The Impact of Antenatal Azithromycin and Monthly Sulfadoxine-Pyrimethamine on Maternal Malaria during Pregnancy and Fetal Growth : A Randomized Controlled Trial

Maternal malaria and infections during pregnancy are risk factors for fetal growth restriction. We assessed the impact of preventive treatment in pregnancy on maternal malaria and fetal growth. Between 2003 and 2006, we enrolled 1,320 pregnant Malawian women, 14-26 gestation weeks, in a randomized trial and treated them with two doses of sulfadoxine-pyrimethamine (SP, control) at enrollment and between 28-34 gestation weeks; with monthly SP from enrollment until 37 gestation weeks; or with monthly SP and azithromycin twice, at enrollment and between 28 and 34 gestation weeks (AZI-SP). Participants were seen at 4-week intervals until 36 completed gestation weeks and weekly thereafter. At each visit, we collected dried blood spots for real-time polymerase chain reaction diagnosing of malaria parasitemia and, in a random subgroup of 341 women, we measured fetal biparietal diameter and femur length with ultrasound. For the monthly SP versus the control group, the odds ratios (OR) (95% CI) of malaria parasitemia during the second, third, and both trimesters combined were 0.79 (0.46-1.37), 0.58 (0.37-0.92), and 0.64 (0.42-0.98), respectively. The corresponding ORs for the AZI-SP versus control group were 0.47 (0.26-0.84), 0.51 (0.32-0.81), and 0.50 (0.32-0.76), respectively. Differences between the AZI-SP and the monthly SP groups were not statistically significant. The interventions did not affect fetal biparietal diameter and femur length growth velocity. The results suggest that preventive maternal treatment with monthly SP reduced malaria parasitemia during pregnancy in Malawi and that the addition of azithromycin did not provide much additional antimalarial effect.publishedVersionPeer reviewe

Lack of Associations between Environmental Exposures and Environmental Enteric Dysfunction among 18-Month-Old Children in Rural Malawi

Environmental enteric dysfunction (EED) is common and contributes to linear growth faltering (stunting) and mortality among children in low-resource settings. A few studies on the environmental causes of EED have been conducted but the exact exposures that cause or predispose children to EED are context-specific and not clear. This study aimed to assess associations between selected environmental exposures and EED markers among 620 18-month-old children. This was a secondary analysis of data from Malawian children who participated in a randomized controlled trial (iLiNS-DYAD, registered at clinicaltrials.gov as NCT01239693) from birth to 18 months of age. Data on environmental exposures, including drinking water source, sanitation, exposure to animals, housing materials, season, residential area, and food insecurity were collected at enrolment. Biomarkers of EED included concentrations of calprotectin, regenerating 1B protein (REG1B), and alpha-1-antitrypsin from stool samples to assess intestinal inflammation, repair, and permeability, respectively. We performed bivariate and multivariable analyses to assess associations between environmental exposures and EED biomarkers. Adjusting for possible confounders, we did not find associations between the selected environmental exposures and the three biomarkers. These results do not provide support for our hypothesis that the studied adverse environmental exposures are associated with increased concentrations of children’s EED markers in rural Malawi.publishedVersionPeer reviewe

Association between asymptomatic infections and linear growth in 18–24-month-old Malawian children

Inadequate diet and frequent symptomatic infections are considered major causes of growth stunting in low-income countries, but interventions targeting these risk factors have achieved limited success. Asymptomatic infections can restrict growth, but little is known about their role in global stunting prevalence. We investigated factors related to length-for-age Z-score (LAZ) at 24 months by constructing an interconnected network of various infections, biomarkers of inflammation (as assessed by alpha-1-acid glycoprotein [AGP]), and growth (insulin-like growth factor 1 [IGF-1] and collagen X biomarker [CXM]) at 18 months, as well as other children, maternal, and household level factors. Among 604 children, there was a continuous decline in mean LAZ and increased mean length deficit from birth to 24 months. At 18 months of age, the percentage of asymptomatic children who carried each pathogen was: 84.5% enterovirus, 15.5% parechovirus, 7.7% norovirus, 4.6% rhinovirus, 0.6% rotavirus, 69.6% Campylobacter, 53.8% Giardia lamblia, 11.9% malaria parasites, 10.2% Shigella, and 2.7% Cryptosporidium. The mean plasma IGF-1 concentration was 12.5 ng/ml and 68% of the children had systemic inflammation (plasma AGP concentration >1 g/L). Shigella infection was associated with lower LAZ at 24 months through both direct and indirect pathways, whereas enterovirus, norovirus, Campylobacter, Cryptosporidium, and malaria infections were associated with lower LAZ at 24 months indirectly, predominantly through increased systemic inflammation and reduced plasma IGF-1 and CXM concentration at 18 months.publishedVersionPeer reviewe

Co-causation of reduced newborn size by maternal undernutrition, infections, and inflammation.

More than 20 million babies are born with low birthweight annually. Small newborns have an increased risk for mortality, growth failure, and other adverse outcomes. Numerous antenatal risk factors for small newborn size have been identified, but individual interventions addressing them have not markedly improved the health outcomes of interest. We tested a hypothesis that in low-income settings, newborn size is influenced jointly by multiple maternal exposures and characterized pathways associating these exposures with newborn size. This was a prospective cohort study of pregnant women and their offspring nested in an intervention trial in rural Malawi. We collected information on maternal and placental characteristics and used regression analyses, structural equation modelling, and random forest models to build pathway maps for direct and indirect associations between these characteristics and newborn weight-for-age Z-score and length-for-age Z-score. We used multiple imputation to infer values for any missing data. Among 1,179 pregnant women and their babies, newborn weight-for-age Z-score was directly predicted by maternal primiparity, body mass index, and plasma alpha-1-acid glycoprotein concentration before 20 weeks of gestation, gestational weight gain, duration of pregnancy, placental weight, and newborn length-for-age Z-score (p < .05). The latter 5 variables were interconnected and were predicted by several more distal determinants. In low-income conditions like rural Malawi, maternal infections, inflammation, nutrition, and certain constitutional factors jointly influence newborn size. Because of this complex network, comprehensive interventions that concurrently address multiple adverse exposures are more likely to increase mean newborn size than focused interventions targeting only maternal nutrition or specific infections

Testing the effects of mass drug administration of azithromycin on mortality and other outcomes among 1–11-month-old infants in Mali (LAKANA) : study protocol for a cluster-randomized, placebo-controlled, double-blinded, parallel-group, three-arm clinical trial

Background: Mass drug administration (MDA) of azithromycin (AZI) has been shown to reduce under-5 mortality in some but not all sub-Saharan African settings. A large-scale cluster-randomized trial conducted in Malawi, Niger, and Tanzania suggested that the effect differs by country, may be stronger in infants, and may be concentrated within the first 3 months after treatment. Another study found no effect when azithromycin was given concomitantly with seasonal malaria chemoprevention (SMC). Given the observed heterogeneity and possible effect modification by other co-interventions, further trials are needed to determine the efficacy in additional settings and to determine the most effective treatment regimen. Methods: LAKANA stands for Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin. The LAKANA trial is designed to address the mortality and health impacts of 4 or 2 annual rounds of azithromycin MDA delivered to 1–11-month-old (29–364 days) infants, in a high-mortality and malaria holoendemic Malian setting where there is a national SMC program. Participating villages (clusters) are randomly allocated in a ratio of 3:2:4 to three groups: placebo (control):4-dose AZI:2-dose AZI. The primary outcome measured is mortality. Antimicrobial resistance (AMR) will be monitored closely before, during, and after the intervention and both among those receiving and those not receiving MDA with the study drugs. Other outcomes, from a subset of villages, comprise efficacy outcomes related to morbidity, growth and nutritional status, outcomes related to the mechanism of azithromycin activity through measures of malaria parasitemia and inflammation, safety outcomes (AMR, adverse and serious adverse events), and outcomes related to the implementation of the intervention documenting feasibility, acceptability, and economic aspects. The enrolment commenced in October 2020 and is planned to be completed by the end of 2022. The expected date of study completion is December 2024. Discussion: If LAKANA provides evidence in support of a positive mortality benefit resulting from azithromycin MDA, it will significantly contribute to the options for successfully promoting child survival in Mali, and elsewhere in sub-Saharan Africa. Trial registration: ClinicalTrials.gov NCT04424511. Registered on 11 June 2020.publishedVersionPeer reviewe

Why small-quantity lipid-based nutrient supplements should be integrated into comprehensive strategies to prevent child undernutrition in nutritionally vulnerable populations : response to Gupta et al.’s commentary

We write in response to the commentary by Gupta et al. (2023) on small-quantity lipid-based nutrient supplements (SQ-LNS) for infants and young children 6 to 24 months of age, which was prompted by the recent brief guidance note from UNICEF (2023) explaining when, why and how SQ-LNS are being prioritized as part of their package of preventive actions to combat early childhood malnutrition. The UNICEF document was disseminated shortly after publication of a correspondence in Nature Food (Aguayo et al. 2023), authored by nutrition leaders from several organizations, that summarized the evidence on the benefits of SQ-LNS and called for this intervention to be scaled up and integrated into programs for populations in which child undernutrition is prevalent and dietary quality is very poor. We agree with Gupta et al. that child malnutrition is the result of many factors and there is no single “quick fix” or “magic bullet”. In fact, the above-cited documents state clearly and frequently that provision of SQ-LNS is not a stand-alone intervention and must be integrated into comprehensive strategies to improve infant and young child feeding (IYCF), including the promotion of dietary diversity, as well as other actions needed to prevent malnutrition. SQ-LNS are intended for vulnerable populations who lack access to an affordable, nutritionally adequate complementary feeding diet and have high rates of stunting, wasting and mortality. In such populations, we agree with Gupta et al. that IYCF messages alone are not enough. This is precisely why SQ-LNS were originally developed

Small-quantity lipid-based nutrient supplements for children age 6-24 months: a systematic review and individual participant data meta-analysis of effects on developmental outcomes and effect modifiers

BACKGROUND: Small-quantity (SQ) lipid-based nutrient supplements (LNSs) provide many nutrients needed for brain development. OBJECTIVES: We aimed to generate pooled estimates of the effect of SQ-LNSs on developmental outcomes (language, social-emotional, motor, and executive function), and to identify study-level and individual-level modifiers of these effects. METHODS: We conducted a 2-stage meta-analysis of individual participant data from 14 intervention against control group comparisons in 13 randomized trials of SQ-LNSs provided to children age 6-24 mo (total n = 30,024). RESULTS: In 11-13 intervention against control group comparisons (n = 23,588-24,561), SQ-LNSs increased mean language (mean difference: 0.07 SD; 95% CI: 0.04, 0.10 SD), social-emotional (0.08; 0.05, 0.11 SD), and motor scores (0.08; 95% CI: 0.05, 0.11 SD) and reduced the prevalence of children in the lowest decile of these scores by 16% (prevalence ratio: 0.84; 95% CI: 0.76, 0.92), 19% (0.81; 95% CI: 0.74, 0.89), and 16% (0.84; 95% CI: 0.76, 0.92), respectively. SQ-LNSs also increased the prevalence of children walking without support at 12 mo by 9% (1.09; 95% CI: 1.05, 1.14). Effects of SQ-LNSs on language, social-emotional, and motor outcomes were larger among study populations with a higher stunting burden (≥35%) (mean difference: 0.11-0.13 SD; 8-9 comparisons). At the individual level, greater effects of SQ-LNSs were found on language among children who were acutely malnourished (mean difference: 0.31) at baseline; on language (0.12), motor (0.11), and executive function (0.06) among children in households with lower socioeconomic status; and on motor development among later-born children (0.11), children of older mothers (0.10), and children of mothers with lower education (0.11). CONCLUSIONS: Child SQ-LNSs can be expected to result in modest developmental gains, which would be analogous to 1-1.5 IQ points on an IQ test, particularly in populations with a high child stunting burden. Certain groups of children who experience higher-risk environments have greater potential to benefit from SQ-LNSs in developmental outcomes.This trial was registered at www.crd.york.ac.uk/PROSPERO as CRD42020159971

Does anthropometric status at 6&nbsp;months predict the over-dispersion of malaria infections in children aged 6-18&nbsp;months? A prospective cohort study.

BackgroundIn malaria-endemic settings, a small proportion of children suffer repeated malaria infections, contributing to most of the malaria cases, yet underlying factors are not fully understood. This study was aimed to determine whether undernutrition predicts this over-dispersion of malaria infections in children aged 6-18&nbsp;months in settings of high malaria and undernutrition prevalence.MethodsProspective cohort study, conducted in Mangochi, Malawi. Six-months-old infants were enrolled and had length-for-age z-scores (LAZ), weight-for-age z-scores (WAZ), and weight-for-length z-scores (WLZ) assessed. Data were collected for 'presumed', clinical, and rapid diagnostic test (RDT)-confirmed malaria until 18&nbsp;months. Malaria microscopy was done at 6 and 18&nbsp;months. Negative binomial regression was used for malaria incidence and modified Poisson regression for malaria prevalence.ResultsOf the 2723 children enrolled, 2561 (94%) had anthropometry and malaria data. The mean (standard deviation [SD]) of LAZ, WAZ, and WLZ at 6&nbsp;months were - 1.4 (1.1), - 0.7 (1.2), and 0.3 (1.1), respectively. The mean (SD) incidences of 'presumed', clinical, and RDT-confirmed malaria from 6 to 18&nbsp;months were: 1.1 (1.6), 0.4 (0.8), and 1.3 (2.0) episodes/year, respectively. Prevalence of malaria parasitaemia was 4.8% at 6&nbsp;months and 9.6% at 18&nbsp;months. Higher WLZ at 6&nbsp;months was associated with lower prevalence of malaria parasitaemia at 18&nbsp;months (prevalence ratio [PR] = 0.80, 95% confidence interval [CI] 0.67 to 0.94, p = 0.007), but not with incidences of 'presumed' malaria (incidence rate ratio [IRR] = 0.97, 95% CI 0.92 to 1.02, p = 0.190), clinical malaria (IRR = 1.03, 95% CI 0.94 to 1.12, p = 0.571), RDT-confirmed malaria (IRR = 1.00, 95% CI 0.94 to 1.06, p = 0.950). LAZ and WAZ at 6&nbsp;months were not associated with malaria outcomes. Household assets, maternal education, and food insecurity were significantly associated with malaria. There were significant variations in hospital-diagnosed malaria by study site.ConclusionIn children aged 6-18&nbsp;months living in malaria-endemic settings, LAZ, WAZ, and WLZ do not predict malaria incidence. However, WLZ may be associated with prevalence of malaria. Socio-economic and micro-geographic factors may explain the variations in malaria, but these require further study. Trial registration NCT00945698. Registered July 24, 2009, https://clinicaltrials.gov/ct2/show/NCT00945698 , NCT01239693. Registered Nov 11, 2010, https://clinicaltrials.gov/ct2/show/NCT01239693

Child growth and neurodevelopment after maternal antenatal antibiotic treatment

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