Isolated parenchymal lesions on cranial ultrasound in very preterm infants in the context of maternal infection.

AIM: To explore the associations between a clinical diagnosis of maternal infection (CDMI) and findings on the initial cranial ultrasound scan in very preterm infants. METHODS: Among infants born at less than 32 weeks gestation, cases of CDMI and controls were identified on the basis of routinely available obstetric data. Neonatal cranial ultrasound scans carried out soon after birth were retrospectively reviewed for evidence of parenchymal echodensity (PED), intraventricular haemorrhage (IVH) or PED contiguous with IVH. RESULTS: Any PED was identified in 20/40 (50%) cases of CDMI and 9/30 (30%) of controls. Logistic regression was used to adjust for differences between the two study groups. When compared with normal scans, isolated PED was more likely with CDMI odds ratio, OR (95% confidence interval, CI), 41.8 (2.64, 662) and lower Apgar score at 5 min 2.89 (1.05, 7.98). IVH was more likely with lower gestational age, OR for each completed week of gestation 0.64 (0.46, 0.88) and a protective effect of female sex, OR 0.25 (0.063, 0.98), PED contiguous with IVH was more likely with lower gestational age OR 0.59 (0.336, 1.04). CONCLUSIONS: CDMI may be associated with isolated PED in very preterm infants. We speculate that isolated PED (including "flares") identify infants who have sustained early brain injury because of intrauterine infection. Isolated PED may be a useful intermediate outcome in perinatal cohort studies.

Absence of leukaemic fusion gene transcripts in preterm infants exposed to diagnostic x rays.

BACKGROUND: Childhood leukaemias express novel, clonotypic fusion genes that may already be present at birth before the clinical manifestation of leukaemia. Exposure of the fetus to diagnostic x rays is reported to increase the risk of childhood leukaemia, and may do so by generating leukaemic fusion genes. Advances in neonatal medicine in the past decade that have extended the limits of viability of preterm babies down to 23 weeks of gestation have resulted in the increased use of diagnostic x rays to monitor neonatal progress. AIM: To investigate whether exposure of very preterm infants to diagnostic x rays in the neonatal period leads to the development of leukaemic fusion genes. METHODS: Peripheral blood samples were collected at birth from very preterm infants (23-30 weeks gestation) and following exposure to diagnostic x rays at intervals of two weeks, until discharge. Cord blood samples from normal full term infants served as controls. Total RNA was extracted from the blood and the expression of the fusion genes TEL-AML1, MLL-AF4, and BCR-ABL, characteristic of three subtypes of childhood leukaemia, was investigated in the preterm and full term infant samples using a nested reverse transcriptase polymerase chain reaction method. Serial pre- and post-x ray samples from 42 preterm babies, pre-x ray samples from an additional 46 preterm infants, and cord blood samples from 100 normal full term infants were screened for fusion gene transcripts. RESULTS: No leukaemic fusion gene transcripts were detected in preterm infants following exposure to diagnostic x rays. A BCR-ABL transcript was identified in a single preterm infant prior to x ray exposure. TEL-AML1 transcripts were detected in cord blood samples from two full term infants. MLL-AF4 transcripts were not detected in any of the pre- or full term infants tested. CONCLUSIONS: Exposure of the preterm infants to x rays in this small series and at the doses used for diagnostic purposes did not induce leukaemic fusion gene expression, but we cannot exclude the possibility that a small proportion of preterm infants may be unusually sensitive to x rays.

Evidence for the role of demyelination, HLA-DR alleles, and cytokines in the pathogenesis of parvovirus B19 meningoencephalitis and its sequelae.

OBJECTIVE: To review the clinical and pathological features of parvovirus B19 meningoencephalitis and its sequelae in 12 previously published cases, and to perform additional tests to determine the pathogenesis of the disease. METHODS: Cases were reviewed and available serum and cerebrospinal fluid (CSF) tested for antiganglioside antibodies and a range of cytokines. In situ hybridisation for parvovirus B19 DNA was performed on postmortem brain tissue in two cases. HLA-DRB1 typing was undertaken on genomic DNA extracted from peripheral blood leucocytes. RESULTS: Cerebellar involvement was suggested either clinically or pathologically in four cases. In the two cases with postmortem histology, there was marked atrophy of the molecular and granular layers of the cerebellum with focal loss of Purkinje cells. Brain scanning by MRI or CT was done in six cases during the acute phase. Three were abnormal with evidence of demyelination. Three had markedly enlarged ventricles, in two of which there was high signal intensity from the white matter on both T1 and T2 weighted images. The three cases with abnormal brain scans had long term neurological sequelae (mental retardation, personality change, altered affect). In situ hybridisation on available postmortem brain tissue was negative in the two cases tested. All cases in which HLA-DR alleles were determined carried at least one of the following alleles: HLA-DRB1*01, *04, *07, *09, *15, *16. Available serum and CSF was tested for antiganglioside antibodies (all negative) and for a panel of cytokines, which had a similar profile in both serum (n = 5) and CSF (n = 1) during the acute phase. Cytokines that were consistently detectable were IL-6 (mean 726.20 pg/ml), TNFalpha (50.64 pg/ml), IFNgamma (39.64 pg/ml), GM-CSF (216.12 pg/ml), and MCP-1 (154.43 pg/ml); IL-1beta, IL-5, and IL-13 were undetectable. CONCLUSIONS: HLA-DR associations, an increased cytokine response, and benefit from immunomodulatory treatment (in one case) support a role for the immune response in the pathogenesis of parvovirus B19 meningoencephalitis.

Antenatal steroids are associated with a reduction in the incidence of cerebral white matter lesions in very low birthweight infants.

AIMS: To investigate whether antenatal steroids reduce the incidence of cerebral white matter lesions in very low birthweight infants. METHODS: A total of 224 newborn infants of < 31 weeks gestational age and weighing < 1500 g was studied between January 1998 and June 2000. Obstetric and neonatal information was obtained from the case notes. The study population was subdivided into two groups according to antenatal steroid exposure. A complete course of treatment consisted of two doses of 12 mg each of betamethasone given at an interval of 12-24 hours. Infants in group 1 were born to mothers who had not received betamethasone, or were delivered within 24 hours of receiving the first dose of steroid. Infants in group 2 were born to mothers who had received one or more complete courses of betamethasone and were delivered > 24 hours after receiving the first dose of steroid. RESULTS: The two groups contained statistically similar proportions of boys and girls, and the infants had similar birth weights and survival rates. Those in group 2, compared with those in group 1, had a lower gestational age (p = 0.02) and a lower incidence of white matter lesions on cranial ultrasound scans (p = 0.03). Stepwise logistic regression analysis showed that gestational age (p = 0.0002) and a complete course of antenatal steroids (p = 0.02) had independent effects on cerebral white matter lesions. CONCLUSIONS: These observations suggest that a complete course of antenatal steroids may have a protective effect against cerebral white matter lesions in very low birthweight infants.

Association of human parvovirus B19 infection with acute meningoencephalitis.

To find out the incidence and clinical presentation of parvovirus B19 meningoencephalitis, we tested samples of cerebrospinal fluid from 162 patients (one from each patient) with undiagnosed meningoencephalitis, who presented between March, 1997, and March, 1998 (an outbreak period) using nested PCR for B19 genes. Seven patients were positive; an incidence of 4.3%. Five additional cases of meningoencephalitis were detected from other years. Three patients with underlying disorders (haemophagocytic lymphohistiocytosis, Cockayne's syndrome, and Turner's syndrome) died. Neurological sequelae were observed in three surviving patients, all of whom had had striking abnormalities detected on brain scans done during the acute phase.

Increased survival and deteriorating developmental outcome in 23 to 25 week old gestation infants, 1990-4 compared with 1984-9.

AIMS: To assess whether changes in survival over time in infants of 23 to 25 weeks of gestational age were accompanied by changes in the incidence of disability in childhood during an 11 year period. METHODS: Obstetric and neonatal variables having the strongest association with both survival to discharge from a regional neonatal medical unit and neurodevelopmental disability in 192 infants of 23 to 25 weeks of gestation, born in 1984 to 1994, were studied as a group and in two cohorts (1984 to 1989 n = 96 and 1990 to 1994 n = 96). The data collected included CRIB (clinical risk index for babies) scores and cranial ultrasound scan findings. The children were followed up at outpatient clinics. RESULTS: Between 1984 and 1989 (cohort 1) and 1990 and 1994 (cohort 2) the rate of survival to discharge increased significantly from 27% to 42% and the rate of disability in survivors increased from 38% to 68%; most of this increase was in mild disability. The proportions of survivors with cerebral palsy did not alter significantly (21% vs 18%), but more survivors with blindness due to retinopathy of prematurity (4% vs 18%), myopia (4% vs 15%) and squints (8% vs 13%) contributed to the increased rate of disability. Clinically significant cranial ultrasound findings and a high CRIB score were strongly associated with death. A high CRIB score was most strongly associated with disability. CONCLUSIONS: The rise in disability with improved survival was not due to cerebral palsy; rather the main contributors were blindness due to retinopathy, myopia, and squint. The causes of these disabilities seem to be linked to high CRIB scores. A system of regular and skilled retinal examination and access to facilities for retinal ablation should be in place in all neonatal units which undertake the care of such extremely preterm infants.

Retinopathy of prematurity: systemic complications associated with different anaesthetic techniques at treatment.

BACKGROUND: Treatment of retinopathy of prematurity (ROP) in the UK is subject to considerable regional variation in terms of anaesthetic support. Change in practice at St Mary's neonatal medical unit from topical to general anaesthesia and, subsequently, to sedation/analgesia allowed comparison of the impact of these three modalities on infants' early postoperative course in a consecutive, non-randomised, observational study. METHODS: The study population consisted of 30 babies undergoing treatment of threshold ROP. Twelve were treated using topical anaesthesia alone (group A), six using general anaesthesia (group B), and 12 using sedation/analgesia combined with elective intubation and artificial ventilation (group C). Daily measurements of infant health were recorded starting 4 days preoperatively and continuing for 7 days postoperatively to facilitate the formulation of a cardiorespiratory stability index as follows: (0) improvement from baseline, (1) no change from baseline, (2) mild instability, (3) marked instability, and (4) life threatening event. RESULTS: Within the first 48 hours postoperatively in group A 5/12 showed mild instability and 4/12 showed marked instability (including three babies suffering life threatening events requiring emergency resuscitation). In group B within the first 48 hours postoperatively 1/6 showed mild and 1/6 showed marked instability, and in group C 5/12 babies showed mild instability alone. There was a significant difference for cardiorespiratory stability scores between the three groups overall for the 7 days postoperatively (repeated measures ANOVA, p = 0.018). CONCLUSIONS: Premature infants undergoing cryotherapy for ROP who were treated using topical anaesthesia alone had more severe and protracted cardiorespiratory complications.

Blood pressure, heart rate, and skin temperature in preterm infants: associations with periventricular haemorrhage.

The mean arterial blood pressure (MABP), heart rate, and skin temperature were monitored every 15 minutes in the first 10 days after birth in 34 preterm infants, gestational age 24 to 33 weeks. Ultrasound brain scans carried out daily showed that a periventricular haemorrhage (PVH) occurred in a subgroup of infants (n = 15) of lower birthweight and gestational age. In infants without PVH the daily median of MABP increased with birthweight and postnatal age; that of heart rate was not affected by postnatal age, body weight, or gestational age; and that of skin temperature showed a slight fall with postnatal age. In infants with PVH, on or before the day of PVH, daily medians of MABP and skin temperature were not significantly different from those of infants without PVH, but the daily median of heart rate tended to be slightly higher. The percentage of positive correlations between the 96 15 minute values per day for heart rate and MABP increased with postnatal age and with birthweight, but did not differ in infants who developed a PVH. The coefficient of variation (CV) of the 96 15 minute values for MABP tended to be higher in infants on the day of PVH, and a similar trend was apparent on the day before. The processes of development of blood pressure, heart rate, and skin temperature are similar in infants with or without PVH but at lower gestational ages altered blood pressure control may cause brain haemorrhage.

Measurement of ionised calcium concentration in neonates.

Whole blood ionised calcium concentration was measured simultaneously in capillary and arterial blood from neonates being nursed on an intensive care unit using an ion selective electrode. The mean arterio-capillary difference was -0.027 mmol/l (95% confidence intervals -0.041 to -0.012 mmol/l) and the limits of agreement between the two measurements were 0.034 and -0.088 mmol/l. Measurement of ionised calcium in capillary blood is acceptable for clinical purposes.

Skin temperature and heart rate rhythms in infants of extreme prematurity.

Nine preterm infants of 26 to 29 weeks' gestational age and 792 to 1200 g birth weight spent six to 17 weeks in our neonatal medical unit. Hourly recordings of skin temperature and heart rate were carried out. The first five to 15 weeks were spent in the intensive care ward, in continuous light, due to various medical conditions. After recovery they were moved to a nursery for one to nine weeks, with 12 hourly periods of light and darkness. Four infants developed circadian rhythms in temperature and three in heart rate in light-dark periods, the remainder failing to do so. Some infants take longer than others to develop circadian rhythms but the reasons for this are not clear. It is suggested that earlier exposure to a light-dark environment may synchronize the 'body clock' to a 24 hour period in more preterm infants.

Gastrointestinal blood flow velocity after the first feed.

Twenty preterm infants (gestational age range 27-36 weeks) who had never been fed enterally were studied. Doppler indices of flow velocity from the superior mesenteric and coeliac arteries were measured immediately before, and at postprandial time intervals up to 60 minutes after, a first feed of 1 ml of milk given through a nasogastric tube. There were no significant differences between the preprandial and postprandial values of blood pressure, heart rate, oxygen and carbon dioxide tensions, and pH. The median peak systolic velocity (PSV) (55.9 cm/sec) and time average mean velocity (TAV) (10.6 cm/sec) before the feed at the superior mesenteric artery rose progressively and significantly to postprandial peaks of 88.5 cm/sec and 20.5 cm/sec at 45 minutes, respectively. Significant postprandial rises in the median PSV and TAV values at the coeliac artery were also observed, with a peak at 45 minutes. There were no significant correlations between blood flow velocity indices (preprandial or postprandial) and gestational age, postnatal age, conceptional age, or birth weight. We conclude that the first exposure of preterm babies to a small volume of milk feed is associated with postprandial changes in blood flow velocity consistent with an increase in blood flow in the superior mesenteric and coeliac arteries, although the mechanism of this response is uncertain.

Ischaemic brain lesions diagnosed at birth in preterm infants: clinical events and developmental outcome.

In 232 newborn babies of less than 32 weeks' gestational age ultrasound brain scans were carried out shortly after birth, daily for the first week of life, and at least twice weekly thereafter. Periventricular echogenicity associated with or progressing to periventricular leukomalacia (ischaemic brain lesions) was present in nine babies within two hours of birth (early onset); 30 other babies subsequently developed similar lesions (late onset). Babies with early onset lesions were more likely to have a history of intrauterine growth retardation and to have recurrent apnoea in the first few hours after birth. By contrast, late onset lesions were associated with hyaline membrane disease. In later childhood four of six survivors with early onset periventricular leukomalacia, and seven of 14 survivors with late onset periventricular leukomalacia, had various disabilities including spastic diplegia, impaired vision, squints, sensorineural hearing loss, and developmental delay. In a third of the children with disabilities ischaemic brain lesions were noted within two hours of birth, raising the possibility that some of this damage had taken place before or during birth.

Skin conductance and arousal in the newborn.

We measured skin conductance continuously from the sole of a foot in babies of different conceptional ages before, during, and for 10 minutes after a 'heel prick' carried out for routine blood sampling. We studied 82 healthy babies whose gestational and postnatal ages ranged from 25-42 weeks, and 1-73 days. The median skin conductance level (preheel prick) in babies of 40-43 weeks' conceptional age was 0.6 microS (microsiemens) and differed significantly between awake babies (1.2 microS) and those who were asleep (0.5 microS). In contrast babies less than 40 weeks had a significantly lower median skin conductive level (0.3 microS) which was identical in awake and asleep babies. In response to the heel prick all babies became aroused and skin conductance rose sharply and immediately in 21 out of 22 (95%) babies 40-43 weeks' conceptional age, and in seven out of 23 (30%) babies 36-39 weeks. The median rise at one minute in babies of 40-43 weeks was significantly higher than those 36-39 weeks (2.7 microS compared with 0.5 microS). No babies less than 36 weeks had a change in their skin conductance after the heel prick. These results are consistent with the notion that 'emotional sweating' is a function of maturity and does not develop until 36 weeks' conceptional age.