Effects of COVID-19 on Maternal and Neonatal Outcomes and Access to Antenatal and Postnatal Care, Malawi.

We used national facility-level data from all government hospitals in Malawi to examine the effects of the second and third COVID-19 waves on maternal and neonatal outcomes and access to care during September 6, 2020-October 31, 2021. The COVID-19 pandemic affected maternal and neonatal health not only through direct infections but also through disruption of the health system, which could have wider indirect effects on critical maternal and neonatal outcomes. In an interrupted time series analysis, we noted a cumulative 15.4% relative increase (63 more deaths) in maternal deaths than anticipated across the 2 COVID-19 waves. We observed a 41% decrease in postnatal care visits at the onset of the second COVID-19 wave and 0.2% by the third wave, cumulative to 36,809 fewer visits than anticipated. Our findings demonstrate the need for strengthening health systems, particularly in resource-constrained settings, to prepare for future pandemic threats.

Comparison of maternal and neonatal outcomes of COVID-19 before and after SARS-CoV-2 omicron emergence in maternity facilities in Malawi (MATSurvey): data from a national maternal surveillance platform.

BACKGROUND: Outcomes of omicron-associated COVID-19 in pregnancy have not been reported from low-resource settings, and data from sub-Saharan Africa before the emergence of omicron are scarce. Using a national maternal surveillance platform (MATSurvey), we aimed to compare maternal and neonatal outcomes of COVID-19 in Malawi during the omicron wave to the preceding waves of beta and delta. METHODS: All pregnant and recently pregnant patients, up to 42 days following delivery, admitted to 33 health-care facilities throughout Malawi with symptomatic, test-proven COVID-19 during the second (beta [B.1.351]: January to April, 2021), third (delta [B.1.617.2]: June to October, 2021), and fourth (omicron [B.1.1.529]: December 2021 to March, 2022) waves were included, with no age restrictions. Demographic and clinical features, maternal outcomes of interest (severe maternal outcome [a composite of maternal near-miss events and maternal deaths] and maternal death), and neonatal outcomes of interest (stillbirth and death during maternal stay in the health-care facility of enrolment) were compared between the fourth wave and the second and third waves using Fisher's exact test. Adjusted odds ratios (ORs) for maternal outcomes were estimated using mixed-effects logistic regression. FINDINGS: Between Jan 1, 2021, and March 31, 2022, 437 patients admitted to 28 health-care facilities conducting MATSurvey had symptoms of COVID-19. SARS-CoV-2 infection was confirmed in 261 patients; of whom 76 (29%) had a severe maternal outcome and 45 (17%) died. These two outcomes were less common during the fourth wave (omicron dominance) than the second wave (adjusted OR of severe maternal outcome: 3·96 [95% CI 1·22-12·83], p=0·022; adjusted OR of maternal death: 5·65 [1·54-20·69], p=0·0090) and the third wave (adjusted OR: 3·18 [1·03-9·80], p=0·044; adjusted OR: 3·52 [0·98-12·60], p=0·053). Shortness of breath was the only symptom associated with poor maternal outcomes of interest (p<0·0001), and was less frequently reported in the fourth wave (23%) than in the second wave (51%; p=0·0007) or third wave (50%; p=0·0004). The demographic characteristics and medical histories of patients were similar across the three waves. During the second and third waves, 12 (13%) of 92 singleton neonates were stillborn or died during maternal stay in the health-care facility of enrolment, compared with 0 of the 25 born in the fourth wave (p=0·067 vs preceding waves combined). INTERPRETATION: Maternal and neonatal outcomes from COVID-19 were less severe during the fourth wave of the SARS-CoV-2 pandemic in Malawi, during omicron dominance, than during the preceding beta and delta waves. FUNDING: Bill & Melinda Gates Foundation, Wellcome Trust, and the National Institute for Health and Care Research. TRANSLATION: For the Chichewa translation of the abstract see Supplementary Materials section.

Effect of 3 Days of Oral Azithromycin on Young Children With Acute Diarrhea in Low-Resource Settings: A Randomized Clinical Trial.

Importance: World Health Organization (WHO) guidelines do not recommend routine antibiotic use for children with acute watery diarrhea. However, recent studies suggest that a significant proportion of such episodes have a bacterial cause and are associated with mortality and growth impairment, especially among children at high risk of diarrhea-associated mortality. Expanding antibiotic use among dehydrated or undernourished children may reduce diarrhea-associated mortality and improve growth. Objective: To determine whether the addition of azithromycin to standard case management of acute nonbloody watery diarrhea for children aged 2 to 23 months who are dehydrated or undernourished could reduce mortality and improve linear growth. Design, Setting, and Participants: The Antibiotics for Children with Diarrhea (ABCD) trial was a multicountry, randomized, double-blind, clinical trial among 8266 high-risk children aged 2 to 23 months presenting with acute nonbloody diarrhea. Participants were recruited between July 1, 2017, and July 10, 2019, from 36 outpatient hospital departments or community health centers in a mixture of urban and rural settings in Bangladesh, India, Kenya, Malawi, Mali, Pakistan, and Tanzania. Each participant was followed up for 180 days. Primary analysis included all randomized participants by intention to treat. Interventions: Enrolled children were randomly assigned to receive either oral azithromycin, 10 mg/kg, or placebo once daily for 3 days in addition to standard WHO case management protocols for the management of acute watery diarrhea. Main Outcomes and Measures: Primary outcomes included all-cause mortality up to 180 days after enrollment and linear growth faltering 90 days after enrollment. Results: A total of 8266 children (4463 boys [54.0%]; mean [SD] age, 11.6 [5.3] months) were randomized. A total of 20 of 4133 children in the azithromycin group (0.5%) and 28 of 4135 children in the placebo group (0.7%) died (relative risk, 0.72; 95% CI, 0.40-1.27). The mean (SD) change in length-for-age z scores 90 days after enrollment was -0.16 (0.59) in the azithromycin group and -0.19 (0.60) in the placebo group (risk difference, 0.03; 95% CI, 0.01-0.06). Overall mortality was much lower than anticipated, and the trial was stopped for futility at the prespecified interim analysis. Conclusions and Relevance: The study did not detect a survival benefit for children from the addition of azithromycin to standard WHO case management of acute watery diarrhea in low-resource settings. There was a small reduction in linear growth faltering in the azithromycin group, although the magnitude of this effect was not likely to be clinically significant. In low-resource settings, expansion of antibiotic use is not warranted. Adherence to current WHO case management protocols for watery diarrhea remains appropriate and should be encouraged. Trial Registration: ClinicalTrials.gov Identifier: NCT03130114.

'Pneumonia has gone': exploring perceptions of health in a cookstove intervention trial in rural Malawi.

INTRODUCTION: Air pollution through cooking on open fires or inefficient cookstoves using biomass fuels has been linked with impaired lung health and with over 4 million premature deaths per annum. However, use of cleaner cookstoves is often sporadic and there are indications that longer-term health benefits are not prioritised by users. There is also limited information about how recipients of cookstoves perceive the health benefits of clean cooking interventions. We therefore conducted a qualitative study alongside the Cooking and Pneumonia Study (CAPS). METHODS: Qualitative methods and the participatory methodology Photovoice were used in an in-depth examination of health perceptions and understandings of CAPS trial participants. Fifty participants in five CAPS intervention villages collected images about cooking. These were discussed in village-level focus groups and in interviews with 12 representative participants. Village community representatives were also interviewed. Four female and eight male CAPS fieldworkers took part in gender-specific focus groups and two female and two male fieldworkers were interviewed. A thematic content approach was used for data analysis. RESULTS: We found a disconnect between locally situated perceptions of health and the biomedically focused trial model. This included the development of potentially harmful understandings such as that pneumonia was no longer a threat and potential confusion between the symptoms of pneumonia and malaria. Study participants perceived health and well-being benefits including: cookstoves saved bodily energy; quick cooking helped maintain family harmony. CONCLUSION: A deeper understanding of narratives of health within CAPS showed how context-specific perceptions of the health benefits of cookstoves were developed. This highlighted the conflicting priorities of cookstove intervention researchers and participants, and unintended and potentially harmful health understandings. The study also emphasises the importance of including qualitative explorations in similar complex interventions where potential pathways to beneficial (and harmful) effects, cannot be completely explicated through biomedical models alone.

Amoxicillin for 3 or 5 Days for Chest-Indrawing Pneumonia in Malawian Children.

BACKGROUND: Evidence regarding the appropriate duration of treatment with antibiotic agents in children with pneumonia in low-resource settings in Africa is lacking. METHODS: We conducted a double-blind, randomized, controlled, noninferiority trial in Lilongwe, Malawi, to determine whether treatment with amoxicillin for 3 days is less effective than treatment for 5 days in children with chest-indrawing pneumonia (cough lasting <14 days or difficulty breathing, along with visible indrawing of the chest wall with or without fast breathing for age). Children not infected with human immunodeficiency virus (HIV) who were 2 to 59 months of age and had chest-indrawing pneumonia were randomly assigned to receive amoxicillin twice daily for either 3 days or 5 days. Children were followed for 14 days. The primary outcome was treatment failure by day 6; noninferiority of the 3-day regimen to the 5-day regimen would be shown if the percentage of children with treatment failure in the 3-day group was no more than 1.5 times that in the 5-day group. Prespecified secondary analyses included assessment of treatment failure or relapse by day 14. RESULTS: From March 29, 2016, to April 1, 2019, a total of 3000 children underwent randomization: 1497 children were assigned to the 3-day group, and 1503 to the 5-day group. Among children with day 6 data available, treatment failure had occurred in 5.9% in the 3-day group (85 of 1442 children) and in 5.2% (75 of 1456) in the 5-day group (adjusted difference, 0.7 percentage points; 95% confidence interval [CI], -0.9 to 2.4) - a result that satisfied the criterion for noninferiority of the 3-day regimen to the 5-day regimen. Among children with day 14 data available, 176 of 1411 children (12.5%) in the 3-day group and 154 of 1429 (10.8%) in the 5-day group had had treatment failure by day 6 or relapse by day 14 (between-group difference, 1.7 percentage points; 95% CI, -0.7 to 4.1). The percentage of children with serious adverse events was similar in the two groups (9.8% in the 3-day group and 8.8% in the 5-day group). CONCLUSIONS: In HIV-uninfected Malawian children, treatment with amoxicillin for chest-indrawing pneumonia for 3 days was noninferior to treatment for 5 days. (Funded by the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT02678195.).

Repeat assessment of examination signs among children in Malawi with fast-breathing pneumonia.

BACKGROUND: As part of a randomised controlled trial of treatment with placebo versus 3 days of amoxicillin for nonsevere fast-breathing pneumonia among Malawian children aged 2-59 months, a subset of children was hospitalised for observation. We sought to characterise the progression of fast-breathing pneumonia among children undergoing repeat assessments to better understand which children do and do not deteriorate. METHODS: Vital signs and physical examination findings, including respiratory rate, arterial oxygen saturation measured by pulse oximetry (S pO2 ), chest indrawing and temperature were assessed every 3 h for the duration of hospitalisation. Children were assessed for treatment failure during study visits on days 1, 2, 3 and 4. RESULTS: Hospital monitoring data from 436 children were included. While no children had S pO2 90-93% at baseline, 7.4% (16 of 215) of children receiving amoxicillin and 9.5% (21 of 221) receiving placebo developed S pO2 90-93% during monitoring. Similarly, no children had chest indrawing at enrolment, but 6.6% (14 of 215) in the amoxicillin group and 7.2% (16 of 221) in the placebo group went on to develop chest indrawing during hospitalisation. CONCLUSION: Repeat monitoring of children with fast-breathing pneumonia identified vital and physical examination signs not present at baseline, including S pO2 90-93% and chest indrawing. This information may support providers and policymakers in developing guidance for care of children with nonsevere pneumonia.

Placebo vs Amoxicillin for Nonsevere Fast-Breathing Pneumonia in Malawian Children Aged 2 to 59 Months: A Double-blind, Randomized Clinical Noninferiority Trial.

Importance: Pneumonia is the leading infectious killer of children. Rigorous evidence supporting antibiotic treatment of children with nonsevere fast-breathing pneumonia in low-resource African settings is lacking. Objective: To assess whether treatment with placebo for nonsevere fast-breathing pneumonia is substantively less effective than 3 days of treatment with amoxicillin. Design, Setting, and Participants: This double-blind, 2-arm, randomized clinical noninferiority trial with follow-up of 14 days screened 1343 HIV-uninfected children aged 2 to 59 months with nonsevere fast-breathing pneumonia at outpatient departments of hospitals in Lilongwe, Malawi, Africa, between June 2016 and June 2017. Interventions: Placebo or amoxicillin dispersible tablets administered twice daily for 3 days. Main Outcomes and Measures: The primary end point was the proportion of children failing treatment by day 4 with a relative noninferiority margin of 1.5 times the failure rate in the amoxicillin group. Primary analyses were performed based on the intention-to-treat principle. Planned secondary analyses included treatment failure or relapse by day 14. Results: In total, 1126 children were randomized to 3 days of amoxicillin (n = 564) or placebo (n = 562) therapy. Baseline demographic and clinical characteristics were similar between the groups. For the entire study population, the mean (SD) age was 21.3 (15.1) months, and 601 (53.4%) were female. After an interim analysis, the data safety monitoring board stopped the study because children receiving amoxicillin had a 4.0% (22 of 552 with outcome data) treatment failure rate by day 4, whereas children receiving placebo had a 7.0% (38 of 543) treatment failure rate (adjusted relative risk, 1.78; 95% CI, 1.07%-2.97%; adjusted absolute difference, 3.0%; 95% CI, 0.4%-5.7%). Among children with known day 14 outcomes, 56 of 552 (10.1%) receiving amoxicillin and 64 of 543 (11.8%) receiving placebo had either treatment failure by day 4 or relapse by day 14 (relative risk, 1.16; 95% CI, 0.83%-1.63%; absolute difference, 1.6%; 95% CI, -2.1% to 5.4%). There were no deaths. Conclusions and Relevance: In HIV-uninfected children aged 2 to 59 months in a malaria-endemic region of Malawi, placebo treatment of nonsevere fast-breathing pneumonia was significantly inferior to treatment with amoxicillin. However, by day 4, approximately 93% of children receiving placebo were without treatment failure, and there was no significant difference between groups in treatment failure or relapse by day 14. The number of children with nonsevere fast-breathing pneumonia that needed amoxicillin treatment for 1 child to benefit was 33. Trial Registration: ClinicalTrials.gov Identifier: NCT02760420.

Use of cleaner-burning biomass stoves and airway macrophage black carbon in Malawian women.

Exposure to particulate matter (PM) from burning of biomass for cooking is associated with adverse health effects. It is unknown whether or not cleaner burning biomass-fuelled cookstoves reduce the amount of PM inhaled by women compared with traditional open fires. We sought to assess whether airway macrophage black carbon (AMBC) - a marker of inhaled dose of carbonaceous PM from biomass and fossil fuel combustion - is lower in Malawian women using a cleaner burning biomass-fuelled cookstove compared with those using open fires for cooking. AMBC was assessed in induced sputum samples using image analysis and personal exposure to carbon monoxide (CO) and PM were measured using Aprovecho Indoor Air Pollution meters. A fossil-fuel exposed group of UK women was also studied. Induced sputum samples were obtained from 57 women from which AMBC was determined in 31. Median AMBC was 6.87µm2 (IQR 4.47-18.5) and 4.37µm2 (IQR 2.57-7.38) in the open fire (n=11) and cleaner burning cookstove groups (n=20), respectively (p=0.028). There was no difference in personal exposure to CO and PM between the two groups. UK women (n=5) had lower AMBC (median 0.89µm2, IQR 0.56-1.13) compared with both Malawi women using traditional cookstoves (p<0.001) and those using cleaner cookstoves (p=0.022). We conclude that use of a cleaner burning biomass-fuelled cookstove reduces inhaled PM dose in a way that is not necessarily reflected by personal exposure monitoring.

Prevalence of paediatric chronic suppurative otitis media and hearing impairment in rural Malawi: A cross-sectional survey.

OBJECTIVE: To estimate the prevalence of World Health Organization-defined chronic suppurative otitis media (CSOM) and mild hearing impairment in a population representative sample of school-entry age children in rural Malawi. A secondary objective was to explore factors associated with CSOM in this population. METHODS: We performed a community-based cross-sectional study of children aged 4-6 years in Chikhwawa District, Southern Malawi, utilising a village-level cluster design. Participants underwent a structured clinical assessment, including video-otoscopy and screening audiometry. Diagnoses were made remotely by two otolaryngologists who independently reviewed clinical data and images collected in the field. Hearing impairment was classified as failure to hear a pure tone of 25dB or greater at 1, 2 or 4kHz. RESULTS: We recruited 281 children across 10 clusters. The prevalence estimates of CSOM, unilateral hearing impairment and bilateral hearing impairment were 5.4% (95%CI 2.2-8.6), 24.5% (95%CI 16.3-30.0), and 12.5% (95%CI 6.2-16.9) respectively. Middle ear disease was seen in 46.9% of children with hearing impairment. A trend towards increased risk of CSOM was observed with sleeping in a house with >2 other children. INTERPRETATION: We found a high burden of middle ear disease and preventable hearing impairment in our sample of school-entry age children in rural Malawi. There are important public health implications of these findings as CSOM and hearing impairment can affect educational outcomes, and may impact subsequent development. The identification and management of middle ear disease and hearing impairment represent major unmet needs in this population.

A cleaner burning biomass-fuelled cookstove intervention to prevent pneumonia in children under 5 years old in rural Malawi (the Cooking and Pneumonia Study): a cluster randomised controlled trial.

BACKGROUND: WHO estimates exposure to air pollution from cooking with solid fuels is associated with over 4 million premature deaths worldwide every year including half a million children under the age of 5 years from pneumonia. We hypothesised that replacing open fires with cleaner burning biomass-fuelled cookstoves would reduce pneumonia incidence in young children. METHODS: We did a community-level open cluster randomised controlled trial to compare the effects of a cleaner burning biomass-fuelled cookstove intervention to continuation of open fire cooking on pneumonia in children living in two rural districts, Chikhwawa and Karonga, of Malawi. Clusters were randomly allocated to intervention and control groups using a computer-generated randomisation schedule with stratification by site, distance from health centre, and size of cluster. Within clusters, households with a child under the age of 4·5 years were eligible. Intervention households received two biomass-fuelled cookstoves and a solar panel. The primary outcome was WHO Integrated Management of Childhood Illness (IMCI)-defined pneumonia episodes in children under 5 years of age. Efficacy and safety analyses were by intention to treat. The trial is registered with ISRCTN, number ISRCTN59448623. FINDINGS: We enrolled 10 750 children from 8626 households across 150 clusters between Dec 9, 2013, and Feb 28, 2016. 10 543 children from 8470 households contributed 15 991 child-years of follow-up data to the intention-to-treat analysis. The IMCI pneumonia incidence rate in the intervention group was 15·76 (95% CI 14·89-16·63) per 100 child-years and in the control group 15·58 (95% CI 14·72-16·45) per 100 child-years, with an intervention versus control incidence rate ratio (IRR) of 1·01 (95% CI 0·91-1·13; p=0·80). Cooking-related serious adverse events (burns) were seen in 19 children; nine in the intervention and ten (one death) in the control group (IRR 0·91 [95% CI 0·37-2·23]; p=0·83). INTERPRETATION: We found no evidence that an intervention comprising cleaner burning biomass-fuelled cookstoves reduced the risk of pneumonia in young children in rural Malawi. Effective strategies to reduce the adverse health effects of household air pollution are needed. FUNDING: Medical Research Council, UK Department for International Development, and Wellcome Trust.