKGROUND: With improvements in neonatal intensive care, more premature infants are surviving the neonatal period. With this increase, more are presenting for surgery in early infancy. Of predominance in this period is the repair of inguinal herniae, appearing in 38% of infants whose birth weight is between 751g and 1000g. Most postoperative studies show that approximately 20% to 30% of otherwise healthy former preterm infants having inguinal herniorrhaphy under general anaesthesia have one or more apnoeas in the postoperative period. Regional anaesthesia might reduce postoperative apnoea in this population. OBJECTIVES: To determine if regional anaesthesia, in preterm infants undergoing inguinal herniorrhaphy, reduces post-operative apnoea, bradycardia, and the use of assisted ventilation, in comparison to those infants undergoing inguinal herniorrhaphy with general anaesthesia. SEARCH STRATEGY: Randomised controlled trials were identified by searching MEDLINE (1966-Nov 2002), EMBASE (1982-Nov 2002), Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2002), reference lists of published trials and abstracts published in Pediatric Research. SELECTION CRITERIA: Randomised and quasi-randomised controlled trials of spinal versus general anaesthesia in preterm infants undergoing inguinal herniorrhaphy in early infancy. DATA COLLECTION AND ANALYSIS: Data were extracted and the analyses performed independently by two reviewers. Authors of each eligible study were contacted for missing data. Studies were analysed for methodologic quality using the criteria of the Cochrane Neonatal Review Group. All data were analysed using RevMan 4.1. When possible meta-analysis was performed to calculate typical relative risk, typical risk difference, along with their 95% confidence intervals (CI). MAIN RESULTS: Four small trials comparing spinal with general anaesthesia in the repair of inguinal hernia were identified. One trial was excluded due to inadequate information. There was no statistically significant difference in the proportions of infants having postoperative apnoea/bradycardia, typical RR 0.69 (0.40, 1.21) or postoperative oxygen desaturations, RR 0.91 (0.61, 1.37). If infants having preoperative sedatives were excluded, then the meta-analysis supported a reduction in postoperative apnoea in the spinal anaesthetic group, typical RR 0.39 (0.19, 0.81). There was a reduction of borderline statistical significance in the use of postoperative assisted ventilation with spinal anaesthesia. There was an increase of borderline statistical significance in anaesthetic placement failure when spinal anaesthesia was attempted. REVIEWER'S CONCLUSIONS: There is no reliable evidence from the trials reviewed concerning the effect of spinal as compared to general anaesthesia on the incidence of post-operative apnoea, bradycardia, or oxygen desaturation in ex-preterm infants undergoing herniorrhaphy. The estimates of effect in this review are based on a total population of only 108 patients or fewer.A large well designed randomised controlled trial is needed to determine if spinal anaesthesia reduces post-operative apnoea in ex-preterm infants not pretreated with sedatives. Adequate blinding, follow up and intention to treat analysis are required.

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

BACKGROUND: Pre-eclampsia is a relatively common complication of pregnancy. Eclampsia, the occurrence of one or more convulsions (fits) in association with the syndrome of pre-eclampsia, is a rare but serious complication. Anticonvulsants are used in the belief they help prevent eclamptic fits and so improve outcome. OBJECTIVES: The objective was to assess the effects of anticonvulsants for pre-eclampsia on the women and their children. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register (28 November 2002), and the Cochrane Controlled Trials Register (The Cochrane Library, Issue 3, 2002). SELECTION CRITERIA: Randomised trials comparing anticonvulsants with placebo or no anticonvulsants or comparisons of different anticonvulsants in women with pre-eclampsia. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trial quality and extracted data independently. MAIN RESULTS: Six trials (11,444 women) compared magnesium sulphate with placebo or no anticonvulsant. There was more than a halving in the risk of eclampsia associated with magnesium sulphate (relative risk (RR) 0.41, 95% confidence interval (CI) 0.29 to 0.58; number needed to treat (NNT) 100, 95% CI 50 to 100). The risk of dying was non-significantly reduced by 46% for women allocated magnesium sulphate (RR 0.54, 95% CI 0.26 to 1.10). For serious maternal morbidity RR 1.08, 95% CI 0.89 to 1.32. Side effects were more common with magnesium sulphate (24% versus 5%; RR 5.26, 95% CI 4.59 to 6.03; NNT for harm 6, 95% CI 6 to 5). The main side effect was flushing. Risk of placental abruption was reduced for women allocated magnesium sulphate (RR 0.64, 95% CI 0.50 to 0.83; NNT 100, 95% CI 50 to 1000). Women allocated magnesium sulphate had a small increase (5%) in the risk of caesarean section (95% CI 1% to 10%). There was no overall difference in the risk of stillbirth or neonatal death (RR 1.04, 95% CI 0.93 to 1.15). Magnesium sulphate was better than phenytoin for reducing the risk of eclampsia (two trials 2241 women; RR 0.05, 95% CI 0.00 to 0.84), but with an increased risk of caesarean section (RR 1.21, 95% CI 1.05 to 1.41). It was also better than nimodipine (1 trial, 1650 women; RR 0.33, 95% CI 0.14 to 0.77). REVIEWER'S CONCLUSIONS: Magnesium sulphate more than halves the risk of eclampsia, and probably reduces the risk of maternal death. It does not improve outcome for the baby, in the short term. A quarter of women have side effects, particularly flushing.

Nasal continuous positive airways pressure immediately after extubation for preventing morbidity in preterm infants.

BACKGROUND: Preterm infants being extubated following a period of intermittent positive pressure ventilation via an endotracheal tube are at risk of developing respiratory failure as a result of apnea, respiratory acidosis and hypoxia. Nasal continuous positive airway pressure appears to stabilise the upper airway, improve lung function and reduce apnea and may therefore have a role in facilitating extubation in this population. OBJECTIVES: In preterm infants having their endotracheal tube removed following a period of intermittent positive pressure ventilation (IPPV), does management with nasal continuous positive airways pressure (NCPAP) lead to an increased proportion remaining free of additional ventilatory support, compared to extubation directly to headbox oxygen? SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE up to November 2002, Cochrane Controlled Trials Register (The Cochrane Library, Issue 4, 2002), previous reviews including cross references, abstracts of conferences and symposia proceedings, expert informants and journal handsearching mainly in the English language. SELECTION CRITERIA: All trials utilising random or quasi-random patient allocation, in which NCPAP (delivered by any method) was compared with headbox oxygen for post-extubation care were included. Methodological quality was assessed independently by the two authors. DATA COLLECTION AND ANALYSIS: Data were extracted independently by the two authors. Prespecified subgroup analysis to determine the impact of different levels of NCPAP, differences in duration of IPPV and use of aminophylline were also performed using the same package. Data were analysed using relative risk (RR), risk difference (RD) and number needed to treat (NNT). MAIN RESULTS: Nasal CPAP, when applied to preterm infants being extubated following IPPV, reduces the incidence of adverse clinical events (apnea, respiratory acidosis and increased oxygen requirements) indicating the need for additional ventilatory support [RR 0.62 (0.49, 0.77), RD -0.17 (-0.24,-0.10), NNT 6 (4,10)]. IMPLICATIONS FOR PRACTICE: nasal CPAP is effective in preventing failure of extubation in preterm infants following a period of endotracheal intubation and IPPV. Implication for research: further definition of the gestational age and weight groups in whom these results apply is required. Optimal levels of NCPAP as well as methods of administration remain to be determined.

Predicting the need for ventilatory support in neonates 30-36 weeks' gestational age.

OBJECTIVES: To determine antenatal factors associated with the need for ventilatory support in babies born between 30 and 36 weeks gestational age and use this information to help referring obstetricians decide which mothers need antenatal transfer. METHODS: Babies born at Royal Prince Alfred Hospital at 30-36 weeks' gestation inclusive between January 1992 to December 1999 were identified in the obstetric and neonatal databases. Information for a wide range of antenatal factors and respiratory outcomes was extracted. Babies with major congenital anomalies were excluded. Statistical analysis using spss for Windows was then undertaken. RESULTS: Data were available for 3102 babies. On univariate analysis, seven factors were significant. Lower gestational age, absence of labour, Caesarean section, antepartum haemorrhage, breech presentation and hypertensive disease of pregnancy were associated with increased risk, while threatened premature labour was protective. On logistic regression analysis, gestational age and absence of labour dominated the model. Other significant factors in the model had a relatively minor impact. CONCLUSIONS: The risk of needing ventilatory support according to antenatal risk factors is described for infants born between 30 and 36 weeks. Gestational age and absence of labour were found to be the major determinants of risk. Delivery without labour increased the risk by the equivalent of about 2 weeks of gestation. For example, to avoid a risk > 20%, the cut off is 33 weeks for mothers who labour, but is increased to 35 weeks when there is no labour. Our results should be interpreted with caution, as the patients in a tertiary obstetric unit may not be typical of the wider community.

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 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 cycles per second. This has been shown to result in less lung injury in experimental studies. OBJECTIVES: The objective of this review is to determine whether the elective use of high frequency oscillatory ventilation as compared to conventional ventilation (CV) in preterm infants who are mechanically ventilated for the respiratory distress syndrome decreases the incidence of chronic lung disease, without adverse effects. 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 October 2002. SELECTION CRITERIA: 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. DATA COLLECTION AND ANALYSIS: 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. Treatment effects were expressed 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. 95% confidence intervals were used. MAIN RESULTS: Meta-analysis of the ten eligible studies 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. HFOV caused a significant reduction in CLD in survivors at term equivalent GA. However, the effect was not large in absolute terms [NNT 17 (10, 50)], and was inconsistent across studies. HFOV caused a significant reduction in the aggregated outcome, death or CLD at term equivalent GA. Again, however, the effect was not large [(NNT 20 (11, 100)] and was not consistent across studies. Pre-specified subgroup analyses according to use of a high volume strategy, or use of surfactant, did not identify subgroups in which there was evidence of effect on death, or in which the size of effect on CLD was substantially increased, or in which heterogeneity of treatment effect on CLD was removed. Short term neurological morbidity caused by HFOV was found in some studies, 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 IVH and of periventricular leukomalacia. An adverse effect of HFOV on longer term neurodevelopment was found in one large trial but not in two other small trials which reported this outcome. REVIEWER'S CONCLUSIONS: There is strong evidence that HFOV had no significant effect on death as this result was consistent across trials. Although HFOV caused a modest reduction in CLD, this evidence is weaker, because of inconsistencies across trials in this effect. In general, subgroup analyses according to use of high volume strategy, or surfactant, did not remove this heterogeneity, which therefore remains largely unexplained. Any future trials on elective HFOV should target those infants who are at most risk of CLD (extremely preterm), compare different strategies for generating HFOV and report important long term pulmonary and neurodevelopmental outcomes. Economic analysis should also be incorporated.

Prophylactic methylxanthines for extubation in preterm infants.

BACKGROUND: When preterm infants have been given intermittent positive pressure ventilation (IPPV) for respiratory failure, weaning from support and tracheal extubation may be difficult. A significant contributing factor is thought to be the relatively poor respiratory drive and tendency to develop hypercarbia and apnea, particularly in very preterm infants. Methylxanthine treatment started before extubation might stimulate breathing and increase the chances of successful weaning from IPPV. OBJECTIVES: In preterm infants being weaned from IPPV and in whom endotracheal extubation is planned, does treatment with methylxanthine reduce the use of intubation and IPPV, without clinically important side effects? SEARCH STRATEGY: The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of the Oxford Database of Perinatal Trials, The Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3 2002), MEDLINE (1966 to October 2002). 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. The second author assessed the quality of trials and extracted data independently. Results are expressed as relative risk (RR) and risk difference (RD) with 95% confidence intervals. MAIN RESULTS: Overall analysis of the six published trials shows that methylxanthine treatment results in a reduction in failure of extubation within one week [summary RR 0.47 (0.32, 0.70)]. Overall there is an absolute reduction of 27 % in the incidence of failed extubation [summary RD -.27 (-.39, -.15)]. Thus, overall in these six trials the number needed to treat (NNT) with methylxanthine to prevent one case of failed extubation is 3.7 (2.7, 6.7). There is significant heterogeneity in the RD meta-analysis (p=0.007) related to the large variation in baseline rate in the control groups (range 20 - 100%). One study (Durand 1987) found that treatment was effective in reducing failed extubation in those born at less than 1000 grams and who were less than one week old. In the small prespecified subgroups in this trial, infants of less than 1 kg birth weight and older than one week and those of birth weight 1000-1250 grams who had failed extubation once, no significant benefit was found. REVIEWER'S CONCLUSIONS: Implications for practice. Methylxanthines increase the chances of successful extubation of preterm infants within one week. One trial suggests that this benefit is principally in infants of extremely low birth weight extubated in the first week. There is insufficient information to assess side effects or longer term effects on child development. Implications for research. Further trials are required comparing methylxanthines with placebo for extubation of very preterm infants. There is a need to stratify infants by gestational age (a better indicator of immaturity) rather than birth weight in future studies. Caffeine, with its wider therapeutic margin (Blanchard 1992, Steer 2002) would be the better treatment to evaluate against placebo. Side effects and neuro-developmental status at follow up should be included as outcomes.