Prospective research on infants with mild encephalopathy: the PRIME study.

OBJECTIVE: To determine short-term outcomes of infants with evidence of hypoxia-ischemia at birth and classified as mild neonatal encephalopathy (NE) at <6 h of age. STUDY DESIGN: Prospective multicenter study. Mild NE was defined as ⩾1 abnormal category in modified Sarnat score. Primary outcome was any abnormality on early amplitude integrated electroencephalogram (aEEG) or seizures, abnormal brain magnetic resonance imaging (MRI) or neurological exam at discharge. RESULTS: A total of 54/63 (86%) of enrolled infants had data on components of the primary outcome, which was abnormal in 28/54 (52%): discontinuous aEEG (n=4), MRI (n=9) and discharge exam (n=22). Abnormal tone and/or incomplete Moro were the most common findings. MRI abnormalities were confined to cerebral cortex but two infants had basal ganglia and/or thalamus involvement. The 18 to 24 months follow-up is ongoing. CONCLUSIONS: A larger than expected proportion of mild NE infants with abnormal outcomes was observed. Future research should evaluate safety and efficacy of neuroprotection for mild NE.

Predictive value of amplitude-integrated EEG (aEEG) after rescue hypothermic neuroprotection for hypoxic ischemic encephalopathy: a meta-analysis.

OBJECTIVE: Amplitude-integrated electroencephalography (aEEG) is a useful bedside tool in predicting the neurodevelopmental outcome after neonatal encephalopathy; however, the prognostic accuracy may be altered by rescue hypothermic neuroprotection. The objective of this study is to examine the prognostic accuracy of aEEG for predicting long-term neurodevelopmental outcomes in term newborn infants undergoing therapeutic hypothermia for neonatal encephalopathy. STUDY DESIGN: We examined all studies (Medline, Cumulative Index to Nursing and Allied Health Literature and the Cochrane Library; 2000 to 2014) comparing aEEG (6, 24, 48 or 72 h) in term encephalopathic babies undergoing therapeutic hypothermia, with neurodevelopmental outcome at 1 year or more. We extracted individual patient data from the eligible studies to calculate prognostic indices with exact confidence intervals (CIs). We considered continuous normal voltage as normal aEEG pattern and discontinuous normal voltage, burst suppression, flat trace and persistently low voltage as abnormal, and defined adverse outcome as death or moderate/severe disability at 1 year. RESULTS: We reviewed a total of 70 articles, 17 of which met the inclusion criteria. Eight studies were excluded and 9 studies (N=520) were included in the meta-analysis. The pooled sensitivity and specificity for an abnormal trace at 6 h of age to predict adverse outcome were 96% (95% CI 91 to 98%) and 39% (95% CI 32 to 46%). The diagnostic odds ratio of an abnormal trace was highest at 48 h (66.9 (95% CI 19.7, 227.2)). CONCLUSIONS: A persistantly abnormal aEEG at 48 h or more is associated with an adverse neurodevelopmal outcome. The positive prognostic value of 6 h aEEG is poor and good outcome may occur despite abnormal aEEG. Conversely, a normal 6 h aEEG has a good negative predictive value although do not exclude adverse outcomes.

Quantification of maceration changes using post mortem MRI in fetuses.

BACKGROUND: Post mortem imaging is playing an increasingly important role in perinatal autopsy, and correct interpretation of imaging changes is paramount. This is particularly important following intra-uterine fetal death, where there may be fetal maceration. The aim of this study was to investigate whether any changes seen on a whole body fetal post mortem magnetic resonance imaging (PMMR) correspond to maceration at conventional autopsy. METHODS: We performed pre-autopsy PMMR in 75 fetuses using a 1.5 Tesla Siemens Avanto MR scanner (Erlangen, Germany). PMMR images were reported blinded to the clinical history and autopsy data using a numerical severity scale (0 = no maceration changes to 2 = severe maceration changes) for 6 different visceral organs (total 12). The degree of maceration at autopsy was categorized according to severity on a numerical scale (1 = no maceration to 4 = severe maceration). We also generated quantitative maps to measure the liver and lung T2. RESULTS: The mean PMMR maceration score correlated well with the autopsy maceration score (R(2) = 0.93). A PMMR score of ≥4.5 had a sensitivity of 91%, specificity of 64%, for detecting moderate or severe maceration at autopsy. Liver and lung T2 were increased in fetuses with maceration scores of 3-4 in comparison to those with 1-2 (liver p = 0.03, lung p = 0.02). CONCLUSIONS: There was a good correlation between PMMR maceration score and the extent of maceration seen at conventional autopsy. This score may be useful in interpretation of fetal PMMR.

Diagnostic accuracy and limitations of post-mortem MRI for neurological abnormalities in fetuses and children.

AIM: To compare the diagnostic accuracy of non-invasive cerebral post-mortem magnetic resonance imaging (PMMRI) specifically for cerebral and neurological abnormalities in a series of fetuses and children, compared to conventional autopsy. MATERIALS AND METHODS: Institutional ethics approval and parental consent was obtained. Pre-autopsy cerebral PMMRI was performed in a sequential prospective cohort (n = 400) of fetuses (n = 277; 185 ≤ 24 weeks and 92 > 24 weeks gestation) and children <16 years (n = 123) of age. PMMRI and conventional autopsy findings were reported blinded and independently of each other. RESULTS: Cerebral PMMRI had sensitivities and specificities (95% confidence interval) of 88.4% (75.5 to 94.9), and 95.2% (92.1 to 97.1), respectively, for cerebral malformations; 100% (83.9 to 100), and 99.1% (97.2 to 99.7) for major intracranial bleeds; and 87.5% (80.1 to 92.4) and 74.1% (68 to 79.4) for overall brain pathology. Formal neuropathological examination was non-diagnostic due to maceration/autolysis in 43/277 (16%) fetuses; of these, cerebral PMMRI imaging provided clinically important information in 23 (53%). The sensitivity of PMMRI for detecting significant ante-mortem ischaemic injury was only 68% (48.4 to 82.8) overall. CONCLUSIONS: PMMRI is an accurate investigational technique for identifying significant neuropathology in fetuses and children, and may provide important information even in cases where autolysis prevents formal neuropathological examination; however, PMMRI is less sensitive at detecting hypoxic-ischaemic brain injury, and may not detect rarer disorders not encountered in this study.

Post-mortem MRI as an alternative to non-forensic autopsy in foetuses and children: from research into clinical practice.

Although post-mortem MRI (PMMR) was proposed as an alternative to conventional autopsy more than a decade ago, the lack of systematic validation has limited its clinical uptake. Minimally invasive autopsy (MIA) using PMMR together with ancillary investigations has now been shown to be as accurate as conventional autopsy in foetuses, newborns and infants and is particularly useful for cerebral, cardiac and genitourinary imaging. Unlike conventional autopsy, PMMR provides a permanent three-dimensional auditable record, with accurate estimation of internal organ volumes. MIA is becoming highly acceptable to parents and professionals, and there is widespread political support and public interest in its clinical implementation in the UK. In the short to medium term, it is desirable that a supraregional network of specialist centres should be established to provide this service within the current National Health Service framework.

Acceptability of a minimally invasive perinatal/paediatric autopsy: healthcare professionals' views and implications for practice.

BACKGROUND: Perinatal autopsy provides essential clinical information, including cause of death; yet, autopsy rates have steadily declined because of parental refusal. Technology now enables less invasive alternatives to traditional autopsy and may increase the acceptability of post-mortem examination. OBJECTIVE: This study aimed to examine the relative acceptability among healthcare professionals of a minimally invasive autopsy (MIA; magnetic resonance imaging and laparoscopic-guided tissue sampling), compared with standard autopsy. METHODS: This study was questionnaire-based survey of healthcare professionals working in clinical settings where paediatric and perinatal deaths occur. RESULTS: Of 250 questionnaires distributed, 224 were returned (90% response rate). Autopsy was generally perceived as acceptable. Demographic factors affecting acceptability included ethnicity and religion but not professional role. MIA compared favourably with traditional autopsy, 50% of respondents reporting both equally acceptable, 40% reporting MIA more acceptable and 10% less acceptable. Healthcare professionals agreed that having a MIA option would make it easier to discuss autopsy with parents (P < 0.001). CONCLUSION: Less invasive autopsy appears an acceptable alternative to traditional autopsy for most respondents. Healthcare professionals should be aware that ethnic and religious opinions influence their own views on autopsy decisions and should be mindful of this when discussing autopsy with parents. Further research is needed to determine parental opinions.

Normal ascent of the conus medullaris: a post-mortem foetal MRI study.

OBJECTIVES: The position of the conus medullaris is considered abnormal if it ends below lumbar vertebrae three (L3) at birth. We used magnetic resonance imaging (MRI) to measure the position of the conus in post-mortem foetuses, to investigate the timing of normal ascent. METHODS: The position of the conus in 84 post-mortem foetuses (mean gestation 26.3 weeks; range 14-41 weeks) was identified using 3D MRI datasets. A numerical scale was used for vertebral levels, from 1 (S2) to 15 (T12). RESULTS: There was significant ascent of the conus medullaris with increasing gestation. At 20 weeks gestation, an estimated 84.2% (95% confidence interval (CI): 72.9, 93.2%) of foetuses have a conus position of L4/5 or higher, but only 22.8% (95% CI 11.7, 34.9%) at L3 or higher. By 26 weeks, an estimated 50.7% (95% CI 34.1, 67.5) will have reached L3, and 94.8% (95% CI 87.0, 98.5%) reach L3 by 40 weeks. CONCLUSION: There is regular ascent of the conus throughout foetal life. Although growth for each individual foetus may be non-linear, most foetuses have a conus level within the normal adult range by 33 weeks gestation.

High quality genomic DNA extraction from postmortem fetal tissue.

OBJECTIVE: We examined the yield and quality of genomic deoxyribonucleic acid (DNA) extracted from various postmortem fetal tissues. METHODS: Fetal tissues were collected at the time of autopsy, and DNA was subsequently extracted. The yield and DNA quality was assessed using ultraviolet spectrometry and agarose gel electrophoresis. We used polymerase chain reaction (PCR) to assess the DNA extracted for genomic testing. RESULTS: The median (range) gestation of the fetuses was 22 (16-41) weeks and the postmortem interval was 5.5 (2-10) days. Non-degraded genomic DNA was successfully extracted from all fetal tissues. Liver tissue had the lowest quality and muscle the highest quality. DNA yield or purity was not influenced by the postmortem interval. CONCLUSION: High quality genomic DNA can be extracted from fetal muscle, despite postmortem intervals of several days.

Ethical and practical issues relating to the global use of therapeutic hypothermia for perinatal asphyxial encephalopathy.

In intensive care settings in the developed world, therapeutic hypothermia is established as a therapy for term infants with moderate to severe neonatal encephalopathy due to perinatal asphyxia. Several preclinical, pilot and clinical trials conducted in such settings over the last decade have demonstrated that this therapy is safe and effective. The greatest burden of birth asphyxia falls, however, in low- and middle-income countries; it is still unclear whether therapeutic hypothermia is safe and effective in this context. In this paper, the issues around treatments that may be proven safe and effective in the developed world and the caution needed in translating these into different settings and populations are explored. It is argued that there are strong scientific and ethical reasons supporting the conduct of rigorous, randomised controlled trials of therapeutic hypothermia in middle-income settings. There also needs to be substantial and sustainable improvements in all facets of antenatal care and in the basic level of newborn resuscitation in low income countries. This will reduce the burden of disease and allow health workers to determine rapidly which infants are most eligible for potential neuroprotection.

Minimally invasive fetal postmortem examination using magnetic resonance imaging and computerised tomography: current evidence and practical issues.

For a variety of reasons, acceptance of traditional postmortem examination following foetal or neonatal death has declined significantly in recent years in the UK. Here, we review the case for the development of less invasive autopsy using combined investigations including imaging techniques, in particular, magnetic resonance imaging and computerised tomography.

Prospective parental consent for autopsy research following sudden unexpected childhood deaths: a successful model.

BACKGROUND: Organ retention issues, recent changes in the Coroners' (Amendment) Rules 2005 and the Human Tissue Act have resulted in pessimism regarding prospective consent for paediatric autopsy research in the UK. OBJECTIVES: To examine the feasibility and acceptability of a prospective telephone consenting model for post-mortem magnetic resonance (MR) imaging research in HM Coroners' cases. DESIGN: Following each autopsy referral from the HM Coroner, permission to contact the family for research was requested. A family liaison sister, with experience in dealing with bereaved families, then contacted the parents by telephone, explained the study and obtained oral, and then written consent for post-mortem imaging. SETTING: London and an area south of London. RESULTS: Of 76 eligible HM Coroners' cases referred during the study period, permission to contact parents (provided by the HM Coroners' Office) was obtained for only 32 cases (42%). The research sister contacted 32 parents during the study period of whom 31 (96.8%) gave oral research consent. "Helping other parents in the future" and "the importance of post-mortem research" were the main reasons for parents wanting to participate in research. CONCLUSIONS: Prospective consenting for HM Coroners' cases for research is feasible in children, and can be done ethically by parental consenting via telephone contact before autopsy by appropriately trained staff. However, close co-ordination between mortuary staff, HM Coroners, research staff and medical staff is required. This model may be useful in performing post-mortem research in HM Coroners' cases and in developing paediatric tissue and brain banks in the UK.

A gestation- and postnatal age-based reference chart for assessing renal function in extremely premature infants.

OBJECTIVE: A single value of plasma creatinine cannot be used to define renal dysfunction in premature babies, as levels are influenced by gestation and postnatal age. The aim of this study was to create reference ranges for plasma creatinine in cohort of extremely premature infants. STUDY DESIGN: Retrospective analysis of plasma creatinine levels in the first 8 weeks of life from 161 consecutively admitted premature infants 28 weeks gestation. RESULT: Babies were divided into three groups according to gestation. Peak (10th, 90th percentiles) creatinine levels were 132 (106,162) in 22 to 24 weeks gestational infants, 127 (89,151) in those from 25 to 26 weeks and 110 (87,134) in those from 27 to 28 weeks (P<0.001). Creatinine at birth was similar across the groups with levels increasing during the first few days. It decreases thereafter before reaching stable levels by 5 weeks of age. CONCLUSION: Gestation- and age-based reference charts should be used for interpretation of creatinine values in extremely premature babies.

Single versus double volume exchange transfusion in jaundiced newborn infants.

BACKGROUND: Double volume exchange transfusion is commonly used in newborns with severe jaundice in order to prevent kernicterus and other toxicity related to hyperbilirubinemia. Most commonly, exchange transfusions are used in infants with rhesus hemolytic disease. OBJECTIVES: To compare the effectiveness of single volume exchange transfusion (SVET) with that of double volume exchange transfusion (DVET) in producing survival without disability and reducing bilirubin levels in newborn infants with severe jaundice. SEARCH STRATEGY: MEDLINE, EMBASE (Excerpta Medica online), The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), SCISEARCH (Science Citation Index), Reference lists from the articles identified in the search of the databases, and from review articles were searched through March 2006. Personal communication with experts in the field was used to identify unpublished data. SELECTION CRITERIA: All Randomised and quasi randomised control trials comparing single volume and double volume exchange transfusions in jaundiced newborn infants were included. DATA COLLECTION AND ANALYSIS: Safety and efficacy of single and double volume exchange compared with regards to long term neurodevelopment, reduction in bilirubin levels and other complications during exchange transfusion. Data was evaluated separately with regards to the cause of jaundice. Relative risk (RR) and weighted mean difference (WMD) were calculated for dichotomous and continuous variables respectively. 95% confidence intervals were used and a fixed effects model was assumed. MAIN RESULTS: Only one study fulfilled the criteria (Amato 1988). 20 full term babies requiring exchange transfusion for hemolytic jaundice due to ABO incompatibility were randomly allocated to receive single or double volume exchange transfusion. Base line characteristics of both groups were similar with regards to birth weight 3260 (SD 390) g vs. 3350 SD (410) g, gestational age 39 (SD 1) week vs. 40 (SD 0.8) week, immediate pre exchange bilirubin level 199 (SD 33) micromol/L vs. 216 (SD 55) micromol/L. Both groups were treated equally apart from the volume of blood used for exchange transfusion. Total bilirubin levels immediately after exchange transfusion were not significantly different in either group. No long term neurodevelopmental outcome was examined in this study. AUTHORS' CONCLUSIONS: There was insufficient evidence to support or refute the use of single volume exchange transfusion as opposed to double volume exchange transfusion in jaundiced newborns. A change from the current practice of double volume exchange transfusions for severe jaundice in newborns infant, cannot be recommended on current evidence.