David J. Henderson-Smart

Antiplatelet drugs for prevention of pre-eclampsia and its consequences: systematic review.

Abstract Objective: To assess the effectiveness and safety of antiplatelet drugs for prevention of pre-eclampsia and its consequences. Design: Systematic review. Data sources: Register of trials maintained by Cochrane Pregnancy and Childbirth Group, Cochrane Controlled Trials Register, and Embase. Included studies: Randomised trials involving women at risk of pre-eclampsia, and its complications, allocated to antiplatelet drug(s) versus placebo or no antiplatelet drug. Main outcomes measures: Pre-eclampsia, preterm birth, fetal or neonatal death, and small for gestational age baby. Studies were assessed for quality of concealment of allocation and losses to follow up. Results: 39 trials (30 563 women) were included, and 45 trials (>3000 women) excluded. Use of antiplatelet drugs was associated with a 15% reduction in the risk of pre-eclampsia (32 trials, 29 331 women; relative risk 0.85, 95% confidence interval 0.78 to 0.92; number needed to treat 100, 59 to 167). There was also an 8% reduction in the risk of preterm birth (23 trials, 28 268 women; 0.92, 0.88 to 0.97; 72, 44 to 200), and a 14% reduction in the risk of fetal or neonatal death (30 trials, 30 093 women; 0.86, 0.75 to 0.98; 250, 125 to >10 000) for women allocated antiplatelet drugs. Small for gestational age babies were reported in 25 trials (20 349 women), with no overall difference between the groups (relative risk 0.92, 0.84 to 1.01). There were no significant differences in other measures of outcome. Conclusions: Antiplatelet drugs, largely low dose aspirin, have small to moderate benefits when used for prevention of pre-eclampsia.

Prenatal Risk Factors for Severe Retinopathy of Prematurity Among Very Preterm Infants of the Australian and New Zealand Neonatal Network

Objective. To identify prenatal and perinatal risk factors for clinically severe (stage 3 or 4) retinopathy of prematurity (ROP). Methods. Data were collected prospectively as part of the ongoing Australian and New Zealand Neonatal Network audit of high-risk infants (birth weight of <1500 g or gestational age [GA] of <32 weeks) admitted to a level III neonatal unit in Australia or New Zealand. Prenatal and perinatal factors to 1 minute of age were examined for the subset of infants with GA of <29 weeks who survived to 36 weeks’ postmenstrual age and were examined for ROP (n = 2105). The factors significantly associated with stage 3 or 4 ROP were entered into a multivariate logistic regression model. Results. Two-hundred three infants (9.6%) had stage 3 or more ROP. Prematurity was the dominant risk factor, with infants with GA of <25 weeks having 20 times greater odds of severe ROP than infants with GA of 28 weeks. Birth weight for GA also had a “dose-response” effect; the more growth-restricted infants had greater risk, with infants below the 3rd percentile of weight for GA having 4 times greater odds of severe ROP than those between the 25th and 75th percentiles. Male gender was also a significant risk factor (odds ratio: 1.73; 95% confidence interval: 1.25–2.40). Conclusions. These data, for a large, essentially population-based cohort, suggest that factors related to the degree of immaturity, intrauterine growth restriction, and male gender contribute to severe ROP.

Clinical Apnea and Brain-Stem Neural Function in Preterm Infants

We assessed the relation between clinical apnea and brain-stem neuronal function in 58 preterm babies. The brain-stem conduction time of the auditory evoked response (Wave V-I interval) was longer in babies with apnea than in those without it at a similar postconceptional age (at 32 to 33 weeks: mean, 6.16 vs. 5.35 msec, P less than 0.001; at 34 to 35 weeks: mean, 5.98 vs. 5.33 msec, P less than 0.002). The number of apneas per day decreased over a period that was similar to the period during which brainstem conduction time decreased. In general, apneas ceased when the conduction time decreased to the levels observed in babies of a similar age who did not have apnea. Short brain-stem conduction times were observed in some infants who had prenatal stress, such as intrauterine growth retardation or maternal hypertension. These results suggest that the occurrence of apnea in preterm infants is correlated with neural function in the brain stem.

How useful are hospital morbidity data for monitoring conditions occurring in the perinatal period

Background:  There is currently no published information on the full range of morbid conditions affecting mothers and newborns in Australia. Hospital morbidity data collections are a possible source of this information, but have not been widely utilised due to concerns about data quality.

High dose caffeine citrate for extubation of preterm infants: a randomised controlled trial

Objective: To compare two dosing regimens for caffeine citrate in the periextubation period for neonates born at less than 30 weeks gestation in terms of successful extubation and adverse effects. Design: A multicentre, randomised, double blind, clinical trial. Setting: Four tertiary neonatal units within Australia. Patients: Infants born less than 30 weeks gestation ventilated for more than 48 hours. Interventions: Two dosing regimens of caffeine citrate (20 v 5 mg/kg/day) for periextubation management. Treatment started 24 hours before a planned extubation or within six hours of an unplanned extubation. Main outcome measure: Failure to extubate within 48 hours of caffeine loading or reintubation and ventilation or doxapram within seven days of caffeine loading. Results: A total of 234 neonates were enrolled. A significant reduction in failure to extubate was shown for the 20 mg/kg/day dosing group (15.0% v 29.8%; relative risk 0.51; 95% confidence interval (CI) 0.31 to 0.85; number needed to treat 7 (95% CI 4 to 24)). A significant difference in duration of mechanical ventilation was shown for infants of less than 28 weeks gestation receiving the high dose of caffeine (mean (SD) days 14.4 (11.1) v 22.1 (17.1); p  =  0.01). No difference in adverse effects was detected in terms of mortality, major neonatal morbidity, death, or severe disability or general quotient at 12 months. Conclusions: This trial shows short term benefits for a 20 mg/kg/day dosing regimen of caffeine citrate for neonates born at less than 30 weeks gestation in the periextubation period, without evidence of harm in the first year of life.

Improved Outcomes of Extremely Premature Outborn Infants: Effects of Strategic Changes in Perinatal and Retrieval Services

OBJECTIVE. The goal was to evaluate the impact of statewide coordinated changes in perinatal support and retrieval services on the outcomes of extremely premature births occurring outside perinatal centers in the state of New South Wales, Australia. METHODS. The intervention included additional, network-coordinated, perinatal telephone advice to optimize in utero transfers and centralization of the neonatal retrieval system, with preferential admission of retrieved infants (outborn infants) to perinatal centers instead of freestanding pediatric hospitals, from the middle of 1995. Population birth and NICU admission cohorts of infants of 23 to 28 weeks of gestation were studied. Outcomes of epoch 1 (1992 to the middle of 1995; 1778 births and 1100 NICU admissions) were compared with those of epoch 2 (1997–2002; 3099 births and 2100 NICU admissions), after an 18-month washout period. RESULTS. There were 25% fewer nontertiary hospital live births (19.7% vs 14.9%) and more prenatal steroid use. Despite an 11.4% average annual increase in NICU admissions between the 2 epochs, fewer infants were outborn (12.0% vs 9.3%) and outborn mortality rates decreased significantly (39.4% vs 25.1%), particularly for those between 27 and 28 weeks of gestation. The overall improvement was equivalent to 1 extra survivor per 16 New South Wales births. There were also significantly fewer serious outcome morbidities in outborn infants during epoch 2, over the improvements in inborn infants. CONCLUSIONS. Statewide coordinated strategies in reducing nontertiary hospital births and optimizing transport of outborn infants to perinatal centers have improved considerably the outcomes of extremely premature infants. These findings have vital implications for health outcomes and resource planning.

Prenatal predictors of mortality in very preterm infants cared for in the Australian and New Zealand Neonatal Network

Aim: To identify antenatal and perinatal risk factors for in-hospital mortality of babies born within the Australian and New Zealand Neonatal Network (ANZNN). Methods: Data were collected prospectively as part of the ongoing audit of high-risk infants (birth weight <1500 g or gestation <32 weeks) admitted to all level III neonatal units in Australia and New Zealand. Antenatal and intrapartum factors to 1 min of age were examined in 11 498 infants with gestational age >24 weeks. Risk and protective factors for mortality were derived from logistic regression models fitted to 1998–9 data and validated on 2000–1 data. Results: For the whole cohort of infants born between 1998 and 2001, prematurity was the dominant risk factor, infants born at 25 weeks having 32 times greater odds of death than infants born at 31 weeks. Low birth weight for gestational age also had a dose–response effect: the more growth restricted the infant the greater the risk of mortality; infants below the 3rd centile had eight times greater odds of death than those between the 25th and 75th centiles. Male sex was also a significant risk factor (odds ratio (OR) 1.55, 95% confidence interval (CI) 1.31 to 1.82). Maternal hypertension in pregnancy was protective (OR 0.46, 95% CI 0.36 to 0.50). The predictive model for mortality had an area under the receiver operating characteristic curve of 0.82. Conclusions: Risk of mortality can be predicted with good accuracy with factors up to the 1 min Apgar score. By using gestation rather than birth weight as the main indicator of maturity, these data confirm that weight for gestational age is an independent risk factor for mortality.

The influence of intra-uterine growth retardation on brainstem development of preterm infants

This study examined brainstem function in 76 appropriate‐for‐gestational‐age (AGA) and 25 small‐for‐gestational‐age (SGA) infants born at less than 35 weeks gestation, using brainstem auditory evoked responses. During the preterm period the mean brainstem conduction time (BCT) of the 25 SGA infants was significantly shorter than that of AGA babies of the same gestation. The BCTs of the AGA infants decreased rapidly during postnatal development to term‐equivalent age; those of the SGA infants did not change significantly. It is likely that prenatal factors are responsible for the alteration of early development in the neural function of non‐asphyxiated SGA infants. This change in neural development may be important in determining later neurological performance.

Protocol for the immediate delivery versus expectant care of women with preterm prelabour rupture of the membranes close to term (PPROMT) Trial [ISRCTN44485060]

BackgroundPreterm prelabour rupture of membranes (PPROM) complicates up to 2% of all pregnancies and is the cause of 40% of all preterm births. The optimal management of women with PPROM prior to 37 weeks, is not known. Furthermore, diversity in current clinical practice suggests uncertainty about the appropriate clinical management.There are two options for managing PPROM, expectant management (a wait and see approach) or early planned birth. Infection is the main risk for women in which management is expectant. This risk need to be balanced against the risk of iatrogenic prematurity if early delivery is planned. The different treatment options may also have different health care costs. Expectant management results in prolonged antenatal hospitalisation while planned early delivery may necessitate intensive care of the neonate for problems associated with prematurity.Methods/DesignWe aim to evaluate the effectiveness of early planned birth compared with expectant management for women with PPROM between 34 weeks and 366 weeks gestation, in a randomised controlled trial. A secondary aim is a cost analysis to establish the economic impact of the two treatment options and establish the treatment preferences of women with PPROM close to term.The early planned birth group will be delivered within 24 hours according to local management protocols. In the expectant management group birth will occur after spontaneous labour, at term or when the attending clinician feels that birth is indicated according to usual care. Approximately 1812 women with PPROM at 34–366 weeks gestation will be recruited for the trial.The primary outcome of the study is neonatal sepsis. Secondary infant outcomes include respiratory distress, perinatal mortality, neonatal intensive care unit admission, assisted ventilation and early infant development. Secondary maternal outcomes include chorioamnionitis, postpartum infection treated with antibiotics, antepartum haemorrhage, induction of labour, mode of delivery, maternal satisfaction with care, duration of hospitalisation, and maternal wellbeing at four months postpartum.DiscussionThis trial will provide evidence on the optimal care for women with PPROM close to term (34–37 weeks gestation). Consideration of both the clinical and economic sequelae of the management of PPROM will enable informed decision making and guideline development.

A randomised comparison of hydralazine and mini-bolus diazoxide for hypertensive emergencies in pregnancy: The PIVOT trial

Aims:  Diazoxide is one of few available agents for treatment of hypertensive emergencies in pregnancy. From previous studies, there is a question concerning safety after moderate‐dose administration caused episodes of hypotension. Rapid control of severe hypertension is necessary to reduce maternal morbidity, for example, stroke and placental abruption. This study was designed to compare the efficacy of mini‐bolus diazoxide with intravenous (i.v.) hydralazine.