Long-term outcome of antenatally diagnosed agenesis of corpus callosum and cerebellar malformations.

Recent advancements in fetal imaging and antenatal care have enabled identification of numerous anomalies including agenesis of corpus callosum and posterior fossa abnormalities. One of the important determinants of long-term prognosis in these conditions is the presence of central nervous system (CNS) and extra-CNS anomalies. The difficulty in confirming the isolated nature of these conditions antenatally and the lack of clear information regarding long-term prognoses makes it difficult for the clinician to provide accurate information to the parents antenatally. Caring for these families would require input from a multidisciplinary team involving obstetricians, geneticists, neurologists, radiologists and neonatologists.

Treatment of asphyxiated newborns with moderate hypothermia in routine clinical practice: how cooling is managed in the UK outside a clinical trial.

BACKGROUND: This is a phase 4 study of infants registered with the UK TOBY Cooling Register from December 2006 to February 2008. The registry was established on completion of enrolLment to the TOBY randomised trial of treatment with whole body hypothermia following perinatal asphyxia at the end of November 2006. METHODS: We collected information about patient characteristics, condition at birth, resuscitation details, severity of encephalopathy, hourly temperature record, clinical complications and outcomes before hospital discharge. RESULTS: 120 infants born at a median of 40 (IQR 38-41) weeks' gestation and weighing a median of 3287 (IQR 2895-3710) g at birth were studied. Cooling was started at a median of 3 h 54 min (IQR 2 h-5 h 32 min) after birth. All but three infants underwent whole body cooling. The mean (SD) rectal temperature from 6 to 72 h of the cooling period was 33.57 degrees C (0.51 degrees C). The daily encephalopathy score fell: median (IQR) 11 (6-15), 9.7 (5-14), 8 (5-13) and 7 (2-12) on days 1-4 after birth, respectively. 51% of the infants established full oral feeding at a median (range) of 9 (4-24) days. 26% of the study infants died. MRI was consistent with hypoxia-ischaemia in most cases. Clinical complications were not considered to be due to hypothermia. CONCLUSION: In the UK, therapeutic hypothermia following perinatal asphyxia is increasingly being provided. The target body temperature is successfully achieved and the clinical complications observed were not attributed to hypothermia. Treatment with hypothermia may have prevented the worsening of the encephalopathy that is commonly observed following asphyxia.

Procedural pain guidelines for the newborn in the United Kingdom.

OBJECTIVE: To assess the use of analgesia guidelines for newborn infants in the United Kingdom. STUDY DESIGN: Postal questionnaire to every neonatal unit in the United Kingdom. RESULT: A total of 192 of 244 units replied (78.7% response). Most units had a guideline for elective intubation (70%), sedation for ventilation (78%) post-operative pain (when appropriate) (74%). Less prevalent were guidelines for painful minor procedures (35%). Only 33% of units gave a sweet-tasting solution for analgesia before routine painful procedures and 12% used a topical anesthetic cream. CONCLUSION: Since the last survey in 2000 there has been a modest increased uptake in measures to prevent pain neonatal pain in the United Kingdom, but no pain guideline was present in almost 25% of units and no guideline for routine painful procedures in the majority.

Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia.

BACKGROUND: Seizures are common following perinatal asphyxia and may exacerbate secondary neuronal injury by increasing cerebral metabolic demand, causing fluctuations in oxygenation and perfusion, and triggering the release of excitatory neurotransmitters. Anticonvulsant therapy has been used in infants with perinatal asphyxia in order to prevent seizures. However, long term anticonvulsant therapy may lead to inhibition of brain development. Therefore, the routine use of anticonvulsant therapy to prevent seizures following perinatal asphyxia needs to be evaluated. OBJECTIVES: To assess the effect of administering anticonvulsants to infants of 37 weeks gestation or more following perinatal asphyxia on death or subsequent severe neurodevelopmental disability and/or the prevention of seizures. SEARCH STRATEGY: Relevant randomised controlled trials were identified using a combination of electronic database searches, hand searches and a search of the Cochrane Controlled Trials Registry. SELECTION CRITERIA: All randomised or quasi-randomised controlled clinical trials that reported data comparing the following outcomes: mortality, neurodevelopmental disability, neonatal seizures and adverse events, following anticonvulsant therapy in term infants (37 weeks or more) compared to controls (with or without placebo) following perinatal asphyxia. DATA COLLECTION AND ANALYSIS: Methodological quality and validity of studies were assessed without consideration of the results. Data relevant to the outcome were extracted and analysed. MAIN RESULTS: Seven randomised or quasi-randomised controlled trials that met the selection criteria were included. No studies were of sufficient methodological quality and size to demonstrate a valid, clinically significant change in the risk of mortality or severe neurodevelopmental disability. A meta-analysis combining five studies comparing barbiturates with conventional therapy following perinatal asphyxia demonstrated no difference in risks of death, severe neurodevelopmental disability, or the combined outcome of death or severe neurodevelopmental disability. AUTHORS' CONCLUSIONS: At the present time, anticonvulsant therapy to term infants in the immediate period following perinatal asphyxia cannot be recommended for routine clinical practice, other than in the treatment of prolonged or frequent clinical seizures. Any future studies should be of sufficient size to have the power to detect clinically important reductions in mortality and severe neurodevelopmental disability.

An ethically justified, clinically comprehensive approach to peri-viability: gynaecological, obstetric, perinatal and neonatal dimensions.

Peri-viability, 22-26 completed weeks' gestational age, has generated ongoing clinical ethical controversies concerning the roles of abortion, caesarean delivery for fetal indication, neonatal resuscitation and limits on life-sustaining treatment of neonates. This paper provides a comprehensive, ethically justified approach to the clinical management of peri-viable fetuses and infants. We reviewed available data about the outcomes of peri-viable fetuses and developed an outcomes-based ethical framework that appeals to the ethical principles of beneficence, autonomy and justice. We identified beneficence-based, autonomy-based and justice-based considerations that should guide clinical judgement, the informed consent process, and decisions about termination of pregnancy, caesarean delivery and setting justified limits on life-sustaining treatment of neonatal patients. Ethics is an essential component of perinatal medicine because it provides physicians with an evidence-based, ethically justified, comprehensive approach to the gynaecological, obstetric, perinatal and neonatal dimensions of peri-viability.

A survey of clinical academic staffing in paediatrics and child health in the UK.

BACKGROUND: The state of academic paediatrics in the United Kingdom is a source of anxiety in view of anecdotal reports of loss of identity within medical schools and reductions in staffing levels. AIMS: To measure the current numbers and recent changes in clinical academic staff in all university departments of paediatrics in the UK. METHODS: A questionnaire was sent to all 24 university departments of paediatrics where undergraduates are taught, and to the postgraduate institute of paediatrics. RESULTS: Full responses were obtained from 24 medical institutions. In the past five years there has been an overall 7.2% decline in clinical academic staff, but among lecturers there has been a 26% reduction. Nine of 24 departments had undergone changes in name with at least some loss of paediatric identity. In 12 of 24 centres it was felt that the research assessment exercise had resulted in some, or severe, detriment. CONCLUSIONS: This study confirms the recent loss of academic training positions, leading to a serious concern about the future of academic paediatrics in some UK centres.

Infant wellbeing at 2 years of age in the Growth Restriction Intervention Trial (GRIT): multicentred randomised controlled trial.

BACKGROUND: Although delivery is widely used for preterm babies failing to thrive in utero, the effect of altering delivery timing has never been assessed in a randomised controlled trial. We aimed to compare the effect of delivering early with delaying birth for as long as possible. METHODS: 548 pregnant women were recruited by 69 hospitals in 13 European countries. Participants had fetal compromise between 24 and 36 weeks, an umbilical-artery doppler waveform recorded, and clinical uncertainty about whether immediate delivery was indicated. Before birth, 588 babies were randomly assigned to immediate delivery (n=296) or delayed delivery until the obstetrician was no longer uncertain (n=292). The main outcome was death or disability at or beyond 2 years of age. Disability was defined as a Griffiths developmental quotient of 70 or less or the presence of motor or perceptual severe disability. Analysis was by intention-to-treat. This trial has been assigned the International Standard Randomised Controlled Trial Number ISRCTN41358726. FINDINGS: Primary outcomes were available on 290 (98%) immediate and 283 (97%) deferred deliveries. Overall rate of death or severe disability at 2 years was 55 (19%) of 290 immediate births, and 44 (16%) of 283 delayed births. With adjustment for gestational age and umbilical-artery doppler category, the odds ratio (95% CrI) was 1.1 (0.7-1.8). Most of the observed difference was in disability in babies younger than 31 weeks of gestation at randomisation: 14 (13%) immediate versus five (5%) delayed deliveries. No important differences in the median Griffiths developmental quotient in survivors was seen. INTERPRETATION: The lack of difference in mortality suggests that obstetricians are delivering sick preterm babies at about the correct moment to minimise mortality. However, they could be delivering too early to minimise brain damage. These results do not lend support to the idea that obstetricians can deliver before terminal hypoxaemia to improve brain development.

Cerebral perfusion in infants and neonates: preliminary results obtained using dynamic susceptibility contrast enhanced magnetic resonance imaging.

BACKGROUND: Previous studies have used the dynamic susceptibility contrast enhanced (DSCE) magnetic resonance (MR) imaging technique to measure cerebral perfusion in adults. OBJECTIVE: To assess the feasibility of the technique in a heterogeneous cohort of sick human infants and identify cerebral perfusion abnormalities. METHODS: Perfusion measurements were made by characterising the changing concentration of an injected bolus of contrast agent using a series of MR images acquired during the first pass of the contrast bolus. Qualitative values of relative cerebral blood flow (rCBF) were then calculated from these data on a pixel by pixel basis to generate parametric maps of perfusion. RESULTS: Images of perfusion were successfully calculated from 12 out of 27 neonates and infants, all with established cerebral pathology. Normal vascular anatomical structures such as the circle of Willis were identified within all calculated images. Values of rCBF were generally larger in grey matter than in white matter. In several patients, perfusion abnormalities resulted in structural abnormalities which were detected in conventional MR imaging at follow up. The acquisition of perfusion data was most difficult when the least mature brains were examined because of motion artefacts and a smaller head size with a lower level of rCBF than adults. CONCLUSIONS: This preliminary study shows that: (a) maps of rCBF can be acquired from neonates and infants; (b) characterisation of the bolus passage becomes progressively easier as the brain matures; (c) early abnormalities in cerebral perfusion may have negative prognostic implications; (d) the main difficulty when using the DSCE technique to study neonates relates to image artefacts resulting from bulk head motion.

Zero-mode waveguides for single-molecule analysis at high concentrations.

Optical approaches for observing the dynamics of single molecules have required pico- to nanomolar concentrations of fluorophore in order to isolate individual molecules. However, many biologically relevant processes occur at micromolar ligand concentrations, necessitating a reduction in the conventional observation volume by three orders of magnitude. We show that arrays of zero-mode waveguides consisting of subwavelength holes in a metal film provide a simple and highly parallel means for studying single-molecule dynamics at micromolar concentrations with microsecond temporal resolution. We present observations of DNA polymerase activity as an example of the effectiveness of zero-mode waveguides for performing single-molecule experiments at high concentrations.

Cerebral venous thrombosis, intraventricular haemorrhage and white matter lesions in a preterm newborn with factor V (Leiden) mutation.

We report a preterm newborn who presented extensive cerebral vein thrombosis on MRI but no abnormal neurological signs. The baby underwent MRI as germinal-matrix intraventricular haemorrhage was revealed by a routine ultrasound brain scan performed on day 16; earlier ultrasound scans (day 2, 7, 12) were all normal. Cerebral vein thrombosis was diagnosed at the first MRI scan together with abnormal restriction in diffusion weighted imaging in the frontal white matter parenchyma. Bilateral microcavitations with a linear pattern of distribution reflecting the distribution of medullary veins developed a week later in the same white matter areas where abnormal diffusion weighted imaging was formerly noted. The baby was later found to be heterozygous for factor V Leiden.

Magnetic resonance imaging of the infant brain: anatomical characteristics and clinical significance of punctate lesions.

OBJECTIVE: To describe the magnetic resonance imaging (MRI) characteristics of punctate brain lesions in neonates (number, appearance, distribution, and association with other brain abnormalities) and to relate them to neurodevelopmental outcome. METHODS: A retrospective analysis was performed of 110 MRI brain scans from 92 infants admitted in 1998 to the neonatal intensive care unit. Results of routine neurodevelopmental follow up (1998-2001) in those infants with punctate brain lesions were analysed. RESULTS: Punctate lesions were observed in 15/50 preterm and 2/42 term infants. In the preterm group, the number of lesions was < 3 in 20%, 3-10 in 27%, and > 10 in 53%. In 14/15 the lesions were linearly organised and located in the centrum semiovale. Other brain abnormalities were absent or minor--that is, "isolated" punctate lesions--in 8/15 and major in 7/15. In the term group, punctate lesions were organised in clusters and no other brain abnormalities were observed. Isolated punctate lesions were observed in 10/17 infants, and a normal neurodevelopmental outcome was seen in 9/10 (mean follow up 29.5 months). One infant showed a slight delay in language development. In the infants with associated brain lesions (7/17, mean follow up 27.5 months), outcome was normal in only two subjects. CONCLUSIONS: Punctate lesions are predominantly seen in preterm infants, are usually linearly organised, and border the lateral ventricles. Isolated punctate lesions may imply a good prognosis, because most of these subjects have a normal neurodevelopmental outcome so far.

The clinical conundrum of neonatal seizures.

There is increasing evidence that neonatal seizures have an adverse effect on neurodevelopmental progression and may predispose to cognitive, behavioural, or epileptic complications later in life. However, given the uncertainty about the efficacy and toxicity of the commonly used anticonvulsants, when and how aggressively to treat such seizures is a difficult decision.

Is thrombophilia a factor in the development of hemiplegic cerebral palsy?

A population-based study of children with hemiplegic cerebral palsy (CP) was performed to investigate whether thrombophilic tendencies are implicated in the aetiology of the condition. Thirty-eight children (23 males, 15 females; mean age 8.7 years, SD 4.1 years) with hemiplegic CP were ascertained. Twenty-seven children(18 males, nine females; mean age 8.4 years, SD 4.3) gave consent for inclusion. The non-study group comprised five males and six females; mean age 9.4 years, SD 4.1. In six children, seven thrombophilic 'abnormalities' were identified. Five of these abnormalities were of an equivocal nature and probably did not represent true clinical thrombophilia; reasons for this interpretation are discussed. Contrary to other published non-population-based studies, we have not shown an association between thrombophilia and hemiplegic CP. More studies, including maternal studies, are required to explore this complex subject further.

Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia.

OBJECTIVES: To assess the benefits and harm of administering anticonvulsants to infants of 37 weeks gestation or more following perinatal asphyxia with the primary aims of prevention of death or subsequent severe neurodevelopmental disability and/or the prevention of seizures. SEARCH STRATEGY: Relevant randomised controlled trials were identified using a combination of electronic database searches (MEDLINE and EMBASE), hand searches and a search of the Cochrane Controlled Trials Registry. SELECTION CRITERIA: All randomised, or quasi-randomised, controlled clinical trials with reported data comparing the following outcomes: mortality, neurodevelopmental disability, neonatal seizures and adverse events, following anticonvulsant therapy in term infants (37 weeks or more), compared to controls with or without placebo, following perinatal asphyxia. DATA COLLECTION AND ANALYSIS: Methodological quality and validity of studies were assessed without consideration of the results. Data relevant to the outcome were extracted and analysed. MAIN RESULTS: Five randomised or quasi-randomised controlled trials which met the selection criteria were identified. No studies were of sufficient methodological quality and size to demonstrate a valid, clinically significant change in the risk of mortality or severe neurodevelopmental disability. A meta-analysis combining three studies comparing barbiturates with conventional therapy following perinatal asphyxia demonstrated no difference in risks of death, severe neurodevelopmental disability, or death or severe neurodevelopmental disability. REVIEWER'S CONCLUSIONS: At the present time, anticonvulsant therapy to term infants in the immediate period following perinatal asphyxia cannot be recommended for routine clinical practice, other than in the treatment of prolonged or frequent clinical seizures. Any future studies should be of high quality: randomised control trials with allocation concealment, performance and outcome assessment blinding. Such studies should be of sufficient size, with minimal attrition, to have the power to detect clinically important reductions in mortality and severe neurodevelopmental disability, as the primary outcome measures.

Cerebral maturation in premature infants: quantitative assessment using MR imaging.

BACKGROUND AND PURPOSE: The assessment of whether brain development is at an appropriate level for age has become an integral part of clinical MR reporting, although few studies have quantitatively defined the developmental changes occurring in premature infants. We have developed a simple scoring system to assess four parameters of cerebral maturation--myelination, cortical folding, glial cell migration, and germinal matrix distribution--to determine the total maturation score (TMS). The aim of this study was to validate this scoring system in a large population of preterm infants across a range of gestational ages. METHODS: A retrospective analysis was conducted of MR images acquired over a 3-year period with an identical imaging protocol. Infants born more than 14 days before the imaging examination and those with a clinical or radiologic history suggestive of neuroabnormality were excluded from the study. The TMS was derived by consensus. Interobserver agreement was evaluated by using the Bland-Altman plot. RESULTS: Images from 134 infants (23-41 weeks' gestational age) were evaluated. The TMS was significantly related to the postmenstrual age of the infant, with the mean TMS for each age group increasing with advancing postmenstrual age. Interobserver agreement was found to be high (mean difference in score = 0.07, SD = 0.56). CONCLUSION: This scoring system provides a standardized method for assessing cerebral maturation in the premature infant. The TMS is easy to calculate from standard MR images, is reproducible, and can help detect changes occurring within a postnatal age of a few weeks.

Screening for severe anaemia in pregnancy in Kenya, using pallor examination and self-reported morbidity.

Severe anaemia in pregnancy is an important preventable cause of maternal and perinatal morbidity and mortality. Different methods of screening for severe anaemia in pregnancy were evaluated in a 2-phased study conducted in Kilifi, Kenya. In phase 1 (in 1994/95), pallor testing was evaluated alone and in addition to raised respiratory/pulse rates: 1787 pregnant women were examined by one of 2 midwives. Sensitivities for detecting severe anaemia (haemoglobin < 7 g/dL) were 62% and 69% and specificities 87% and 77%, respectively for each of the midwives. Addition of high pulse rate increased sensitivity to 77% and 81%, but specificity reduced to 60% and 51%, respectively. In phase 2, following qualitative in-depth work, a screening questionnaire was developed. An algorithm based on screening questions had 80% sensitivity and 40% specificity. Midwife pallor-assessment was conducted following the screening questionnaire. In this phase (conducted in 1997), the midwife performed very highly in detecting severe anaemia, achieving sensitivity of 84% and specificity of 92%. Spending a few minutes asking women questions may have improved the ability to interpret pallor findings. This study demonstrates the value of pallor testing and raises alternative approaches to improving it.

Post-resuscitative management of the asphyxiated term and preterm infant.

Up until the recent past, the treatment for perinatal asphyxia included only supportive measures. Babies were resuscitated and then observed for signs of multi-organ system dysfunction. Apart from standard supportive management, a new arsenal of potential neuroprotective strategies have emerged over the past years, in order to decrease the severity of brain injury following asphyxia. Today, several neuroprotective therapies are being evaluated in human infants.

Magnetic resonance and cranial ultrasound characteristics of periventricular white matter abnormalities in newborn infants.

OBJECTIVE: To characterize the range of abnormalities within the periventricular white matter (PVWM) in a cohort of newborns using magnetic resonance (MR) brain imaging and to compare the focal MR abnormalities with the cranial ultrasound (CUS) findings. METHODS: Retrospective study of MR brain and CUS findings of infants born in the 18-month period 1998-1999. PVWM abnormalities were identified by MR and focal lesions were characterized by size, number and distribution using a grading scale. Correspondence with CUS findings was assessed. RESULTS: 175 MR examinations corresponding to n = 105 preterm infants, (median GA 28, range 23-36 weeks) and n = 25 term infants (median GA 39, range 37-42 weeks) were analysed for PVWM abnormalities. In the preterm group, MR demonstrated a normal PVWM in n = 76, focal areas of altered signal intensity (SI) in PVWM in n = 26 and venous infarction in n = 3. In the term group, MR demonstrated a normal PVWM in n = 15, focal areas of altered SI in PVWM in n = 4, oedematous PVWM in n = 2 and a middle cerebral artery infarction in n = 4. All infants with normal MR had normal CUS findings. A focal PVWM SI abnormality detectable on MR corresponded with an abnormality on CUS in only n = 10/30. CONCLUSIONS: MR appears considerably more sensitive than CUS in demonstrating the existence and extent of focal PVWM lesions in newborn infants. Satisfactory correspondence between the two imaging investigations is obtained only for cystic PVWM lesions.

Evidence of selection bias in preterm survival studies: a systematic review.

OBJECTIVE: To determine by how much selection bias in preterm infant cohort studies results in an overestimate of survival. DESIGN: Systematic review of studies reporting survival in infants less than 28 weeks of gestation published 1978-1998. Studies were graded according to cohort definition: A, stillbirths and live births; B, live births; C, neonatal unit admissions. Proportions of infants surviving to discharge were calculated for each week of gestation. RESULTS: Sixty seven studies report data on 55 cohorts (16 grade A, 23 grade B, 16 grade C). Studies that are more selective report significantly higher survival between 23 and 26 weeks of gestation (grade C > grade B > grade A, p < 0.01), exaggerating survival by 100% and 56% at 23 and 24 weeks respectively. CONCLUSION: To minimise the potential for overestimating survival around the limits of viability, future studies should endeavour to report the outcome of all pregnancies for each week of gestation (terminations, miscarriages, stillbirths, and all live births).