Simon Cousens

4 million neonatal deaths: When? Where? Why?

The proportion of child deaths that occurs in the neonatal period (38% in 2000) is increasing, and the Millennium Development Goal for child survival cannot be met without substantial reductions in neonatal mortality. Every year an estimated 4 million babies die in the first 4 weeks of life (the neonatal period). A similar number are stillborn, and 0.5 million mothers die from pregnancy-related causes. Three-quarters of neonatal deaths happen in the first week--the highest risk of death is on the first day of life. Almost all (99%) neonatal deaths arise in low-income and middle-income countries, yet most epidemiological and other research focuses on the 1% of deaths in rich countries. The highest numbers of neonatal deaths are in south-central Asian countries and the highest rates are generally in sub-Saharan Africa. The countries in these regions (with some exceptions) have made little progress in reducing such deaths in the past 10-15 years. Globally, the main direct causes of neonatal death are estimated to be preterm birth (28%), severe infections (26%), and asphyxia (23%). Neonatal tetanus accounts for a smaller proportion of deaths (7%), but is easily preventable. Low birthweight is an important indirect cause of death. Maternal complications in labour carry a high risk of neonatal death, and poverty is strongly associated with an increased risk. Preventing deaths in newborn babies has not been a focus of child survival or safe motherhood programmes. While we neglect these challenges, 450 newborn children die every hour, mainly from preventable causes, which is unconscionable in the 21st century.

Global, regional, and national causes of child mortality in 2008: a systematic analysis

BACKGROUND Up-to-date information on the causes of child deaths is crucial to guide global efforts to improve child survival. We report new estimates for 2008 of the major causes of death in children younger than 5 years. METHODS We used multicause proportionate mortality models to estimate deaths in neonates aged 0-27 days and children aged 1-59 months, and selected single-cause disease models and analysis of vital registration data when available to estimate causes of child deaths. New data from China and India permitted national data to be used for these countries instead of predictions based on global statistical models, as was done previously. We estimated proportional causes of death for 193 countries, and by application of these proportions to the country-specific mortality rates in children younger than 5 years and birth rates, the numbers of deaths by cause were calculated for countries, regions, and the world. FINDINGS Of the estimated 8.795 million deaths in children younger than 5 years worldwide in 2008, infectious diseases caused 68% (5.970 million), with the largest percentages due to pneumonia (18%, 1.575 million, uncertainty range [UR] 1.046 million-1.874 million), diarrhoea (15%, 1.336 million, 0.822 million-2.004 million), and malaria (8%, 0.732 million, 0.601 million-0.851 million). 41% (3.575 million) of deaths occurred in neonates, and the most important single causes were preterm birth complications (12%, 1.033 million, UR 0.717 million-1.216 million), birth asphyxia (9%, 0.814 million, 0.563 million-0.997 million), sepsis (6%, 0.521 million, 0.356 million-0.735 million), and pneumonia (4%, 0.386 million, 0.264 million-0.545 million). 49% (4.294 million) of child deaths occurred in five countries: India, Nigeria, Democratic Republic of the Congo, Pakistan, and China. INTERPRETATION These country-specific estimates of the major causes of child deaths should help to focus national programmes and donor assistance. Achievement of Millennium Development Goal 4, to reduce child mortality by two-thirds, is only possible if the high numbers of deaths are addressed by maternal, newborn, and child health interventions. FUNDING WHO, UNICEF, and Bill & Melinda Gates Foundation.

Global, regional, and national causes of child mortality: an updated systematic analysis for 2010 with time trends since 2000

BACKGROUND Information about the distribution of causes of and time trends for child mortality should be periodically updated. We report the latest estimates of causes of child mortality in 2010 with time trends since 2000. METHODS Updated total numbers of deaths in children aged 0-27 days and 1-59 months were applied to the corresponding country-specific distribution of deaths by cause. We did the following to derive the number of deaths in children aged 1-59 months: we used vital registration data for countries with an adequate vital registration system; we applied a multinomial logistic regression model to vital registration data for low-mortality countries without adequate vital registration; we used a similar multinomial logistic regression with verbal autopsy data for high-mortality countries; for India and China, we developed national models. We aggregated country results to generate regional and global estimates. FINDINGS Of 7·6 million deaths in children younger than 5 years in 2010, 64·0% (4·879 million) were attributable to infectious causes and 40·3% (3·072 million) occurred in neonates. Preterm birth complications (14·1%; 1·078 million, uncertainty range [UR] 0·916-1·325), intrapartum-related complications (9·4%; 0·717 million, 0·610-0·876), and sepsis or meningitis (5·2%; 0·393 million, 0·252-0·552) were the leading causes of neonatal death. In older children, pneumonia (14·1%; 1·071 million, 0·977-1·176), diarrhoea (9·9%; 0·751 million, 0·538-1·031), and malaria (7·4%; 0·564 million, 0·432-0·709) claimed the most lives. Despite tremendous efforts to identify relevant data, the causes of only 2·7% (0·205 million) of deaths in children younger than 5 years were medically certified in 2010. Between 2000 and 2010, the global burden of deaths in children younger than 5 years decreased by 2 million, of which pneumonia, measles, and diarrhoea contributed the most to the overall reduction (0·451 million [0·339-0·547], 0·363 million [0·283-0·419], and 0·359 million [0·215-0·476], respectively). However, only tetanus, measles, AIDS, and malaria (in Africa) decreased at an annual rate sufficient to attain the Millennium Development Goal 4. INTERPRETATION Child survival strategies should direct resources toward the leading causes of child mortality, with attention focusing on infectious and neonatal causes. More rapid decreases from 2010-15 will need accelerated reduction for the most common causes of death, notably pneumonia and preterm birth complications. Continued efforts to gather high-quality data and enhance estimation methods are essential for the improvement of future estimates. FUNDING The Bill & Melinda Gates Foundation.

Evidence-based, cost-effective interventions: how many newborn babies can we save?

In this second article of the neonatal survival series, we identify 16 interventions with proven efficacy (implementation under ideal conditions) for neonatal survival and combine them into packages for scaling up in health systems, according to three service delivery modes (outreach, family-community, and facility-based clinical care). All the packages of care are cost effective compared with single interventions. Universal (99%) coverage of these interventions could avert an estimated 41-72% of neonatal deaths worldwide. At 90% coverage, intrapartum and postnatal packages have similar effects on neonatal mortality--two-fold to three-fold greater than that of antenatal care. However, running costs are two-fold higher for intrapartum than for postnatal care. A combination of universal--ie, for all settings--outreach and family-community care at 90% coverage averts 18-37% of neonatal deaths. Most of this benefit is derived from family-community care, and greater effect is seen in settings with very high neonatal mortality. Reductions in neonatal mortality that exceed 50% can be achieved with an integrated, high-coverage programme of universal outreach and family-community care, consisting of 12% and 26%, respectively, of total running costs, plus universal facility-based clinical services, which make up 62% of the total cost. Early success in averting neonatal deaths is possible in settings with high mortality and weak health systems through outreach and family-community care, including health education to improve home-care practices, to create demand for skilled care, and to improve care seeking. Simultaneous expansion of clinical care for babies and mothers is essential to achieve the reduction in neonatal deaths needed to meet the Millennium Development Goal for child survival.

Global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis

BACKGROUND Trend data for causes of child death are crucial to inform priorities for improving child survival by and beyond 2015. We report child mortality by cause estimates in 2000-13, and cause-specific mortality scenarios to 2030 and 2035. METHODS We estimated the distributions of causes of child mortality separately for neonates and children aged 1-59 months. To generate cause-specific mortality fractions, we included new vital registration and verbal autopsy data. We used vital registration data in countries with adequate registration systems. We applied vital registration-based multicause models for countries with low under-5 mortality but inadequate vital registration, and updated verbal autopsy-based multicause models for high mortality countries. We used updated numbers of child deaths to derive numbers of deaths by causes. We applied two scenarios to derive cause-specific mortality in 2030 and 2035. FINDINGS Of the 6·3 million children who died before age 5 years in 2013, 51·8% (3·257 million) died of infectious causes and 44% (2·761 million) died in the neonatal period. The three leading causes are preterm birth complications (0·965 million [15·4%, uncertainty range (UR) 9·8-24·5]; UR 0·615-1·537 million), pneumonia (0·935 million [14·9%, 13·0-16·8]; 0·817-1·057 million), and intrapartum-related complications (0·662 million [10·5%, 6·7-16·8]; 0·421-1·054 million). Reductions in pneumonia, diarrhoea, and measles collectively were responsible for half of the 3·6 million fewer deaths recorded in 2013 versus 2000. Causes with the slowest progress were congenital, preterm, neonatal sepsis, injury, and other causes. If present trends continue, 4·4 million children younger than 5 years will still die in 2030. Furthermore, sub-Saharan Africa will have 33% of the births and 60% of the deaths in 2030, compared with 25% and 50% in 2013, respectively. INTERPRETATION Our projection results provide concrete examples of how the distribution of child causes of deaths could look in 15-20 years to inform priority setting in the post-2015 era. More evidence is needed about shifts in timing, causes, and places of under-5 deaths to inform child survival agendas by and beyond 2015, to end preventable child deaths in a generation, and to count and account for every newborn and every child. FUNDING Bill & Melinda Gates Foundation.

Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion

BACKGROUND Variant Creutzfeldt-Jakob disease (vCJD) is a novel human prion disease caused by infection with the agent of bovine spongiform encephalopathy (BSE). Epidemiological evidence does not suggest that sporadic CJD is transmitted from person to person via blood transfusion, but this evidence may not apply to vCJD. We aimed to identify whether vCJD is transmissible through blood transfusion. METHODS The national CJD surveillance unit reported all cases of probable or definite vCJD to the UK blood services, which searched for donation records at blood centres and hospitals. Information on named recipients and donors was provided to the surveillance unit to establish if any matches existed between recipients or donors and the database of cases of vCJD. Recipients were also flagged at the UK Office of National Statistics to establish date and cause of death. FINDINGS 48 individuals were identified as having received a labile blood component from a total of 15 donors who later became vCJD cases and appeared on the surveillance units register. One of these recipients was identified as developing symptoms of vCJD 6.5 years after receiving a transfusion of red cells donated by an individual 3.5 years before the donor developed symptoms of vCJD. INTERPRETATION Our findings raise the possibility that this infection was transfusion transmitted. Infection in the recipient could have been due to past dietary exposure to the BSE agent. However, the age of the patient was well beyond that of most vCJD cases, and the chance of observing a case of vCJD in a recipient in the absence of transfusion transmitted infection is about 1 in 15000 to 1 in 30000.

Diagnosis of new variant Creutzfeldt-Jakob disease

As of December 31, 1998, 35 deaths had been attributed to new variant Creutzfeldt‐Jakob disease (nvCJD) in the United Kingdom, of which 33 cases had been neuropathologically confirmed and 2 classified as probable nvCJD. Fifteen cases were male and 20 female. The median illness duration was 14 months (range, 8–38 months) and the median age at death was 29 years (range, 18–53 years). The clinical features were consistent with previous descriptions. In nearly all cases, there were early psychiatric symptoms after a median period of 6 months ataxia developed, followed by involuntary movements and cognitive impairment. Electroencephalograms did not show the “typical” appearances found in sporadic CJD, about half the cases tested had a positive 14‐3‐3 immunoassay, and over 70% of cases had bilateral pulvinar high signal on magnetic resonance brain scanning. Prion protein gene analysis showed that all cases were homozygous for methionine at codon 129. Diagnostic criteria for nvCJD have been formulated, which have a high sensitivity and specificity. Ann Neurol 2000;47:575–582

Group B streptococcal disease in infants aged younger than 3 months: systematic review and meta-analysis

BACKGROUND Despite widespread use of intrapartum antibiotic prophylaxis, group B streptococcus remains a leading cause of morbidity and mortality in infants in Europe, the Americas, and Australia. However, estimates of disease burden in many countries outside of these regions is not available. We aimed to examine the current global burden of invasive disease and the serotype distribution of group B streptococcus isolates. METHODS We searched Medline, Embase, and Wholis databases for studies on invasive early-onset (day 0-6) and late-onset (day 7-89) group B streptococcal disease. Eligible studies were those that described incidence, deaths, or serotypes. We also reviewed reference lists and contacted experts to seek unpublished data and data missed by our search. Random effects meta-analysis was used to pool data. FINDINGS 74 studies met the inclusion criteria; 56 studies reported incidence, 29 case fatality, and 19 serotype distribution. An additional search for studies that reported serotype distribution from Jan 1, 1980, yielded a total of 38 articles. Only five low-income countries were represented in the review and contributed 5% weight to the meta-analysis. 47 (69%) studies reported use of any intrapartum antibiotic prophylaxis. Substantial heterogeneity existed between studies. Mean incidence of group B streptococcus in infants aged 0-89 days was 0·53 per 1000 livebirths (95% CI 0·44-0·62) and the mean case fatality ratio was 9·6% (95% CI 7·5-11·8). Incidence of early-onset group B streptococcus (0·43 per 1000 livebirths [95% CI 0·37-0·49]) and case fatality (12·1%, [6·2-18·3]) were two-times higher than late-onset disease. Serotype III (48·9%) was the most frequently identified serotype in all regions with available data followed by serotypes Ia (22·9%), Ib (7·0%), II (6·2%), and V (9·1%). Studies that reported use of any intrapartum antibiotic prophylaxis were associated with lower incidence of early-onset group B streptococcus (0·23 per 1000 livebirths [95% CI 0·13-0·59]) than studies in which patients did not use prophylaxis (0·75 per 1000 livebirths [0·58-0·89]). INTERPRETATION More high-quality studies are needed to accurately estimate the global burden of group B streptococcus, especially in low-income countries. A conjugate vaccine incorporating five serotypes (Ia, Ib, II, III, V) could prevent most global group B streptococcal disease. FUNDING Child Epidemiology Reference Group (CHERG), WHO.

Neonatal Mortality Levels for 193 Countries in 2009 with Trends since 1990: A Systematic Analysis of Progress, Projections, and Priorities

Mikkel Oestergaard and colleagues develop annual estimates for neonatal mortality rates and neonatal deaths for 193 countries for 1990 to 2009, and forecasts into the future.

The pulvinar sign on magnetic resonance imaging in variant Creutzfeldt-Jakob disease.

BACKGROUND There is a need for an accurate non-invasive diagnostic test for variant Creutzfeldt-Jakob disease (vCJD). We investigated the sensitivity and specificity of bilateral pulvinar high signal on magnetic resonance imaging (MRI) for the diagnosis of vCJD. METHODS MRI from patients with vCJD and controls (patients with suspected CJD) were analysed. Scans were reviewed on two separate occasions by two neuroradiologists and scored for the distribution of changes, and likely final diagnosis. Scans from vCJD cases were reassessed to reach a consensus on all abnormalities. FINDINGS We analysed 36 patients and 57 controls. vCJD patients were correctly identified based on bilateral pulvinar high signal in 29 of 36 and 32 of 36 cases on the first assessment by the two radiologists, and 32 of 36 and 31 of 36 on their second assessment. Bilateral increased pulvinar signal was identified in one of 57 and one of 57 controls on the first assessment and two of 57 and three of 57 controls on the second assessment. These reported changes in controls were graded as minimal/equivocal in six of seven patients and moderate in one (<0.5% of all control assessments). 80% of the assessments in vCJD cases were graded as moderate or substantial. On consensus review, 28 of 36 cases and none of 57 controls had prominent bilateral pulvinar signal-sensitivity 78% (95% CI 60-90%) and specificity 100% (95% CI 94-100%). Other common MRI features of vCJD were medial thalamic and periaqueductal grey matter high signal, and the notable absence of cerebral atrophy. Pulvinar high signal correlated with histological gliosis. INTERPRETATION In the appropriate clinical context the MRI identification of bilaterally increased pulvinar signal is a useful non-invasive test for the diagnosis of vCJD.