Clinical and nutritional correlates of bacterial diarrhoea aetiology in young children: a secondary cross-sectional analysis of the ABCD trial.

OBJECTIVE: The objective was to assess the association between nutritional and clinical characteristics and quantitative PCR (qPCR)-diagnosis of bacterial diarrhoea in a multicentre cohort of children under 2 years of age with moderate to severe diarrhoea (MSD). DESIGN: A secondary cross-sectional analysis of baseline data collected from the AntiBiotics for Children with Diarrhoea trial (NCT03130114). PATIENTS: Children with MSD (defined as >3 loose stools within 24 hours and presenting with at least one of the following: some/severe dehydration, moderate acute malnutrition (MAM) or severe stunting) enrolled in the ABCD trial and collected stool sample. STUDY PERIOD: June 2017-July 2019. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Likely bacterial aetiology of diarrhoea. Secondary outcomes included specific diarrhoea aetiology. RESULTS: A total of 6692 children with MSD had qPCR results available and 28% had likely bacterial diarrhoea aetiology. Compared with children with severe stunting, children with MAM (adjusted OR (aOR) (95% CI) 1.56 (1.18 to 2.08)), some/severe dehydration (aOR (95% CI) 1.66 (1.25 to 2.22)) or both (aOR (95% CI) 2.21 (1.61 to 3.06)), had higher odds of having likely bacterial diarrhoea aetiology. Similar trends were noted for stable toxin-enterotoxigenic Escherichia coli aetiology. Clinical correlates including fever and prolonged duration of diarrhoea were not associated with likely bacterial aetiology; children with more than six stools in the previous 24 hours had higher odds of likely bacterial diarrhoea (aOR (95% CI) 1.20 (1.05 to 1.36)) compared with those with fewer stools. CONCLUSION: The presence of MAM, dehydration or high stool frequency may be helpful in identifying children with MSD who might benefit from antibiotics.

Efficacy of typhoid vaccines against culture-confirmed Salmonella Typhi in typhoid endemic countries: a systematic review and meta-analysis.

BACKGROUND: Typhoid is a serious public health threat in many low-income and middle-income countries. Several vaccines for typhoid have been recommended by WHO for typhoid prevention in endemic countries. This study aimed to review the efficacy of typhoid vaccines against culture-confirmed Salmonella enterica serovar Typhi. METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase for studies published in English between Jan 1, 1986 and Nov 2, 2023. We included randomised controlled trials (RCTs) comparing typhoid vaccines with a placebo or another vaccine. This meta-analysis evaluated the efficacy and safety of several typhoid vaccines, including live attenuated oral Ty21a vaccine, Vi capsular polysaccharide (Vi-PS), Vi polysaccharide conjugated to recombinant Pseudomonas aeruginosa exotoxin A vaccine (Vi-rEPA), and Vi-tetanus toxoid conjugate vaccine (TCV). The certainty of evidence for key outcomes was evaluated using Grading of Recommendations, Assessment, Development, and Evaluations methodology. The outcome of interest was typhoid fever confirmed by the isolation of Salmonella enterica serovar Typhi in blood and adverse events following immunisation. This study is registered with PROSPERO (CRD42021241043). FINDINGS: We included 14 RCTs assessing four different vaccines (Ty21a: four trials; Vi-PS: five trials; Vi-rEPA: one trial; TCV: four trials) involving 585 253 participants. All trials were conducted in typhoid endemic countries and the age of participants ranged from 6 months to 50 years. The pooled efficacy against typhoid fever was 45% (95% CI 33-55%; four trials; 247 649 participants; I2 59%; moderate certainty) for Ty21a and 58% (44-69%; five trials; 214 456 participants; I2 34%; moderate certainty) for polysaccharide Vi-PS. The cumulative efficacy of two doses of Vi-rEPA vaccine at 2 years was 91% (88-96%; one trial; 12 008 participants; moderate certainty). The pooled efficacy of a single shot of TCV at 2 years post-immunisation was 83% (77-87%; four trials; 111 130 participants; I2 0%; moderate certainty). All vaccines were safe, with no serious adverse effects reported in the trials. INTERPRETATION: The existing data from included trials provide promising results regarding the efficacy and safety of the four recommended typhoid vaccines. TCV and Vi-rEPA were found to have the highest efficacy at 2 years post-immunisation. However, follow-up data for Vi-rEPA are scarce and only TCV is pre-qualified by WHO. Therefore, roll-out of TCV into routine immunisation programmes in typhoid endemic settings is highly recommended. FUNDING: There was no funding source for this study.

Guidance on sexual, reproductive, maternal, newborn, child and adolescent health in humanitarian and fragile settings: a scoping review.

INTRODUCTION: Progress related to sexual, reproductive, maternal, newborn, child and adolescent health (SRMNCAH) has stalled. COVID-19, conflict and climate change threaten to reverse decades of progress and to ensure the health and well-being of vulnerable populations in humanitarian and fragile settings (HFS) going forward, there is a need for tailored guidance for women, children and adolescents (WCA). This review seeks to map and appraise current resources on SRMNCAH in HFS. METHODS: In line with the updated Joanna Briggs Institute guidance and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews framework, a manual literature review was conducted of global and regional guidance published between January 2008 and May 2023 from members of the Global Health Cluster, the Global Nutrition Cluster and the Inter-Agency Working Group on Reproductive Health in Crises. A content analysis was conducted. Scores were then calculated according to the Appraisal of Guidelines for Research and Evaluation II scoring tool and subsequently categorised as high quality or low quality. RESULTS: A total of 730 documents were identified. Of these, 141 met the selection criteria and were analysed. Available guidance for delivering SRMNCH services exists, which can inform policy and programming for the general population and WCA. Important gaps related to beneficiaries, health services and health system strengthening strategies were identified. CONCLUSION: The review revealed there is evidence-based guidance available to support interventions targeting WCA in HFS, including: pregnant and lactating women, women of reproductive age, adolescents, newborns, small vulnerable newborns, stillbirths, refugees and internally displaced persons and WCA with disabilities. However, gaps related to beneficiaries, health services and health system strengthening strategies must be addressed in updated guidance that is created, disseminated and monitored in a standardised way that is mindful of the need to respond rapidly in HFS.

WHO's essential medicines and AWaRe: recommendations on first- and second-choice antibiotics for empiric treatment of clinical infections.

The WHO Model List of Essential Medicines (EML) prioritizes medicines that have significant global public health value. The EML can also deliver important messages on appropriate medicine use. Since 2017, in response to the growing challenge of antimicrobial resistance, antibiotics on the EML have been reviewed and categorized into three groups: Access, Watch, and Reserve, leading to a new categorization called AWaRe. These categories were developed taking into account the impact of different antibiotics and classes on antimicrobial resistance and the implications for their appropriate use. The 2023 AWaRe classification provides empirical guidance on 41 essential antibiotics for over 30 clinical infections targeting both the primary health care and hospital facility setting. A further 257 antibiotics not included on the EML have been allocated an AWaRe group for stewardship and monitoring purposes. This article describes the development of AWaRe, focussing on the clinical evidence base that guided the selection of Access, Watch, or Reserve antibiotics as first and second choices for each infection. The overarching objective was to offer a tool for optimizing the quality of global antibiotic prescribing and reduce inappropriate use by encouraging the use of Access antibiotics (or no antibiotics) where appropriate. This clinical evidence evaluation and subsequent EML recommendations are the basis for the AWaRe antibiotic book and related smartphone applications. By providing guidance on antibiotic prioritization, AWaRe aims to facilitate the revision of national lists of essential medicines, update national prescribing guidelines, and supervise antibiotic use. Adherence to AWaRe would extend the effectiveness of current antibiotics while helping countries expand access to these life-saving medicines for the benefit of current and future patients, health professionals, and the environment.

Neonatal mortality risk of vulnerable newborns by fine stratum of gestational age and birthweight for 230 679 live births in nine low- and middle-income countries, 2000-2017.

OBJECTIVE: To describe the mortality risks by fine strata of gestational age and birthweight among 230 679 live births in nine low- and middle-income countries (LMICs) from 2000 to 2017. DESIGN: Descriptive multi-country secondary data analysis. SETTING: Nine LMICs in sub-Saharan Africa, Southern and Eastern Asia, and Latin America. POPULATION: Liveborn infants from 15 population-based cohorts. METHODS: Subnational, population-based studies with high-quality birth outcome data were invited to join the Vulnerable Newborn Measurement Collaboration. All studies included birthweight, gestational age measured by ultrasound or last menstrual period, infant sex and neonatal survival. We defined adequate birthweight as 2500-3999 g (reference category), macrosomia as ≥4000 g, moderate low as 1500-2499 g and very low birthweight as <1500 g. We analysed fine strata classifications of preterm, term and post-term: ≥42+0 , 39+0 -41+6 (reference category), 37+0 -38+6 , 34+0 -36+6 ,34+0 -36+6 ,32+0 -33+6 , 30+0 -31+6 , 28+0 -29+6 and less than 28 weeks. MAIN OUTCOME MEASURES: Median and interquartile ranges by study for neonatal mortality rates (NMR) and relative risks (RR). We also performed meta-analysis for the relative mortality risks with 95% confidence intervals (CIs) by the fine categories, stratified by regional study setting (sub-Saharan Africa and Southern Asia) and study-level NMR (≤25 versus >25 neonatal deaths per 1000 live births). RESULTS: We found a dose-response relationship between lower gestational ages and birthweights with increasing neonatal mortality risks. The highest NMR and RR were among preterm babies born at <28 weeks (median NMR 359.2 per 1000 live births; RR 18.0, 95% CI 8.6-37.6) and very low birthweight (462.8 per 1000 live births; RR 43.4, 95% CI 29.5-63.9). We found no statistically significant neonatal mortality risk for macrosomia (RR 1.1, 95% CI 0.6-3.0) but a statistically significant risk for all preterm babies, post-term babies (RR 1.3, 95% CI 1.1-1.5) and babies born at 370 -386 weeks (RR 1.2, 95% CI 1.0-1.4). There were no statistically significant differences by region or underlying neonatal mortality. CONCLUSIONS: In addition to tracking vulnerable newborn types, monitoring finer categories of birthweight and gestational age will allow for better understanding of the predictors, interventions and health outcomes for vulnerable newborns. It is imperative that all newborns from live births and stillbirths have an accurate recorded weight and gestational age to track maternal and neonatal health and optimise prevention and care of vulnerable newborns.

Risk factors for moderate acute malnutrition among children with acute diarrhoea in India and Tanzania: a secondary analysis of data from a randomized trial.

BACKGROUND: Moderate acute malnutrition (MAM) affects over 30 million children aged < 5 years worldwide. MAM may confer a greater risk of developing severe malnutrition and even mortality in children. Assessing risk factors for MAM may allow for earlier recognition of children at risk of deleterious health outcomes. OBJECTIVE: To determine risk factors associated with the prevalence and development of MAM among children aged 6 to 59 months with acute diarrhoea who received treatment with oral rehydration solution and zinc supplementation. METHODS: We conducted a secondary analysis of data from a randomized, dose-finding trial of zinc among children with acute diarrhoea in India and Tanzania. We used regression models to assess risk factors for prevalent MAM at the start of diarrhoea treatment and to identify risk factors associated with the development of MAM at 60 days. MAM was defined as weight for length (or height) Z score ≤-2 and > -3 or mid-upper arm circumference < 12.5 and ≥ 11.5 cm. RESULTS: A total of 4,500 children were enrolled; 593 (13.2%) had MAM at the baseline. MAM at baseline was significantly less common among children in Tanzania than in India (adjusted risk ratio [aRR] 0.37, 95% confidence interval [CI]: 0.30, 0.44, P < 0.001), in children aged 24- < 60 months versus 6- < 12 months (aRR 0.46, 95% CI: 0.38, 0.56, P < 0.001), and in families with household wealth index higher than the median (aRR 0.79, 95% CI: 0.68, 0.92, P = 0.002). Sixty days after outpatient treatment and follow-up, 87 (2.5%) children developed MAM. When compared to children aged 6- < 12 months, children aged 24- < 60 months had a 52% lower risk of developing MAM. Every one unit increase in weight for length (or height) Z score at enrolment was associated with a 93% lower risk of developing MAM during follow-up. CONCLUSIONS: Among children with diarrhoea, younger children and those from households with lower wealth were at greater risk of MAM. These children may benefit from targeted interventions focusing on feeding (targeted nutrition support for at-risk households) and follow up in order to reduce the occurrence of MAM and its consequences.

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

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

Statistical analysis plan for the LAKANA trial: a cluster-randomized, placebo-controlled, double-blinded, parallel group, three-arm clinical trial testing the effects of mass drug administration of azithromycin on mortality and other outcomes among 1-11-month-old infants in Mali.

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.

Effect of dietary intervention on the prevalence of asymptomatic malaria among 6-18-month-old children in rural Malawi.

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.

Child Aflatoxin Exposure is Associated with Poor Child Growth Outcomes: A Prospective Cohort Study in Rural Malawi.

Background: Aflatoxin (AF) exposure is associated with child growth faltering in cross-sectional studies, with limited findings from longitudinal studies. Objectives: To evaluate the relationship between maternal AF B1-lysine adduct concentration, child AF B1-lysine adduct concentration, and child growth in the first 30 mo of life. Methods: AF B1-lysine adduct was measured in mother-child dyad plasma samples using isotope dilution mass spectrometry. Using linear regression, we assessed the relationship between AF B1-lysine adduct concentration and child weight, height, and head and mid-upper arm circumferences at 1 wk, 6, 12, 18, 24, and 30 mo of age. Results: In adjusted models, maternal prenatal AF B1-lysine adduct (pg/µL) was positively associated with newborn anthropometric outcomes; largest beta coefficients for associations between standardized values were for newborn weight-for-age z-score [ß = 0.13; 95% confidence interval (CI): 0.02, 0.24; P < 0.05 and ß = 0.11; 95% CI: 0.00, 0.22; P < 0.05 for second and third trimester AF, respectively]. Child AF B1-lysine adduct (pg/µL) at 6 mo was negatively associated with head circumference-for-age z-score at 6, 18, 24, and 30 mo, with beta coefficients ranging from ß = -0.15; 95% CI: -0.28, -0.02 to ß = -0.17; 95% CI: -0.31, -0.03; P < 0.05); 18-mo AF was negatively associated with anthropometric outcomes at 18, 24, and 30 mo, most consistently with length-for-age z-score (ß = -0.18; 95% CI: -0.32, -0.04, ß = -0.21; 95% CI: -0.35, -0.07, ß = -0.18; 95% CI: -0.32, -0.03 at 18, 24 and 30 mo, respectively). Conclusions: Child AF exposure was associated with impaired child growth, but maternal AF exposure was not. Exposure during infancy was linked to persistent deficit in head circumference, implying reduced brain size lasting beyond the age of 2 years. Exposure at 18 mo was linked to persistent linear growth deficit. Further research should elucidate mechanisms through which AF affects child growth.

Parental acceptance of typhoid conjugate vaccine for children aged 6 months to 15 years in an outbreak setting of Lyari Town Karachi, Pakistan.

BACKGROUND: This study aimed to evaluate the parental acceptance of Typhoid Conjugate Vaccine (TCV) and to determine the predictors of TCV vaccination status among children in an outbreak setting of extensively drug resistant (XDR) typhoid fever in Karachi, Pakistan. METHODS: A cross-sectional survey using the WHO recommended rapid vaccine coverage assessment technique was conducted. Out of 11, four union councils (UCs) in Lyari Town were randomly selected. A parent or primary caretaker from the eligible household was interviewed. Data were collected using a locally validated vaccine attitudes scale (VAS). Sum of scores was calculated for VAS. A higher score denoted negative attitudes and perceptions regarding TCV and vice versa. Multivariable logistic regression was performed to determine the predictors of TCV vaccination status. RESULTS: Based on the 14-item parental VAS, 78.0 % of the parents had a score between 0 to <40 and 22 % had a score ≥40. VAS score of <40 was significantly associated with higher odds of receiving TCV during the campaign setting (adjusted Odds Ratio (aOR): 1.30; 95 % Confidence Interval (CI): 1.02, 1.66). The odds of receiving TCV vaccination were higher among children whose parents were aware of the ongoing vaccination campaign in the area (aOR: 4.57; 95 % CI: 2.93, 7.12) and expressed willingness to get their child vaccinated against typhoid fever (aOR: 2.54; 95 % CI: 1.82, 3.55). CONCLUSION: Parental awareness of the ongoing vaccination campaign, positive perception and attitudes towards vaccine were found to be significantly associated with TCV vaccination among children. Appropriately structured pre-vaccination awareness campaigns focused on childhood vaccination targeted towards parents are necessary to improve parental awareness, attitude and behavior towards vaccination.

What more can be done? Prioritizing the most promising antenatal interventions to improve birth weight.

BACKGROUND: Low birth weight (LBW) is associated with neonatal mortality and sequelae of lifelong health problems; prioritizing the most promising antenatal interventions may guide resource allocation and improve health outcomes. OBJECTIVE: We sought to identify the most promising interventions that are not yet included in the policy recommendations of the World Health Organization (WHO) but could complement antenatal care and reduce the prevalence of LBW and related adverse birth outcomes in low- and middle-income settings. METHODS: We utilized an adapted Child Health and Nutrition Research Initiative (CHNRI) prioritization method. RESULTS: In addition to procedures already recommended by WHO for the prevention of LBW, we identified six promising antenatal interventions that are not currently recommended by WHO with an indication for LBW prevention, namely: (1) provision of multiple micronutrients; (2) low-dose aspirin; (3) high-dose calcium; (4) prophylactic cervical cerclage; (5) psychosocial support for smoking cessation; and (6) other psychosocial support for targeted populations and settings. We also identified seven interventions for further implementation research and six interventions for efficacy research. CONCLUSION: These promising interventions, coupled with increasing coverage of currently recommended antenatal care, could accelerate progress toward the global target of a 30% reduction in the number of LBW infants born in 2025 compared to 2006-10.

Antenatal interventions to reduce risk of low birth weight related to maternal infections during pregnancy.

BACKGROUND: Maternal infections during pregnancy have been linked to increased risk of adverse birth outcomes, including low birth weight (LBW), preterm birth (PTB), small for gestational age (SGA), and stillbirth (SB). OBJECTIVES: The purpose of this article was to summarize evidence from published literature on the effect of key interventions targeting maternal infections on adverse birth outcomes. METHODS: We searched MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and CINAHL Complete between March 2020 and May 2020 with an update to cover until August 2022. We included randomized controlled trials (RCTs) and reviews of RCTs of 15 antenatal interventions for pregnant women reporting LBW, PTB, SGA, or SB as outcomes. RESULTS: Of the 15 reviewed interventions, the administration of 3 or more doses of intermittent preventive treatment in pregnancy with sulphadoxine-pyrimethamine [IPTp-SP; RR: 0.80 (95% CI: 0.69, 0.94)] can reduce risk of LBW compared with 2 doses. The provision of insecticide-treated bed nets, periodontal treatment, and screening and treatment of asymptomatic bacteriuria may reduce risk of LBW. Maternal viral influenza vaccination, treatment of bacterial vaginosis, intermittent preventive treatment with dihydroartemisinin-piperaquine compared with IPTp-SP, and intermittent screening and treatment of malaria during pregnancy compared with IPTp were deemed unlikely to reduce the prevalence of adverse birth outcomes. CONCLUSIONS: At present, there is limited evidence from RCTs available for some potentially relevant interventions targeting maternal infections, which could be prioritized for future research.

A modular systematic review of antenatal interventions to address undernutrition during pregnancy in the prevention of low birth weight.

BACKGROUND: Poor nutrition during pregnancy can lead to adverse birth outcomes including low birth weight (LBW). OBJECTIVE: This modular systematic review aimed to provide evidence for the effects of seven antenatal nutritional interventions on the risks of LBW, preterm birth (PTB), small-for-gestational-age (SGA) and stillbirth (SB). METHODS: We searched MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and CINAHL Complete between April and June 2020, with a further update in September 2022 (Embase only). We included randomized controlled trials (RCTs) and reviews of RCTs to estimate the effect sizes of the selected interventions on the four birth outcomes. RESULTS: Evidence suggests that balanced protein and energy (BPE) supplementation for pregnant women with undernutrition can reduce the risk of LBW, SGA and SB. Evidence from low and lower middle-income countries (MIC) suggests that multiple micronutrient (MMN) supplementation can reduce the risk of LBW and SGA in comparison with iron or iron and folic acid supplementation and lipid-based nutrient supplements (LNS) with any quantity of energy can reduce the risk of LBW in comparison with MMN supplementation. Evidence from high and upper MIC suggests that supplementation with omega-3 fatty acids (O3FA) can reduce the risk and supplementation with high-dose calcium might possibly reduce the risk of LBW and PTB. Antenatal dietary education programs might possibly reduce the risk of LBW in comparison with standard-of-care. No RCTs were identified for monitoring weight gain followed by interventions to support weight gain in women who are underweight. CONCLUSIONS: Provision of BPE, MMN and LNS to pregnant women in populations with undernutrition can reduce the risk of LBW and related outcomes. The benefits of O3FA and calcium supplementation to this population require further investigation. Targeting interventions to pregnant women who are not gaining weight has not been tested with RCTs.

Antenatal interventions to address harmful behaviors and psychosocial risk factors in the prevention of low birth weight.

BACKGROUND: Risk factors related to the harmful behaviors, psychosocial wellbeing, and socio-economic circumstances in the lives of pregnant women can lead to adverse birth outcomes, including low birth weight (LBW). OBJECTIVE: This systematic search and review aims to provide a comparative evidence synthesis on the effect of eleven antenatal interventions targeted to address psychosocial risk factors on adverse birth outcomes. METHODS: We searched MEDLINE, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials and CINAHL Complete between March 2020 and May 2020. We included randomized controlled trials (RCTs) and reviews of RCTs of eleven antenatal interventions for pregnant females reporting LBW, preterm birth (PTB), small-for-gestational-age or stillbirth as outcomes. For interventions where randomization was either not feasible or unethical, we accepted non-randomized controlled studies. RESULTS: Seven records contributed data to the quantitative estimates of the effect sizes and 23 contributed to narrative analysis. Psychosocial interventions for reducing smoking in pregnancy likely reduced the risk of LBW, and professionally provided psychosocial support for at-risk women possibly reduced the risk of PTB. Financial incentives or nicotine replacement therapy as smoking cessation aids, or virtually delivered psychosocial support did not appear to reduce the risk of adverse birth outcomes. The available evidence on these interventions was primarily from high-income countries. For other reviewed interventions (psychosocial interventions to reduce alcohol use, group based psychosocial support programs, intimate partner violence prevention interventions, antidepressant medication, and cash transfers) there was little evidence in any direction regarding the efficacy or the data was conflicting. CONCLUSIONS: Professionally provided psychosocial support during pregnancy in general and specifically as a means to reduce smoking can potentially contribute to improved newborn health. The gaps in the investments for research and implementation of psychosocial interventions should be addressed to better meet the global targets in LBW reduction.

A modular systematic review of antenatal interventions targeting modifiable environmental exposures in improving low birth weight.

BACKGROUND: Low birth weight (LBW) increases the risk of short- and long-term morbidity and mortality from early life to adulthood. Despite research effort to improve birth outcomes the progress has been slow. OBJECTIVE: This systematic search and review of English language scientific literature on clinical trials aimed to compare the efficacy antenatal interventions to reduce environmental exposures including a reduction of toxins exposure, and improving sanitation, hygiene, and health-seeking behaviors, which target pregnant women to improve birth outcomes. METHODS: We performed eight systematic searches in MEDLINE (OvidSP), Embase (OvidSP), Cochrane Database of Systematic Reviews (Wiley Cochrane Library), Cochrane Central Register of Controlled Trials (Wiley Cochrane Library), CINAHL Complete (EbscoHOST) between 17 March 2020 and 26 May 2020. RESULTS: Four documents identified describe interventions to reduce indoor air pollution: two randomised controlled trials (RCTs), one systematic review and meta-analysis (SRMA) on preventative antihelminth treatment and one RCT on antenatal counselling against unnecessary caesarean section. Based on the published literature, interventions to reduce indoor air pollution (LBW: RR: 0.90 [0.56, 1.44], PTB: OR: 2.37 [1.11, 5.07]) or preventative antihelminth treatment (LBW: RR: 1.00 [0.79, 1.27], PTB: RR: 0.88 [0.43, 1.78]) are not likely to reduce the risk of LBW or Preterm birth (PTB). Data is insufficient on antenatal counselling against caesarian-sections. For other interventions, there is lack of published research data from RCTs. CONCLUSIONS: We conclude that there is a paucity of evidence from RCT on interventions that modify environmental risk factors during pregnancy to potentially improve birth outcomes. Magic bullets approach might not work and that it would be important to study the effect of the broader interventions, particularly in LMIC settings. Global interdisciplinary action to reduce harmful environmental exposures, is likely to help to reach global targets for LBW reduction and sustainably improve long-term population health.

Fetal sex and risk of pregnancy-associated malaria in Plasmodium falciparum-endemic regions: a meta-analysis.

In areas of moderate to intense Plasmodium falciparum transmission, malaria in pregnancy remains a significant cause of low birth weight, stillbirth, and severe anaemia. Previously, fetal sex has been identified to modify the risks of maternal asthma, pre-eclampsia, and gestational diabetes. One study demonstrated increased risk of placental malaria in women carrying a female fetus. We investigated the association between fetal sex and malaria in pregnancy in 11 pregnancy studies conducted in sub-Saharan African countries and Papua New Guinea through meta-analysis using log binomial regression fitted to a random-effects model. Malaria infection during pregnancy and delivery was assessed using light microscopy, polymerase chain reaction, and histology. Five studies were observational studies and six were randomised controlled trials. Studies varied in terms of gravidity, gestational age at antenatal enrolment and bed net use. Presence of a female fetus was associated with malaria infection at enrolment by light microscopy (risk ratio 1.14 [95% confidence interval 1.04, 1.24]; P = 0.003; n = 11,729). Fetal sex did not associate with malaria infection when other time points or diagnostic methods were used. There is limited evidence that fetal sex influences the risk of malaria infection in pregnancy.

Low length-for-age Z-score within 1 month after birth predicts hyperdynamic circulation at the age of 21 years in rural Malawi.

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 < 0.01). Left cardiac work was 6.8% and 6.9% higher in the lowest tertile than in the middle and highest tertiles, respectively (p < 0.01). To conclude, in a low-income environment, low length-for-age Z-score after birth predicted hyperdynamic circulation at 21 years of age without changes in blood pressure and metabolic variables.

Neonatal mortality risk of vulnerable newborns: A descriptive analysis of subnational, population-based birth cohorts for 238 203 live births in low- and middle-income settings from 2000 to 2017.

OBJECTIVE: We aimed to understand the mortality risks of vulnerable newborns (defined as preterm and/or born weighing smaller or larger compared to a standard population), in low- and middle-income countries (LMICs). DESIGN: Descriptive multi-country, secondary analysis of individual-level study data of babies born since 2000. SETTING: Sixteen subnational, population-based studies from nine LMICs in sub-Saharan Africa, Southern and Eastern Asia, and Latin America. POPULATION: Live birth neonates. METHODS: We categorically defined five vulnerable newborn types based on size (large- or appropriate- or small-for-gestational age [LGA, AGA, SGA]), and term (T) and preterm (PT): T + LGA, T + SGA, PT + LGA, PT + AGA, and PT + SGA, with T + AGA (reference). A 10-type definition included low birthweight (LBW) and non-LBW, and a four-type definition collapsed AGA/LGA into one category. We performed imputation for missing birthweights in 13 of the studies. MAIN OUTCOME MEASURES: Median and interquartile ranges by study for the prevalence, mortality rates and relative mortality risks for the four, six and ten type classification. RESULTS: There were 238 203 live births with known neonatal status. Four of the six types had higher mortality risk: T + SGA (median relative risk [RR] 2.6, interquartile range [IQR] 2.0-2.9), PT + LGA (median RR 7.3, IQR 2.3-10.4), PT + AGA (median RR 6.0, IQR 4.4-13.2) and PT + SGA (median RR 10.4, IQR 8.6-13.9). T + SGA, PT + LGA and PT + AGA babies who were LBW, had higher risk compared with non-LBW babies. CONCLUSIONS: Small and/or preterm babies in LIMCs have a considerably increased mortality risk compared with babies born at term and larger. This classification system may advance the understanding of the social determinants and biomedical risk factors along with improved treatment that is critical for newborn health.