Hannah Blencowe

Stillbirths: Where? When? Why? How to make the data count?

Despite increasing attention and investment for maternal, neonatal, and child health, stillbirths remain invisible-not counted in the Millennium Development Goals, nor tracked by the UN, nor in the Global Burden of Disease metrics. At least 2·65 million stillbirths (uncertainty range 2·08 million to 3·79 million) were estimated worldwide in 2008 (≥1000 g birthweight or ≥28 weeks of gestation). 98% of stillbirths occur in low-income and middle-income countries, and numbers vary from 2·0 per 1000 total births in Finland to more than 40 per 1000 total births in Nigeria and Pakistan. Worldwide, 67% of stillbirths occur in rural families, 55% in rural sub-Saharan Africa and south Asia, where skilled birth attendance and caesarean sections are much lower than that for urban births. In total, an estimated 1·19 million (range 0·82 million to 1·97 million) intrapartum stillbirths occur yearly. Most intrapartum stillbirths are associated with obstetric emergencies, whereas antepartum stillbirths are associated with maternal infections and fetal growth restriction. National estimates of causes of stillbirths are scarce, and multiple (>35) classification systems impede international comparison. Immediate data improvements are feasible through household surveys and facility audit, and improvements in vital registration, including specific perinatal certificates and revised International Classification of Disease codes, are needed. A simple, programme-relevant stillbirth classification that can be used with verbal autopsy would provide a basis for comparable national estimates. A new focus on all deaths around the time of birth is crucial to inform programmatic investment.

UK health performance: findings of the Global Burden of Disease Study 2010

BACKGROUND The UK has had universal free health care and public health programmes for more than six decades. Several policy initiatives and structural reforms of the health system have been undertaken. Health expenditure has increased substantially since 1990, albeit from relatively low levels compared with other countries. We used data from the Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010) to examine the patterns of health loss in the UK, the leading preventable risks that explain some of these patterns, and how UK outcomes compare with a set of comparable countries in the European Union and elsewhere in 1990 and 2010. METHODS We used results of GBD 2010 for 1990 and 2010 for the UK and 18 other comparator nations (the original 15 members of the European Union, Australia, Canada, Norway, and the USA; henceforth EU15+). We present analyses of trends and relative performance for mortality, causes of death, years of life lost (YLLs), years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE). We present results for 259 diseases and injuries and for 67 risk factors or clusters of risk factors relevant to the UK. We assessed the UKs rank for age-standardised YLLs and DALYs for their leading causes compared with EU15+ in 1990 and 2010. We estimated 95% uncertainty intervals (UIs) for all measures. FINDINGS For both mortality and disability, overall health has improved substantially in absolute terms in the UK from 1990 to 2010. Life expectancy in the UK increased by 4·2 years (95% UI 4·2-4·3) from 1990 to 2010. However, the UK performed significantly worse than the EU15+ for age-standardised death rates, age-standardised YLL rates, and life expectancy in 1990, and its relative position had worsened by 2010. Although in most age groups, there have been reductions in age-specific mortality, for men aged 30-34 years, mortality rates have hardly changed (reduction of 3·7%, 95% UI 2·7-4·9). In terms of premature mortality, worsening ranks are most notable for men and women aged 20-54 years. For all age groups, the contributions of Alzheimers disease (increase of 137%, 16-277), cirrhosis (65%, ?15 to 107), and drug use disorders (577%, 71-942) to premature mortality rose from 1990 to 2010. In 2010, compared with EU15+, the UK had significantly lower rates of age-standardised YLLs for road injury, diabetes, liver cancer, and chronic kidney disease, but significantly greater rates for ischaemic heart disease, chronic obstructive pulmonary disease, lower respiratory infections, breast cancer, other cardiovascular and circulatory disorders, oesophageal cancer, preterm birth complications, congenital anomalies, and aortic aneurysm. Because YLDs per person by age and sex have not changed substantially from 1990 to 2010 but age-specific mortality has been falling, the importance of chronic disability is rising. The major causes of YLDs in 2010 were mental and behavioural disorders (including substance abuse; 21·5% [95 UI 17·2-26·3] of YLDs), and musculoskeletal disorders (30·5% [25·5-35·7]). The leading risk factor in the UK was tobacco (11·8% [10·5-13·3] of DALYs), followed by increased blood pressure (9·0 % [7·5-10·5]), and high body-mass index (8·6% [7·4-9·8]). Diet and physical inactivity accounted for 14·3% (95% UI 12·8-15·9) of UK DALYs in 2010. INTERPRETATION The performance of the UK in terms of premature mortality is persistently and significantly below the mean of EU15+ and requires additional concerted action. Further progress in premature mortality from several major causes, such as cardiovascular diseases and cancers, will probably require improved public health, prevention, early intervention, and treatment activities. The growing burden of disability, particularly from mental disorders, substance use, musculoskeletal disorders, and falls deserves an integrated and strategic response. FUNDING Bill & Melinda Gates Foundation.

Folic acid to reduce neonatal mortality from neural tube disorders

Background Neural tube defects (NTDs) remain an important, preventable cause of mortality and morbidity. High-income countries have reported large reductions in NTDs associated with folic acid supplementation or fortification. The burden of NTDs in low-income countries and the effectiveness of folic acid fortification/supplementation are unclear. Objective To review the evidence for, and estimate the effect of, folic acid fortification/supplementation on neonatal mortality due to NTDs, especially in low-income countries. Methods We conducted systematic reviews, abstracted data meeting inclusion criteria and evaluated evidence quality using adapted Grading of Recommendations, Assessment, Development and Evaluation (GRADE) methodology. Where appropriate, meta-analyses were performed. Results Meta-analysis of three randomized controlled trials (RCTs) of folic acid supplementation for women with a previous pregnancy with NTD indicates a 70% [95% confidence interval (CI): 35–86] reduction in recurrence (secondary prevention). For NTD primary prevention through folic acid supplementation, combining one RCT with three cohort studies which adjusted for confounding, suggested a reduction of 62% (95% CI: 49–71). A meta-analysis of eight population-based observational studies examining folic acid food fortification gave an estimated reduction in NTD incidence of 46% (95% CI: 37–54). In low-income countries an estimated 29% of neonatal deaths related to visible congenital abnormalities are attributed to NTD. Assuming that fortification reduces the incidence of NTDs, but does not alter severity or case-fatality rates, we estimate that folic acid fortification could prevent 13% of neonatal deaths currently attributed to congenital abnormalities in low-income countries. Discussion Scale-up of periconceptional supplementation programmes is challenging. Our final effect estimate was therefore based on folic acid fortification data. If folic acid food fortification achieved 100% population coverage the number of NTDs in low-income countries could be approximately halved. Conclusion The evidence supports both folic acid supplementation and fortification as effective in reducing neonatal mortality from NTDs.

Stillbirths: Rates, risk factors, and acceleration towards 2030

An estimated 2.6 million third trimester stillbirths occurred in 2015 (uncertainty range 2.4-3.0 million). The number of stillbirths has reduced more slowly than has maternal mortality or mortality in children younger than 5 years, which were explicitly targeted in the Millennium Development Goals. The Every Newborn Action Plan has the target of 12 or fewer stillbirths per 1000 births in every country by 2030. 94 mainly high-income countries and upper middle-income countries have already met this target, although with noticeable disparities. At least 56 countries, particularly in Africa and in areas affected by conflict, will have to more than double present progress to reach this target. Most (98%) stillbirths are in low-income and middle-income countries. Improved care at birth is essential to prevent 1.3 million (uncertainty range 1.2-1.6 million) intrapartum stillbirths, end preventable maternal and neonatal deaths, and improve child development. Estimates for stillbirth causation are impeded by various classification systems, but for 18 countries with reliable data, congenital abnormalities account for a median of only 7.4% of stillbirths. Many disorders associated with stillbirths are potentially modifiable and often coexist, such as maternal infections (population attributable fraction: malaria 8.0% and syphilis 7.7%), non-communicable diseases, nutrition and lifestyle factors (each about 10%), and maternal age older than 35 years (6.7%). Prolonged pregnancies contribute to 14.0% of stillbirths. Causal pathways for stillbirth frequently involve impaired placental function, either with fetal growth restriction or preterm labour, or both. Two-thirds of newborns have their births registered. However, less than 5% of neonatal deaths and even fewer stillbirths have death registration. Records and registrations of all births, stillbirths, neonatal, and maternal deaths in a health facility would substantially increase data availability. Improved data alone will not save lives but provide a way to target interventions to reach more than 7000 women every day worldwide who experience the reality of stillbirth.

Mortality risk in preterm and small-for-gestational-age infants in low-income and middle-income countries: a pooled country analysis

BACKGROUND Babies with low birthweight (<2500 g) are at increased risk of early mortality. However, low birthweight includes babies born preterm and with fetal growth restriction, and not all these infants have a birthweight less than 2500 g. We estimated the neonatal and infant mortality associated with these two characteristics in low-income and middle-income countries. METHODS For this pooled analysis, we searched all available studies and identified 20 cohorts (providing data for 2,015,019 livebirths) from Asia, Africa, and Latin America that recorded data for birthweight, gestational age, and vital statistics through 28 days of life. Study dates ranged from 1982 through to 2010. We calculated relative risks (RR) and risk differences (RD) for mortality associated with preterm birth (<32 weeks, 32 weeks to <34 weeks, 34 weeks to <37 weeks), small-for-gestational-age (SGA; babies with birthweight in the lowest third percentile and between the third and tenth percentile of a US reference population), and preterm and SGA combinations. FINDINGS Pooled overall RRs for preterm were 6·82 (95% CI 3·56-13·07) for neonatal mortality and 2·50 (1·48-4·22) for post-neonatal mortality. Pooled RRs for babies who were SGA (with birthweight in the lowest tenth percentile of the reference population) were 1·83 (95% CI 1·34-2·50) for neonatal mortality and 1·90 (1·32-2·73) for post-neonatal mortality. The neonatal mortality risk of babies who were both preterm and SGA was higher than that of babies with either characteristic alone (15·42; 9·11-26·12). INTERPRETATION Many babies in low-income and middle-income countries are SGA. Preterm birth affects a smaller number of neonates than does SGA, but is associated with a higher mortality risk. The mortality risks associated with both characteristics extend beyond the neonatal period. Differentiation of the burden and risk of babies born preterm and SGA rather than with low birthweight could guide prevention and management strategies to speed progress towards Millennium Development Goal 4--the reduction of child mortality. FUNDING Bill & Melinda Gates Foundation.

National and regional estimates of term and preterm babies born small for gestational age in 138 low-income and middle-income countries in 2010

Summary Background National estimates for the numbers of babies born small for gestational age and the comorbidity with preterm birth are unavailable. We aimed to estimate the prevalence of term and preterm babies born small for gestational age (term-SGA and preterm-SGA), and the relation to low birthweight (<2500 g), in 138 countries of low and middle income in 2010. Methods Small for gestational age was defined as lower than the 10th centile for fetal growth from the 1991 US national reference population. Data from 22 birth cohort studies (14 low-income and middle-income countries) and from the WHO Global Survey on Maternal and Perinatal Health (23 countries) were used to model the prevalence of term-SGA births. Prevalence of preterm-SGA infants was calculated from meta-analyses. Findings In 2010, an estimated 32·4 million infants were born small for gestational age in low-income and middle-income countries (27% of livebirths), of whom 10·6 million infants were born at term and low birthweight. The prevalence of term-SGA babies ranged from 5·3% of livebirths in east Asia to 41·5% in south Asia, and the prevalence of preterm-SGA infants ranged from 1·2% in north Africa to 3·0% in southeast Asia. Of 18 million low-birthweight babies, 59% were term-SGA and 41% were preterm. Two-thirds of small-for-gestational-age infants were born in Asia (17·4 million in south Asia). Preterm-SGA babies totalled 2·8 million births in low-income and middle-income countries. Most small-for-gestational-age infants were born in India, Pakistan, Nigeria, and Bangladesh. Interpretation The burden of small-for-gestational-age births is very high in countries of low and middle income and is concentrated in south Asia. Implementation of effective interventions for babies born too small or too soon is an urgent priority to increase survival and reduce disability, stunting, and non-communicable diseases. Funding Bill & Melinda Gates Foundation by a grant to the US Fund for UNICEF to support the activities of the Child Health Epidemiology Reference Group (CHERG).

Preterm-associated visual impairment and estimates of retinopathy of prematurity at regional and global levels for 2010

Background:Retinopathy of prematurity (ROP) is a leading cause of potentially avoidable childhood blindness worldwide. We estimated ROP burden at the global and regional levels to inform screening and treatment programs, research, and data priorities.Methods:Systematic reviews and meta-analyses were undertaken to estimate the risk of ROP and subsequent visual impairment for surviving preterm babies by level of neonatal care, access to ROP screening, and treatment. A compartmental model was used to estimate ROP cases and numbers of visually impaired survivors.Results:In 2010, an estimated 184,700 (uncertainty range: 169,600–214,500) preterm babies developed any stage of ROP, 20,000 (15,500–27,200) of whom became blind or severely visually impaired from ROP, and a further 12,300 (8,300–18,400) developed mild/moderate visual impairment. Sixty-five percent of those visually impaired from ROP were born in middle-income regions; 6.2% (4.3–8.9%) of all ROP visually impaired infants were born at >32-wk gestation. Visual impairment from other conditions associated with preterm birth will affect larger numbers of survivors.Conclusion:Improved care, including oxygen delivery and monitoring, for preterm babies in all facility settings would reduce the number of babies affected with ROP. Improved data tracking and coverage of locally adapted screening/treatment programs are urgently required.

Tetanus toxoid immunization to reduce mortality from neonatal tetanus

Background Neonatal tetanus remains an important and preventable cause of neonatal mortality globally. Large reductions in neonatal tetanus deaths have been reported following major increases in the coverage of tetanus toxoid immunization, yet the level of evidence for the mortality effect of tetanus toxoid immunization is surprisingly weak with only two trials considered in a Cochrane review. Objective To review the evidence for and estimate the effect on neonatal tetanus mortality of immunization with tetanus toxoid of pregnant women, or women of childbearing age. Methods We conducted a systematic review of multiple databases. Standardized abstraction forms were used. Individual study quality and the overall quality of evidence were assessed using an adaptation of the GRADE approach. Meta-analyses were performed. Results Only one randomised controlled trial (RCT) and one well-controlled cohort study were identified, which met inclusion criteria for meta-analysis. Immunization of pregnant women or women of childbearing age with at least two doses of tetanus toxoid is estimated to reduce mortality from neonatal tetanus by 94% [95% confidence interval (CI) 80–98%]. Additionally, another RCT with a case definition based on day of death, 3 case–control studies and 1 before-and-after study gave consistent results. Based on the consistency of the mortality data, the very large effect size and that the data are all from low/middle-income countries, the overall quality of the evidence was judged to be moderate. Conclusion This review uses a standard approach to provide a transparent estimate of the high impact of tetanus toxoid immunization on neonatal tetanus.

Intrapartum-related neonatal encephalopathy incidence and impairment at regional and global levels for 2010 with trends from 1990

Background:Intrapartum hypoxic events (“birth asphyxia”) may result in stillbirth, neonatal or postneonatal mortality, and impairment. Systematic morbidity estimates for the burden of impairment outcomes are currently limited. Neonatal encephalopathy (NE) following an intrapartum hypoxic event is a strong predictor of long-term impairment.Methods:Linear regression modeling was conducted on data identified through systematic reviews to estimate NE incidence and time trends for 184 countries. Meta-analyses were undertaken to estimate the risk of NE by sex of the newborn, neonatal case fatality rate, and impairment risk. A compartmental model estimated postneonatal survivors of NE, depending on access to care, and then the proportion of survivors with impairment. Separate modeling for the Global Burden of Disease 2010 (GBD2010) study estimated disability adjusted life years (DALYs), years of life with disability (YLDs), and years of life lost (YLLs) attributed to intrapartum-related events.Results:In 2010, 1.15 million babies (uncertainty range: 0.89–1.60 million; 8.5 cases per 1,000 live births) were estimated to have developed NE associated with intrapartum events, with 96% born in low- and middle-income countries, as compared with 1.60 million in 1990 (11.7 cases per 1,000 live births). An estimated 287,000 (181,000–440,000) neonates with NE died in 2010; 233,000 (163,000–342,000) survived with moderate or severe neurodevelopmental impairment; and 181,000 (82,000–319,000) had mild impairment. In GBD2010, intrapartum-related conditions comprised 50.2 million DALYs (2.4% of total) and 6.1 million YLDs.Conclusion:Intrapartum-related conditions are a large global burden, mostly due to high mortality in low-income countries. Universal coverage of obstetric care and neonatal resuscitation would prevent most of these deaths and disabilities. Rates of impairment are highest in middle-income countries where neonatal intensive care was more recently introduced, but quality may be poor. In settings without neonatal intensive care, the impairment rate is low due to high mortality, which is relevant for the scale-up of basic neonatal resuscitation.

Stillbirths: recall to action in high-income countries

Variation in stillbirth rates across high-income countries and large equity gaps within high-income countries persist. If all high-income countries achieved stillbirth rates equal to the best performing countries, 19,439 late gestation (28 weeks or more) stillbirths could have been avoided in 2015. The proportion of unexplained stillbirths is high and can be addressed through improvements in data collection, investigation, and classification, and with a better understanding of causal pathways. Substandard care contributes to 20-30% of all stillbirths and the contribution is even higher for late gestation intrapartum stillbirths. National perinatal mortality audit programmes need to be implemented in all high-income countries. The need to reduce stigma and fatalism related to stillbirth and to improve bereavement care are also clear, persisting priorities for action. In high-income countries, a woman living under adverse socioeconomic circumstances has twice the risk of having a stillborn child when compared to her more advantaged counterparts. Programmes at community and country level need to improve health in disadvantaged families to address these inequities.