Reducing Neonatal Mortality in Resource-poor Settings: What works?

Every year over 3 million newborn babies die during their first month of life. Although the situation has improved greatly over the last two decades, survival beyond the neonatal period is still a challenge in resource-poor settings. When crude numbers are examined, most of these deaths occur in India, Nigeria, Pakistan, China and the Democratic Republic of Congo (DRC) but high neonatal mortality rates can be seen throughout the developing world, particularly in Sub-Saharan Africa. Basic interventions are unavailable in many resource-poor settings. There is, however, a growing body of evidence which can guide clinicians and policymakers in these environments in the use of inexpensive, yet effective, interventions to help reduce the burden of neonatal mortality. It is estimated that effective implementation and high coverage of these interventions could prevent up to 70% of neonatal deaths globally.


The Global Picture
Every year over 3 million newborn babies die during their first month of life [1], with 99% of these deaths occurring in low and middle income countries [1]. Huge disparities in neonatal mortality rates exist between the most affluent countries and those in the poorest regions of the world, as illustrated by the data presented in table 1. Although neonatal mortality globally has reduced by almost 40% since 1990 [2], survival beyond the first month of life is still a challenge in many low-resource countries. The reductions seen in neonatal deaths have also not kept pace with the reductions in overall child mortality, meaning that newborns now make up an increasing proportion of under-5 deaths [3]. Deaths within the first month of life make up over 40% of the total under-5 child deaths [3].  There is now a good evidence base supporting some important interventions, which could reduce newborn morbidity and mortality and help redress this imbalance. It is estimated that up to 70% of neonatal deaths could be prevented if proven interventions were effectively implemented with high coverage where they are needed most [4]. This paper will focus on describing selected first-line interventions, with recent evidence for their efficacy, which have the potential to contribute to a cost-effective strategy for improving neonatal survival in low resource settings.

Neonatal Resuscitation Training
More than one-third of newborns who die within the neonatal period don't survive their first day of life and three-quarters do not survive past their first week of life [1]. Evidence for the effectiveness of immediate care for newborns in the delivery room is growing. It has been shown that clinical staff in many low-resource settings struggle to appropriately manage the care of newborns needing resuscitation at birth [5][6][7]. In recent years, much work has been done to address this important gap in skills globally. The American Academy of Pediatrics has developed a neonatal resuscitation program for use specifically in developing countries. Known as Helping Babies Breathe (HBB) [8,9], this program is based on simple stimulation and bag-mask ventilation techniques. It has yielded some significant successes, with, for example, a reported 47% reduction in early neonatal mortality and a 25% reduction in fresh still births, which was sustained over a 2 year period in Tanzania [10]. Similar reductions in neonatal mortality [11] or fresh stillbirth rates [12,13] as well as improvements in resuscitation skills [14,15] have been observed with other locally developed or locally adapted training courses in low-resource settings.
The optimal way to implement neonatal resuscitation programs in low-resource countries is still not clear though, with investigators reporting that increased skills did not always transfer into improved neonatal care in some parts of Tanzania [16] and others reporting that clinical skills deteriorated to unsatisfactory levels three months after HBB training [17] (A finding consistent with the picture seen in high income settings [18]). Nonetheless, Save the Children estimates that equipping delivery facilities with basic neonatal resuscitation equipment could save 229,000 lives per year in low-resource settings [1]. In addition, meta-analysis suggests that implementing neonatal resuscitation programs throughout the developing world could reduce term intrapartum related deaths by 30% [19]. The role of neonatal resuscitation programs in reducing mortality rates amongst preterm neonates is less certain, with some evidence to suggest that neonatal resuscitation training had no effect on neonatal mortality, stillbirth rates or perinatal mortality rates in a population of neonates weighing less than 1.5kg within community or primary care settings [20].

Preventing Neonatal Sepsis
Surviving the "golden hour" after delivery is important. However, 65% [1] of babies who die within the neonatal period do so after they leave the labour ward. These newborns tend to die of sepsis and complications of prematurity [21,22]. An increasingly important tool in the prevention of neonatal sepsis and cord infection (omphalitis) is the use of chlorhexidine to clean the umbilicus after delivery. Clinicians in resource-poor settings have been using chlorhexidine for many years [23], though the practice is not widespread. However, the evidence base for its use has become stronger in the last 3 years. A recent Cochrane review [24] and meta-analysis [25] of the effect of 4% chlorhexidine on the umbilical stump after delivery show a reduction in neonatal mortality of 23% and a reduction in omphalitis of up to 56%. It should be noted, however, that these reductions in mortality were seen only in community settings. The evidence for use of chlorhexidine in the hospital setting is less certain, though mortality reductions have been reported in a neonatal intensive care unit [26].

Managing Neonatal Sepsis
When neonatal sepsis in the community does occur, hospitalization is clearly the most desirable outcome, but is often impractical or unavailable, so clinic -based antibiotic treatment is the only available option in many cases. There has long been uncertainty about which antibiotic regime is most suitable in this environment. Recent evidence from a community setting in Pakistan [27], where the neonatal mortality rate is particularly high, suggests that a combination of intramuscular (IM) procaine penicillin and IM gentamicin has the greatest efficacy, in reducing neonatal mortality and treatment failure. This combination was significantly more effective than the combination of oral trimethoprim and sulfamethoxazole with IM gentamicin. IM ceftriaxone was slightly less effective, though this was not statistically significant, but is a more expensive option. It should be noted that in this study little information on suspected source of sepsis was available, and cases of suspected bacterial meningitis were excluded. Only 5% of infants had microbiological identification of a pathogen (with Pseudomonas aeruginosa the most common pathogen) and no resistance patterns were reported. The importance of tailoring empirical therapy to suspected source of sepsis and local resistance patterns (if available) must be emphasized: in many settings ceftriaxone may be the more rational choice, despite these findings.

Reducing Mortality from Prematurity
Preterm birth is the leading cause of neonatal death globally [3]. Those who die of prematurity often succumb to hypothermia, with 80% of newborns weighing below 1.5kg dying if their core temperature falls below 33C [28]. For these babies, "Kangaroo Mother Care" (KMC) can be a life-saving intervention. This inexpensive technique involves the mother and baby having continuous skin-to-skin contact, in an effort to improve thermoregulation, breastfeeding and bonding. A systematic review [29] and a large meta-analysis [30] have shown that KMC care has a significant effect in reducing low birth weight neonatal mortality in low-resource countries. It showed a reduction in neonatal mortality of up to 51% in preterm neonates without significant co-morbidity.

The role of breastfeeding
Breastfeeding has long been encouraged as a public health strategy in developing countries. Nonetheless, exclusive breastfeeding rates are low in many resource-poor settings. In Africa, Asia, Latin America and the Caribbean, only around half of babies under 2 months of age are exclusively breastfed, with this figure dropping to around 30% by 5 months of age [31]. A recent systematic review suggests that, within the non-exclusively breastfed population, infants who started breastfeeding within 24 hours of delivery had lower all-cause mortality rates than those who had delayed feeding [32]. This benefit seems to disappear in exclusively breast fed infants. Given the suboptimal rates of exclusive breastfeeding, as well as the documented risks of nonexclusive breastfeeding, in many low-resource settings, focus on early initiation of breastfeeding is a potentially high impact intervention.

The role of antenatal corticosteroids
Over the last 5 years, there has been an increased focus on the use of antenatal corticosteroids for the prevention of death secondary to preterm labour in low-resource settings. Steroid use is one of the most effective interventions available to prevent preterm death in highincome countries [33]. There have been calls to roll out this intervention globally [33,34], though some authors have argued for a more cautious approach [35]. A large, multi-country RCT is currently underway [36] to address the lack of data in this area. This should provide a clearer picture for policy-makers and clinicians in the near future.

Conclusions
The interventions above have the potential to expand the options available to those working with newborns in resource-poor environments, and improve neonatal survival. Although they are all relatively inexpensive and should ideally be accessible to most health workers in low-resource countries, their implementation and coverage have so far been limited, even in high-burden settings.
Of course, clinical interventions cannot be viewed in isolation. They need to be delivered within the context of a broader neonatal strategy, which recognizes the need to strengthen health systems at all levels. Structural factors, public health policies and the state of maternal health [17,33] play a pivotal role in the fight against neonatal deaths. In the post-2015, post Millennium Development Goal [34] environment, there is a significant opportunity to push ahead with efforts to reduce mortality in this population. New evidence to guide clinical practice means that clinicians are now better equipped than ever before to offer care to sick newborns in resource-poor environments in a cost-effective way. It is vital that closer links are fostered between those who generate evidence and those who use it to set priorities, so that the lag between evidence being published and appropriate interventions being implemented is minimized. Policymakers and funders need to be especially responsive to the rapidly changing evidence base available to them, so that policy and priorities are flexible enough to keep pace with a rapidly changing evidence landscape. If the global community comes together on this issue, the tools are now at our disposal to offer an unprecedented level of care to this especially vulnerable subset of children.