Born Too Soon: Accelerating actions for prevention and care of 15 million newborns born too soon

Preterm birth complication is the leading cause of neonatal death resulting in over one million deaths each year of the 15 million babies born preterm. To accelerate change, we provide an overview of the comprehensive strategy required, the tools available for context-specific health system implementation now, and the priorities for research and innovation. There is an urgent need for action on a dual track: (1) through strategic research to advance the prevention of preterm birth and (2) improved implementation and innovation for care of the premature neonate. We highlight evidence-based interventions along the continuum of care, noting gaps in coverage, quality, equity and implications for integration and scale up. Improved metrics are critical for both burden and tracking programmatic change. Linked to the United Nation's Every Women Every Child strategy, a target was set for 50% reduction in preterm deaths by 2025. Three analyses informed this target: historical change in high income countries, recent progress in best performing countries, and modelling of mortality reduction with high coverage of existing interventions. If universal coverage of selected interventions were to be achieved, then 84% or more than 921,000 preterm neonatal deaths could be prevented annually, with antenatal corticosteroids and Kangaroo Mother Care having the highest impact. Everyone has a role to play in reaching this target including government leaders, professionals, private sector, and of course families who are affected the most and whose voices have been critical for change in many of the countries with the most progress. Declaration This article is part of a supplement jointly funded by Save the Children's Saving Newborn Lives programme through a grant from The Bill & Melinda Gates Foundation and March of Dimes Foundation and published in collaboration with the Partnership for Maternal, Newborn and Child Health and the World Health Organization (WHO). The original article was published in PDF format in the WHO Report "Born Too Soon: the global action report on preterm birth" (ISBN 978 92 4 150343 30), which involved collaboration from more than 50 organizations. The article has been reformatted for journal publication and has undergone peer review according to Reproductive Health's standard process for supplements and may feature some variations in content when compared to the original report. This co-publication makes the article available to the community in a full-text format.

requiring innovations for both prevention and care. Finally we detail the analyses for a mortality reduction target for preterm specifi c neonatal deaths and outline the specifi c roles all actors must play in this global eff ort to reduce preterm birth and care for premature babies, which is a marker of the health and care of women and girls, as well as of progress for child survival and development.
Th e actions identifi ed aim to support the goals of the Global Strategy for Women's and Children's Health launched by the United Nations (UN) Secretary-General Ban Ki-moon in September 2010 to further advance progress for the Millennium Development Goal 4 for child survival and the Every Woman Every Child movement to mobilise action and resources for these goals [7]. By pooling our eff orts with each organisation playing to its strengths, our shared goal, as epitomised in Every Woman Every Child, can be realised -a day when pregnancies are wanted and safe, women survive, babies everywhere get a healthy start in life, and children thrive.

Accelerating evidence-based action for prevention and care
Addressing the burden of preterm birth has a dual track-prevention and care ( Figure 1). Reducing risks before, during, and between pregnancies through preconception and antenatal care packages may help preterm birth prevention [4,5]. Actions taken during labour and birth, and particularly improved care of the neonate have been shown to have major impact [5,6]. For example, antenatal corticosteroids administered to a preg nant woman in preterm labour can prevent respiratory distress syndrome in premature babies reducing newborn mortality and morbidity [5]. In addition, many of these interventions, such as obstetric care and antibiotics for prelabour premature rupture of membranes (pPROM), also benefi t maternal health and prevent stillbirths [8]. Interventions that have been identifi ed through global reviews of the evidence are summarised elsewhere [4][5][6] and shown in Figure 1.

Prevention of preterm birth is primarily a knowledge gap
Despite the burden of preterm birth, few eff ective prevention strategies are available for clinicians, policymakers and program managers. Multiple studies in highincome contexts have attempted to prevent preterm birth, but have not yet identifi ed high-impact interventions in the preconception and antenatal periods. Many interventions have been evaluated, and some have been identifi ed as benefi cial though limited in public health impact, such as therapy with progestational agents, which have only been studied in certain high-risk populations. Preliminary studies of interventions to reduce rates of elective caesarean births or inductions without medical indication before the recommended 39 completed weeks of gestation suggest an impact on prevention of early term deliveries in some high-and middle-income countries [9,10]. A recent study published in Th e Lancet examined preterm birth prevention potential in 39 highincome countries and estimated that if fi ve interventions reached high coverage there would only be a 5% relative reduction of preterm birth rate from 9·59% to 9·07% of livebirths by 2015, averting an estimated 58,000 preterm births and saving US$3 billion annually [11]. Th ese fi ve interventions were: smoking cessation (0·01 rate reduction), decreasing multiple embryo transfers during assisted reproductive technologies (0·06), cervical cerclage (0·15), use of progesterone agents (0·01), and reduction of elective labour induction or caesarean delivery without medical indication (0·29). Th e limited number and eff ectiveness of available interventions for preterm prevention further underscores this critical major knowledge gap, and makes the case for a strategic and coordinated research eff ort to advance understanding of causes and mechanisms of preterm birth and identi fication of innovative solutions.
However, the low-and middle -income countries with the highest burden of preterm births also carry the greatest burden of higher-risk conditions for preterm birth that are preventable or treatable. Interventions such as family planning; prevention and management of sexually transmitted infections (STIs); use of insecticidetreated bednets and intermittent preventive treatment for malaria; identifi cation and treatment of preeclampsia, and reduction of physical workload are examples of strategies that could improve birth outcomes in in low-and middle-income settings. Unfortunately, to date, few studies have assessed the impact of these interventions on preterm birth in these countries, particularly with accurate measures of gestational age [12]. Th e greatest potential for the global prevention of preterm birth, therefore, lies in a comprehensive, strategic, and suffi ciently-funded research agenda of the causes of preterm birth and novel strategies for prevention [13]. Th is should be vigorously pursued.
Th ere are some signifi cant intrapartum interventions that reduce the impact of preterm birth. Antenatal corticosteroid injections given to women in preterm labour are highly eff ective at preventing respiratory distress syndrome in premature babies and associated mortality and long-term impairment, but remain underused in many low-and some middle-income countries. Th ere is, thus, a need for delivery research that can help understand context-specifi c reasons for the continued low coverage in these countries and identify ways to adapt known eff ective strategies for use in low-resource settings [14]. Tocolytic medicines rarely stop preterm labour, but may help delay labour for hours or days, allowing the baby additional precious time to develop before birth. Of course, any strategies to prolong labour, including delaying caesarean birth, must be evaluated against the potential risk of continued exposure of woman and foetus to sub-optimal conditions that may result in harmful eff ects. Further research is needed on short and long-term health consequences for mother and baby from eff orts to prevent preterm labour [5] .

Care of premature babies is primarily an action gap
As evidenced by the large survival gap between babies born in high-income countries and those born in lowand middle-income countries, eff ective interventions exist to reduce death and disability in premature babies, yet this care does not reach the poor and most disadvantaged populations where the burden is highest [6]. Th ere is a "know-do gap", or a gap between what is known to work and what is done in practice. Bridging this gap will be critical for saving premature babies globally, and must be linked to implementation research and context specifi c adaptation and innovation.
More than 60% of all premature babies are born in South Asia and sub-Saharan Africa which have the highest preterm birth rates [15] and half of births are currently in facilities. Most preterm births occur over 32 weeks of gestation (84%), and deaths in these babies can almost all be prevented and in most cases, intensive care is not needed [6] (Figure 1). It is possible to implement some evidence-based interventions for the care of premature babies at the community level through behaviour change initiatives and women's groups [16], as well as home-visit packages with extra care for premature babies, particularly breastfeeding support and awareness of the importance of seeking care when danger signs occur [17]. In a few countries, case management of neonatal sepsis is being scaled up using communitybased health workers [18]. However, the highest impact interventions, notably access to quality intrapartum care and emergency obstetric and newborn care [19], require facility-based services. Antenatal corticosteroids and Kangaroo Mother Care (KMC) are evidence-based interventions that are feasible to scale up in low-resource settings and may serve as entry points for strengthening health systems [20,21].

Scaling up preterm birth interventions within the existing health system
Th ere is increasing global consensus around essential reproductive, maternal, newborn and child health (RMNCH) interventions [22,23], including those to address preterm birth ( Figure 2). Th e goal is to achieve universal, equitable coverage and high quality in all these RMNCH interventions. Newborn babies, and especially premature newborns, are the most sensitive test of health systems function as these babies can die within minutes without the right care. For sustainable eff ect, interventions to prevent preterm birth in the preconception and antenatal periods and to reduce death and disability in premature babies must be integrated within the existing health system.
Th e continuum of care is a core organising principle for health systems emphasising linkages between healthcare packages across time and through various service delivery strategies [2]. An eff ective continuum of care addresses the health needs of the adolescent, woman, mother, newborn and child throughout the life cycle, wherever care is provided, whether it be at the home, primary care level or district and regional hospitals. Integrated service delivery packages of evidence-based interventions within the continuum of care have many advantages: cost-eff ectiveness is enhanced; available human resources are maximised; and services are more family-friendly, reducing the need for multiple visits [24]. Most importantly, they can help prevent stillbirths, improve prevention and care of premature babies and avert death and disability in women, newborns and children [25][26][27].
Interventions with the highest impact on the prevention of preterm birth and care of the premature baby in high-mortality and lower-resource settings can be integrated into these health service delivery packages, which exist in most health systems and involve links with maternal and child health services, as well as immunisation, malaria, HIV/AIDS, nutrition, family planning, and other related programs [22]. A schematic matrix of the basic health packages ( Figure 2) outlines these packages spanning the continuum of care and through various service delivery modes within the health system, highlighting the interventions included to address preterm birth. Th e interventions within each package are based on multiple systematic reviews and are consistent with the Partnership for Maternal, Newborn and Child Health Essential Interventions report [23].
While these packages may exist in nearly all health systems, lower-income countries cannot scale up and implement all the individual RMNCH interventions within all the packages at once [25]. Packages usually are initially comprised of the essential interventions and then increase in complexity over time according to local needs and capacity. For example, the Antenatal Care package may start as the WHO focused four visit package and then later add on diabetes screening and routine ultrasound as the system capacity and funding increases [26]. Th e functionality of health systems, such as human resource capacity, health facility infrastructure, supply and demand systems, fi nancial resources, government stewardship, district-level management and use of data, will also determine the coverage, quality and rate of change within the continuum of care [28].

Closing gaps in coverage, equity and quality
In order for health services to save the maximum number of lives, coverage, quality and equity need to be high; thus ensuring high coverage of care means reaching every woman, mother-to-be, mother, newborn, child and family with targeted interventions. Providing quality care involves doing the right thing at the right time. Providing equitable care means ensuring care for all according to need, rather than income, gender or other social grouping. Th is holds true for the existing inequalities in care within and across high-income as well as low-and middle-income countries. Previous papers in this supplement have identifi ed gaps in coverage, quality, equity and metrics for care during preconception, pregnancy and care of preterm newborns [4][5][6].
Current coverage levels for eight indicators across the continuum of care, chosen by the United Nations Commission on Information and Accountability for Women's and Children's Health, are tracked for the 75 priority Countdown to 2015 countries which collectively account for 90% of maternal, newborn and child deaths [29]. Currently, essential care reaches only half of the people in need (Figure 3), and there is a wide variation in coverage levels among countries, with some countries achieving nearly universal coverage and others reaching less than a quarter of the population. Demand for family planning satisfi ed and antenatal care coverage, even though feasible through primary care services, still leave out many women, especially the poorest. In addition, quality gaps are a missed opportunity for reaching families; for example, when a midwife is present at birth but is not equipped to prevent post partum haemorrhage or to resuscitate a baby who does not breathe [5,6]. Substantial progress is still needed for the reduction of maternal and newborn deaths, especially for eff ective, high quality at the vital contact times (e.g., skilled attendant at birth and postnatal care) [29]. Currently, there are no routine data available for many of the interventions for preterm birth prevention and care.

A research pipeline to address preterm birth
Greater investment in research and, in particular, into discovery of the many complex and interrelated factors causing preterm birth is needed to strengthen prevention and off ers a potential over the longer term for signifi cant reductions in mortality, childhood disability and healthcare expenditure. For care of preterm babies, the emphasis is on rapidly scaling up implementations, so that the maximum number of preterm babies and their mothers benefi t. Implementation research is needed to understand the most effi cient means of scaling up evidenced based solutions. In this way, hundreds of thousands of lives could be saved with the application of current knowledge.
Preterm birth is not a single condition, but a single outcome (birth before 37 completed weeks) due to multiple causes. Hence, there will not be a single solution, but rather an array of solutions that address the various biological, clinical, behavioural and social risk factors that result in preterm birth. Th is supplement identifi es risks for preterm birth and the solutions needed to reduce those risks across the RMNCH continuum; yet for many of these risks, we do not have eff ective solutions. Important research priorities have been highlighted [4][5][6]. A strategic research approach is needed to understand why babies are born preterm or as stillbirths, how to identify women at risk, to test strategies for prevention and care, and reduce death and disability rates for preterm neonates.
Important research themes can be summarised across the research pipeline of description, discovery, development and delivery science, showing the dual agenda of preventing preterm birth and addressing the care and survival gap for babies born preterm (Table 1) [30]. For the preterm prevention research agenda, the greatest emphasis is on discovery and descriptive research, which is a longer-term investment. For the premature baby care agenda, the greatest emphasis is on development and delivery research, with a shorter timeline to impact at scale.

Descriptive research
Improved and consistently applied epidemiologic defi nitions and methods, with clearly defi ned preterm phenotypes, are the foundation for improved understanding of the burden of preterm birth [31,32] and addressing the multiple and often interrelated causes of preterm birth. Simpler and lower-cost methods for measuring gestational age are particularly needed in low-and middleincome countries where the burden of preterm birth is highest. Social and racial disparities in preterm birth rates are a major issue, yet remain poorly under stood. Another important need is for standardised methods for diagnosing and treating prematurity-related impairment in childhood and more consistent measures and timing for assessing multi-domain impairments [33,34].

Discovery research
Discovery research focuses on better understanding the causes and mechanisms of preterm birth and elucidating factors that regulate uterine quiescence, initiation of labour, and the multiple host, agent, and environmental factors that cause aberrations in these normal processes of pregnancy. Understanding the reasons for racial and ethnic disparities in preterm birth will advance the fi eld of pregnancy health broadly, as well as accelerate solutions for those populations most in need. A multidisciplinary approach is needed to identify women at risk and discover new strategies for prevention including potential biomarkers, such as genomic, microbial, immunologic, and hormonal factors.
Although infectious and infl ammatory processes contribute to a high proportion of early spontaneous preterm births [35], antibiotic treatment of reproductive tract infections, especially bacterial vaginosis and other remote site infections, has generally failed to reduce preterm risk [36]. Many pre-existing chronic conditions and medical complications of pregnancy may result in increased risk of preterm delivery, such as pre-eclampsia, hypertension, aberrations in placentation and placental growth, diabetes and infectious diseases. Identifying mechanisms of these conditions, and strategies for early detection, prevention, and care, represent an important need for reducing the global burden of preterm birth. New strategies for prevention are particularly urgent for use in low-and middle-income settings where rates are highest.

Development research
Equipment and commodities are considered essential for neonatal care units in high-income countries, yet for many such units in low-income settings, basic equipment and essential medicines are not available or functional. Development of robust, fi t-for-purpose equipment, is a critical next frontier for referral care for premature babies in the settings where most die, especially for care in hospitals [6]. Some examples include technologies for ventilatory support, novel surfactant formulations, safe and eff ective intravenous fl uid and drug administration, devices for testing bilirubin levels for jaundice and innovative phototherapy equipment [6]. New and eff ective methods for monitoring and management of maternal complications and preterm labour could make a major contribution. Commodities, such as antenatal corticosteroids, could reach more women and babies though innovation for example in single-dose syringes or, ideally, needle-free devices [37].

Delivery research
Delivery or implementation research addresses how interventions can be best implemented, especially in resource-constrained settings where coverage inequalities are more pronounced so that all families are reached with eff ective care. Implementation research and program evaluation evaluates how best to achieve wide scale coverage of interventions, including prevention particularly family planning and such as care of women with infectious diseases such as malaria, HIV and STIs; improved nutrition; smoking cessation; and reducing maternal workload. In many high-income countries and those with emerging economies, there is evidence of an increase in late preterm deliveries due to elective inductions and caesareans without clear medical indication [38]. More information is urgently needed from both providers and patients on the reasons for these shifts in clinical practice and how to promote more conservative obstetric management.
Th e vast majority of published studies on neonatal care relate to high-technology care in high-income settings [39]. Implementation research from low-and middleincome settings is critical to inform and accelerate the scale up of high-impact care, such as KMC and neonatal resuscitation [19,21,40]. Evaluation of context-specifi c neonatal care packages regarding outcome, cost and economic results is important, including adaptations such as task shifting to various cadres and use of innovative technologies [41]. Th ere is also a need to understand how to screen more eff ectively for and treat possible prematurity-related cognitive, motor and behavioural disabilities, including in older children. In addition, the economics of preterm birth prevention and care, including the cost-benefi t and cost-eff ectiveness of interventions delivered singly or as a package across the continuum of care and in diff erent settings and populations as well as the costs of doing nothing, need to be better studied [12,42].

Building the platform to accelerate research
Underlying this entire research agenda is the development and implementation of the capacity to advance the science of prevention of preterm birth, manage preterm labour and improve care of premature babies. Standard case defi nitions of the types and causes of preterm birth are being developed [31,32] and will be critical to accelerating discovery and making comparisons across studies from basic science to clinical trials and program evaluation. Multi-country studies in middle-and lowincome countries tracking pregnant women with improved and accurate gestational dating may help contribute to improved pregnancy monitoring and a better understanding of all pregnancy outcomes for women, stillbirths and newborns. Improved communication and collaboration among researchers investigating these linked outcomes will provide an opportunity to accelerate the discovery, development and delivery of innovation, especially across disciplines and between laboratory benches and remote and under-resourced hospitals. Expanding training, research opportunities and mentorship for researchers in low-income settings hold great promise in developing a pipeline of expertise to advance the science with the skills to use this science eff ectively to promote change [30].

Potential for lives saved
To understand the impact of evidence-based interventions on deaths due to complications of preterm birth, we considered analyses including historical data from high income countries (Figure 4), recent change in middle income countries (Figures 5 and 6) and a new analysis using lives saved modelling. Several low-and middle-income countries have demonstrated a 50% reduc on in preterm-spec c neonatal deaths in low-or middle-resource ngs ( Figure 6). Two of these countries -Sri Lanka and Turkey -are brie y described here. erences between approaches are immediately apparent, as countries customise their approach to availability of resources and health systems context.

TURKEY
Turkey, an upper middle-income country, has made signi cant progress in health care over the past decade. Health system transforma on was comprehensive, but maternal and neonatal health policies in par cular played a central role. As a result, the neonatal mortality rate dropped from 21 per 1,000 live births in 2000 to 10 per 1,000 live births in 2010 [63]. Births with a skilled endant rose from 83% in 2003 to more than 90% in 2009, and ins tu onal facility births rose to more than 90% by 2009 [64]. In fact, Turkey achieved in a decade what took 30 years in the OECD countries.
Part of Turkey's success was through the implementa on of demand and supply strategies. There was sig cant promo on of antenatal care and facility births, including cash incen ves and free accommod on in maternity wai ng homes in ci es for expectant women from remote areas [65]. In , wider public health approaches were an important foun n, such as focused e on of maternal and neonatal tetanus, br eeding promo on and UNICEF "baby-friendly" hospitals campaigns. Turkey invested in health systems improvements, such as systema zing referral to neonatal care with transport systems, and upgrading neonatal intensive care units, focusing on nursing sta skills and standardiza on of care, especially for neonatal resuscita on [66].

SRI LANKA
Sri Lanka, a lower middle-income country, has ted from re on in NMR as a result of policies and gradual improvements in health care that have been con nually implemented over the past ve decades. Despite rela low per capita income, Sri Lanka has achieved impressive results and has o en been cited as an example of success for on of maternal mortality through a primary health care approach [67].
Many of these advances have come due to Sri Lanka's investment in primary care ini a ves, as well as provision of free health care at government fac es. Antenatal care coverage is at 99% for the country, with approximately 51% of pregnant woman having more than 9 antenatal visits. Skilled birth endance at delivery is universal (99%). Postnatal care is also robust, with 90% of women receiving public health midwife visits within 10 days of discharge [68,69].
From an NMR of 80 per 1,000 live births in 1945, Sri Lanka progressed steadily to 22 per 1,000 live births by 1980, and now to around 10 per 1,000 live births [63,69]. More recent advances included reinvigora on of community-based health care, including maternity clinics, and strengthening of referral and transporta networks, such that women in preterm labour are rapidly transported to appropriate secondary and ter ry care centres. A recent focus has been addi onal investment in ter ary care centres equipped for neonatal intensive care, training of specialists and investment in more complex technologies (personal co Prof. D.G. Harendra de Silva). http://www.reproductive-health-journal.com/content/10/S1/S6

History lessons from neonatal mortality reduction in high income countries
Th e historical data from the United States and United Kingdom (Figure 4) shows that a moderate increase in coverage of selected interventions results in a mortality reduction, even in the absence of neonatal intensive care. A number of lessons can be drawn from this historical data: Basic care and infection case management interventions have an eff ect on neonatal deaths and on deaths amongst moderate and late preterm births, which account for over 80% of preterm births.
More targeted care is necessary for reducing deaths among babies 28 to <32 weeks and this reduction could be accelerated as higher-impact interventions are now known, such as antenatal corticosteroids, surfactant, KMC and other enhanced methods of infant warming and feeding which were not available in the mid-20th century in the United States and United Kingdom.
Intensive care may be necessary to reduce deaths among extremely premature babies (< 28 weeks), who account for 5% of all premature babies though a larger proportion of deaths. LiST is a free and widely used module in a demographic software package called Spectrum, which allows the user to compare the eff ects of diff erent interventions on the numbers of maternal, neonatal and child deaths and stillbirths, as well as stunting and wasting [43]. Th e modelling methods have been widely published including discussions of the limitations, which are particularly related to the lack of coverage data for many of the specifi c interventions [44][45][46][47]. Table 2 shows the interventions included in the LiST analysis that prevent preterm births and improve survival of premature babies. We considered the period from 2010 to 2015 and then through 2025 to allow for a more feasible time frame to scale up care and progress on the prevention agenda. Th e results of the LiST analysis found that 84% of premature babies (more than 921,000 lives) could be saved in 2025 if these interventions were made universally available (95%). Full coverage of antenatal corticosteroids alone resulted in high mortality reductions, a 41% decrease from 2010 [20]. Implementing KMC alone also suggests that a high reduction of deaths could be achieved [21], averting approximately 531,000 neonatal deaths in 2025. If these two interventions were added to existing health system packages, especially noting the recent shifts to more facility births in Africa and Asia, then a high impact is possible even in a relatively short time frame. Note: interventions marked with M will also save maternal lives, SB would avert stillbirth, and N will save newborns dying from causes other than preterm birth. * Family planning scaled to 60% coverage or to a level whereby the total fertility rate is 2.5. Note that obstetric care would also have an impact, but is not estimated separately

Targets for action by 2025
Th e Born Too Soon report initiated a process towards achieving goals for preterm birth prevention and presented a new goal for the reduction of deaths due to complications of preterm birth (Figure 7) [48]. Th e latter goal was set through consultation by a group of technical experts, and several analyses were undertaken to inform this target, notably (1) projections by country of the deaths due to preterm birth from now until 2025, assuming no change in trends and assuming expected changes in Gross National Income (GNI); (2) reduction in preterm-specifi c neonatal mortality if the historical trends from the United Kingdom or the United States ( Figure 4) [50]. Using the results from analyses of the three future scenarios (Figure 8), a target for mortality reduction of preterm births was set and agreed by the technical experts (Figure 7).

Scenario 1: "Business as usual"
Should governments and the global community take no further direct action to address deaths due to preterm birth, mortality will decline by 24% by 2025 according to an analysis of regional trends over the past decade and forward projection (or 16%, if the projection is based on forecasted GNI change) ( Figure 4). Given this scenario and taking into account changing numbers of births, the global total of preterm deaths will not reduce signifi cantly by 2025, with around 900,000 premature babies continuing to die every year.

Scenario 2: Countries take action to catch up with top performers within their region
Preterm mortality could be halved by 2025 if governments took action now to match the top performers within their regions or to match the historical reductions in the United States and the United Kingdom from basic interventions before widespread use of intensive care (Figure 4). Th e examples of Sri Lanka and Turkey (see Figure 5) present examples of signifi cant reduction in mortality, halving deaths in 10 years linked to scale up of intensive care. Even those countries with higher mortality rates that are not yet ready to scale up intensive care could see a 50% reduction as shown in the mid-20th century in the United States and the United Kingdom.

Targets for care of preterm babies
The Born Too Soon report included a new goal for the reduc on of deaths due to preterm birth [48]. The global goal is broken down into two di erent country groups: those that have already achieved a low level of neonatal mortality (less than 5 per 1,000 live births) and those countries that have not yet achieved this level. Three scenarios informed the target se ng for mortality redu on for premature babies (Figure 8).
-For the countries that have already reached a neonatal mortality rate (NMR) of 5 per 1,000 live births or below by 2010: The goal is to eliminate remaining preventable preterm deaths, focusing on equitable care for all and quality of care to minimise long-term impairment. -For countries with a neonatal mortality rate above 5 per 1,000 live births in 2010: The goal is to reduce their preterm birth-a ributable mortality by 50% between 2010 and 2025. This re on will mean that 550,000 premature babies will be saved each year by the target year of 2025. In addi on, more babies will be saved who are moderately preterm but die of other causes (e.g. infe ons).

Target for preterm birth preven on
The Born Too Soon report also called for a technical expert group to create a goal for re on of preterm birth rate by 2025 for announcement on World Prematurity Day 2012 [48]. The group published a paper in The Lancet detailing the ndings of a comprehensive analysis of preterm prevalence data (2000-10) with analyses and projec ons for 39 countries with reliable trend data [11]. The authors suggested the conserva ve target of a re ve re on in preterm birth rates of 5% by 2015. This recomme on is based on analysis that if these highest-income countries were to fully implement ve interven ons to prevent preterm births, including smoking on and reducing the number of elec caesareans, an average 5% re reduction in preterm birth could be achieved by 2015, varying from 8% on in the USA to much smaller re in most European countries, and only 2% in the UK. These re limited impact and none are simple to implement. The ndings highlight the urgent need for preterm birth research especially in low-income se ngs with the highest burden where the causes of prematurity might di er and have simpler solu ons such as birth spacing and treatment of infec ons in pregnancy.
Th is reduction is achievable with improved essential care of premature babies and better case management of infections and respiratory distress syndrome, especially since the deaths of moderately-preterm babies are the most common and preventable ones.
Th ere are high-impact, cost-eff ective interventions currently at low coverage [5,6], such as antenatal corticosteroids and KMC, that could signifi cantly accelerate progress, which were not available in the United States and the United Kingdom in the middle of the 20th century when the neonatal mortality rate (NMR) was signifi cantly reduced. Hence, it would be expected, with the inclusion of these and other innovations, that mortality reduction could be more rapid than for the historical examples.

Scenario 3: Countries achieve universal coverage of basic interventions
Should governments adopt universal coverage of interventions (95%) ensuring that every woman and child who needs an intervention receives it, then, according to the LiST analysis (Table 2) and the historical data (Figure 4), countries could achieve an 84% reduction of 1.1 million deaths due to preterm birth complications. While ensuring a 95% coverage rate is ideal and would result in a major mortality reduction, this process will take time. Initiating these changes can start to move countries toward their goal of preterm mortality reduction while also preventing death due to other causes of newborn death, as well as maternal deaths and stillbirths, through shared interventions such as skilled care at birth.

Call to action
Born Too Soon is sobering in the news of a large burden and in the personal stories of loss behind that burden. Yet this is also a story of hope in the signifi cant opportunities for change, especially as we approach the fi nal sprint for the MDG 4 target and aim to maintain momentum beyond 2015. Th ese fi rst-ever country estimates of preterm birth leave us without the excuse of ignorance [3]. In 2010, 15 million babies -more than 1 in 10 births -were born too soon, an emotional and economic toll on families, communities and countries. Th e problem is increasingfor the countries with 20-year trend data, the majority show an increase in preterm birth rates [3]. Additionally, the burden is not shared equally, with the impact of preterm birth falling most severely on the poorest families and in low-and middle-income countries where health systems are less prepared to respond. Th ere are also high preterm birth rates in many high-income countries, including the United States. Preterm birth is a problem that we all share; therefore, the solutions must also be shared, and won through cooperation, collaboration and co ordination of the many constituencies and stakeholders.  [50,52,53]. Note: Analysis is for countries with NMR of more than 5 per 1,000 live births; other countries are excluded. Interventions in the LiST analysis included KMC, antenatal corticosteroids, antibiotics for pPRoM, skilled birth attendance, and others.

Table 3. Everyone has a role to play: actions for the six key constituency groups involved in Every Women Every Child
Governments and policy-makers at local, national, regional and global levels: Invest • Set national targets for improved survival of premature babies and increase funding to ensuring equitable access to quality care to meet these targets by 2025. Implement • Strengthen health systems for quality maternal and neonatal care, including improved community awareness and demand for RMNCH services and adopt policies to promote universal access to quality preconception and maternal and perinatal services. Innovate • Promote the discovery, development and delivery of aff ordable and essential medicines, new technologies and novel models for training and services to prevent preterm birth and improve care of premature babies. Inform • Improve systems for collecting, evaluating and disseminating data on preterm birth rates, mortality, disability, quality of life and equitable coverage of evidence-based interventions to track progress towards MDGs 4 and 5 for maternal and child survival.

The United Nations and other multilateral organistions:
Invest • Support countries develop and align their national health plans, including costing and tracking implementation to achieve the health MDGs and preterm birth mortality-reduction targets. Implement • Defi ne norms and guidelines to support eff orts to improve women's and children's health, and encourage their adoption through provision of technical assistance and programmatic support for the prevention and treatment of preterm births. Innovate • Generate and disseminate evidence on preterm birth and provide a platform for sharing best practices, and use the UN Commodities Commission to address gaps for essential equipment and medicines (e.g., antenatal corticosteroids). Inform • Support the production, dissemination and use of coverage data for evidence-based interventions through the Countdown to 2015 and Commission for Information and Accountability through the independent Expert Review Group.

Donors and philanthropic institutions:
Invest • Provide sustained long-term support in line with national health policies and RMNCH plans that incorporate preterm births and are harmonised with other related global health initiatives. Innovate • Support high-priority research eff orts to address solution gaps and implementation research to inform the scale up of evidence-based interventions to reduce preterm deaths. Inform • Promote transparent tracking of commitments and accountability and of long-term improvements in national health management and information systems.

The business community:
Invest • Invest additional resources to develop and adapt devices and commodities to prevent and treat preterm birth in low-income settings using innovative partnerships and business models. Implement • Scale up best practices and partner with the public sector to improve service delivery and infrastructure for prevention and management of preterm birth. Innovate • Develop aff ordable new diagnostics, medicines, technologies and other interventions, including social and behavioural change, for preterm birth and make them available to the most vulnerable and marginalised. Inform • Use and strengthen existing tracking systems for commodities and devices to improve supply chain logistics.

Academic and research institutions:
Invest • Agree upon and promote an innovative research agenda for prevention of preterm birth and improved pregnancy outcomes and implementation research to reduce deaths from preterm birth. Implement • Build capacity at research institutions, especially in low-and middle-income countries, and train professionals. Innovate • Advance policy development by improving the metrics for impairment outcomes as well as preterm birth rates, and link to other pregnancy outcomes, reporting on trends and emerging issues relating to preterm births.

Continued overleaf
Lawn et al. Reproductive Health 2013, 10(Suppl 1):S6 http://www.reproductive-health-journal.com/content/10/S1/S6 A number of specifi c actions, pursued by all partners and applied across the RMNCH continuum of care, will help prevent preterm birth and associated mortality, and have an immediate, profound and sustained impact on human capital. Th e seven constituencies, as identifi ed by Every Woman Every Child [7], have four action themes, which link closely to the principles of Act, Monitor and Review recommended by the Commission on Information and Accountability for Women's and Children's Health.

Invest
Bring both fi nancial and other resources to address maternal and newborn health and the burden of preterm birth.

Implement
• Adapt integrated packages of care, considering contexts, and tailored to local health service delivery channels.
• Increase reach of existing preventive interventions in the preconception period, especially family planning, and including adolescent-friendly services. • Ensure that every woman receives the high-quality care she needs during pregnancy, birth and postnatally, especially if she is at risk of preterm birth. Th ere should be greater emphasis on the universal provision of ante natal corticosteroids, building on the work of the UN Commission on Life-Saving Commodities for Women and Children as an opportunity to accelerate progress. • Undertake immediate action to scale up KMC as a standard of care for all preterm babies under 2,000 grams, regardless of resource setting. • Improve methods for diagnosing and treating prematurity-related impairment in childhood. • Ensure that every family has the support they need, immediately after birth of a premature baby, following its loss, or living with a child with prematurityassociated disability.

Inform
• Strengthen global networks to disseminate new research fi ndings and best practice related to preterm birth through leveraging the momentum from Born Too Soon and commitments of these institutions.
Health care workers and their professional organisations: Invest • Advocate for and participate in evidence-based training, deployment and retention of workers with the necessary skills to address the burden of preterm birth. Implement • Use evidence-based standards to prevent or treat preterm births; implement training; and update curricula with evidence-based interventions. Treat women, newborns and children with respect and sensitivity. Innovate • Work in partnership to provide universal access to the essential package of interventions, including both prevention and care, and involving task shifting where appropriate. Inform • Improve data collection to track preterm births and measurements, such as consistent assessment of gestational age, birthweight, cause of death, data on impairment and retinopathy of prematurity.

Civil society: Invest
• Advocate for increased attention to the health of women, newborns and children through strengthening parent groups and conducting national campaigns focusing on preterm birth. Implement • Strengthen community and local capabilities to scale up implementation of interventions for preterm birth and support families who have lost babies or require long-term support for disability. Innovate • Develop and test innovative approaches to deliver essential services for prevention and care, particularly ones aimed at the most vulnerable and marginalised people. Inform • Educate, engage and mobilise communities to improve health education and care, beginning in adolescence; promote cost-eff ective solutions; track progress and hold all stakeholders at global, regional, national and local levels accountable for their commitments; promote accountability through the issuance of annual Countdown to 2015 country data profi les and global and national reports that document preterm birth rates and associated mortality and coverage of evidence-based interventions.
Source: adapted from Born Too Soon report, chapter 6 [48] Inform Improve the data for preterm birth rates, mortality, impair ment and their causes, with regular tracking of coverage, quality and equity gaps, as is done through Countdown to 2015 and linked to the work of the Commission for Information and Accountability using the data for action and accountability, including the establishment of national birth registrations.

Innovate
Conduct multi-country collaborative research on the: • Etiology of preterm birth, advancing the understanding of strategies to prevent and treat maternal health conditions associated with preterm birth (e.g., preeclampsia and gestational diabetes) and improving identifi cation of diagnostic markers and related screening tools. • Implementation research to develop and deliver innovations to reach the poorest. Table 3 details actions for the seven constituencies and Figures 9-14 provide examples of action. Th is agenda is ambitious, yet it can and must be accomplished if the actions are to be given the visibility, funding and attention they deserve. To be successful in our goals, the constituencies identifi ed must work together collaboratively and in partnership in ways that are transparent to all, vigorous and accountable.
All of the partners, donors and contributors involved in the Born Too Soon movement see the report and this supplement as important next steps towards a world Parents, advocates and civil society have captured the e on of governments and monitored progress in the United States through support of an annual Premature Birth Report Card. The Report Card, a familiar means of assessing progress for school-age children, has been a powerful tool used in the United States to prevent preterm birth and its serious health consequences. These grades, used as a rallying point, have helped bring visibility and promote change. Issued by the March of Dimes every year since 2008, the Report Cards assign a le er grade to the United States and to each of 50 state governments. In on, they summarise the that must be taken to fund preven on programs, address health care access and bring about needed change in health care systems. Transparency and ob of the data and analysis are important factors in the success of the Report Cards. Each year, great care is taken to explain the methodology for grade determin and the basis of comparison to other states. Use of the Report Card grades by state governments has grown since the Report Cards were t launched in 2008, and coverage by local media is consistently strong. One southern U.S. state, with the second highest preterm birth rate in the country, has received an "F" on its Report Card every year since 2008. The failing grade mobilised state health o cials in early 2012 to launch a statewide a ve with the goal of reducing rates. In this state and many others, media events featuring prominent public als are held to announce Report Card grades or report on state progress to address preterm birth. The U.S. Surgeon General has also par cipated in media outreach to publicise the Report Cards and their recommended Sustained ort by healthcare leaders and advocates at all levels, inside and outside of government, has elevated the issue of preterm birth on the na on's health agenda, contrib ng to an announcement of new federal resources to test promising in February 2012. Soon a er, the Associa on of State and Territorial Health O cials (ASTHO) joined with the March of Dimes to ask state health cials to pledge to reduce preterm birth rates in their states, and the pledge was incorporated into Report Cards. Top health o cials in every state, along with Puerto Rico and the District of Columbia, signed the pledge.
As federal and state governments devote e on and resources to the problem, the Report Cards will con nue to mobilise stakeholders and mark progress.
More informa on is available at ://www.marchofdimes.com/mission/prematurity-reportcard.aspx where every woman, every newborn and every child is given the best chance to survive and thrive.

Conclusion -Together rapid change is possible
Over the last decade, the world has changed. Just as it is no longer acceptable for people with HIV/AIDS to remain untreated because they live in poor countries, it is no longer acceptable for women to die while giving birth. Likewise it should be unacceptable for almost 3 million newborns, to die, including those who are born too soon. Over three-quarters of premature babies who die could be saved if basic care reached them and their mothers. Rapid progress is possible. At the same time, research and innovation for preterm birth prevention is urgent.
Th ese actions would reduce disability and chronic disease, improve reproductive and maternal health, and build sustainable health systems. We need more frontline health workers who are skilled and confi dent in newborn care. We need facilities equipped with life-saving commodities, and girls, and women who are educated, and enabled, can protect their own health, and that of their babies.
Additional File Figure 10. The United Nations -Life-saving Commodities for Women and Children-potential for action to reduce preterm deaths.
The United Na ons (UN) Secretary General's The Global Strategy for Women's and Children's Health highlighted inequi for women and children around the world and advocated for universal access to basic health care for all es medicines and other commodi es necessary to achieve MDGs 4, 5 and 6. Too , cost-e ec ve, high-impact health commodi es do not reach the women and children who need them. Some of the barriers to access include the lack of ordable products, lack of ageappropriate formula ons, weak supply chains, lack of awareness of how, why and when to use these commo es and inadequate regulatory capacity at the country level to protect the public from substandard or counterfeit medicines that cause harm.
The UN has established a Commission to address this issue, bringing together industry, civil society and technical experts to champion the e ort to reduce the barriers that obstruct access to essen al health commo Selected commo will be: 1. High-impact and e e ve, addressing major causes of death and disease among children under years of age and women during pregnancy and childbirth 2. Inadequately funded by exis ng mechanisms 3. Ready for innova on and rapid scale up in product development and market shaping: A list of 13 commo es has been selected, and includes four with poten al to reduce the 3 million deaths amongst newborns, especially those who are preterm. All of these commodi es are high-impact, low-coverage, and none has had previous global funding: Antenatal steroids reduce the risk of severe respiratory complica ons by half if given by inje on to women in preterm labour, but this commodity is low-coverage even in middle-income countries, due to a number of supply and regula on issues and low awareness among health care providers. It has been es mated that up to 400,000 babies could be saved with this interven on, and the unit costs, if dexamethasone is used, is around one dollar per dose.
Chlorhexidine cord care has recently been shown to be ec ve in reducing neonatal deaths due to sepsis: 320,000 neonates die each year of sepsis and many of them are moderately preterm. Rapid policy and program uptake of chlorhexidine could save many of these babies.
Resuscita on devices and training mannequins have undergone recent innova ons, but are not widely available in many high-burden countries with scope to reduce neonatal deaths from intrapartum insults, as well as from preterm birth complica ons.
Inje on an bio cs, including gentamicin, are crucial for neonatal infe ons and yet, due to low dosing, are en mis-administered; inno such as pre-packaged doses and needle-free technology could have a major e ect on reaching the poorest.
Prom on of a robust supply of quality products with fair pricing is a unique opportunity to accelerate progress and save lives of women and children, and could contribute to halving the 1.1 million deaths due to preterm birth. More informa on available at p://www.everywomaneverychild.org/resources/un-commission-on-life-savingcommodi es Additional fi le 1. In line with the journal's open peer review policy, copies of the reviewer reports are included as additional fi le 1.

Figure 11. Donors and philanthropic institutions -Helping Babies Breathe as an example of a public-private alliance to save newborns.
In 2010, the United States Agency for Inte onal Development (USAID) ed a formal blicprivate partnership, called Global Development Alliance, to accelerate the scale p of a d neonatal ita on package, called Helping Babies Breathe (HBB). HBB bro ght together ering skills with a professional association, American Academy of Pediatrics (AAP), civil society and stry. Key constraints that had impeded scale p of neonatal res scita on were in the lack of r st, t-forp rpose e ipment and the complexity of g idelines and training. AAP and others developed an evidence-based simpli ed pictorial algorithm for basic neonatal re on. Laerdal designed and ac low-cost eq pment, incl ding bag and mask, a peng in on device and Neonatalie (a rob st training manne n). A non-partnership with Laerdal facilitated the availability of these devices, as well as those of other m c rers. Save the Children's role facilitated take, in on and s stainable scale with ministries of health in lower-income ies. The U.S. Na onal In t tes of Health (NIH) helped with eval a on. Other partners, Johnson & Johnson and the La er-day Saints Char es, have joined and generated mome at global and co ntry level.
HBB was developed in response to evidence that neonatal re training in es red ces term intrapart m-related deaths by 30% t the coverage is low in re ce-limited areas [19,70]. In less than two years, 34 co ntries have introd ced HBB, 10 of which have developed na onal r plans. Evidence from several developing c ntries s ggests that basic neonatal res scita on is an e e approach at scale to newborn mortality [71,72].
More informa on available at h p://www.helpingbabiesbreathe.org/GDAinform on Figure 12. The business community -Industry partnership for innovative technology for preterm baby care in Asia.
Many countries lack the technical capacity and human and nancial resources to successfully implement facility-based neonatal intensive care. Equipment failures, management and personnel training, and stock outs of consumables hamper health delivery orts. GE Healthcare and the East Meets West Found on (EMW) have forged an alliance to solve these challenges. Building on the success of a program called Breath of Life, EMW and GE Healthcare are cre ng a suite of neonatal technologies that are durable, require few consumables, are easy to use and are cally designed for sustainability in low-resource se ngs. The equipment is delivered in the context of a -year program of training, monitoring, clinical supervision and technical support. Since its launch by EMW in 2005, the Breath of Life program has been implemented in more than 280 hospitals across eight countries of South Asia, currently trea g more than 55,000 babies a year.
Designed locally in Vietnam, EMW's neonatal equipment has maintained a failure rate below 5% compared to more than 80% for donated equipment from Western countries. Beyond core technologies of bubble CPAP, LED phototherapy and radiant warmers, the program also provides infe on-control systems, ambu-bags, baby bonnets and a long list of ancillary equipment. Monitoring and training -a pervasive shortcoming of many technology-based programs -are core strengths of the Breath of Life program. EMW sta typically monitor every hospital in the network 3 to 5 mes per week, and visit as en as twice a month for extended technical and clinical training and supervision.
In partnership with GE Healthcare, the Breath of Life program will be signi cantly expanded in scope and scale. Future devices will be engineered according to local design principles and follow stringent quality and regulatory review processes. As a global leader in the design and manufacture of advanced neonatal intensive care equipment, GE Healthcare can deliver and service these neonatal devices virtually anywhere in the world. Volume manufacturing should result in both lower costs and higher quality. This alliance of EMW and GE Healthcare is a powerful example of what partnerships can accomplish to help reduce the rate of preterm birth.

Figure 13. Health care workers -Health care providers as champions of change for mothers and newborns.
A premature baby's survival is dependent on both his mother's survival and on care received from several health care professional groups: Obstetricians, who provide e ec ve care to the woman, prevent or manage preterm labour Midwives, who ensure safe delivery and resuscitate if necessary Paediatricians, who undertake advanced resuscita on and ongoing care if needed. Where most premature babies are born and die, there are few paediatricians and almost no neonatologists.
This cross-unit team can save lives; however, if none of these groups takes responsibility for premature babies, where minutes count between life and death, then more babies will die. Indeed, nurses and midwives are the front line workers for millions of premature babies in facili es in low-and middleincome countries. However, there is an acute shortage intern lly of neonatal nurses, or nurses who receive speci c training in newborn care, par ly in low-income countries [73]. Those nurses, who commit to newborn care, en receive li le or no recog on for providing excellent care against all the odds.
Regina Obeng has worked in the neonatal unit at the Komfo Anokye Teaching Hospital in Kumasi, Ghana for over 20 years [74]. Not acce ng newborn deaths as inevitable, she has dedicated her life to saving babies in her crowded ward, where 350 to 400 newborns are cared for each month. She has been a consistent voice for these babies and their mothers, speaking up for more space, be er supplies and, especially, more and ways to retain skilled sta , and places for mothers to stay. Regina was awarded the Inte nal Neonatal Nursing Excellence Award in 2010, given by the Intern onal Conference of Neonatal Nurses (ICNN) together with Save the Children, the Council of Interna onal Neonatal Nurses (COINN) and the Neonatal Nurses As n of South Africa (NNASA). Now her voice is even stronger in Ghana, raising public awareness about the issues facing mothers and newborn babies, par cularly prematurity, and has uenced even the highest levels of the Ministry of Health to ensure neonatal nurses' training will start in Ghana.

Figure 14. Civil society -Chinese parents mobilising for their preterm babies.
Groups of parents a ected by preterm birth are an in al civil society group, suppor ng ted families and being their voice in government and among health policy planners. The Home for Premature Babies (HPB) is an example of a parent group advoca ng for improvements in care and support. As the largest preterm birth associ on of parents and families among Chinese-speaking n ons, the membership of HPB now exceeds 400,000 families. Formed in 2005 by Mrs. Jianian Ma, a mother of a very preterm baby, HPB now encompasses several founda ons that provide na nwide services in support of preven on and care. With the sponsorship of the China N ee for the Well-being of the Youth, HPB was established as a semigovernmental organi on. This close central government e has helped ensure con nuity of HPB's funding and the ability to partner more e ec vely with other organiza ons in China.
HPB has established three centres dedicated to the care of children with prematurity-related disabili es; launched an inte ve website to allow parents and prosp ve parents to ask qua ed medical experts about ways to help minimise the risk of having a preterm birth and how to care for their preterm baby; implemented a telephone hotline to provide immediate responses to parents' ques ons; and established a "Green Track" in more than 100 hospitals e that allows families with a sick preterm child to see a paediatrician quickly.
"As we have experienced in China, groups of parents by preterm birth can be an independent and uniquely powerful grassroots voice, calling on government, professional organiza ons, civil society, the business community and other partners in their countries to work together to prevent prematurity, improve care of the preterm baby and help support ected families." Dr. Nanbert Zhong, Chair, Advisory Comm ee for Science and Inter onal A airs, HPB.