Initiation of breathing is critical in the physiologic transition from intra-uterine to extra-uterine life. Between 5-10% of all newborns require assistance to establish breathing at birth [1–6], and simple warming, drying, stimulation and resuscitation may reduce neonatal mortality and morbidity. Each year an estimated 814,000 neonatal deaths [8] are related to intrapartum hypoxic events in term infants, previously termed “birth asphyxia” [7], and over one intrapartum million stillbirths occur. Especially in under-resourced settings it may be challenging to distinguish a stillborn from a severely depressed newborn. In addition over one million newborns die from complications of preterm birth, such as respiratory distress syndrome [10], and these babies also require assistance to breathe at birth.

Neonatal resuscitation is defined as the set of interventions at the time of birth to support the establishment of breathing and circulation [6]. Of 136 million births annually, an estimated 10 million will require some level of intervention [1]. Some non-breathing babies with primary apnea will respond to simple stimulation alone, such as drying and rubbing (Figure 1). Basic resuscitation with a bag-and-mask is required for an estimated 6 million of these babies each year, and is sufficient to resuscitate most neonates with secondary apnea, as their bradycardia primarily results from hypoxemia and respiratory failure[6]. More advanced measures, including endotracheal intubation, chest compressions and medications are required in <1% of births (Figure 1) [3, 11], and most of these babies require ongoing intensive care which is not available in most low income country settings. Supplemental oxygen is not associated with survival benefit in term infants [12], although the effect may differ in very preterm infants [13–15].

While systematic training in resuscitation of the newborn is a cornerstone of modern neonatology, there have been few rigorous evaluations of its effectiveness, partly because the intervention was standard practice before the advent of randomized controlled trials (RCTs), and randomization of individuals or clusters to no treatment would now be considered unethical. However, in low income countries, particularly in South Asia and sub-Saharan Africa, which account for over two-thirds of the world’s neonatal deaths [10], resuscitation is not available for the majority of newborns who are born either at poorly staffed and equipped first-level health facilities, or at home (60 million births annually), where birth attendants may lack skills or may perform practices that delay effective ventilation [1].

The objective of this review is to provide estimates for use in the Lives Saved Tool (LiST), of the effect of immediate newborn assessment and stimulation, and the additional effect of basic neonatal resuscitation, on neonatal mortality from two causes of neonatal death (intrapartum-related deaths in term infants (“birth asphyxia”) and complications of preterm birth) and in two contexts (facility and community).

This review is one of a series of standard reviews to provide consistent and transparent estimates of mortality effect used in the Lives Saved Tool (LiST), a model to assist evidence-based program planning. LiST is described in greater detail elsewhere [21]. In LiST, the estimation of lives saved depends on national estimates of causes of death for mothers, newborns and children under five, and the planned changes in national coverage estimates for given interventions, with a resultant reduction in cause-specific mortality. The sources and methods for each input are being provided in the public domain. The cause of death data is developed by the Child Health Epidemiology Reference Group (CHERG) with the United Nations each year and includes a country review process [8]. Intervention coverage data is based on national coverage estimates, or in the absence of appropriate recent data, the assumptions are described elsewhere [22, 23]. This mortality effect review follows standard methods adapted from GRADE [24] by the CHERG as described previously [21].

In the literature review, we identified 818 titles of articles of potential interest (Figure 2), and after initial screening of titles and abstracts, we retrieved 62 papers, reports or conference abstracts for review. We located 24 studies that reported the impact of neonatal resuscitation training on mortality outcomes: 16 studies in facilities, and 8 studies in community settings. Conference abstracts for 3 studies were identified and authors were contacted for further data, and there was one unpublished program report. All studies except one were from low or middle income settings. No studies were identified that examined the effect of newborn assessment and stimulation alone. The details of the studies are given in tables 2, 3 and 6.

The Delphi panel included eighteen experts (90% response rate) representing five WHO regions [Americas (n=6); Southeast Asia (n=4); Eastern Mediterranean (n=2); Africa (n=4); Europe (n=2)], from the following specialties: neonatology (n=7); general pediatrics (n=11) and pediatric infectious disease (n=1). Expert opinion was requested for 5 mortality effects (see additional file 2): facility- based basic resuscitation on preterm mortality, community-based basic resuscitation and immediate newborn assessment and stimulation on both intrapartum-related and preterm mortality. Consensus was reached in the first round for all 5 estimates.

Despite the wide acceptance of neonatal resuscitation as a standard of care, there is limited evidence of its impact on neonatal outcomes, in part due to the ethical challenges of undertaking individually randomized RCTs. To our knowledge, this is the first systematic review, meta-analysis and expert panel convened to provide estimates of the reduction in neonatal mortality that could be achieved through neonatal resuscitation training. Immediate assessment and stimulation of the newborn is more feasible without equipment or skilled workers. Our expert panel estimated that this simple action could reduce both term intrapartum-related (ie. “birth asphyxia”) and preterm mortality by 10%. Our meta-analysis suggests that neonatal resuscitation training in facilities was associated with an additional 30% reduction in intrapartum-related neonatal mortality. Studies have not consistently assessed the effects on preterm deaths, and there is no high or moderate quality evidence addressing this; expert opinion estimated a 10% reduction in prematurity-related neonatal deaths following resuscitation in health facilities. Current evidence for neonatal resuscitation in community settings is heterogeneous, and experts estimated a 20% reduction in term intrapartum-related deaths and 5% reduction in deaths attributed to preterm birth for community-based resuscitation either with a midwife alone at home or a TBA.

Simple immediate newborn assessment and warming, drying and tactile stimulation is the first step of neonatal resuscitation and was estimated by experts to result in a small (10%) reduction in intrapartum-related (“birth asphyxia”) and preterm deaths. In resource limited settings, these simple initial steps are feasible to be performed by a family member or primary healthcare provider with minimal skills – for example, rubbing the baby dry with a cloth– and might save lives, but this is expected to have limited effect. Observational studies suggest that between 6-42% of newborns who do not breathe at birth require ventilation [2, 54, 55], indicating that the majority of non-breathing babies may respond to simple steps alone. Although the anticipated mortality impact is low, the cost is also likely to be low as no equipment is required.

Our meta-analyses evaluating the impact of facility-based neonatal resuscitation training included low quality before-after studies, but at least comparable in intervention and outcome definitions for intrapartum-related and early neonatal mortality. Consistent effect sizes were observed for intrapartum-related mortality and all cause early neonatal mortality. The China NRP study [41] was excluded but it is notable that the reduction in labour room mortality for term babies (33%) was of similar magnitude. It is disappointing that the majority of the 16 facility studies identified did not meet inclusion criteria. However, given mortality effect consistency across the studies and generalizability to low-middle income countries, applying adapted GRADE criteria the evidence level was moderate (table 7). For all included studies, the comparison groups involved some pre-training management of the non-breathing baby, thus, these estimates reflect the impact of additional training for resuscitation, incremental to immediate newborn assessment and stimulation. Implementing basic neonatal resuscitation in a setting where no simple immediate newborn care is in place, such as peripheral maternity clinics, may have a greater effect. On the other hand, some of the effect may have been due to improved post-resuscitation care in two of the studies [2, 44]. While some data was available on the impact of facility-based resuscitation on preterm mortality, the data was too heterogeneous to pool. However, there is strong biologic plausibility that resuscitation may reduce mortality in moderate-late preterms who require minimal assistance with positive-pressure ventilation to initiate breathing, without requiring ongoing assisted ventilation; experts estimated a10% effect at facility level.

The impact of resuscitation training may be greater in higher mortality settings where obstetric care is more limited. In Bulgaria, an upper-middle income country where the baseline intrapartum-related mortality was relatively low, the estimated effect was smaller (16%) than in higher mortality settings such as Zambia and India, where neonatal resuscitation training was associated with a 30-43% reduction in intrapartum-related mortality. In settings with high coverage of high quality intrapartum management, the majority of term infants who die from intrapartum-related causes may be severely asphyxiated infants who require interventions beyond neonatal resuscitation alone, such as ongoing ventilation and therapeutic hypothermia.

The evidence for basic resuscitation in community settings was too heterogeneous to combine: study designs varied substantially, resuscitation training was one of numerous interventions in newborn care packages, and the outcome measure of cause-specific mortality differed across studies, often reflecting reduction in other causes of death such as preterm birth and infections. Significant reductions in all-cause neonatal or perinatal mortality were observed in 4 studies, ranging from 25-61% [5, 53–55], and reported “asphyxia” specific mortality was reduced in four studies, ranging from 61-70% [5, 53–55]. In the multi-center “First Breath” study [52], although no overall impact on PMR was observed, there was a significant 19% PMR reduction for deliveries with trained birth attendants, and a reduction in intrapartum-related morbidity (prevalence of 5 minute Apgar scores <4 and abnormal neurologic exams at 7 days). On the other hand, preliminary results from a cRCT in Bangladesh failed to demonstrate a reduction in ENMR with the additional training of TBAs in bag-mask resuscitation beyond immediate care and mouth-to-mouth resuscitation. Although it was not possible to derive a cause-specific mortality estimate from existing evidence, our expert panel agreed on the presence of an effect (20% for intrapartum-related mortality, 5% for preterm mortality), albeit slightly smaller than for facility based resuscitation, reflecting the additional challenges in implementation in such contexts, with a single provider and variable cadres. There is a need for consistency in future studies with respect to intervention content, study design, outcome measurement and definitions in order to more precisely evaluate the potential impact of resuscitation training at community level.

Important programmatic considerations for resuscitation training in resource limited settings include the benefit of teaching advanced procedures, provider competency, and skill maintenance. Two of the studies in our meta-analysis included some aspects of advanced neonatal resuscitation; however, advanced procedures are more complex to teach (i.e. chest compressions, intubation, or medications) and are required for ~2% of all babies who do not breathe at birth[2, 56], and fewer than 1% of all babies born[6, 11]. Basic neonatal resuscitation is sufficient for most babies who would be saved by resuscitation in low-middle income settings, and the additional benefit of advanced procedures is likely to be low. For the purposes of this LiST estimate, the effect of facility based neonatal resuscitation was assumed to be achievable with basic neonatal resuscitation, which is the clear priority for rapid scale up in facilities in low and middle income countries, given feasibility, skills required, and equipment costs. Furthermore, training programs should emphasize routine assessment of provider knowledge, competency and skill maintenance. Provider knowledge and performance skills to conduct resuscitation decline significantly over time[57]. Regular refresher training programs, practice drills, and DVD videos of resuscitation are methods of ensuring skill maintenance and program effectiveness[1, 58] .

A reduction in stillbirth rate has been observed in 2 community-based studies, after training programs including bag-mask resuscitation [5, 52]. A live newborn with severe neonatal depression is difficult to distinguish from a stillborn, and there is the potential for misclassification in low-resource settings where newborns are not typically assessed for signs of life at birth (particularly heart rate) [59, 60]. In addition to reducing misclassification, training in neonatal assessment and resuscitation may also increase survival in apparently stillborn infants (Apgar score assessed as 0 at 1 minute). Among apparently stillbirth infants who were resuscitated, case fatality ranges between 16-65% in high income settings [61–63], with major intensive care support, and long term outcomes that are significantly worse than for resuscitated babies who did have a heart rate detected [64]. These findings emphasize the need to accurately count stillbirths and assess long term outcomes to capture the full impact of obstetric and immediate newborn care interventions [65, 66].

Consistent case definitions are required for comparable population-level surveillance of disease burden and for evaluation of intervention effectiveness. A survey of policy makers revealed that “confusing terminology” and “lack of valid measurement indicators at the community level” were key barriers to obtaining the necessary information to make policy decisions[19]. Recent advances have been made in case definitions and verbal autopsy hierarchies to distinguish intrapartum-related events in term or almost term babies from preterm babies, although the issue of distinguishing growth restricted infants remains a challenge and is especially important in South Asia. Consistent use of such verbal autopsy tools, and more importantly the hierarchies, is critical [67]. This review emphasizes the need to minimize misclassification of live births as stillbirths, and to apply standardized definitions for intrapartum-related neonatal deaths, as opposed to clinical definitions such as “birth asphyxia.” Definitions and measurement varied across studies and between facility and community/home-based studies. Even in facility settings, the few studies that reported preterm mortality used inconsistent birth weight and gestational age cut-offs. There is a marked lack of data regarding effect of resuscitation on preterm babies. The long-term developmental outcomes following resuscitation also require further research. Particularly in low-middle resource settings, where health systems and families have limited resources to care for survivors with chronic disability, there is a dearth of comparable long term developmental outcome data (ACL, personal communication for CHERG/GBD neonatal encephalopathy estimates group).

This review has important implications for the scale up of neonatal resuscitation. The immediate opportunity is for facility based resuscitation. Even in facilities, equipment is lacking and few providers are trained in neonatal resuscitation. In 6 African national service provision assessments (DHS Macro), between 2-12% of delivery staff had been trained in neonatal resuscitation and fewer than one quarter of hospitals had newborn bag-masks available [1]. Given these challenges, achieving high coverage with basic neonatal resuscitation should be prioritized, as advanced resuscitation is infrequently required and may have limited additional mortality impact in low-resource settings. Establishing resuscitation training for pre-service education of midwives, doctors and nurses who provide newborn care is a crucial step. Recent advances in simpler training and robust, low cost equipment hold great promise for rapid scale up at much lower cost [68]. Furthermore, for the 60 million births a year outside facilities, while implementing basic neonatal resuscitation at the community level is controversial, there may be a role in some high-mortality settings where most births occur at home, skilled attendance is not achievable in the foreseeable future, alternative cadres already attend the majority of deliveries, and the case load per attendant is high enough to justify the training, equipment inputs and skill maintenance.

There is evidence from facility-based studies in low and middle-income countries that neonatal resuscitation training reduces neonatal mortality from intrapartum-related events (ie. “birth asphyxia”) by 30%, potentially saving 93,700 each year just by addressing missed opportunities for current facility births, and up to 192,000 babies at 90% coverage [69], only considering the effect on intrapartum-related neonatal deaths. In order to achieve maximal reduction in intrapartum-related neonatal deaths, preterm birth and intrapartum stillbirths, effective obstetric care remains the most important intervention [70, 71] and this should be complemented with immediate newborn care and resuscitation. There is increasing investment in obstetric care, yet to be matched by effective implementation, scale-up, and sustainability of immediate newborn care and basic neonatal resuscitation.

In the community, immediate simple care at birth is feasible, although estimated by experts to be low impact (10% on preterm and on intrapartum related neonatal deaths). Community-based neonatal resuscitation may reduce all-cause neonatal and perinatal mortality, but data is heterogeneous to presently estimate an effect size from the evidence. Future studies should attempt to address limitations identified here particularly in terms of intervention definitions, design, comparison groups, outcome definitions and misclassification of stillbirths and neonatal deaths.

While the quality of evidence for stimulation at birth and for neonatal resuscitation is low, partly because they are considered standard of care, there is sufficient and consistent evidence of impact. Yet such basic care remains a rarity especially for the world’s 60 million home births. Simplified training programs, and robust, low cost equipment are now available. Every baby born alive has the right to breathe at birth and to solutions helping those who do not breathe – the question remains if this right will be systematically advanced in policies and programs or will be left to chance depending on where a baby is born.

This work was supported by the Bill & Melinda Gates Foundation through a grant to US Fund for UNICEF for work on LiST and to the Saving Newborn Lives program of Save the Children US.