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Research on simplified antibiotic regimens for outpatient treatment of 'Possible Serious Bacterial Infection' (PSBI) and the subsequent World Health Organization (WHO) guidelines provide an opportunity to increase treatment coverage. This multi-country implementation research initiative aimed to learn how to implement the WHO guideline in diverse contexts. These experiences have been individually published; this overview paper provides a summary of results and lessons learned across sites. A common mixed qualitative and quantitative methods protocol for implementation research was used in eleven sites in the Democratic Republic of Congo (Equateur province), Ethiopia (Tigray and Oromia regions), India (Haryana, Himachal Pradesh, Maharashtra, and Uttar Pradesh states), Malawi (Central Region), Nigeria (Kaduna and Oyo states), and Pakistan (Sindh province). Key steps in implementation research were: i) policy dialogue with the national government and key stakeholders, ii) the establishment of a 'Technical Support Unit' with the research team and district level managers, and iii) development of an implementation strategy and its refinement using an iterative process of implementation, programme learning and evaluation. All sites successfully developed and evaluated an implementation strategy to increase coverage of PSBI treatment. During the study period, a total of 6677 young infants from the study catchment area were identified and treated at health facilities in the study area as inpatients or outpatients among 88179 live births identified. The estimated coverage of PSBI treatment was 75.7% (95% CI 74.8% to 78.6%), assuming a 10% incidence of PSBI among all live births. The treatment coverage was variable, ranging from 53.3% in Lucknow, India to 97.3% in Ibadan, Nigeria. The coverage of inpatient treatment ranged from 1.9% in Zaria, Nigeria, to 33.9% in Tigray, Ethiopia. The outpatient treatment coverage ranged from 30.6% in Pune, India, to 93.6% in Zaria, Nigeria. Overall, the case fatality rate (CFR) was 14.6% (95% CI 11.5% to 18.2%) for 0-59-day old infants with critical illness, 1.9% (95% CI 1.5% to 2.4%) for 0-59-day old infants with clinical severe infection and 0.1% for fast breathing in 7-59 days old. Among infants treated as outpatients, CFR was 13.7% (95% CI 8.7% to 20.2%) for 0-59-day old infants with critical illness, 0.9% (95% CI 0.6% to 1.2%) for 0-59-day old infants with clinical severe infection, and 0.1% for infants 7-59 days old with fast breathing. Important lessons on how to conduct each step of implementation research, and the challenges and facilitators for implementation of PSBI management guideline in routine health systems are summarised and discussed. These lessons will be used to introduce and scale-up implementation in relevant Low- and middle-income countries.

Small vulnerable newborn (SVN) types, defined by combinations of being born too soon or too small, have distinct determinants, health consequences, and prevention strategies. The effects of prenatal balanced energy and protein (BEP) supplementation on SVN types remain unknown. We conducted a systematic review and meta-analysis of individual participant data from eight randomized controlled trials of prenatal BEP supplements (N = 10,252, with 5,164 in the BEP arm and 5,088 in the control arm) in low- and middle-income countries were used. The control arms varied across studies and included context-specific standards of care, iron and folic acid supplements, or multiple micronutrient supplements. Newborns were classified into 10 groups through the combinations of preterm birth, small for gestational age (SGA) birth, and low birthweight (LBW), such as term-appropriate-for-gestational-age (AGA)-nonLBW, preterm-SGA-LBW, preterm-large-for-gestational-age-LBW, term-SGA-LBW, preterm-AGA-nonLBW, and other permutations. Newborns were also analyzed using a four-group categorization that included term-nonSGA, preterm-nonSGA, term-SGA, and preterm-SGA. Log-binomial models were used to estimate study-specific risk ratios (RRs), which were pooled using meta-analyses. Subgroup analyses were conducted by maternal age, parity, gestational age at enrollment, early pregnancy body mass index, and maternal anemia status. In the 10-group categorization of SVNs, on average, prenatal BEP supplementation led to a 30% lower risk of preterm-SGA-LBW (RR: 0.70; 95% CI [0.53, 0.91]; P = 0.009), a 25% lower risk of preterm-AGA-LBW (RR: 0.75; 95% CI [0.60, 0.93]; P = 0.009), and a 20% lower risk of term-SGA-LBW (RR: 0.80; 95% CI [0.72, 0.90]; P < 0.001). In the four-group categorization, prenatal BEP supplementation led to a 31% lower risk of preterm-SGA (RR: 0.69; 95% CI [0.52, 0.91]; P = 0.008) and a 12% lower risk of term-SGA (RR: 0.88; 95% CI [0.81, 0.96]; P = 0.005). The protective effect of prenatal BEP supplementation on preterm-SGA was stronger among multiparous women and women without anemia. The protective effects on all three SVN types under the four-group categorization were stronger among women enrolled before 20 weeks of gestation. The main limitations of the study included the absence of some BEP trials and the small event numbers for some SVN types. Prenatal BEP supplementation reduces the risk of SVNs to varying extents. Further research is needed to determine the optimal targeting approach for providing BEP supplements to vulnerable pregnant women who are most likely to benefit from the supplementation.

Background: Sepsis remains a significant cause of morbidity and mortality in preterm and low birth weight (LBW) neonates, especially in low- and middle-income countries (LMICs). Lactoferrin, a glycoprotein present in breast milk with antimicrobial activity, is a low-cost, readily available, and promising intervention currently under investigation. The available literature presents conflicting results on the impact of lactoferrin on the risk of late-onset sepsis (LOS). This study evaluated the effectiveness of two doses of bovine lactoferrin (bLF) supplementation in preventing LOS and necrotizing enterocolitis (NEC) in preterm and LBW neonates in Pakistan. Methods: A three-arm, double-blind, placebo-controlled, randomized clinical trial in the neonatal intensive care unit of Aga Khan University was conducted from July 2019 to August 2020. Preterm (28 to 36 + 5 weeks gestational age) and low birth weight (≥1000 g to <2500 g) neonates who established enteral feeding by 72 h were eligible. The exclusion criteria included sepsis before randomization, maternal history of chorioamnionitis or group B streptococcus colonization, and congenital anomalies. Enrolled neonates were randomly assigned in a 1:1:1 ratio using a computer-generated random allocation sequence to receive placebo (D-glucose), 150 mg bLF, or 300 mg bLF mixed with breast milk once daily for 28 days. The study staff, parents, and outcome assessors were blinded to the allocation. The primary outcome was late-onset sepsis from the trial entry to 28 days. The secondary outcome was NEC from the trial entry to 28 days. Neonates were followed weekly for 28 ± 2 days, and episodes of LOS and NEC were recorded. Results: Of 305 neonates enrolled, 102, 102, and 101, respectively, were randomized to receive a placebo (arm A), 150 mg bLF (arm B), and 300 mg bLF (arm C), respectively. Outcome data of 291 participants (99 in arm A, 95 in arm B, and 97 in arm C) were available for inclusion in the intention-to-treat analysis. The frequency of culture-proven sepsis was 8/102 (7.8%) in arm A compared to 1/102 (0.98%) (p = 0.020) in arm B and 5/101 (4.9%) in arm C (p = 0.390). We did not find any difference in episodes of NEC between arms A (n = 3, 3%) and B (n = 0, 0%) (p = 0.087) or between arms A and C (n = 2, 2%) (p = 0.650). We reported compliance rates of 79 (79.79%) in arm A, 78 (82.1%) in arm B, and 82 (84.53%) in arm C for investigational products. Arm C recorded two deaths, but neither was attributed to the intervention. Conclusions: Bovine lactoferrin supplementation did not prevent late-onset sepsis in neonates of preterm and low birth weight in our trial. However, given the small sample size, further trials with larger sample sizes are required to investigate its efficacy in these at-risk groups.

Introduction: Anemia is a global public health concern affecting mainly women of reproductive age (WRA) and preschoolers (PSC, 6–59 months) due to their higher demand for iron. The etiology of anemia is multifactorial, and nutritional anemia is the most common type worldwide and is predominantly due to deficiencies in iron, vitamin B12, and folate. This study aimed to assess the associated factors, etiology, and prevalence of anemia among WRA and preschoolers in the Gorno-Badakhshan Autonomous Oblast (GBAO) region in Tajikistan. Methods: We conducted a cross-sectional study in the GBAO region of Tajikistan between April 2021 and September 2021, enrolling 500 non-pregnant WRA and 500 children aged 6–59 months in pairs (mother–PSC dyads) from six districts of the GBAO region. The survey was administered through a structured questionnaire at the household level, and information was collected on sociodemographic characteristics, reproductive history, dietary intake, nutritional status, and maternal factors. Blood and stool samples were also collected for micronutrient deficiencies and helminthic infections. Data analysis began with univariate analysis, followed by multivariate logistic regression in Stata (version 18). Results: Biochemical assessment of 473 WRA and 390 preschoolers was carried out; 17.3% of WRA were anemic, and 15.4% of PSC were anemic. Anemia prevalence was 17.3% among WRA and 15.4% among PSC. Among women, low ferritin and elevated serum transferrin receptor (sTfR) levels were associated with higher odds of anemia, whereas overweight status, higher gravidity, and vitamin B12 deficiency were associated with lower odds. Among children, low maternal education, maternal anemia, age < 24 months, and low ferritin were associated with increased odds of anemia. Conclusions: Anemia prevalence in GBAO was substantially lower than reported in the 2016 national survey, potentially reflecting methodological and contextual differences. Findings highlight iron deficiency as a dominant contributor, particularly in young children, underscoring the need for context-specific maternal and child nutrition interventions.

Chronic childhood malnutrition, or stunting, remains a persistent barrier to achieve optimal cognitive development, child growth and ability to reach full potential. Almost half of children under-five years of age are stunted in the province of Sindh, Pakistan. The primary objective of this study was to test the hypothesis that the provision of lipid-based nutrient supplement-medium-quantity (LNS-MQ) known as Wawamum will result in a 10% reduction in risk of being stunted at the age of 24 months in the intervention group compared with the control group. A cluster randomized controlled trial was conducted in Thatta and Sujawal districts of Sindh province, Pakistan. A total of 870 (419 in intervention; 451 in control) children between 6-18 months old were enrolled in the study. The unit of randomization was union council and considered as a cluster. A total of 12 clusters, 6 in each study group were randomly assigned to intervention and control group. All children received standard government health services, while children in the intervention group also received 50 grams/day of Wawamum. Children who received Wawamum were found to have a significantly reduced risk of stunting (RR = 0.91, 95% CI; 0.88-0.94, p<0.001) and wasting (RR = 0.78, 95% CI; 0.67-0.92, p = 0.004) as compared to children who received the standard government health services. There was no evidence of a reduction in the risk of underweight (RR = 0.94, 95% CI; 0.85-1.04, p = 0.235) in the intervention group compared to the control group. Statistically significant reduction in anaemia in the intervention group was also found as compared to the control group (RR = 0.97, 95% CI; 0.94-0.99, p = 0.042). The subgroup analysis by age, showed intervention effect is significant in reduction of risk of stunting in younger children of aged 6-12 month (RR = 0.83, 95% CI; 0.81-0.86, p = <0.001) and their older peers aged 13-18 month- (RR = 0.90, 95% CI; 0.83-0.97, p = 0.008). The mean compliance of Wawamum was 60% among children. The study confirmed that the provision of Wawamum to children 6-23 months of age is effective in reducing the risk of stunting, wasting and anaemia. This approach should be scaled up among the most food insecure areas/households with a high prevalence of stunting to achieve positive outcomes for nutrition and health. This study was registered at clinicaltrials.gov as NCT02422953.

The World Health Organization (WHO) launched a guideline in 2015 for managing Possible Serious Bacterial Infection (PSBI) when referral is not feasible in young infants aged 0-59 days. This guideline was implemented across 303 Basic Health Unit (BHU) Plus primary health care (PHC) facilities in peri-urban and rural settings of Sindh, Pakistan. We evaluated the implementation of PSBI guideline, and the quality of care provided to sick young infants at these facilities. Thirty (10%) out of 303 BHU Plus facilities were randomly selected for evaluation. A survey team visited each facility for one day, assessed the health system support, observed the management of sick young infants by health care providers (HCP), validated their management, interviewed HCPs and caretakers of sick infants. HCPs who were unable to see a young infant on the day of survey were evaluated using pre-prepared case scenarios. Thirty (100%) BHU Plus facilities had oral amoxicillin, injectable gentamicin, thermometers, baby weighing scales and respiratory timers available; 29 (97%) had disposable syringes and needles; 28 (93%) had integrated management of childhood illness (IMCI)/PSBI chart booklets and job aids and 18 (60%) had a functional ambulance. Each facility had at least one HCP trained in PSBI, and 21 (70%) facilities had been visited by a supervisor in the preceding six months. Of 42 HCPs, 19 (45.3%) were trained within the preceding 12 months. During the survey, 26 sick young infants were identified in 18 facilities. HCPs asked about history of breastfeeding in 23 (89%) infants, history of vomiting in 17 (65%), and history of convulsions in 14 (54%); weighed 25 (97%) infants; measured respiratory rate in all (100%) and temperature in 24 (92%); assessed 20 (77%) for movement and 14 (54%) for chest indrawing. HCPs identified two infants with fast breathing pneumonia and managed them correctly per IMCI/PSBI protocol. HCPs identified six (23%) infants with clinical severe infection (CSI), two of them were referred to a higher-level facility, only one accepted the referral advice. Only one CSI patient was managed correctly per IMCI/PSBI protocol at the outpatient level. HCPs described the PSBI danger signs to eight (31%) caretakers. Caretakers of five infants with CSI and two with pneumonia were not counselled for PSBI danger signs. Five of the six CSI cases categorized by HCPs were validated as CSI on re-examination, whereas one had pneumonia. Similarly, one of the two pneumonia patients categorized by HCPs had CSI and one identified as local bacterial infection was classified as CSI upon re-examination. Health system support was adequate but clinical management and counselling by HCPs was sub-optimal particularly with CSI cases who are at higher risk of adverse outcomes. Scaling up PSBI management is potentially feasible in PHC facilities in Pakistan, provided that HCPs are trained well and mentored, receive refresher training to appropriately manage sick young infants, and have adequate supplies and counselling skills.

Background: Stunting, a form of chronic malnutrition, is a global health concern, especially in South Asia. Stunting remains a significant public health issue in Pakistan, particularly in remote regions like Gilgit-Baltistan and Chitral, where geographic isolation and socioeconomic challenges exacerbate malnutrition. The Aga Khan Development Network is leading the implementation of a program, Central Asia Stunting Initiative (CASI), with an aim to reduce stunting through community-driven maternal and child health interventions in the targeted areas of Gilgit Baltistan and Chitral. This study aimed to evaluate the effectiveness of CASI in improving child nutritional outcomes in Gilgit-Baltistan and Chitral. Methods: In this study, a single-group pre–post evaluation design was employed using baseline and midline cross-sectional surveys among households with children aged 0–59 months in Gilgit-Baltistan and Chitral. Data on child anthropometry, household food security, maternal education, and child feeding practices were collected from over 500 households using stratified sampling. Results: Results showed improvement in child health indicators between baseline and midline. Between baseline and midline, stunting declined from 40.9% to 35.4% in GBC (p = 0.02), with severe stunting dropping significantly (17.8% to 10.9%, p < 0.001). Wasting and underweight rates also showed marked reductions. Improvements in breastfeeding rates (71.3% to 88.3%) and dietary diversity (4.0% to 26.8%) were observed. However, food security declined sharply from 95.2% to 11.9%, underscoring persistent economic stress. Conclusions: CASI interventions yielded substantial improvements in child nutrition and maternal behaviours. However, sustained progress requires integrated strategies addressing food insecurity, economic empowerment, and long-term resilience. Future programs should adopt a multi-sectoral approach to tackle chronic malnutrition comprehensively. Despite this, results indicated an overall improvement due to CASI interventions, signifying the importance of integrated, community-based approaches in addressing stunting.

Growth impairment is common in low- and middle-income countries (LMIC) and may begin during early infancy, increasing morbidity and mortality. To ensure healthy infant growth, healthcare providers in high-income countries (HIC) track newborn weight change using tools developed and validated in HIC. To understand the utility of these tools for LMIC, we conducted a secondary analysis to compare weight trajectories in the first 5 days of life among newborns born in our LMIC cohort to an existing HIC newborn weight tool designed to track early weight change. Between April 2019 and March 2020, a convenience sample of 741 singleton healthy breastfeeding newborns who weighed ≥ 2000 g at birth were enrolled at selected health facilities in Guinea-Bissau, Nepal, Pakistan, and Uganda. Using a standardized protocol, newborn weights were obtained within 6 h of birth and at 1, 2, 3, 4, and 5 days, and nomograms depicting newborn weight change were generated. The trajectories of early newborn weight change in our cohort were largely similar to published norms derived from HIC infants, with the exceptions that initial newborn weight loss in Guinea-Bissau was more pronounced than HIC norms and newborn weight gain following weight nadir was more pronounced in Guinea-Bissau, Pakistan, and Uganda than HIC norms. These data demonstrate that HIC newborn weight change tools may have utility in LMIC settings.

Background/Objectives: In Pakistan, 41.7% of women of reproductive age and 53.7% of children aged 6–59 months are anaemic. This study aimed to evaluate the effectiveness of a nutritional supplementation programme, underpinned with behaviour change communication and implemented through Lady Health Workers (LHWs), in reducing anaemia among pregnant and lactating women as well as 6–59-month-old children. Methods: This study used a quasi-experimental design with an intervention and a control group. A total of 2821 and 2410 pregnant and lactating women and 3397 and 3277 children aged 6–59 months participated in the baseline and endline surveys, respectively. The study areas were matched for demographic and economic characteristics, and both had routine public-sector health and nutrition programmes, including iron–folic acid supplementation during pregnancy. The participants in the intervention group received additional nutritional support. Throughout the pregnancy and in the first six months of exclusive breast feeding, women were provided 5 kg (165 g/day) of wheat soya blend (WSB) per month. Children aged 6–23 months received lipid-based nutrient supplements (LNS), and those aged 24–59 months received micronutrient powder. We applied a difference-in-difference (DID) analysis with kernel propensity score matching to assess the impact on anaemia, a secondary outcome of a stunting prevention programme. Results: Maternal anaemia (both pregnant and breastfeeding women) declined substantially in the intervention areas from 80.4% to 62.6% compared with a smaller reduction in the control areas (80.0% to 72.9%). The DID estimate showed a 10.7-percentage-point (pp) greater decline in maternal anaemia (p ≤ 0.001). Both pregnant and lactating women benefited, with DID reductions of 16.7 pp (p ≤ 0.001) and 9.4 pp (p = 0.005), respectively. The largest gains occurred among women in higher-wealth quintiles, with reductions up to 22.6 pp (p ≤ 0.001). In contrast, childhood anaemia showed no overall significant difference between intervention and control areas (DID = −0.7 pp, p = 0.73). However, significant improvements were observed among male children (DID = −10.3 pp, p = 0.001) and those in higher-wealth quintiles (DID = −15.0 pp, p = 0.002). Conclusions: Overall, the findings suggest that LHWs can effectively reduce maternal anaemia when iron–folic acid supplementation is complemented with WSB and targeted behaviour change communication.