This systematic analysis of ACS use in 11 high-burden countries, which together account for over half of maternal and newborn deaths, has identified commonly experienced health system bottlenecks to scaling up ACS for management of preterm birth. A comprehensive approach to preterm birth should include strategies for prevention as well as management; however, the menu for high-impact, evidence-based preterm birth prevention is currently limited [26]. In high-income settings, reductions in the burden of preterm birth can largely be traced to improved care of preterm infants, which has yet to achieve major traction or wide-scale use even for simpler care such as feeding support, kangaroo mother care and infection prevention and treatment [27]. There is also considerable scope for impact through management of preterm birth, including ACS which is highly effective when provided by adequately trained health professionals in hospital settings where adequate maternal and neonatal follow-up and support are possible.
The important principle of "do no harm" and potential risks of ACS have been highlighted recently through the ACT trial. The benefits of ACS are dependent on high coverage in preterm babies <34 weeks; benefit is not expected or is marginal after 34 weeks, and risks increase close to term. Targeting based on gestational age and more accurate diagnosis of imminent preterm birth are therefore key aspects of effective, safe use as underscored in WHO guidelines. In addition, ACS alone cannot be a magic bullet; the preterm infant still requires a minimum of supportive care including warmth and feeding support, and if <32 weeks gestation is more likely to require oxygen therapy and respiratory support. Approximately half of the births in the ACT trial occurred at home or low-level primary care facilities [12].
Despite variation across the 11 countries that responded to the survey, the greatest barriers were consistent, highlighting three priority health system building blocks--health information systems, health service delivery and essential medical products and technologies--with the most critical common bottlenecks. Drawing from country programme experience, and evidence from literature (Table 2), this paper outlines potential solutions for programme managers and policymakers facing similar barriers.
Health information systems priority actions
Data on ACS coverage, use, and outcomes including safety were absent in nearly all countries. To enable continuous and quantitative assessment of ACS programmes, appropriate indicators need to be defined, and these data integrated into existing health information systems in order to allow tracking and comparison at facility, district, and national levels. ACS coverage data are one of the priority indicators identified in the Every Newborn Action Plan [28]. Coverage data are lacking and should also aim to assess false positives (women treated whose babies are born after 34 completed weeks).
Use of data for quality improvement would be aided if ACS were systematically included in safe childbirth checklists, partographs, clinical audits, and perinatal death reviews [29]. Data are also needed on process such as logistics and stock out. Two case studies of in-country implementation programmes provide examples of data collection and recordkeeping systems for ACS use, and how audit and feedback mechanisms using these records can be harnessed to improve quality of care for the management of preterm birth (Figure 4).
Health service delivery priority actions
Estimates suggest ACS coverage in LMICs is generally low even in tertiary facilities (Table 1), consistent with the poor grading of health service delivery among respondent country teams. All 11 countries in this analysis are among the 75 Countdown to 2015 countries with an estimate of 41% (weighted average) coverage of preterm births in secondary and tertiary facilities. Eight of 11 countries were also included in the WHO Multicountry Survey estimate of coverage in high-volume facilities; these were DRC (16%), Kenya (32%), Nigeria (30%), Uganda (27%), India (69%), Nepal (20%), Pakistan (63%), and Vietnam (52%). These estimates are likely to be higher than the national average as the survey methodology sampled only large facilities from the capital city and two randomly selected provinces. National population coverage with ACS is likely to be much lower than facility coverage estimates, as a large proportion of births take place outside of high-volume facilities or outside any facility. In the 11 countries, institutional delivery rates (in any facility) ranged from 33% in Bangladesh to 92% in Vietnam, according to data compiled by UNICEF in 2015 [30].
Available evidence supports focusing scale-up efforts in facilities with the capacity for gestational age assessment and diagnosis of women at risk of imminent preterm birth, as well as ongoing support for preterm infants and well-functioning maternity wards [4]. The recent study (ACT) which extended ACS to include non-hospital facilities in six countries (including Kenya, India, and Pakistan) found increased perinatal mortality as well as increased rates of presumed maternal infection [12]. The specific cause(s) of newborn mortality were not ascertainable, but service delivery challenges included limited ability to estimate gestational age and accurately diagnose high risk of preterm birth. As a consequence, ACS was under prescribed for preterm and early preterm babies likely to benefit from treatment and overprescribed to babies born at or near term, when ACS may have increased risks.
With clear evidence for use in hospitals in HICs with adequate neonatal support and reason for caution at lower-level facilities in LIC settings, programmatic scale-up is best focused on higher-level and high-volume facilities, where resources can also be used to produce significant impact cost-effectively and also improve targeting and safety tracking. Increased population coverage will then depend on increased and timely identification and referral of at-risk women, both in lower-level facilities and in homes. Systemic improvements are needed to encourage institutional deliveries with skilled birth attendants and to strengthen referral systems, while guidelines and training at lower levels of care will be critical to building capacity for timely identification. Expanded care such as a pre-referral dose may also improve care by allowing a longer time for ACS to take effect. However, such steps must be considered cautiously by each country based on the capacity of lower-level facilities to provide adequate care to ensure safety.
Human resource and skills for service delivery
Within hospitals, coverage is often limited by inadequate numbers of physicians or other providers present and also adequately trained to assess gestational age, diagnose high risk of preterm birth, and authorised to prescribe and administer ACS. The majority of countries reported both a shortage of health workers at higher cadres and a mismatch between provider cadres allowed to prescribe ACS and those cadres likely to be caring for women at risk of preterm birth (Table S2, additional file 2).
Expanded prescribing authority for midwives providing care to pregnant women could greatly increase the capacity of hospitals to manage preterm birth with ACS. However, any change in policy must be considered based on the capability to correctly diagnose conditions, which lead to preterm birth and provide adequate supportive care to both mother and baby. Currently WHO only recommends administration of ACS by doctors and advanced level associate clinicians and recommends against use by nurses and auxiliary nurses. Prescription and administration of ACS by non-advanced associate clinicians has not been evaluated by the WHO due to lack of rigorous evaluation of this question [31]. The WHO recommends cautious consideration of ACS administration by midwives and auxiliary nurse-midwives (ANMs) in LMICs with shortages of physicians-those settings described by respondent countries. Consideration of expanded prescribing authority should be made in the context of rigorous research [31]. In the absence of prescribing authority, health workers providing care to mothers still have an important role in identifying potential risk of preterm birth and ensuring rapid and safe referral.
All countries reported a lack of training in assessing gestational age, recognition of high risk of preterm birth and in management of preterm birth using ACS as well as inadequate supervision and mentoring systems. In-service training and increased support, both for cadres authorised to prescribe and administer ACS and for cadres involved in identification of risk and referral, are also critical to any scale-up effort.
Guidelines implementation and quality improvement
For any policy to reach every mother and every newborn, clear guidelines and adequate training must reach all relevant cadres of health worker and levels of care. As indicated by the country teams' responses to leadership and governance questions, it is critical both to develop clear guidelines and to ensure active dissemination. An active model of dissemination should ideally integrate systems of supervision, mentoring, and monitoring of quality improvement - all areas reported as inadequate by all 11 country teams.
A study of active dissemination in the United States showed that use of local opinion leaders, technical updates, reminders, interactive small-group learning, and audit and feedback were effective in accelerating facility uptake of ACS. These five elements were also effective in increasing use of a maternal health intervention in LMICs, with a structure reflecting the differing needs of low-resource settings. Figure 5 shows the five-component structure of the interventions in these two RCTs and details their implementation in each setting. Figure 6 outlines a program with similar features currently being studied in a facility in Cambodia. In particular, the audit and feedback component provides one model for continuous quality monitoring and improvement, an essential part of quality implementation of guidelines. This pilot model also provides a further example of the role of the continuous use of outcome data in improving safety and quality of care.
Essential medical products and technologies priority actions
Corticosteroids for ACS treatment are inexpensive (often under 1 USD for a full course) and are often assumed to be widely available. Yet most respondents indicated shortages at the country level, primarily attributed to a lack of supporting policy or effective logistics systems. NEML listing for the fetal lung maturation indication is essential to prioritisation for procurement as well as integration into supply chain, from forecasting to distribution.
Adequate procurement further depends on development and dissemination of guidelines on ACS use, including clarity on the choice of corticosteroid and appropriate regimen. Two corticosteroids, dexamethasone and betamethasone, have been shown to be safe and effective to manage preterm birth. Betamethasone is sometimes preferred in HICs due to limited evidence suggesting better outcomes (44% reduction in RDS and 33% reduction in neonatal mortality versus placebo or no treatment, compared with 20% reduction in RDS and 28% reduction in neonatal mortality for dexamethasone versus placebo or no treatment) and potentially lower risk of maternal infection [4].
However, evidence on dexamethasone still conclusively supports its overall safe and effective use for management of preterm birth. A meta-analysis of 9 studies directly comparing dexamethasone with betamethasone further found no statistically significant differences apart from a greater reduction in intraventricular haemorrhage using dexamethasone (RR 0.44, 95% CI 0.21 to 0.92, 4 studies, 549 infants). A large RCT directly comparing dexamethasone to betamethasone is currently underway [32].
Critically, only dexamethasone is a feasible choice for scale-up in most LMICs. While dexamethasone is widely available from international suppliers for a variety of indications, the formulation of betamethasone supported by most evidence (a suspension of betamethasone acetate in betamethasone phosphate, rather than betamethasone phosphate alone) has been subject to global shortages [33] and costs 25 times as much as dexamethasone per course of ACS [34].
Dexamethasone also faces fewer policy hurdles to increased use for management of preterm birth. With a variety of uses, dexamethasone in the recommended formulation is already registered, listed on the NEML, and included in procurement and supply chain in all 11 countries, for other indications. Dexamethasone is the only ACS listed on the WHO EML with a fetal lung maturation indication [35].
National policies, in line with the current WHO guideline, should therefore focus on promoting appropriate use of dexamethasone through procurement policy, clear guidelines, and integration into forecasting, procurement, and supply chain.
Limitations and implications for further research
Soliciting responses from a wide range of in-country partners and practitioners in maternal and newborn health captured context-specific challenges and generated collaborative solution ideas. The grading process also created consensus around priority bottlenecks and health system building blocks to be addressed. However, these consensus views are subjective. The quality and amount of information also varied depending on the level of knowledge of participants on health system issues and on workshop facilitation. In addition, bottlenecks were reported as perceived bottlenecks relative to the other health system building blocks. National-level assessment may mask regional disparities, particularly between urban and rural areas. This comprehensive questionnaire may have led to respondent fatigue, but this effect is least significant for ACS as the first intervention in the bottleneck analysis tool. For India and Pakistan, subnational responses may not mirror all national-level challenges. However, Pakistan submitted responses from all regions except two tribal territories, and although India returned data from only three of its 28 states, these areas are amongst the poorest states and include populations similar to those of Vietnam, Kenya, and DRC [36].
Further research is needed to establish the effectiveness of the solutions described here, especially in the context of ACS use in LMIC hospital settings where most of the world's births now occur. To date the evidence on ACS is primarily from HIC settings with neonatal intensive care [4] or the ACT trial from low-level settings with less-skilled workers [12]. The evidence base could be greatly advanced in LMIC settings, for instance through a multi-country, cluster-randomised trial in LMIC hospitals to assess the mortality impact and safety of a package optimising gestational age (where first trimester ultrasound is not routine) and clinical assessment of mothers, including risk of preterm birth and possible maternal infection, whilst providing appropriate maternal and newborn care. Given the lack of pharmacokinetic and dynamics data for both dexamethasone and betamethasone, other research questions include optimal dosage regimens. Data are now even more critically important and this gap is urgent to address, possibly for coverage and outcome data that could be tracked in routine health management information systems [29]. Further work is also needed to define signal functions for newborns by level of care. A signal function on ACS could be incorporated into existing monitoring systems, such as the signal functions for basic and comprehensive emergency obstetric care, to ensure consistent tracking of maternal and newborn interventions along the continuum of care [37].
Another important track of research is to improve the accuracy and also feasibility of gestational age assessment, including testing tools to improve accuracy of last menstrual period assessment, use of ultrasound dating in later pregnancy and ways to promote better recording in notes and use of the data by clinicians. Key messages and actions are summarised in Figure 7.
