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.

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.

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.

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.

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.

Upper airway muscle activity during nasal occlusion in newborn babies.

Submental electromyorgams (SM EMG) were recorded from 20 preterm babies (gestational age 30 +/- 2 wk, postmenstrual age at study 35 +/- 2 wk) (mean +/- SD) and 3 full-term infants (7-14 days old). SM EMG was evaluated during eupnea and brief experimental airway occlusion. Phasic inspiratory SM EMG was rarely seen during eupnea. SM EMG tended to increase on the first occluded effort, although this increase was not statistically significant in most babies. All infants showed progressive breath-by-breath augmentation of phasic SM EMG during occlusions in rapid-eye-movement (REM) as well as quiet (QS) sleep; phasic increases in SM EMG were similar during REM and QS occlusions in the majority (16/22) of babies. Periods of airway closure were detected during 24 occlusions in 5 infants; phasic SM EMG was reduced on these occasions. The results are consistent with the idea that recruitment of upper airway muscles contributes to the stability of the airway of the preterm human.

Upper airway stability and apnea during nasal occlusion in newborn infants.

Brief end-expiratory airway occlusions were performed in 22 preterm babies, 17 with and 5 without clinical apnea, and 4 full-term babies, 1 with Pierre-Robin syndrome. Airway stability was evaluated by comparing pressures measured simultaneously in the chest and nasal passages during occluded inspiratory efforts. The airway remained patent throughout all 301 trials in 20 babies during rapid-eye-movement (REM) and quiet sleep. Airway closure occurred during 31/102 trials in 6 babies (5 preterm and 1 term with Pierre-Robin syndrome), more commonly in quiet than in REM sleep. Overall and within individuals, mean closing pressures were significantly lower than the mean maximum falls in airway pressure recorded during occlusions without closure. Mixed-obstructive and obstructive apnea was significantly more frequent in babies with airway closure than in those without (5.3 +/- 4.0 vs. 0.4 +/- 0.8 episodes/h). Pauses in breathing greater than or equal to 3 s occurred during 28% of occlusions in preterm infants and 2% of occlusions in full-term babies. There was no significant difference between the mean frequency of pauses during occlusion and during the preceding control period or in the incidence of pauses in occlusions with vs. those without closure. It is concluded that the airway of most preterm and full-term babies is remarkably stable under load. Intermittent closure occurs in certain infants and may be related to airway muscle dysfunction.

Clonidine hydrochloride--a safe and effective antihypertensive agent in pregnancy.

A prospective, double-blind, randomized controlled trial was carried out, comparing alpha-methyldopa and clonidine hydrochloride in 100 pregnant women with hypertension. There was no difference in hypotensive effect or reported maternal side effects with either agent. There was one neonatal loss in each group (98% survival). Neither drug caused clinically significant hypotension nor rebound hypertension in the neonates. Clonidine hydrochloride, like methyldopa, appears to be a safe antihypertensive agent in pregnancy.

Brainstem auditory evoked response development in preterm and term baboons (Papio hamadryas).

Brainstem auditory evoked responses were recorded longitudinally from 11 neonatal baboons (Papio hamadryas), 6 of which were preterm. Recordings were made in unsedated animals from day 161 to day 362 after conception (term = 182 days). The pattern of development of both waveform morphology and of wave latency was consistent with that seen in the human neonate, with a rapid maturation of the response during the perinatal period, and then a slower development to adult values. Brainstem conduction time was measured from the wave I to wave IV interval, and this demonstrated a similar pattern, with a rapid decrease in latency up to term, and then decreasing more slowly to reach adult values by 4 months of age in the baboon.

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.

Perinatal risk factors for major intraventricular haemorrhage in the Australian and New Zealand Neonatal Network, 1995-97.

BACKGROUND: In 1995, large differences were identified in rates of grade 3-4 intraventricular/periventricular haemorrhage (major IVH) among neonatal intensive care units (NICUs) in the Australian and New Zealand Neonatal Network. AIMS: To develop a predictive model for major IVH in order to allow risk adjustment for the variation in rates of major IVH among NICUs. METHODS: Rates of IVH were determined in 5712 infants of 24-30 weeks gestation born from 1995 to 1997. Significant antenatal and perinatal variables for major IVH in 1995 and 1996 were identified by univariate and multivariate analysis. A predictive model was developed and then validated on 1997 data. RESULTS: Rates of all grades of IVH fell from 1995 to 1997 (30.4 to 24.3%) but wide interunit variation remained. Seven antenatal and perinatal characteristics had significant association with major IVH: fetal distress, intrauterine growth restriction (protective), antenatal corticosteroids (protective), gestational age, 1 minute Apgar <4, male gender, and transfer after birth. A predictive model based on the last five of these variables was developed using data from 1995 and 1996 which gave an area under the receiver operator characteristic (ROC) curve of 0.76. This model was then validated on the 1997 dataset where an identical ROC curve resulted. CONCLUSIONS: Antenatal and perinatal factors are important in the pathogenesis of major IVH. The predictive model developed from these factors can be used to adjust for confounders in interunit outcome comparison.

Screening for auditory dysfunction in high risk neonates.

Brainstem auditory evoked responses were recorded in 117 pre-term and 71 full-term infants from the general population of infants born at a referral obstetric unit. The threshold intensity required to evoke a reliable BAER was determined at different post-menstrual ages (PMAs) and in many cases at follow-up clinics. The BAER thresholds for 12 infants born and tested at less than 31 wk PMA were all greater than or equal to 50 dBHL. Sixty-two low-gestational-age infants who were tested between 31 and 36 wk PMA had BAER thresholds between less than or equal to 30 dBHL and greater than or equal to 80 dBHL. The majority of pre-term and term infants tested at term equivalent age had BAER thresholds less than or equal to 30 dBHL. Longitudinal studies also indicated that BAER thresholds can decline rapidly during the pre-term period. Follow-up studies showed that those pre-term and term infants with BAER thresholds less than or equal to 30 dBHL had normal auditory thresholds as determined using conventional behavioural testing at 4 or more months of age. Of those infants with BAER thresholds greater than or equal to 40 dBHL at the time of discharge or at term equivalent age, 67% (n = 16) were confirmed later as having a moderate to profound hearing deficit. The remaining 8 infants in this group had had BAER thresholds at term of 40 or 50 dBHL and had normal BAER and behavioural thresholds at follow-up. The cross-sectional and longitudinal data indicate that the majority of low-gestational-age infants who are at risk of hearing deficit achieve BAER thresholds less than or equal to 30 dBHL by term equivalent age. We recommend that auditory screening of infants in this group is best performed at the time of discharge from hospital or at term equivalent age, whichever is the later. Those infants with thresholds greater than or equal to 40 dBHL at that time should be encouraged to attend follow-up testing and, if high thresholds persist, they should then be referred on for behavioural testing and assessment for habilitative support.

The early development of head control in preterm infants.

This study documents the longitudinal development of head control in 104 infants born at 25-33 weeks gestation. Protective side turning of the head was found to have a developmental sequence of reducing spinal extension. In the 93 infants with normal motor outcome, individual differences in the rate of development correlated with caudo-cephalic muscle development (P less than 0.001, r = 0.5) but not with the length of extra-uterine experience. As a group, the 11 infants with later motor handicap showed a persistence of the early form of movement at 35-39 weeks post-menstrual age, without a significant correlation with the ratio of upper-lower limb muscle development. Head control, supine to sitting, in the infants with normal motor outcome showed variations in the rate of preterm development. The infants born at less than 31 weeks showed significantly higher scores at 33-35 weeks post-menstrual age than those born at 31-33 weeks (P less than 0.01). There was no difference at later ages. The spinal extension movement accompanying protective side turning of the head is age specific to the preterm infant. Individual rates of normal preterm development can be evaluated by longitudinal standardised examination. As a group, the infants with subsequent abnormal motor development showed delay at preterm age but this was not individually significant.

Peripheral nerve conduction velocity and brainstem auditory evoked responses in small for gestational age preterm infants.

Ulnar nerve conduction velocity (NCV) and brainstem auditory evoked responses (BAER) were measured in each of 11 preterm small for gestational age (SGA) infants born at less than 35 weeks gestation. The mean motor NCV in the SGA infants was similar to that reported for infants who were appropriately grown for their gestational age (AGA). However, the mean central conduction time of the BAER in SGA infants was significantly shorter than that of AGA infants of the same post-menstrual age. Thus, the precocious development of auditory brainstem neural function in preterm SGA infants is not accompanied by changes in functional maturation of the peripheral motor nerves.

Doxapram versus methylxanthine for apnea in preterm infants.

BACKGROUND: Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. Doxapram and methylxanthine drugs have been used to stimulate breathing and so prevent apnea and its consequences. OBJECTIVES: To assess the effects of doxapram compared with methylxanthine in preterm infants with recurrent apnea. SEARCH STRATEGY: The Cochrane Collaboration Clinical Trials Register (Cochrane Library issue 3, 2000), MEDLINE (1966- July 2000), reference lists of relevant articles and conference proceedings. SELECTION CRITERIA: Randomized and quasi-randomized trials of doxapram compared with methylxanthine (e.g. theophylline, aminophylline or caffeine) for the treatment of apnea in preterm infants. DATA COLLECTION AND ANALYSIS: The methodological quality of each trial was reviewed by the second reviewer blinded to trial authors and institution(s). Additional information was requested from authors. Each reviewer extracted the data separately, then they were compared and differences resolved. Meta-analysis was carried out with use of relative risk and risk difference. MAIN RESULTS: Three trials involving 56 infants were included. No difference was detected between intravenous doxapram or methylxanthine in the incidence of failed treatment within 48 hours (relative risk 1.16, 95% confidence interval 0.43 to 3.13). No infants were reported to have been given mechanical ventilation on either treatment. No adverse effects were reported. REVIEWER'S CONCLUSIONS: Intravenous doxapram and intravenous methylxanthine appear to be similar in their short term effects for treating apnea in preterm infants, although these trials are too small to exclude an important difference between the two treatments or to exclude the possibility of less common adverse effects. Longer term outcome of infants treated in these trials has not been reported. Further studies would require a large number of infants to clarify whether there might be differences in responses or adverse effects with these two drugs at different ages.

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. The use of drugs to lower blood pressure will reduce this risk for the women, and possibly also for the baby. OBJECTIVES: The objective of this review was to compare different antihypertensive drugs used for treatment of severe hypertension during pregnancy. SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group trials register (April 2002), the Cochrane Controlled Trials Register (The Cochrane Library, Issue 2 2002) and MEDLINE (April 2002). SELECTION CRITERIA: Studies were randomised trials. Quasi random designs were excluded. Participants were women with severe hypertension during pregnancy. Women postpartum at trial entry were excluded. Interventions were any comparisons of one antihypertensive agent with another. DATA COLLECTION AND ANALYSIS: Data were extracted independently by two reviewers to assess eligibility and describe the trial characteristics, and by one reviewer for the meta-analyses. Discrepancies were resolved by discussion. There was no blinding of authorship or results. Whenever possible, unpublished data were sought from investigators. MAIN RESULTS: Twenty trials were included (1637 women) and 19 were excluded. There were ten different comparisons. Hydralazine was the most common drug for others to be evaluated against. Diazoxide, given as 75mg bolus injections, appears to be associated with maternal hypotension requiring treatment, and ketanserin is less effective than hydralazine at reducing blood pressure. There is no other clear evidence that any one of the other antihypertensive agents is better than another for women with severe hypertension during pregnancy. REVIEWER'S CONCLUSIONS: Until better evidence is available, the choice of antihypertensive should depend on the experience and familiarity of an individual clinician with a particular drug, and on what is known about adverse maternal and fetal side-effects. Exceptions are diazoxide and ketanserin, which are probably not good choices.

Methylxanthine treatment for apnea in preterm infants.

BACKGROUND: Recurrent apnea is common in preterm infants, particularly at very early gestational ages. These episodes of loss of effective breathing can lead to hypoxemia and bradycardia which may be severe enough to require resuscitation including use of positive pressure ventilation. Methylxanthines have been used to stimulate breathing and prevent apnea and its consequences. OBJECTIVES: The objective of this review is to determine if methylxanthine treatment in preterm infants with recurrent apnea leads to a clinically important reduction in apnea and use of intermittent positive pressure ventilation (IPPV), without clinically important side effects. SEARCH STRATEGY: Searches were made of the Oxford Database of Perinatal Trials, MEDLINE, EMBASE, previous reviews including cross references, abstracts of conferences and symposia proceedings, expert informants, journal handsearching mainly in the English language. SELECTION CRITERIA: All trials utilizing random or quasi-random patient allocation, in which methylxanthine (theophylline or caffeine) was compared with placebo or no treatment for apnea in preterm infants, were included. DATA COLLECTION AND ANALYSIS: Methodological quality was assessed independently by the two authors. Data were extracted independently by the two authors. Treatment effects were expressed as relative risk (RR) and risk difference (RD) and their 95% confidence intervals, using a fixed effect model. For significant results, the inverse of the risk difference (1/RD) was used to calculate the number needed to treat (NNT). MAIN RESULTS: The results of five trials which enrolled a total of 192 preterm infants with apnea indicate that methylxanthine therapy leads to a reduction in apnea and use of IPPV in the first 2 - 7 days. There are insufficient data to evaluate side effects and no data to examine effects within different gestational age groups. There are no trial data which examine long term effects. REVIEWER'S CONCLUSIONS: Methylxanthines are effective in reducing the number of apneic attacks and the use of mechanical ventilation in the two to seven days after starting treatment. In view of its lower toxicity, caffeine would be the preferred drug. The effects of methylxanthines on longterm outcome are not known and this should be addressed in any new trials.