Efficacy of typhoid conjugate vaccine: final analysis of a 4-year, phase 3, randomised controlled trial in Malawian children.

BACKGROUND: Randomised controlled trials of typhoid conjugate vaccines among children in Africa and Asia have shown high short-term efficacy. Data on the durability of protection beyond 2 years are sparse. We present the final analysis of a randomised controlled trial in Malawi, encompassing more than 4 years of follow-up, with the aim of investigating vaccine efficacy over time and by age group. METHODS: In this phase 3, double-blind, randomised controlled efficacy trial in Blantyre, Malawi, healthy children aged 9 months to 12 years were randomly assigned (1:1) by an unmasked statistician to receive a single dose of Vi polysaccharide conjugated to tetanus toxoid vaccine (Vi-TT) or meningococcal capsular group A conjugate (MenA) vaccine. Children had to have no previous history of typhoid vaccination and reside in the study areas for inclusion and were recruited from government schools and health centres. Participants, their parents or guardians, and the study team were masked to vaccine allocation. Nurses administering vaccines were unmasked. We did surveillance for febrile illness from vaccination until follow-up completion. The primary outcome was first occurrence of blood culture-confirmed typhoid fever. Eligible children who were randomly assigned and vaccinated were included in the intention-to-treat analyses. This trial is registered at ClinicalTrials.gov, NCT03299426. FINDINGS: Between Feb 21, 2018, and Sept 27, 2018, 28 130 children were vaccinated; 14 069 were assigned to receive Vi-TT and 14 061 to receive MenA. After a median follow-up of 4·3 years (IQR 4·2-4·5), 24 (39·7 cases per 100 000 person-years) children in the Vi-TT group and 110 (182·7 cases per 100 000 person-years) children in the MenA group were diagnosed with a first episode of blood culture-confirmed typhoid fever. In the intention-to-treat population, efficacy of Vi-TT was 78·3% (95% CI 66·3-86·1), and 163 (129-222) children needed to be vaccinated to prevent one case. Efficacies by age group were 70·6% (6·4-93·0) for children aged 9 months to 2 years; 79·6% (45·8-93·9) for children aged 2-4 years; and 79·3% (63·5-89·0) for children aged 5-12 years. INTERPRETATION: A single dose of Vi-TT is durably efficacious for at least 4 years among children aged 9 months to 12 years and shows efficacy in all age groups, including children younger than 2 years. These results support current WHO recommendations in typhoid-endemic areas for mass campaigns among children aged 9 months to 15 years, followed by routine introduction in the first 2 years of life. FUNDING: Bill & Melinda Gates Foundation.

Azithromycin for Bacterial Watery Diarrhea: A Reanalysis of the AntiBiotics for Children With Severe Diarrhea (ABCD) Trial Incorporating Molecular Diagnostics.

BACKGROUND: Bacterial pathogens cause substantial diarrhea morbidity and mortality among children living in endemic settings, yet antimicrobial treatment is only recommended for dysentery or suspected cholera. METHODS: AntiBiotics for Children with severe Diarrhea was a 7-country, placebo-controlled, double-blind efficacy trial of azithromycin in children 2-23 months of age with watery diarrhea accompanied by dehydration or malnutrition. We tested fecal samples for enteric pathogens utilizing quantitative polymerase chain reaction to identify likely and possible bacterial etiologies and employed pathogen-specific cutoffs based on genomic target quantity in previous case-control diarrhea etiology studies to identify likely and possible bacterial etiologies. RESULTS: Among 6692 children, the leading likely etiologies were rotavirus (21.1%), enterotoxigenic Escherichia coli encoding heat-stable toxin (13.3%), Shigella (12.6%), and Cryptosporidium (9.6%). More than one-quarter (1894 [28.3%]) had a likely and 1153 (17.3%) a possible bacterial etiology. Day 3 diarrhea was less common in those randomized to azithromycin versus placebo among children with a likely bacterial etiology (risk difference [RD]likely, -11.6 [95% confidence interval {CI}, -15.6 to -7.6]) and possible bacterial etiology (RDpossible, -8.7 [95% CI, -13.0 to -4.4]) but not in other children (RDunlikely, -0.3% [95% CI, -2.9% to 2.3%]). A similar association was observed for 90-day hospitalization or death (RDlikely, -3.1 [95% CI, -5.3 to -1.0]; RDpossible, -2.3 [95% CI, -4.5 to -.01]; RDunlikely, -0.6 [95% CI, -1.9 to .6]). The magnitude of risk differences was similar among specific likely bacterial etiologies, including Shigella. CONCLUSIONS: Acute watery diarrhea confirmed or presumed to be of bacterial etiology may benefit from azithromycin treatment. CLINICAL TRIALS REGISTRATION: NCT03130114.

Safety and Efficacy of a Typhoid Conjugate Vaccine in Malawian Children.

BACKGROUND: Typhoid fever caused by multidrug-resistant H58 Salmonella Typhi is an increasing public health threat in sub-Saharan Africa. METHODS: We conducted a phase 3, double-blind trial in Blantyre, Malawi, to assess the efficacy of Vi polysaccharide typhoid conjugate vaccine (Vi-TCV). We randomly assigned children who were between 9 months and 12 years of age, in a 1:1 ratio, to receive a single dose of Vi-TCV or meningococcal capsular group A conjugate (MenA) vaccine. The primary outcome was typhoid fever confirmed by blood culture. We report vaccine efficacy and safety outcomes after 18 to 24 months of follow-up. RESULTS: The intention-to-treat analysis included 28,130 children, of whom 14,069 were assigned to receive Vi-TCV and 14,061 were assigned to receive the MenA vaccine. Blood culture-confirmed typhoid fever occurred in 12 children in the Vi-TCV group (46.9 cases per 100,000 person-years) and in 62 children in the MenA group (243.2 cases per 100,000 person-years). Overall, the efficacy of Vi-TCV was 80.7% (95% confidence interval [CI], 64.2 to 89.6) in the intention-to-treat analysis and 83.7% (95% CI, 68.1 to 91.6) in the per-protocol analysis. In total, 130 serious adverse events occurred in the first 6 months after vaccination (52 in the Vi-TCV group and 78 in the MenA group), including 6 deaths (all in the MenA group). No serious adverse events were considered by the investigators to be related to vaccination. CONCLUSIONS: Among Malawian children 9 months to 12 years of age, administration of Vi-TCV resulted in a lower incidence of blood culture-confirmed typhoid fever than the MenA vaccine. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT03299426.).

Immediate "Kangaroo Mother Care" and Survival of Infants with Low Birth Weight.

BACKGROUND: "Kangaroo mother care," a type of newborn care involving skin-to-skin contact with the mother or other caregiver, reduces mortality in infants with low birth weight (<2.0 kg) when initiated after stabilization, but the majority of deaths occur before stabilization. The safety and efficacy of kangaroo mother care initiated soon after birth among infants with low birth weight are uncertain. METHODS: We conducted a randomized, controlled trial in five hospitals in Ghana, India, Malawi, Nigeria, and Tanzania involving infants with a birth weight between 1.0 and 1.799 kg who were assigned to receive immediate kangaroo mother care (intervention) or conventional care in an incubator or a radiant warmer until their condition stabilized and kangaroo mother care thereafter (control). The primary outcomes were death in the neonatal period (the first 28 days of life) and in the first 72 hours of life. RESULTS: A total of 3211 infants and their mothers were randomly assigned to the intervention group (1609 infants with their mothers) or the control group (1602 infants with their mothers). The median daily duration of skin-to-skin contact in the neonatal intensive care unit was 16.9 hours (interquartile range, 13.0 to 19.7) in the intervention group and 1.5 hours (interquartile range, 0.3 to 3.3) in the control group. Neonatal death occurred in the first 28 days in 191 infants in the intervention group (12.0%) and in 249 infants in the control group (15.7%) (relative risk of death, 0.75; 95% confidence interval [CI], 0.64 to 0.89; P = 0.001); neonatal death in the first 72 hours of life occurred in 74 infants in the intervention group (4.6%) and in 92 infants in the control group (5.8%) (relative risk of death, 0.77; 95% CI, 0.58 to 1.04; P = 0.09). The trial was stopped early on the recommendation of the data and safety monitoring board owing to the finding of reduced mortality among infants receiving immediate kangaroo mother care. CONCLUSIONS: Among infants with a birth weight between 1.0 and 1.799 kg, those who received immediate kangaroo mother care had lower mortality at 28 days than those who received conventional care with kangaroo mother care initiated after stabilization; the between-group difference favoring immediate kangaroo mother care at 72 hours was not significant. (Funded by the Bill and Melinda Gates Foundation; Australian New Zealand Clinical Trials Registry number, ACTRN12618001880235; Clinical Trials Registry-India number, CTRI/2018/08/015369.).

Quantifying health facility service readiness for small and sick newborn care: comparing standards-based and WHO level-2 + scoring for 64 hospitals implementing with NEST360 in Kenya, Malawi, Nigeria, and Tanzania.

BACKGROUND: Service readiness tools are important for assessing hospital capacity to provide quality small and sick newborn care (SSNC). Lack of summary scoring approaches for SSNC service readiness means we are unable to track national targets such as the Every Newborn Action Plan targets. METHODS: A health facility assessment (HFA) tool was co-designed by Newborn Essential Solutions and Technologies (NEST360) and UNICEF with four African governments. Data were collected in 68 NEST360-implementing neonatal units in Kenya, Malawi, Nigeria, and Tanzania (September 2019-March 2021). Two summary scoring approaches were developed: a) standards-based, including items for SSNC service readiness by health system building block (HSBB), and scored on availability and functionality, and b) level-2 + , scoring items on readiness to provide WHO level-2 + clinical interventions. For each scoring approach, scores were aggregated and summarised as a percentage and equally weighted to obtain an overall score by hospital, HSBB, and clinical intervention. RESULTS: Of 1508 HFA items, 1043 (69%) were included in standards-based and 309 (20%) in level-2 + scoring. Sixty-eight neonatal units across four countries had median standards-based scores of 51% [IQR 48-57%] at baseline, with variation by country: 62% [IQR 59-66%] in Kenya, 49% [IQR 46-51%] in Malawi, 50% [IQR 42-58%] in Nigeria, and 55% [IQR 53-62%] in Tanzania. The lowest scoring was family-centred care [27%, IQR 18-40%] with governance highest scoring [76%, IQR 71-82%]. For level-2 + scores, the overall median score was 41% [IQR 35-51%] with variation by country: 50% [IQR 44-53%] in Kenya, 41% [IQR 35-50%] in Malawi, 33% [IQR 27-37%] in Nigeria, and 41% [IQR 32-52%] in Tanzania. Readiness to provide antibiotics by culture report was the highest-scoring intervention [58%, IQR 50-75%] and neonatal encephalopathy management was the lowest-scoring [21%, IQR 8-42%]. In both methods, overall scores were low (< 50%) for 27 neonatal units in standards-based scoring and 48 neonatal units in level-2 + scoring. No neonatal unit achieved high scores of > 75%. DISCUSSION: Two scoring approaches reveal gaps in SSNC readiness with no neonatal units achieving high scores (> 75%). Government-led quality improvement teams can use these summary scores to identify areas for health systems change. Future analyses could determine which items are most directly linked with quality SSNC and newborn outcomes.

Target product profiles for neonatal care devices: systematic development and outcomes with NEST360 and UNICEF.

BACKGROUND: Medical devices are critical to providing high-quality, hospital-based newborn care, yet many of these devices are unavailable in low- and middle-income countries (LMIC) and are not designed to be suitable for these settings. Target Product Profiles (TPPs) are often utilised at an early stage in the medical device development process to enable user-defined performance characteristics for a given setting. TPPs can also be applied to assess the profile and match of existing devices for a given context. METHODS: We developed initial TPPs for 15 newborn product categories for LMIC settings. A Delphi-like process was used to develop the TPPs. Respondents completed an online survey where they scored their level of agreement with each of the proposed performance characteristics for each of the 15 devices. Characteristics with < 75% agreement between respondents were discussed and voted on using Mentimeter™ at an in-person consensus meeting. FINDINGS: The TPP online survey was sent to 180 people, of which 103 responded (57%). The majority of respondents were implementers/clinicians (51%, 53/103), with 50% (52/103) from LMIC. Across the 15 TPPs, 403 (60%) of the 668 performance characteristics did not achieve > 75% agreement. Areas of disagreement were voted on by 69 participants at an in-person consensus meeting, with consensus achieved for 648 (97%) performance characteristics. Only 20 (3%) performance characteristics did not achieve consensus, most (15/20) relating to quality management systems. UNICEF published the 15 TPPs in April 2020, accompanied by a report detailing the online survey results and consensus meeting discussion, which has been viewed 7,039 times (as of January 2023). CONCLUSIONS: These 15 TPPs can inform developers and enable implementers to select neonatal care products for LMIC. Over 2,400 medical devices and diagnostics meeting these TPPs have been installed in 65 hospitals in Nigeria, Tanzania, Kenya, and Malawi through the NEST360 Alliance. Twenty-three medical devices identified and qualified by NEST360 meet nearly all performance characteristics across 11 of the 15 TPPs. Eight of the 23 qualified medical devices are available in the UNICEF Supply Catalogue. Some developers have adjusted their technologies to meet these TPPs. There is potential to adapt the TPP process beyond newborn care.

Plasma Rotavirus-specific IgA and Risk of Rotavirus Vaccine Failure in Infants in Malawi.

BACKGROUND: Rotavirus vaccine efficacy is reduced in low-income populations, but efforts to improve vaccine performance are limited by lack of clear correlates of protection. Although plasma rotavirus (RV)-specific immunoglobulin A (IgA) appears strongly associated with protection against rotavirus gastroenteritis in high-income countries, weaker association has been observed in low-income countries. We tested the hypothesis that lower RV-specific IgA is associated with rotavirus vaccine failure in Malawian infants. METHODS: In a case-control study, we recruited infants presenting with severe rotavirus gastroenteritis following monovalent oral rotavirus vaccination (RV1 vaccine failures). Conditional logistic regression was used to determine the odds of rotavirus seronegativity (RV-specific IgA < 20 U/mL) in these cases compared 1:1 with age-matched, vaccinated, asymptomatic community controls. Plasma RV-specific IgA was determined by enzyme-linked immunosorbent assay for all participants at recruitment, and for cases at 10 days after symptom onset. Rotavirus infection and genotype were determined by antigen testing and reverse transcription-polymerase chain reaction, respectively. RESULTS: In 116 age-matched pairs, infants with RV1 vaccine failure were more likely to be RV-specific IgA seronegative than controls: odds ratio, 3.1 (95% confidence interval [CI], 1.6-5.9), P=.001. In 60 infants with convalescent serology, 42/45 (93%; 95% CI. 81-98) infants seronegative at baseline became seropositive. Median rise in RV-specific IgA concentration following acute infection was 112.8 (interquartile range, 19.1-380.6)-fold. CONCLUSIONS: In this vaccinated population with high residual burden of rotavirus disease, RV1 vaccine failure was associated with lower RV-specific IgA, providing further evidence of RV-specific IgA as a marker of protection. Robust convalescent RV-specific IgA response in vaccine failures suggests differences in wild-type and vaccine-induced immunity, which informs future vaccine development.

Challenges and recommendations to improve implementation of phototherapy among neonates in Malawian hospitals.

BACKGROUND: Severe neonatal jaundice can result in long term morbidities and mortality when left untreated. Phototherapy is the main-stay intervention for treating moderate jaundice and for prevention of the development of severe jaundice. However, in resource-limited health care settings, phototherapy has been inconsistently used. The objective of this study is to evaluate barriers and facilitators for phototherapy to treat neonatal jaundice at Malawian hospitals. METHODS: We conducted a convergent mixed-method study comprised of a facility assessment and qualitative interviews with healthcare workers and caregivers in southern Malawi. The facility assessment was conducted at three secondary-level hospitals in rural districts. In-depth interviews following a semi-structured topic guide were conducted at a district hospital and a tertiary-level hospital. Interviews were thematically analysed in NVivo 12 software (QSR International, Melbourne, Australia). RESULTS: The facility assessment found critical gaps in initiating and monitoring phototherapy in all facilities. Based on a total of 31 interviews, participants identified key challenges in diagnosing neonatal jaundice, counselling caregivers, and availability of infrastructure. Participants emphasized the need for transcutaneous bilirubinometers to guide treatment decisions. Caregivers were sometimes fearful of potential harmful effects of phototherapy, which required adequate explanation to mothers and family members in non-medical language. Task shifting and engaging peer support for caregivers with concerns about phototherapy was recommended. CONCLUSION: Implementation of a therapeutic intervention is limited if accurate diagnostic tests are unavailable. The scale up of therapeutic interventions, such as phototherapy for neonatal jaundice, requires careful holistic attention to infrastructural needs, supportive services such as laboratory integration as well as trained human resources.

Mothers' quality of life delivering kangaroo mother care at Malawian hospitals: a qualitative study.

INTRODUCTION: Kangaroo mother care is known to help save the lives of preterm and low birthweight infants, particularly in resource-limited health settings, yet barriers to implementation have been documented. Mothers and their families are very involved in the process of providing kangaroo mother care and the impact on their well-being has not been well explored. The objective of this research was to investigate the perspectives and experiences of a mother's quality of life while delivering facility-based kangaroo mother care. METHODS: This study is a secondary analysis of the qualitative data collected within the "Integrating a neonatal healthcare package for Malawi" project. Twenty-seven health workers and 24 caregivers engaged with kangaroo mother care at four hospitals in southern Malawi were interviewed between May-August 2019. All interviews were face-to-face and followed a topic guide. Content analysis was conducted on NVivo 12 (QSR International, Melbourne, Australia) based on the six World Health Organization Quality of Life domains (physical, psychological, level of independence, social relationships, environment, spirituality). RESULTS: Fifty-one interviews were conducted with 24 caregivers and 14 health workers. Mothers experienced multidimensional challenges to their quality of life while delivering facility-based KMC. Though kangaroo mother care was considered a simple intervention, participants highlighted that continuous kangaroo mother care was difficult to practice. Kangaroo mother care was an exhausting experience for mothers due to being in one position for prolonged periods, compromised sleep, restricted movement, boredom, and isolation during their stay at the hospital as well as poor support for daily living needs such as food. DISCUSSION: A heavy burden is placed on mothers who become the key person responsible for care during kangaroo mother care, especially in resource-limited health settings. More focus is needed on supporting caregivers during the delivery of kangaroo mother care through staff support, family inclusion, and conducive infrastructure.

Barriers and facilitators of facility-based kangaroo mother care in sub-Saharan Africa: a systematic review.

BACKGROUND: Hospital-based kangaroo mother care can help reduce preventable newborn deaths and has been recommended by the World Health Organization in the care of low birthweight babies weighing 2000 g or less. However, implementation has been limited. The objective of this review is to understand the barriers and facilitators of kangaroo mother care implementation in health facilities in sub-Saharan Africa, where there are the highest rates of neonatal mortality in the world. METHODS: A systematic search was performed on MEDLINE, Web of Science, Cumulative Index to Nursing and Allied Health, African Journals Online, African Index Medicus as well as the references of relevant articles. Inclusion criteria included primary research, facility-based kangaroo mother care in sub-Saharan Africa. Studies were assessed by the Critical Appraisal Skills Programme Qualitative Checklist and the National Institutes of Health quality assessment tools and underwent narrative synthesis. RESULTS: Thirty studies were included in the review. This review examined barriers and facilitators to kangaroo mother care practice at health systems level, health worker experiences and perspectives of mothers and their families. Strong local leadership was essential to overcome barriers of inadequate space, limited budget for supplies, inadequate staffing, lack of guidelines and policies and insufficient supportive supervision. Workload burdens, knowledge gaps and staff attitudes were highlighted as challenges at health workers' level, which could be supported by sharing of best practices and success stories. Support for mothers and their families was also identified as a gap. CONCLUSION: Building momentum for kangaroo mother care in health facilities in sub-Saharan Africa continues to be a challenge. Strengthening health systems and communication, prioritizing preterm infant care in public health strategies and supporting health workers and mothers and their families as partners in care are important to scale up. This will support sustainable kangaroo mother care implementation as well as strengthen quality of newborn care overall. PROSPERO registration: CRD42020166742.

Clinical diagnosis in paediatric patients at urban primary health care facilities in southern Malawi: a longitudinal observational study.

BACKGROUND: Despite health centres being the first point of contact of care, there are challenges faced in providing care to patients at this level. In Malawi, service provision barriers reported at this level included long waiting times, high numbers of patients and erratic consultation systems which lead to mis-diagnosis and delayed referrals. Proper case management at this level of care is critical to prevent severe disease and deaths in children. We aimed to adopt Emergency, Triage, Assessment and Treatment algorithm (ETAT) to improve ability to identify severe illness in children at primary health centre (PHC) through comparison with secondary level diagnoses. METHODS: We implemented ETAT mobile Health (mHealth) at eight urban PHCs in Blantyre, Malawi between April 2017 and September 2018. Health workers and support staff were trained in mHealth ETAT. Stabilisation rooms were established and equipped with emergency equipment. All PHCs used an electronic tracking system to triage and track sick children on referral to secondary care, facilitated by a unique barcode. Support staff at PHC triaged sick children using ETAT Emergency (E), Priority (P) and Queue (Q) symptoms and clinician gave clinical diagnosis. The secondary level diagnosis was considered as a gold standard. We used statistical computing software R (v3.5.1) and used exact 95% binomial confidence intervals when estimating diagnosis agreement proportions. RESULTS: Eight-five percentage of all cases where assigned to E (9.0%) and P (75.5%) groups. Pneumonia was the most common PHC level diagnosis across all three triage groups (E, P, Q). The PHC level diagnosis of trauma was the most commonly confirmed diagnosis at secondary level facility (85.0%), while a PHC diagnosis of pneumonia was least likely to be confirmed at secondary level (39.6%). The secondary level diagnosis least likely to have been identified at PHC level was bronchiolitis 3 (5.2%). The majority of bronchiolitis cases (n = 50; (86.2%) were classified as pneumonia at the PHC level facility. CONCLUSIONS: Implementing a sustainable and consistent ETAT approach with stabilisation and treatment capacity at PHC level reinforce staff capacity to diagnose and has the potential to reduce other health system costs through fewer, timely and appropriate referrals.

Feeding practices and association of fasting and low or hypo glycaemia in severe paediatric illnesses in Malawi - a mixed method study.

BACKGROUND: The presence of low or hypo glycaemia in children upon admission to hospital in low income countries is a marker for poor outcome. Fasting during illness may contribute to low blood glucose and caretakers' feeding practices during childhood illnesses may thus play a role in the development of low or hypo glycaemia. This study aims to describe the caretaker's feeding practices and association of fasting with low or hypo glycaemia in sick children in Malawi. METHODS: A mixed method approach was used combining quantitative cross-sectional data for children aged 0-17 years admitted to Queen Elizabeth Central Hospital (QECH), a tertiary hospital in Malawi, with qualitative focus group discussions conducted with caretakers of young children who were previously referred to QECH from the five health centres around QECH. Logistic regression was used to analyse the quantitative data and thematic content analysis was conducted for qualitative data analysis. RESULTS: Data for 5131 children who were admitted through the hospital's Paediatric Accident and Emergency Department (A&E) were analysed whereof 2.1% presented with hypoglycaemia (< 2.5 mmol/l) and 6.6% with low glycaemia (≥2.5mmoll/l - < 5 mmol/l). Fasting for more than eight hours was associated with low glycaemia as well as hypoglycaemia with Adjusted Odds Ratios (AOR) of 2.9 (95% Confidence Interval (CI) of 2.3-3.7) and 4.6, (95% CI 3.0-7.0), respectively. Caretakers demonstrated awareness of the importance of feeding during childhood illness and reported intensified feeding attention to sick children but face feeding challenges when illness becomes severe causing them to seek care at a health facility. CONCLUSION: Results suggests that caretakers understand the importance of feeding during illness and make efforts to intensify feeding a sick child but challenges occur when illness is severe leading to fasting. Fasting among children admitted to hospitals may serve as a marker of severe illness and determine those at risk of low and hypoglycaemia.

Health workers' views on factors affecting caregiver engagement with bubble CPAP.

BACKGROUND: Severe respiratory distress is a leading cause of mortality among neonates in Malawi. Despite evidence on the safety, cost effectiveness and efficacy of bubble continuous positive airway pressure (CPAP) in managing the condition, its use in Malawian health facilities is limited and little is known about caregivers' engagement with perspectives of bubble CPAP. The purpose of this study was to explore caregiver perspectives for bubble CPAP at both central and district hospitals and key factors that enable effective caregiver engagement in Malawi. METHODS: This was a descriptive qualitative study employing secondary analysis of 46 health care worker in-depth interviews. We interviewed the health workers about their thoughts on caregiver perspectives regarding use of bubble CPAP. We implemented the study at a tertiary facility and three district hospitals in southern Malawi. This was a part of a larger study to understand barriers and facilitators to implementing neonatal innovations in resource-constrained hospitals. Interviews were thematically analysed in NVivo 12 software (QSR International, Melbourne, Australia). Health workers were purposively selected to include nurses, clinicians and district health management involved in the use of bubble CPAP. RESULTS: Emerging issues included caregiver fears around bubble CPAP equipment as potentially harmful to their new-borns and how inadequate information provided to caregivers exacerbated knowledge gaps and was associated with refusal of care. However, good communication between health care providers and caregivers was associated with acceptance of care. Caregivers' decision-making was influenced by relatives and peer advocates were helpful in supporting caregivers and alleviating fears or misconceptions about bubble CPAP. CONCLUSIONS: Since caregivers turn to relatives and peers for support, there is need to ensure that both relatives and peers are counselled on bubble CPAP for improved understanding and uptake. Health workers need to provide simplified, accurate, up-to-date information on the intervention as per caregivers' level of understanding. Notably, contextualised comprehensible information will help alleviate caregivers' fear and anxieties about bubble CPAP.

"It brought hope and peace in my heart:" Caregivers perceptions on kangaroo mother care services in Malawi.

BACKGROUND: Kangaroo mother care (KMC) is an effective intervention for preterm and low birth weight infants. Effective implementation of KMC relies on a multidisciplinary team centering on the newborn's caregiver, who delivers care with support from health care workers. This study explored the experiences of caregivers on the implementation of KMC. METHODS: We conducted a descriptive qualitative study in the phenomenological tradition, an interpretative approach to describe the caregivers' lived experience with KMC at four health facilities in Malawi from April and June 2019 through 10 non-participatory observations and 24 face-to-face interviews. We drew a purposive sample of 14 mothers, six fathers, three grandmothers, and one grandfather of infants receiving KMC in three secondary and one tertiary level hospitals. Data were analyzed following a thematic approach. RESULTS: Caregivers had limited information on KMC before admission with most of the information learned from peers rather than medical professionals. Stories of positive outcomes following KMC contributed to a shift in perceptions of premature babies and acceptability of KMC as an effective intervention. Unintended consequences resulting from admission due to KMC disrupts responsibilities around the home and disrupts economic activities. Gender division of roles exists with the implementation of KMC and a mother's support networks are crucial. CONCLUSION: Kangaroo mother care is feasible and acceptable among caregivers. KMC babies are described more positively with the potential to grow into strong and healthy children. KMC remains focused on the mother, which undervalues the important roles of her support network. A change in the nomenclature from kangaroo mother care to kangaroo care would include fathers and others delivering care.

Assessing quality of newborn care at district facilities in Malawi.

BACKGROUND: Malawi is celebrated as one of the few countries in sub-Saharan Africa to meet the Millennium Development Goal of reducing under-5 mortality by two-thirds between 1990 and 2015. However, within this age range neonatal mortality rates are the slowest to decline, even though rates of facility births are increasing. Examining the quality of neonatal care at district-level facilities where most deliveries occur is warranted. OBJECTIVE: The objective of this paper is to evaluate the quality of neonatal care in three district hospitals and one primary health centre in southern Malawi as well as to report the limitations and lessons learned on using the WHO integrated quality of care assessment tool. METHODS: These facility assessments were part of the "Integrating a neonatal healthcare package for Malawi" project, a part of the Innovating for Maternal and Child Health in Africa (IMCHA) initiative. The WHO integrated quality of care assessment tool was used to assess quality of care and availability and quantity of supplies and resources. The modules on infrastructure, neonatal care and labour and delivery were included. Facility assessments were administered in November 2017 and aspects of care were scored on a Likert scale from one to five (a score of 5 indicating compliance with WHO standards of care; one as lowest indicating inadequate care). RESULTS: The continuum of labour, delivery and neonatal care were assessed to identify areas that required improvements to meet standards of care. Critical areas for improvements included infection control (mean score 2.9), equipment, supplies and setup for newborn care in the labor ward (2.3), in the surgical theater (3.3), and nursery (3.4 nursery facilities, 3.0 supplies and equipment), as well as for management of sick newborns (3.2), monitoring and follow-up (3.6). Only one of the 12 domains, laboratory, met the standards of care with only minor improvements needed (4.0). CONCLUSION: The WHO integrated quality of care assessment tool is a validated tool that can shed light on the complex quality of care challenges faced by district-level health facilities. The results reveal that the quality of care needs improvement, particularly for sick and vulnerable newborns.

Point-of-care device to diagnose and monitor neonatal jaundice in low-resource settings.

Newborns are at increased risk of jaundice, a condition in which excess bilirubin accumulates in blood. Left untreated, jaundice can lead to neurological impairment and death. Jaundice resulting from unconjugated hyperbilirubinemia is easily treated with exposure to blue light, and phototherapy systems have been developed for low-resource settings; however, there are no appropriate solutions to diagnose and monitor jaundice in these settings. To address this need we present BiliSpec, a low-cost reader and disposable lateral flow card designed to measure the concentration of total bilirubin from several drops of blood at the point of care. We evaluated the performance of BiliSpec, using blood from normal volunteers spiked with varying amounts of bilirubin; results measured using BiliSpec correlated well with a reference laboratory bilirubinometer (r = 0.996). We then performed a pilot clinical study using BiliSpec to measure total bilirubin in neonates at risk for jaundice at Queen Elizabeth Central Hospital in Blantyre, Malawi. Concentrations measured using BiliSpec correlated well with those measured using a laboratory reference standard in 94 patient samples ranging from 1.1 mg/dL to 23.0 mg/dL in concentration (r = 0.973). The mean difference between bilirubin levels measured with BiliSpec and the reference standard was 0.3 mg/dL (95[Formula: see text] CI: -1.7-2.2 mg/dL).

Association of Neonatal Hypothermia with Morbidity and Mortality in a Tertiary Hospital in Malawi.

OBJECTIVES: To evaluate associations with neonatal hypothermia in a tertiary-level neonatal unit (NU) in Malawi. METHODS: Neonates with a birth weight >1000 g were recruited and temperatures were recorded 5 min after birth, on admission and 4 h thereafter. Clinical course and outcome were reviewed. Data were analysed using Stata v.15 and p < 0.05 was considered statistically significant. RESULTS: Between August 2018 to March 2019, 120 neonates were enrolled, and 112 were included in the data analysis. Hypothermia at 5 min after birth was noted in 74%, 77% on admission to the NU and 38% at 24 h. Neonates who had hypothermia 5 min after birth were more likely to have hypothermia on admission to the NU compared with normothermic subjects (p < 0.01). All neonates with hypothermia on admission to the NU died (100 vs.72%, p = 0.02), but hypothermia at 5 min nor at 24 h were not associated with mortality. After adjusting for potential confounders, the odds ratio of hypothermia at 5 min for hypothermia on admission to NU was 13.31 (95% CI 4.17-42.54). DISCUSSION: A large proportion of hospitalized neonates is hypothermic on admission and has associated morbidity and mortality. Our findings suggest that a strong predictor of mortality is neonatal hypothermia on admission to the NU, and that early intervention in the immediate period after delivery could decrease the incidence of hypothermia and reduce associated morbidity and mortality.

Emerging Resistance to Empiric Antimicrobial Regimens for Pediatric Bloodstream Infections in Malawi (1998-2017).

BACKGROUND: The adequacy of the World Health Organization's Integrated Management of Childhood Illness (IMCI) antimicrobial guidelines for the treatment of suspected severe bacterial infections is dependent on a low prevalence of antimicrobial resistance (AMR). We describe trends in etiologies and susceptibility patterns of bloodstream infections (BSI) in hospitalized children in Malawi. METHODS: We determined the change in the population-based incidence of BSI in children admitted to Queen Elizabeth Central Hospital, Blantyre, Malawi (1998-2017). AMR profiles were assessed by the disc diffusion method, and trends over time were evaluated. RESULTS: A total 89643 pediatric blood cultures were performed, and 10621 pathogens were included in the analysis. Estimated minimum incidence rates of BSI for those ≤5 years of age fell from a peak of 11.4 per 1000 persons in 2002 to 3.4 per 1000 persons in 2017. Over 2 decades, the resistance of Gram-negative pathogens to all empiric, first-line antimicrobials (ampicillin/penicillin, gentamicin, ceftriaxone) among children ≤5 years increased from 3.4% to 30.2% (P < .001). Among those ≤60 days, AMR to all first-line antimicrobials increased from 7.0% to 67.7% (P < .001). Among children ≤5 years, Klebsiella spp. resistance to all first-line antimicrobial regimens increased from 5.9% to 93.7% (P < .001). CONCLUSIONS: The incidence of BSI among hospitalized children has decreased substantially over the last 20 years, although gains have been offset by increases in Gram-negative pathogens' resistance to all empiric first-line antimicrobials. There is an urgent need to address the broader challenge of adapting IMCI guidelines to the local setting in the face of rapidly-expanding AMR in childhood BSI.

Nonsecretor Histo-blood Group Antigen Phenotype Is Associated With Reduced Risk of Clinical Rotavirus Vaccine Failure in Malawian Infants.

BACKGROUND: Histo-blood group antigen (HBGA) Lewis/secretor phenotypes predict genotype-specific susceptibility to rotavirus gastroenteritis (RVGE). We tested the hypothesis that nonsecretor/Lewis-negative phenotype leads to reduced vaccine take and lower clinical protection following vaccination with G1P[8] rotavirus vaccine (RV1) in Malawian infants. METHODS: A cohort study recruited infants receiving RV1 at age 6 and 10 weeks. HBGA phenotype was determined by salivary enzyme-linked immunosorbent assay (ELISA). RV1 vaccine virus shedding was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in stool collected on alternate days for 10 days post-immunization. Plasma rotavirus-specific immunoglobulin A was determined by ELISA pre- and post-immunization. In a case-control study, HBGA phenotype distribution was compared between RV1-vaccinated infants with RVGE and 1:1 age-matched community controls. Rotavirus genotype was determined by RT-PCR. RESULTS: In 202 cohort participants, neither overall vaccine virus fecal shedding nor seroconversion differed by HBGA phenotype. In 238 case-control infants, nonsecretor phenotype was less common in infants with clinical vaccine failure (odds ratio [OR], 0.39; 95% confidence interval [CI], 0.20-0.75). Nonsecretor phenotype was less common in infants with P[8] RVGE (OR, 0.12; 95% CI, 0.03-0.50) and P[4] RVGE (OR, 0.17; 95% CI, 0.04-0.75). Lewis-negative phenotype was more common in infants with P[6] RVGE (OR, 3.2; 95% CI, 1.4-7.2). CONCLUSIONS: Nonsecretor phenotype was associated with reduced risk of rotavirus vaccine failure. There was no significant association between HBGA phenotype and vaccine take. These data refute the hypothesis that high prevalence of nonsecretor/Lewis-negative phenotypes contributes to lower rotavirus vaccine effectiveness in Malawi.