Data sharing among data monitoring committees and responsibilities to patients and science.

Over the past three decades it has become increasingly recognized that systematic assessment of as high a proportion as possible of relevant research evidence is needed to protect the best interests of patients and the public. For example, this principle is manifested in clinical guidelines and, increasingly, in the design and monitoring of new research. For scientific and ethical reasons, those responsible for monitoring the progress of ongoing clinical trials may need to seek unpublished and interim data to protect the interests of actual or potential participants in research. The challenge facing data monitoring committees has received relatively little attention, however. In this paper we review some of the commentaries on the issue and the few accounts of actual data monitoring committee experiences. We then present details of our own recent experience as members of the data monitoring committee for the BOOST-II UK trial (ISRCTN:0084226), one of five concurrent trials assessing the level of arterial oxygen which should be targeted in the care of very premature neonates. We conclude that efficient protection both of the interests of actual or potential participants in research and of science requires that data monitoring committees have access to all relevant research, including unpublished and interim data.

Oculomotor control in children who were born very prematurely.

PURPOSE: Preterm infants are at increased risk of a variety of cerebral lesions, involving the white matter, cortex, cerebellum, thalamus, and caudate nucleus, many of which could compromise the control of eye movement. Visual problems and disorders of binocularity and alignment have been reported, but little if any quantitative assessment of oculomotor control has been undertaken. The purpose of this study was to extend the initial pilot study and quantitatively examine the control of saccades, smooth pursuit, and antisaccades in children who were born very prematurely. METHODS: A group of preterm (PT) children aged 8 to 11 years (<32 weeks' gestation), who had normal IQ (>or=85) and were free of major disabilities (cerebral palsy, blindness, or deafness), and full-term (FT) control subjects of similar age were recruited from a geographically defined cohort. Antisaccades were examined in 36 preterm and 33 full-term subjects and smooth pursuit and saccades in 21 preterm and 19 full-term subjects, by using infrared oculography. Saccade and antisaccade targets were presented at an amplitude of 5 degrees according to a standard synchronous paradigm, and pursuit was assessed by using a step-ramp paradigm with a target velocity of 14 deg/s. RESULTS: There were no statistically significant differences between the preterm and the full-term subjects in relation to saccade gain, latency, duration, peak velocity, or the proportion of express saccades. Smooth-pursuit latencies tended to be slightly longer in the preterm subjects (leftward: P = 0.17, rightward: P = 0.02), but there were no significant differences between them and the full-term subjects in pursuit acceleration, open-loop velocity, or peak slow-eye velocity. The main area of deficit in the preterm children occurred in the voluntary control of saccades, with significantly higher antisaccade directional error rates (PT: 73.3% +/- 18.1%, FT: 54.2% +/- 16.9%, mean +/- SD; P < 0.001). The latency of the antisaccade error tended to be shorter in preterm subjects (P = 0.065), with a greater proportion of errors with latency in the express range (P = 0.08). CONCLUSIONS: Despite the increased risk of cerebral lesions, the control of saccades and pursuit was largely normal in the preterm children, suggesting that pathways at the level of the brain stem were principally intact. However, the preterm children had difficulties with the voluntary control of saccades, particularly in the area of inhibition, which may be indicative of a deficit in the region of the dorsolateral prefrontal cortex. This finding is consistent with other reports in preterm children in whom executive function has been found to be compromised, and both these aspects of behavior are likely to share similar areas of cortical control.

Conventional birth weight standards obscure fetal growth restriction in preterm infants.

BACKGROUND AND OBJECTIVE: It has been suggested that fetal growth restriction (FGR) is associated with fetal maturation so that, compared with appropriately grown preterm infants, mortality and some neonatal morbidities may be reduced. The evidence for this is conflicting, and severe FGR has been shown to be harmful. In addition excessive growth has also been shown to be associated with poorer outcomes. As preterm infants are often also growth restricted, centiles for birth weights are distorted and may conceal the degree of growth restriction in a given infant. This study investigated whether using estimated fetal weights (EFW) might reveal the effects of hidden FGR. POPULATION AND METHODS: Using a 25-year database of preterm admissions to a single neonatal unit the ORs for mortality and neonatal morbidities for z scores for birth weight above and below the mean were computed and compared with those computed for z scores for EFW. RESULTS: In 7898 infants born at less than 35 weeks' gestation, the OR for mortality was lowest for birth weights between 1 SD and 3 SD above the mean, but was lowest for EFW between -2 SD and 0 SD below the mean. For periventricular haemorrhage, increasing FGR below the mean reduced the OR with both birth weight and EFW. Apparent reductions in OR for septicaemia, chronic lung disease, persistent ductus arteriosus and necrotising enterocolitis with birth weights of >1 SD above the mean were not seen with EFW. FGR of >-3 SD was associated with increased OR for necrotising enterocolitis with both birth weight and EFW. CONCLUSION: Using fetal growth rather than birth weight standards gives a better indication of the incidence and role of FGR in neonatal disease.

Good practice in consent.

Informed parental consent reminds the health professional to respect parent autonomy with respect to their infant's health care. It involves at least four elements: information, assessment of understanding, assessment of capacity, and freedom to choose. Critical issues are training of staff, timing of approach, and quality and presentation of information. In the newborn period, additional problems include parental distress and competence, consent for research into emergency treatments (exceptions to this are proposed below); screening for future disease, circumcision and withdrawing intensive care are considered as special cases. Variation in practice and policies in European neonatal units is described.

Reduction of oxidative stress marker in lung fluid of preterm infants after administration of intra-tracheal liposomal glutathione.

BACKGROUND: Low levels of glutathione are associated with subsequent chronic lung disease in preterm infants. Incorporation of glutathione into liposomes offers a method of increasing levels with a prolonged half-life compared with direct inhalation. OBJECTIVES: The aim of this study was to examine the clinical feasibility of administering a single dose of liposomal glutathione and its effectiveness at raising glutathione at 12 and 24 h after treatment. METHODS: Fourteen ventilated preterm infants from the Regional Neonatal Intensive Care Unit at Liverpool Women's Hospital received 1 mg/kg or 10 mg/kg liposomal glutathione intra-tracheally and bronchoalveolar lavage fluid was collected prior to treatment, 12 and 24 h after dosing for glutathione and malondialdehyde estimation. RESULTS: Mean glutathione was initially 12.2 micromol/l, increasing to 52.8 micromol/l at 12 h (p = 0.006). Mean malondialdehyde was initially 265.6 nmol/l decreasing to 11.2 nmol/l at 12 h (p = 0.018). CONCLUSIONS: Intra-tracheal liposomal glutathione instillation offers a feasible method of raising pulmonary glutathione in preterm infants and shows biochemical antioxidant effects.

Genetic polymorphisms and retinopathy of prematurity.

PURPOSE: Retinopathy of prematurity (ROP) is a major problem among very preterm survivors of neonatal intensive care. Neovascularization of the retina is prominent in the proliferative stages of ROP and is under the control of several factors such as vascular endothelial growth factor (VEGF). This study was undertaken on the hypothesis that genetic polymorphisms of VEGF, transforming growth factor (TGF)-beta1, and tumor necrosis factor (TNF)-alpha would occur more frequently in preterm infants with progressive ROP than in those with mild or no disease. METHODS: The frequencies of VEGF -634 G-->C, VEGF *936 C-->T, TNF-alpha -308 G-->A, and TGF-beta -509 C-->T were determined in DNA from 91 infants who had received treatment for threshold ROP and 97 comparison infants. RESULTS: The frequencies of the VEGF *936 C-->T, TNF-alpha -308 G-->A and TGF-beta -509 C-->T polymorphisms were similar in both groups. The distribution of alleles at VEGF -634 was significantly different between the two groups (P = 0.03). Homozygotes for the G allele, associated with higher VEGF production were twice as likely to have threshold ROP. CONCLUSIONS: The progression of ROP to threshold ROP in very preterm infants may be influenced by genetic differences in VEGF production. Future efforts at prevention of threshold ROP may be directed toward blocking excess production of VEGF.

Caudate and hippocampal volumes, intelligence, and motor impairment in 7-year-old children who were born preterm.

Children who survive very preterm birth without major disability have a high prevalence of learning difficulty, attention deficit, and minor motor impairment (MMI). To determine whether these difficulties are associated with structural brain abnormalities, we studied 105 preterm children (<32 wk) at 7 y with tests of IQ and MMI (Movement ABC) and detailed magnetic resonance brain scans. Scans were assessed qualitatively for visible cerebral lesions. Volume measurements of the caudate nuclei and hippocampal formations were made. Total brain volume (TBV) was estimated from the head circumference. Qualitative assessment of the scans showed evidence of cerebral lesions in 20 (19%), which were associated with lower IQ and more frequent MMI. IQ correlated with right and left caudate volume (Spearman's rho 0.304 and 0.349; p < 0.01). This association persisted (except for verbal IQ) when caudate volume was expressed as a percentage of estimated TBV to allow for overall brain size. No significant correlations with hippocampal volumes were observed. These differences persisted when only scans from children without visible lesions on scan were considered. MMI was significantly associated only with TBV and was more common in children with evidence of thinning of the posterior corpus callosum, although most children with MMI have a normal corpus callosum. Lower IQs in children who were born preterm are related to poorer development of the caudate relative to the rest of the brain, independent of other lesions. These findings suggest abnormal brain development after perinatal injury or postnatal nutritional deficits is responsible for cognitive deficits in preterm children.

Magnetic resonance imaging and T2 relaxometry of cerebral white matter and hippocampus in children born preterm.

The objective of this study was to determine whether intelligence and minor motor impairments in children who are born preterm without major disability are associated with cerebral white matter (CWM) and hippocampal abnormalities on magnetic resonance imaging (MRI). A total of 103 preterm children were studied at age 7 y with detailed magnetic resonance brain scans, including a T2-mapping sequence from which T2 relaxation times of the CWM and hippocampal formations were calculated. All of the children had no major motor disability, attended normal school, and had undergone assessment of IQ and a test for minor motor impairment (MMI). Twenty children had visible lesions on MRI, which were associated with lower IQ and more frequent MMI. Mean (SD) IQ was 90 (14.1). Twenty-five children were shown to have MMI (Movement ABC at below the fifth centile). This group was shown to have significantly longer T2 relaxation times for CWM (mean difference 2.1 ms right, 3.1 ms left) but not the hippocampus than the children without MMI. These differences persisted when only children without visible lesions on scans were considered (mean difference 1.5 ms bilaterally). There was no significant correlation between IQ and T2 relaxation times. Children who are born preterm without subsequent major neurodisability may, in addition to visible lesions on MRI scans, have a diffuse abnormality of CWM, manifest as an increase in T2 relaxation time. This abnormality shows a close correlation with minor motor impairment but not with full-scale IQ.