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Objectives Malaria and curable sexually transmitted and reproductive tract infections (STIs/RTIs) are associated with adverse pregnancy outcomes. This study reports the prevalence and risk factors of curable STIs/RTIs, STI/RTI co-infection and STI/RTI and malaria co-infection among HIV-negative pregnant women at their first antenatal care visit in Kenya, Malawi and Tanzania.Methods HIV-negative pregnant women of all gravidae (n=4680) were screened for syphilis with point-of-care tests and treated if positive. Separately, women provided blood samples (n=4569) for rapid plasma reagin (RPR) testing; positive cases were confirmation by Treponema pallidum particle agglutination (TPPA). Women also provided dried blood spots for batch testing of malaria by retrospective polymerase chain reaction (PCR (n=4226) methods. A randomly selected subgroup of women provided vaginal swabs for chlamydia, gonorrhoea and trichomoniasis testing by retrospective PCR batch testing (n=1431), and bacterial vaginosis diagnosis by Nugent scoring (n=1402).Results Malaria prevalence was 14.6% (95% CI 13.6 to 15.7), 45.9% (43.4 to 48.4) of women were positive for at least one curable STI/RTI and 6.7% (5.5 to 8.1) were co-infected with malaria and a curable STI/RTI. Prevalence of individual STIs/RTIs ranged from 28.5% (26.2 to 30.9) for bacterial vaginosis to 14.5% (12.7 to 16.4) for trichomoniasis, 13.8% (12.1 to 15.7) for chlamydia, 2.7% (1.9 to 3.6) for gonorrhoea and 1.7% (1.4 to 2.2) for RPR/TPPA-confirmed syphilis. The prevalence of STI/RTI co-infection was 10.1% (8.7 to 11.8). Paucigravidae, at highest risk of malaria, were also at greater risk of having chlamydia, gonorrhoea and bacterial vaginosis than multigravidae.Conclusions Of women infected with malaria, 49.0% also had a curable STI/RTI and one in five women with at least one STI/RTI were co-infected with more than one STI/RTI. Current antenatal interventions that address malaria and curable STIs/RTIs remain suboptimal. New approaches to preventing and managing these infections in pregnancy are urgently needed.Trial registration number NCT03208179.

Abstract Background The Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin (LAKANA) trial in Mali aims to evaluate the efficacy and safety of azithromycin (AZI) mass drug administration (MDA) to 1–11-month-old infants as well as the impact of the intervention on antimicrobial resistance (AMR) and mechanisms of action of azithromycin. To improve the transparency and quality of this clinical trial, we prepared this statistical analysis plan (SAP). Methods/design LAKANA is a cluster randomized trial that aims to address the mortality and health impacts of biannual and quarterly AZI MDA. AZI is given to 1–11-month-old infants in a high-mortality setting where a seasonal malaria chemoprevention (SMC) program is in place. The participating villages are randomly assigned to placebo (control), two-dose AZI (biannual azithromycin-MDA), and four-dose AZI (quarterly azithromycin-MDA) in a 3:4:2 ratio. The primary outcome of the study is mortality among the intention-to-treat population of 1–11-month-old infants. We will evaluate relative risk reduction between the study arms using a mixed-effects Poisson model with random intercepts for villages, using log link function with person-years as an offset variable. We will model outcomes related to secondary objectives of the study using generalized linear models with considerations on clustering. Conclusion The SAP written prior to data collection completion will help avoid reporting bias and data-driven analysis for the primary and secondary aims of the trial. If there are deviations from the analysis methods described here, they will be described and justified in the publications of the trial results. Trial registration ClinicalTrials.gov ID NCT04424511 . Registered on 11 June 2020.

Abstract Background The complex interaction between malaria and undernutrition leads to increased mortality and morbidity rate among young children in malaria-endemic regions. Results from previous interventions suggest that improving nutritional status of young children may reduce the burden of malaria. This study tested a hypothesis that provision of lipid-based nutrient supplements (LNS) or corn-soy blend (CSB) supplementation to 6–18-month-old children in Malawi would reduce the prevalence of asymptomatic malaria among them. Methods A total of 840 6-month-old children were enrolled in a randomized trial. The participants received 12-month supplementation with three different daily dietary supplementations: CSB, soy-LNS, or milk-LNS, and one control group without supplementation. The prevalence rate of asymptomatic Plasmodium falciparum was determined by real-time PCR from the participant’s dried blood spots (DBS) collected at the baseline and every 3 months. The global null hypothesis was tested using modified Poisson regression to estimate the prevalence ratio (PR) between the control group and three intervention groups at all ages combined. All the models were adjusted for malaria at baseline, season of DBS sample collection, site of enrolment, and household asset Z-score. Results All children combined, the prevalence of P. falciparum was 14.1% at enrollment, 8.7% at 9 months, 11.2% at 12 months, 13.0% at 15 months and 22.4% at 18 months of age. Among all samples that were taken after enrolment, the prevalence was 12.1% in control group, 12.2% in milk-LNS, 14.0% in soy-LNS, and 17.2% in CSB group. Compared to children in the control group the prevalence ratio of positive malaria tests was 1.19 (95% CI 0.81–1.74; P = 0.372) in the milk-LNS group, 1.32 (95% CI 0.88–1.96; P = 0.177) in the soy-LNS group and 1.72 (95% CI 1.19–2.49; P = 0.004) in the CSB group. Conclusion The study findings do not support a hypothesis that LNS or CSB supplementation would reduce the prevalence of asymptomatic malaria among Malawian children. In contrast, there was a signal of a possible increase in malaria prevalence among children supplemented with CSB.

Abstract Low birth weight predisposes to the development of hypertension in middle- and high-income countries. We examined the relation of early life length-for-age score (Z-score) on cardiovascular function in young adults in Malawi, a low-income country. Capture of supine, seated, and standing brachial pulse waveforms (Mobil-O-Graph) were performed in 223 females and 152 males (mean age 21 years), and analyzed according to the length-for-age Z-score tertiles during the first month of life. Plasma LDL cholesterol in young adulthood was slightly lower in the lowest versus highest tertile. Otherwise, blood hemoglobin and plasma chemistry were similar in all tertiles. Irrespective of posture, blood pressure, forward and backward wave amplitudes, and pulse wave velocity were corresponding in all tertiles. In the three postures, the lowest tertile presented with 4.5% lower systemic vascular resistance than the highest tertile (p = 0.005), and 4.4% and 5.5% higher cardiac output than the middle and highest tertiles, respectively (p

Abstract Background Low birth weight (LBW) is a significant public health concern given its association with early-life mortality and other adverse health consequences that can impact the entire life cycle. In many countries, accurate estimates of LBW prevalence are lacking due to inaccuracies in collection and gaps in available data. Our study aimed to determine LBW prevalence among facility-born infants in selected areas of Kenya and Tanzania and to assess whether the introduction of an intervention to improve the accuracy of birth weight measurement would result in a meaningfully different estimate of LBW prevalence than current practice. Methods We carried out a historically controlled intervention study in 22 health facilities in Kenya and three health facilities in Tanzania. The intervention included: provision of high-quality digital scales, training of nursing staff on accurate birth weight measurement, recording and scale calibration practices, and quality maintenance support that consisted of enhanced supervision and feedback (prospective arm). The historically controlled data were birth weights from the same facilities recorded in maternity registers for the same calendar months from the previous year measured using routine practices and manual scales. We calculated mean birth weight (95% confidence interval CI), mean difference in LBW prevalence, and respective risk ratio (95% CI) between study arms. Results Between October 2019 and February 2020, we prospectively collected birth weights from 8441 newborns in Kenya and 4294 in Tanzania. Historical data were available from 9318 newborns in Kenya and 12,007 in Tanzania. In the prospective sample, the prevalence of LBW was 12.6% (95% confidence intervals [CI]: 10.9%–14.4%) in Kenya and 18.2% (12.2%–24.2%) in Tanzania. In the historical sample, the corresponding prevalence estimates were 7.8% (6.5%–9.2%) and 10.0% (8.6%–11.4%). Compared to the retrospective sample, the LBW prevalence in the prospective sample was 4.8% points (3.2%–6.4%) higher in Kenya and 8.2% points (2.3%–14.0%) higher in Tanzania, corresponding to a risk ratio of 1.61 (1.38–1.88) in Kenya and 1.81 (1.30–2.52) in Tanzania. Conclusion Routine birth weight records underestimate the risk of LBW among facility-born infants in Kenya and Tanzania. The quality of birth weight data can be improved by a simple intervention consisting of provision of digital scales and supportive training.

Abstract 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.

Abstract Background The prevalence of small for gestational age (SGA) may vary depending on the chosen weight-for-gestational-age reference chart. An individual participant data meta-analysis was conducted to assess the implications of using a local reference (STOPPAM) instead of a universal reference (Intergrowth-21) on the association between malaria in pregnancy and SGA. Methods Individual participant data of 6,236 newborns were pooled from seven conveniently identified studies conducted in Tanzania and Malawi from 2003–2018 with data on malaria in pregnancy, birthweight, and ultrasound estimated gestational age. Mixed-effects regression models were used to compare the association between malaria in pregnancy and SGA when using the STOPPAM and the Intergrowth-21 references, respectively. Results The 10th percentile for birthweights-for-gestational age was lower for STOPPAM than for Intergrowth-21, leading to a prevalence of SGASTOPPAM of 14.2% and SGAIG21 of 18.0%, p

Abstract Little is known about the impact of small‐quantity lipid‐based nutrient supplements (SQ‐LNSs) on maternal morbidity. This secondary outcome analysis aimed to compare morbidity symptoms among women in two trials evaluating the efficacy of SQ‐LNSs. From enrolment (≤20‐week gestation) to 6 months postpartum, Ghanaian (n = 1320) and Malawian (n = 1391) women were assigned to consume daily: 60 mg iron and 400 µg folic acid until childbirth and placebo thereafter (iron and folic acid [IFA] group); or multiple micronutrients (MMN); or 20 g/day SQ‐LNSs. Within country, we used repeated measures logistic regression and analysis of variance models to compare group differences in the period prevalence and percentage of days of monitoring when women had fever, gastrointestinal, reproductive, and respiratory symptoms during the second and third trimesters of pregnancy (n ~ 1243 in Ghana, 1200 in Malawi) and 0–3 and 3–6 months postpartum (n ~ 1212 in Ghana, 730 in Malawi). Most outcomes did not differ significantly among groups, with the following exceptions: in Ghana, overall, the prevalence of vomiting was lower in the LNS (21.5%) than MMN (25.6%) group, with the IFA group (23.2%) in‐between (p = 0.046); mean ± SD percentage of days with nausea was greater in the LNS (3.5 ± 10.3) and MMN (3.3 ± 10.4) groups than the IFA (2.7 ± 8.3) group (p = 0.002). In Malawi, during 3–6 month postpartum, the prevalence of severe diarrhoea was greater in the LNS (8.1%) than the MMN (2.9%) group, with IFA (4.6%) in‐between, p = 0.041). We conclude that the type of nutrient supplement received during pregnancy and lactation generally does not influence morbidity symptoms in these settings. Clinicaltrials.gov identifiers: NCT00970866; NCT01239693.

BackgroundBody composition can be measured by several methods, each with specific benefits and disadvantages. Bioelectric impedance offers a favorable balance between accuracy, cost and ease of measurement in a range of settings. In this method, bioelectric measurements are converted to body composition measurements by prediction equations specific to age, population and bioimpedance device. Few prediction equations exist for populations in low-resource settings. We formed a prediction equation for total body water in Malawian adolescents using deuterium dilution as reference.MethodsWe studied 86 boys and 92 girls participating in the 11-14-year follow-up of the Lungwena Antenatal Intervention Study, a randomized trial of presumptive infection treatment among pregnant women. We measured body composition by Seca m515 bioimpedance analyser. Participants ingested a weight-standardized dose of deuterium oxide, after which we collected saliva at baseline, at 3 and 4 h post-ingestion, measured deuterium concentration using Fourier-transform infrared spectroscopy and calculated total body water. We formed predictive equations for total body water using anthropometrics plus resistance and reactance at a range of frequencies, applying multiple regression and repeated cross-validation in model building and in prediction error estimation.ResultsThe best predictive model for percentage total body water (TBW %) was 100*(1.11373 + 0.0037049*height (cm)2/resistance(Ω) at 50 kHz- 0.25778*height(m)- 0.01812*BMI(kg/m2)- 0.02614*female sex). Calculation of absolute TBW (kg) by multiplying TBW (%) with body weight had better predictive power than a model directly constructed to predict absolute total body water (kg). This model explained 96.4% of variance in TBW (kg) and had a mean prediction error of 0.691 kg. Mean bias was 0.01 kg (95% limits of agreement -1.34, 1.36) for boys and -0.01 kg (1.41, 1.38) for girls.ConclusionsOur equation provides an accurate, cost-effective and participant-friendly body composition prediction method among adolescents in clinic-based field studies in rural Africa, where electricity is available.

Abstract 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.

Abstract Background There is an unmet need for review methods to support priority-setting, policy-making and strategic planning when a wide variety of interventions from differing disciplines may have the potential to impact a health outcome of interest. This article describes a Modular Literature Review, a novel systematic search and review method that employs systematic search strategies together with a hierarchy-based appraisal and synthesis of the resulting evidence. Methods We designed the Modular Review to examine the effects of 43 interventions on a health problem of global significance. Using the PICOS (Population, Intervention, Comparison, Outcome, Study design) framework, we developed a single four-module search template in which population, comparison and outcome modules were the same for each search and the intervention module was different for each of the 43 interventions. A series of literature searches were performed in five databases, followed by screening, extraction and analysis of data. “ES documents”, source documents for effect size (ES) estimates, were systematically identified based on a hierarchy of evidence. The evidence was categorised according to the likely effect on the outcome and presented in a standardised format with quantitative effect estimates, meta-analyses and narrative reporting. We compared the Modular Review to other review methods in health research for its strengths and limitations. Results The Modular Review method was used to review the impact of 46 antenatal interventions on four specified birth outcomes within 12 months. A total of 61,279 records were found; 35,244 were screened by title-abstract. Six thousand two hundred seventy-two full articles were reviewed against the inclusion criteria resulting in 365 eligible articles. Conclusions The Modular Review preserves principles that have traditionally been important to systematic reviews but can address multiple research questions simultaneously. The result is an accessible, reliable answer to the question of “what works?”. Thus, it is a well-suited literature review method to support prioritisation, decisions and planning to implement an agenda for health improvement.

Abstract In populations with a high prevalence of childhood and adolescent undernutrition, supplementation during pregnancy aiming at improving maternal nutritional status and preventing fetal growth restriction might theoretically lead to cephalopelvic disproportion and delivery complications. We investigated whether the prenatal provision of small‐quantity lipid‐based nutrient supplements (SQ‐LNS) was associated with an increased risk of caesarean section (CS) or other delivery complications. Pregnant Malawian women were randomised to receive daily i) iron–folic acid (IFA) capsule (control), ii) multiple micronutrient (MMN) capsule of 18 micronutrients (second control), or iii) SQ‐LNS with similar micronutrients as MMN, plus four minerals and macronutrients contributing 118 kcal. We analysed the associations of SQ‐LNS, CS, and other delivery complications using log‐binomial regressions. Among 1391 women enrolled, 1255 had delivery information available. The incidence of CS and delivery complications was 6.3% and 8.2%, respectively. The incidence of CS was 4.0%, 6.0%, and 8.9% (p = 0.017) in the IFA, MMN, and LNS groups, respectively. Compared to the IFA group, the relative risk (95% confidence interval) of CS was 2.2 (1.3–3.8) (p = 0.006) in the LNS group and 1.5 (0.8–2.7) (p = 0.200) in the MMN group. We found no significant differences for other delivery complications. Provision of SQ‐LNS to pregnant women may have increased the incidence of CS. The baseline rate was, however, lower than recommended. It is unclear if the higher CS incidence in the SQ‐LNS group resulted from increased obstetric needs or more active health seeking and a better supply of services. Trial registered at clinicaltrials.gov, NCT01239693.

Abstract Lipid‐based nutrient supplements (LNS) have been found to improve child growth and reduce child mortality. However, the mechanistic pathways for these improvements warrant exploration. One potential pathway is linked to improvement in intestinal health. Our study aimed to test a hypothesis that small‐quantity LNS (SQ‐LNS) could reduce the levels of intestinal inflammation, repair and permeability of children. As intestinal health markers we measured fecal calprotectin, regenerating 1B protein (REG1B) and alpha‐1‐antitrypsin concentrations at 18 months of age (after 12 months of supplementation) and 1 year later (12 months after cessation of supplementation). In this analysis, we included data of 735 children who participated in a randomised dietary supplementation trial in rural Malawi; 243 children who received 20 g/day SQ‐LNS from 6 to 18 months of age were in the SQ‐LNS group, while the others who received no dietary supplementation during this period were in the control group. At 18 months of age, the mean concentrations of calprotectin, REG1B and alpha‐1‐antitrypsin were 241, 105 µg/g and 7.1 mg/dl, respectively, in the SQ‐LNS group, and 224, 105 µg/g and 7.4 mg/dl, respectively, in the control group, and did not differ between the SQ‐LNS and control groups. We conclude that SQ‐LNS provision did not have an impact on children's intestinal health in rural Malawi.

Summary: Background: Adolescence is a critical period of maturation when nutrient needs are high, especially among adolescents entering pregnancy. Using individual-level data from 140,000 participants, we examined socioeconomic, nutrition, and pregnancy and birth outcomes for adolescent mothers (10–19 years) compared to older mothers in low and middle-income countries. Methods: This study was conducted between March 16, 2018 and May 25, 2021. Data were obtained from 20 randomised controlled trials of micronutrient supplementation in pregnancy. Stratified analyses were conducted by age (10–14 years, 15–17 years, 18–19 years, 20–29 years, 30–39 years, 40+ years) and geographical region (Africa, Asia). Crude and confounder-adjusted means, prevalence and relative risks of pregnancy, nutrition and birth outcomes were estimated using multivariable linear and log-binomial regression models with 95% confidence intervals. Findings: Adolescent mothers comprised 31.6% of our data. Preterm birth, small-for-gestational age (SGA), low birthweight (LBW) and newborn mortality followed a U-shaped trend in which prevalence was highest among the youngest mothers (10–14 years) and then reduced gradually, but increased again for older mothers (40+ years). When compared to mothers aged 20–29 years, there was a 23% increased risk of preterm birth, a 60% increased risk of perinatal mortality, a 63% increased risk of neonatal mortality, a 28% increased risk of LBW, and a 22% increased risk of SGA among mothers 10–14 years. Mothers 40+ years experienced a 22% increased risk of preterm birth and a 103% increased risk of stillbirth when compared to the 20–29 year group. Interpretation: The youngest and oldest mothers suffer most from adverse pregnancy and birth outcomes. Policy and programming agendas should consider both biological and socioeconomic/environmental factors when targeting these populations. Funding: Bill and Melinda Gates Foundation (Grant No: OP1137750).

Background Cardiovascular risk is higher in men than in women, but little information exists about sex‐related differences in cardiovascular function from low‐income countries. We compared hemodynamics between sexes in rural Malawi in a cohort followed up since their birth. Methods and Results Supine, seated, and standing hemodynamics were recorded from 251 women and 168 men (mean age, 21 years; body mass index, 21 kg/m2) using oscillometric brachial waveform analyses (Mobil‐O‐Graph). The results were adjusted for estimated glomerular filtration rate, and plasma potassium, lipids, and glucose. Men had higher brachial and aortic systolic blood pressure and stroke index regardless of posture (P

Abstract Diarrheal disease, still a major cause of childhood illness, is caused by numerous, diverse infectious microorganisms, which are differentially sensitive to environmental conditions. Enteropathogen‐specific impacts of climate remain underexplored. Results from 15 studies that diagnosed enteropathogens in 64,788 stool samples from 20,760 children in 19 countries were combined. Infection status for 10 common enteropathogens—adenovirus, astrovirus, norovirus, rotavirus, sapovirus, Campylobacter, ETEC, Shigella, Cryptosporidium and Giardia—was matched by date with hydrometeorological variables from a global Earth observation dataset—precipitation and runoff volume, humidity, soil moisture, solar radiation, air pressure, temperature, and wind speed. Models were fitted for each pathogen, accounting for lags, nonlinearity, confounders, and threshold effects. Different variables showed complex, non‐linear associations with infection risk varying in magnitude and direction depending on pathogen species. Rotavirus infection decreased markedly following increasing 7‐day average temperatures—a relative risk of 0.76 (95% confidence interval: 0.69–0.85) above 28°C—while ETEC risk increased by almost half, 1.43 (1.36–1.50), in the 20–35°C range. Risk for all pathogens was highest following soil moistures in the upper range. Humidity was associated with increases in bacterial infections and decreases in most viral infections. Several virus species' risk increased following lower‐than‐average rainfall, while rotavirus and ETEC increased with heavier runoff. Temperature, soil moisture, and humidity are particularly influential parameters across all enteropathogens, likely impacting pathogen survival outside the host. Precipitation and runoff have divergent associations with different enteric viruses. These effects may engender shifts in the relative burden of diarrhea‐causing agents as the global climate changes.

Background Selenium (Se), an essential trace mineral, has been implicated in preterm birth (PTB). We aimed to determine the association of maternal Se concentrations during pregnancy with PTB risk and gestational duration in a large number of samples collected from diverse populations.Methods Gestational duration data and maternal plasma or serum samples of 9946 singleton live births were obtained from 17 geographically diverse study cohorts. Maternal Se concentrations were determined by inductively coupled plasma mass spectrometry analysis. The associations between maternal Se with PTB and gestational duration were analysed using logistic and linear regressions. The results were then combined using fixed-effect and random-effect meta-analysis.Findings In all study samples, the Se concentrations followed a normal distribution with a mean of 93.8 ng/mL (SD: 28.5 ng/mL) but varied substantially across different sites. The fixed-effect meta-analysis across the 17 cohorts showed that Se was significantly associated with PTB and gestational duration with effect size estimates of an OR=0.95 (95% CI: 0.9 to 1.00) for PTB and 0.66 days (95% CI: 0.38 to 0.94) longer gestation per 15 ng/mL increase in Se concentration. However, there was a substantial heterogeneity among study cohorts and the random-effect meta-analysis did not achieve statistical significance. The largest effect sizes were observed in UK (Liverpool) cohort, and most significant associations were observed in samples from Malawi.Interpretation While our study observed statistically significant associations between maternal Se concentration and PTB at some sites, this did not generalise across the entire cohort. Whether population-specific factors explain the heterogeneity of our findings warrants further investigation. Further evidence is needed to understand the biologic pathways, clinical efficacy and safety, before changes to antenatal nutritional recommendations for Se supplementation are considered.

Abstract Background In 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 months in settings of high malaria and undernutrition prevalence. Methods Prospective 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 months. Malaria microscopy was done at 6 and 18 months. Negative binomial regression was used for malaria incidence and modified Poisson regression for malaria prevalence. Results Of the 2723 children enrolled, 2561 (94%) had anthropometry and malaria data. The mean (standard deviation [SD]) of LAZ, WAZ, and WLZ at 6 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 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 months and 9.6% at 18 months. Higher WLZ at 6 months was associated with lower prevalence of malaria parasitaemia at 18 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 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. Conclusion In children aged 6–18 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

Abstract Background Although poor complementary feeding is associated with poor child growth, nutrition interventions only have modest impact on child growth, due to high burden of infections. We aimed to assess the association of malaria with linear growth, hemoglobin, iron status, and development in children aged 6–18 months in a setting of high malaria and undernutrition prevalence. Methods Prospective cohort study, conducted in Mangochi district, Malawi. We enrolled six-months-old infants and collected weekly data for ‘presumed’ malaria, diarrhea, and acute respiratory infections (ARI) until age 18 months. Change in length-for-age z-scores (LAZ), stunting, hemoglobin, iron status, and development were assessed at age 18 months. We used ordinary least squares regression for continuous outcomes and modified Poisson regression for categorical outcomes. Results Of the 2723 children enrolled, 2016 (74.0%) had complete measurements. The mean (standard deviation) incidences of ‘presumed’ malaria, diarrhea, and ARI, respectively were: 1.4 (2.0), 4.6 (10.1), and 8.3 (5.0) episodes/child year. Prevalence of stunting increased from 27.4 to 41.5% from 6 to 18 months. ‘Presumed’ malaria incidence was associated with higher risk of stunting (risk ratio [RR] = 1.04, 95% confidence interval [CI] = 1.01 to 1.07, p = 0.023), anemia (RR = 1.02, 95%CI = 1.00 to 1.04, p = 0.014) and better socio-emotional scores (B = − 0.21, 95%CI = − 0.39 to − 0.03, p = 0.041), but not with change in LAZ, haemoglobin, iron status or other developmental outcomes. Diarrhea incidence was associated with change in LAZ (B = − 0.02; 95% CI = − 0.03 to − 0.01; p = 0.009), stunting (RR = 1.02; 95% CI = 1.01 to 1.03; p = 0.005), and slower motor development. ARI incidence was not associated with any outcome except for poorer socio-emotional scores. Conclusion In this population of young children living in a malaria-endemic setting, with active surveillance and treatment, ‘presumed’ malaria is not associated with change in LAZ, hemoglobin, or iron status, but could be associated with stunting and anemia. Diarrhea was more consistently associated with growth than was malaria or ARI. The findings may be different in contexts where active malaria surveillance and treatment is not provided. Trial registration NCT00945698 (July 24, 2009) and NCT01239693 (November 11, 2010).

Theoretical and empirical considerations suggest that individual differences in infant visual attention correlate with variations in cognitive skills later in childhood. Here we tested this hypothesis in infants from rural Malawi (n = 198-377, depending on analysis), who were assessed with eye tracking tests of visual orienting, anticipatory looks, and attention to faces at 9 months, and more conventional tests of cognitive control (A-not-B), motor, language, and socioemotional development at 18 months. The results showed no associations between measures of infant attention at 9 months and cognitive skills at 18 months, either in analyses linking infant visual orienting with broad cognitive outcomes or analyses linking specific constructs between the two time points (i.e., switching of anticipatory looks and manual reaching responses), as correlations varied between -0.08 and 0.14. Measures of physical growth, and family socioeconomic characteristics were also not correlated with cognitive outcomes at 18 months in the current sample (correlations between -0.10 and 0.19). The results do not support the use of the current tests of infant visual attention as a predictive tool for 18-month-old infants' cognitive skills in the Malawian setting. The results are discussed in light of the potential limitations of the employed infant tests as well as potentially unique characteristics of early cognitive development in low-resource settings.

Abstract Background Since the adoption of United Nations’ Sustainable Goal 4.2 to ensure that all children have access to quality early child development (ECD) so that they are ready for primary education, the demand for valid ECD assessments has increased in contexts where they do not yet exist. The development of early language ability is important for school readiness. Our objective was to evaluate the validity of a method to develop vocabulary checklists in new languages to assess early language development, based on the MacArthur-Bates Communicative Development Inventories. Methods Through asking mothers of young children what words their children say and through pilot testing, we developed 100-word vocabulary checklists in multilingual contexts in Malawi and Ghana. In Malawi, we evaluated the validity of the vocabulary checklist among 29 children age 17–25 months compared to three language measures assessed concurrently: Developmental Milestones Checklist-II (DMC-II) language scale, Malawi Developmental Assessment Tool (MDAT) language scale, and the number of different words (NDW) in 30-min recordings of spontaneous speech. In Ghana, we assessed the predictive validity of the vocabulary checklist at age 18 months to forecast language, pre-academic, and other skills at age 4–6 years among 869 children. We also compared the predictive validity of the vocabulary checklist scores to that of other developmental assessments administered at age 18 months. Results In Malawi, the Spearman’s correlation of the vocabulary checklist score with DMC-II language was 0.46 (p = 0.049), with MDAT language was 0.66 (p = 0.016) and with NDW was 0.50 (p = 0.033). In Ghana, the 18-month vocabulary checklist score showed the strongest (rho = 0.12–0.26) and most consistent (8/12) associations with preschool scores, compared to the other 18-month assessments. The largest coefficients were the correlations of the 18-month vocabulary score with the preschool cognitive factor score (rho = 0.26), language score (0.25), and pre-academic score (0.24). Conclusions We have demonstrated the validity of a method to develop vocabulary checklists in new languages, which can be used in multilingual contexts, using a feasible adaptation process requiring about 2 weeks. This is a promising method to assess early language development, which is associated with later preschool language, cognitive, and pre-academic skills.

AimIntermittent preventive treatment in pregnancy (IPTp) with azithromycin and monthly sulfadoxine-pyrimethamine increased the mean child weight, mid-upper arm and head circumference at four weeks of age in a rural low-income setting. Now we assess for how long these gains were sustained during 0-5 years of age.MethodsWe enrolled 1320 pregnant Malawian women in a randomized trial and treated them with two doses of sulfadoxine-pyrimethamine (control) or monthly sulfadoxine-pyrimethamine as IPTp against malaria, or monthly sulfadoxine-pyrimethamine and two doses of azithromycin (AZI-SP) as IPTp against malaria and reproductive tract infections. Child weight, mid-upper arm circumference, head circumference and weight-for-height Z-score were recorded at one, six, 12, 24, 36, 48, and 60 months.ResultsThroughout follow-up, the mean child weight was approximately 100 g higher (difference in means 0.12 kg, 95% CI 0.04-0.20, P = 0.003 at one month; 0.19 kg, 95% CI 0.05-0.33, P = 0.007, at six months), mean head circumference 2 mm larger (0.3 cm, 95% CI 0.1 to 0.5, P = 0.004 at one month) and the cumulative incidence of underweight by five years of age was lower (hazard ratio 0.74, 95% CI 0.60 to 0.90, P = 0.002) in the AZI-SP group than in the control group. The 2 mm difference in the mean mid-upper arm circumference at one month (0.2 cm, 95% CI 0.0 to 0.3, P = 0.007) disappeared after three years of age. There was no difference in mean weight-for-height Z-score at any time point.ConclusionIn Malawi, IPTp with azithromycin and monthly sulfadoxine-pyrimethamine has a modest, 3-5-year positive impact on child weight, mid-upper arm circumference and head circumference, but not on weight-for-height Z-score.

ObjectivesBoth maternal HIV infection and antiretroviral therapy are associated with adverse birth outcomes. The role of antenatal nutrient supplements with regard to adverse birth outcomes in HIV infected women exposed to antiretroviral therapy is not well known. We assessed the association between HIV and birth outcomes and explored whether antenatal lipid-based nutrient supplements (LNS) modulated this association.MethodsWe analysed a nested cohort of pregnant Malawian women who received daily LNS, multiple micronutrients (MMN) or iron and folic acid (IFA). Birth weight, length-for-age z-score (LAZ) and weight-for-age z-score (WAZ) were analysed as continuous outcomes and proportion of stunting and small-for-gestational age (SGA) as dichotomous outcomes.Results134 HIV infected (46 LNS, 39 MMN, 49 IFA) and 833 HIV uninfected (271 LNS, 287 MMN, 275 IFA) women were included. Maternal HIV infection was associated with a lower mean birth weight (-129g (-209, -48), P = 0.002); LAZ (-0.34 (-0.54, -0.13), P = 0.002) and WAZ (-0.21 (-0.40, -0.02), P = 0.041) and a higher risk of stunting (RR (95% confidence interval), 1.87 (1.24, 2.83), P = 0.003) and SGA (1.66 (1.21, 2.26), P = 0.001) in the newborn. If the women received LNS, HIV was not associated with LAZ (mean difference (95%); -0.02 (-0.35, 0.31), P = 0.918) or newborn stunting (RR (95% CI), 0.84 (0.34, 2.03), P = 0.691). However HIV tended to be associated with LAZ if the women received MMN (-0.42 (-0.80, -0.03), P = 0.053); and was significantly associated with LAZ if the women received IFA (-0.52 (-0.89, -0.14), P = 0.021) and with newborn stunting if they received MMN (2.40 (1.15, 4.98), P = 0.029) or IFA (2.40 (1.26, 4.59), P = 0.024).ConclusionsFurther research to investigate the impact of LNS on various aspects of foetal growth in HIV infected women is warranted.

BACKGROUND:Whereas poor maternal nutritional status before and during pregnancy is widely associated with adverse birth outcomes, studies quantifying this association in low income countries are scarce. We examined whether maternal pre-pregnancy body mass index (BMI) and weight gain during pregnancy are associated with birth outcomes in rural Malawi. METHODS:We analyzed the associations between pre-pregnancy BMI and average weekly gestational weight gain (WWG) and birth outcomes [duration of gestation, birth weight, length-for-age z-score (LAZ), and head circumference-for-age z-score (HCZ)]. We also determined whether women with low or high pre-pregnancy BMI or women with inadequate or excessive WWG were at increased risk of adverse birth outcomes. RESULTS:The analyses included 1287 women with a mean BMI of 21.8 kg/m2, of whom 5.9% were underweight (< 18.5 kg/m2), 10.9% were overweight (≥ 25 kg/m2), 71.8% had low WWG [below the lower limit of the Institute of Medicine (IOM) recommendation], and 5.2% had high WWG (above IOM recommendation). In adjusted models, pre-pregnancy BMI was not associated with duration of pregnancy (p = 0.926), but was positively associated with birth weight and HCZ (

Preterm birth is a major cause of neonatal mortality and morbidity worldwide. Bacterial infection and the subsequent inflammatory response are recognised as an important cause of preterm birth. It is hypothesised that these organisms ascend the cervical canal, colonise placental tissues, cause chorioamnionitis and in severe cases infect amniotic fluid and the foetus. However, the presence of bacteria within the intrauterine cavity does not always precede chorioamnionitis or preterm birth. Whereas previous studies observing the types of bacteria present have been limited in size and the specificity of a few predetermined organisms, in this study we characterised bacteria found in placental tissues from a cohort of 1391 women in rural Malawi using 16S ribosomal RNA gene sequencing. We found that specific bacteria found concurrently on placental tissues associate with chorioamnionitis and delivery of a smaller newborn. Severe chorioamnionitis was associated with a distinct difference in community members, a higher bacterial load and lower species richness. Furthermore, Sneathia sanguinengens and Peptostreptococcus anaerobius found in both matched participant vaginal and placental samples were associated with a lower newborn length-for-age Z-score. This is the largest study to date to examine the placental microbiome and its impact of birth outcomes. Our results provide data on the role of the vaginal microbiome as a source of placental infection as well as the possibility of therapeutic interventions against targeted organisms during pregnancy.

A novel qualitative point-of-care test of activated matrix metalloproteinase-8 (aMMP-8) using noninvasive oral rinse sampling procedures has been developed for the early detection of collagen breakdown indicating periodontal tissue destruction. The main object of this study was to assess the reliability of the test in a low-income setting to identify participants with history of periodontal destruction detected as alveolar bone loss (ABL) in radiographs. This cross-sectional study included 486 women who had recently delivered in rural Malawi. The aMMP-8 test and dental panoramic radiographs were taken within 48 h of delivery. The performance of the test in comparison to radiological examinations was tested by following the standards for reporting of diagnostic accuracy studies protocol (STARD) with respective statistical measures and 95% confidence intervals. From the 486 eligible participants, 461 mothers with complete data, aged from 15 to 46 years (mean 24.8, SD 6.0) were included in the analysis. ABL was identified in 116 of 461 participants. There was 56% agreement between the aMMP-8 test results and detected ABL (yes or no) in radiographs. Calculated sensitivity of the test was 80% (72–87%), specificity 48% (43–54%), positive predictive value 34% (31–37%), negative predictive value 88% (83–91%), positive likelihood ratio 1.55 (1.35–1.77), and negative likelihood ratio 0.41(0.28–0.60). The aMMP-8 test sensitivity and negative predictive value to identify the ABL cases were relatively high, but there was additionally a high rate of test-positive results in participants without ABL, especially in young mothers, leading to low overall agreement between the test results and radiological bone loss. Further longitudinal studies are needed to examine if the test positive subjects are in risk of future bone loss before the detectable signs of periodontitis in radiographs.

Rehabilitation in Finland is a good example of functions divided among several welfare sectors, such as health services and social services. The rehabilitation system in Finland is a complex one and there have been many efforts to create a coordinated entity. The purpose of this study is to open up a complex welfare system at the upper policy level and to understand the meaning of coordination at the level of service delivery. We shed light in particular on the national rehabilitation policy in Finland and how the policy has tried to overcome the negative effects of institutional complexity.In this study we used qualitative content analysis and frame analysis. As a result we identified four different welfare state frames with distinct features of policy problems, policy alternatives and institutional failure.The rehabilitation policy in Finland seems to be divided into different components which may cause problems at the level of service delivery and thus in the integration of services. Bringing these components together could at policy level enable a shared view of the rights of different population groups, effective management of integration at the level of service delivery and also an opportunity for change throughout the rehabilitation system.