Simplified Regimens for Management of Neonates and Young Infants With Severe Infection When Hospital Admission Is Not Possible

Background: In resource-limited settings, most young infants with signs of severe infection do not receive the recommended inpatient treatment with intravenous broad spectrum antibiotics for 10 days or more because such treatment is not accessible, acceptable or affordable to families. This trial was initiated in the Democratic Republic of Congo, Kenya and Nigeria to assess the safety and efficacy of simplified treatment regimens for the young infants with signs of severe infection who cannot receive hospital care. Methods: This is a randomized, open-label equivalence trial in which 3600 young infants with signs of clinical severe infection will be enrolled. The primary outcome is treatment failure in 7 days after enrollment, which includes death or worsening of the clinical condition on any day, or no improvement in the clinical condition by day 4 of treatment. Secondary outcomes include compliance with study therapy, adverse effects due to the study drugs and relapse or death during the week after completion of treatment. Discussion: The results of this study, along with ongoing studies in Pakistan and Bangladesh, will inform the development of global policy for treatment of severe neonatal infections in resource-limited settings

Treatment of fast breathing in neonates and young infants with oral amoxicillin compared with penicillin-gentamicin combination: study protocol for a randomized, open-label equivalence trial

Background: The World Health Organization recommends hospitalization and injectable antibiotic treatment for young infants (0–59 days old), who present with signs of possible serious bacterial infection. Fast breathing alone is not associated with a high mortality risk for young infants and has been treated with oral antibiotics in some settings. This trial was designed to examine the safety and efficacy of oral amoxicillin for young infants with fast breathing compared with that of an injectable penicillin–gentamicin combination. The study is currently being conducted in the Democratic Republic of Congo, Kenya and Nigeria Methods/Design: This is a randomized, open-label equivalence trial. All births in the community are visited at home by trained community health workers to identify sick infants who are then referred to a trial study nurse for assessment. The primary outcome is treatment failure by day 8 after enrollment, defined as clinical deterioration, development of a serious adverse event including death, persistence of fast breathing by day 4 or recurrence up to day 8. Secondary outcomes include adherence to study therapy, relapse, death between days 9 and 15 and adverse effects associated with the study drugs. Study outcomes are assessed on days 4, 8, 11 and 15 after randomization by an independent outcome assessor who is blinded to the treatment being given. Discussion: The results of this study will help inform the development of policies for the treatment of fast breathing among neonates and young infants in resource-limited settings

Ensuring Quality in AFRINEST and SATT: Clinical Standardization and Monitoring

Background: Three randomized open-label clinical trials [Simplified Antibiotic Therapy Trial (SATT) Bangladesh, SATT Pakistan and African Neonatal Sepsis Trial (AFRINEST)] were developed to test the equivalence of simplified antibiotic regimens compared with the standard regimen of 7 days of parenteral antibiotics. These trials were originally conceived and designed separately; subsequently, significant efforts were made to develop and implement a common protocol and approach. Previous articles in this supplement briefly describe the specific quality control methods used in the individual trials; this article presents additional information about the systematic approaches used to minimize threats to validity and ensure quality across the trials. Methods: A critical component of quality control for AFRINEST and SATT was striving to eliminate variation in clinical assessments and decisions regarding eligibility, enrollment and treatment outcomes. Ensuring appropriate and consistent clinical judgment was accomplished through standardized approaches applied across the trials, including training, assessment of clinical skills and refresher training. Standardized monitoring procedures were also applied across the trials, including routine (day-to-day) internal monitoring of performance and adherence to protocols, systematic external monitoring by funding agencies and external monitoring by experienced, independent trial monitors. A group of independent experts (Technical Steering Committee/Technical Advisory Group) provided regular monitoring and technical oversight for the trials. Conclusions: Harmonization of AFRINEST and SATT have helped to ensure consistency and quality of implementation, both internally and across the trials as a whole, thereby minimizing potential threats to the validity of the trials’ results

Scientific rationale for study design of community-based simplified antibiotic therapy trials in newborns and young infants with clinically diagnosed severe infections or fast breathing in South Asia and sub-Saharan Africa.

Background: Newborns and young infants suffer high rates of infections in South Asia and sub-Saharan Africa. Timely access to appropriate antibiotic therapy is essential for reducing mortality. In an effort to develop community case management guidelines for young infants, 0–59 days old, with clinically diagnosed severe infections, or with fast breathing, 4 trials of simplified antibiotic therapy delivered in primary care clinics (Pakistan, Democratic Republic of Congo, Kenya and Nigeria) or at home (Bangladesh and Nigeria) are being conducted. Methods: This article describes the scientific rationale for these trials, which share major elements of trial design. All the trials are in settings of high neonatal mortality, where hospitalization is not feasible or frequently refused. All use procaine penicillin and gentamicin intramuscular injections for 7 days as reference therapy and compare this to various experimental arms utilizing comparatively simpler combination regimens with fewer injections and oral amoxicillin. Conclusion: The results of these trials will inform World Health Organization policy regarding community case management of young infants with clinical severe infections or with fast breathing

Antenatal corticosteroids for women at risk of imminent preterm birth in low-resource countries: the case for equipoise and the need for efficacy trials

The scientific basis for antenatal corticosteroids (ACS) for women at risk of preterm birth has rapidly changed in recent years. Two landmark trials—the Antenatal Corticosteroid Trial and the Antenatal Late Preterm Steroids Trial—have challenged the long-held assumptions on the comparative health benefits and harms regarding the use of ACS for preterm birth across all levels of care and contexts, including resource-limited settings. Researchers, clinicians, programme managers, policymakers and donors working in low-income and middle-income countries now face challenging questions of whether, where and how ACS can be used to optimise outcomes for both women and preterm newborns. In this article, we briefly present an appraisal of the current evidence around ACS, how these findings informed WHO’s current recommendations on ACS use, and the knowledge gaps that have emerged in the light of new trial evidence. Critical considerations in the generalisability of the available evidence demonstrate that a true state of clinical equipoise exists for this treatment option in low-resource settings. An expert group convened by WHO concluded that there is a clear need for more efficacy trials of ACS in these settings to inform clinical practice

Preterm care during the COVID-19 pandemic: A comparative risk analysis of neonatal deaths averted by kangaroo mother care versus mortality due to SARS-CoV-2 infection.

BACKGROUND: COVID-19 is disrupting health services for mothers and newborns, particularly in low- and middle-income countries (LMIC). Preterm newborns are particularly vulnerable. We undertook analyses of the benefits of kangaroo mother care (KMC) on survival among neonates weighing ≤2000 g compared with the risk of SARS-CoV-2 acquired from infected mothers/caregivers. METHODS: We modelled two scenarios over 12 months. Scenario 1 compared the survival benefits of KMC with universal coverage (99%) and mortality risk due to COVID-19. Scenario 2 estimated incremental deaths from reduced coverage and complete disruption of KMC. Projections were based on the most recent data for 127 LMICs (~90% of global births), with results aggregated into five regions. FINDINGS: Our worst-case scenario (100% transmission) could result in 1,950 neonatal deaths from COVID-19. Conversely, 125,680 neonatal lives could be saved with universal KMC coverage. Hence, the benefit of KMC is 65-fold higher than the mortality risk of COVID-19. If recent evidence of 10% transmission was applied, the ratio would be 630-fold. We estimated a 50% reduction in KMC coverage could result in 12,570 incremental deaths and full disruption could result in 25,140 incremental deaths, representing a 2·3-4·6% increase in neonatal mortality across the 127 countries. INTERPRETATION: The survival benefit of KMC far outweighs the small risk of death due to COVID-19. Preterm newborns are at risk, especially in LMICs where the consequences of disruptions are substantial. Policymakers and healthcare professionals need to protect services and ensure clearer messaging to keep mothers and newborns together, even if the mother is SARS-CoV-2-positive. FUNDING: Eunice Kennedy Shriver National Institute of Child Health & Human Development; Bill & Melinda Gates Foundation; Elma Philanthropies; Wellcome Trust; and Joint Global Health Trials scheme of Department of Health and Social Care, Department for International Development, Medical Research Council, and Wellcome Trust

Small and sick newborn care during the COVID-19 pandemic: global survey and thematic analysis of healthcare providers' voices and experiences.

INTRODUCTION: The COVID-19 pandemic is disrupting health systems globally. Maternity care disruptions have been surveyed, but not those related to vulnerable small newborns. We aimed to survey reported disruptions to small and sick newborn care worldwide and undertake thematic analysis of healthcare providers' experiences and proposed mitigation strategies. METHODS: Using a widely disseminated online survey in three languages, we reached out to neonatal healthcare providers. We collected data on COVID-19 preparedness, effects on health personnel and on newborn care services, including kangaroo mother care (KMC), as well as disruptors and solutions. RESULTS: We analysed 1120 responses from 62 countries, mainly low and middle-income countries (LMICs). Preparedness for COVID-19 was suboptimal in terms of guidelines and availability of personal protective equipment. One-third reported routine testing of all pregnant women, but 13% had no testing capacity at all. More than 85% of health personnel feared for their own health and 89% had increased stress. Newborn care practices were disrupted both due to reduced care-seeking and a compromised workforce. More than half reported that evidence-based interventions such as KMC were discontinued or discouraged. Separation of the mother-baby dyad was reported for both COVID-positive mothers (50%) and those with unknown status (16%). Follow-up care was disrupted primarily due to families' fear of visiting hospitals (~73%). CONCLUSION: Newborn care providers are stressed and there is lack clarity and guidelines regarding care of small newborns during the pandemic. There is an urgent need to protect life-saving interventions, such as KMC, threatened by the pandemic, and to be ready to recover and build back better

Strengthening retinopathy of prematurity screening and treatment services in Nigeria: a case study of activities, challenges and outcomes 2017-2020.

OBJECTIVES: Retinopathy of prematurity (ROP) will become a major cause of blindness in Nigerian children unless screening and treatment services expand. This article aims to describe the collaborative activities undertaken to improve services for ROP between 2017 and 2020 as well as the outcome of these activities in Nigeria. DESIGN: Descriptive case study. SETTING: Neonatal intensive care units in Nigeria. PARTICIPANTS: Staff providing services for ROP, and 723 preterm infants screened for ROP who fulfilled screening criteria (gestational age <34 weeks or birth weight ≤2000 g, or sickness criteria). METHODS AND ANALYSIS: A WhatsApp group was initiated for Nigerian ophthalmologists and neonatologists in 2018. Members participated in a range of capacity-building, national and international collaborative activities between 2017 and 2018. A national protocol for ROP was developed for Nigeria and adopted in 2018; 1 year screening outcome data were collected and analysed. In 2019, an esurvey was used to collect service data from WhatsApp group members for 2017-2018 and to assess challenges in service provision. RESULTS: In 2017 only six of the 84 public neonatal units in Nigeria provided ROP services; this number had increased to 20 by 2018. Of the 723 babies screened in 10 units over a year, 127 (17.6%) developed any ROP; and 29 (22.8%) developed type 1 ROP. Only 13 (44.8%) babies were treated, most by intravitreal bevacizumab. The screening criteria were revised in 2020. Challenges included lack of equipment to regulate oxygen and to document and treat ROP, and lack of data systems. CONCLUSION: ROP screening coverage and quality improved after national and international collaborative efforts. To scale up and improve services, equipment for neonatal care and ROP treatment is urgently needed, as well as systems to monitor data. Ongoing advocacy is also essential

Scientific rationale for study design of community-based simplified antibiotic therapy trials in newborns and young infants with clinically diagnosed severe infections or fast breathing in South Asia and sub-Saharan Africa

Background: Newborns and young infants suffer high rates of infections in South Asia and sub-Saharan Africa. Timely access to appropriate antibiotic therapy is essential for reducing mortality. In an effort to develop community case management guidelines for young infants, 0-59 days old, with clinically diagnosed severe infections, or with fast breathing, 4 trials of simplified antibiotic therapy delivered in primary care clinics (Pakistan, Democratic Republic of Congo, Kenya and Nigeria) or at home (Bangladesh and Nigeria) are being conducted.Methods: This article describes the scientific rationale for these trials, which share major elements of trial design. All the trials are in settings of high neonatal mortality, where hospitalization is not feasible or frequently refused. All use procaine penicillin and gentamicin intramuscular injections for 7 days as reference therapy and compare this to various experimental arms utilizing comparatively simpler combination regimens with fewer injections and oral amoxicillin.CONCLUSION: The results of these trials will inform World Health Organization policy regarding community case management of young infants with clinical severe infections or with fast breathing