What can work and how? An overview of evidence-based interventions and delivery strategies to support health and human development from before conception to 20 years.

Progress has been made globally in improving the coverage of key maternal, newborn, and early childhood interventions in low-income and middle-income countries, which has contributed to a decrease in child mortality and morbidity. However, inequities remain, and many children and adolescents are still not covered by life-saving and nurturing care interventions, despite their relatively low costs and high cost-effectiveness. This Series paper builds on a large body of work from the past two decades on evidence-based interventions and packages of care for survival, strategies for delivery, and platforms to reach the most vulnerable. We review the current evidence base on the effectiveness of a variety of essential and emerging interventions that can be delivered from before conception until age 20 years to help children and adolescents not only survive into adulthood, but also to grow and develop optimally, support their wellbeing, and help them reach their full developmental potential. Although scaling up evidence-based interventions in children younger than 5 years might have the greatest effect on reducing child mortality rates, we highlight interventions and evidence gaps for school-age children (5-9 years) and the transition from childhood to adolescence (10-19 years), including interventions to support mental health and positive development, and address unintentional injuries, neglected tropical diseases, and non-communicable diseases.

Training health workers in clinical breast examination for early detection of breast cancer in low- and middle-income countries.

BACKGROUND: Most women living in low- and middle-income countries (LMICs) present with advanced-stage breast cancer. Limitations of poor serviceable health systems, restricted access to treatment facilities, and lack of breast cancer screening programmes all likely contribute to the late presentation of women with breast cancer living in these countries. Women are diagnosed with advanced disease and frequently do not complete their care due to a number of factors, including financial reasons as health expenditure is largely out of pocket resulting in financial toxicity; health system failures, such as missing services or health worker lack of awareness on common signs and symptoms of cancer; and sociocultural barriers, such as stigma and use of alternative therapies. Clinical breast examination (CBE) is an inexpensive early detection technique for breast cancer in women with palpable breast masses. Training health workers from LMICs to conduct CBE has the potential to improve the quality of the technique and the ability of health workers to detect breast cancers early. OBJECTIVES: To assess whether training in CBE affects the ability of health workers in LMICs to detect early breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Specialised Registry, CENTRAL, MEDLINE, Embase, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) search portal, and ClinicalTrials.gov up to 17 July 2021. SELECTION CRITERIA: We included randomised controlled trials (RCTs) (including individual and cluster-RCTs), quasi-experimental studies and controlled before-and-after studies if they fulfilled the eligibility criteria. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for inclusion, and extracted data, assessed risk of bias, and assessed the certainty of the evidence using the GRADE approach. We performed statistical analysis using Review Manager software and presented the main findings of the review in a summary of findings table. MAIN RESULTS: We included four RCTs that screened a total population of 947,190 women for breast cancer, out of which 593 breast cancers were diagnosed. All included studies were cluster-RCTs; two were conducted in India, one in the Philippines, and one in Rwanda. Health workers trained to perform CBE in the included studies were primary health workers, nurses, midwives, and community health workers. Three of the four included studies reported on the primary outcome (breast cancer stage at the time of presentation). Amongst secondary outcomes, included studies reported CBE coverage, follow-up, accuracy of health worker-performed CBE, and breast cancer mortality. None of the included studies reported knowledge attitude practice (KAP) outcomes and cost-effectiveness. Three studies reported diagnosis of breast cancer at early stage (at stage 0+I+II), suggesting that training health workers in CBE may increase the number of women detected with breast cancer at an early stage compared to the non-training group (45% detected versus 31% detected; risk ratio (RR) 1.44, 95% confidence interval (CI) 1.01 to 2.06; three studies; 593 participants; I2 = 0%; low-certainty evidence). Three studies reported diagnosis at late stage (III+IV) suggesting that training health workers in CBE may slightly reduce the number of women detected with breast cancer at late stage compared to the non-training group (13% detected versus 42%, RR 0.58, 95% CI 0.36 to 0.94; three studies; 593 participants; I2 = 52%; low-certainty evidence). Regarding secondary outcomes, two studies reported breast cancer mortality, implying that the evidence is uncertain for the impact on breast cancer mortality (RR 0.88, 95% CI 0.24 to 3.26; two studies; 355 participants; I2 = 68%; very low-certainty evidence). Due to the study heterogeneity, we could not conduct meta-analysis for accuracy of health worker-performed CBE, CBE coverage, and completion of follow-up, and therefore reported narratively using the 'Synthesis without meta-analysis' (SWiM) guideline. Sensitivity of health worker-performed CBE was reported to be 53.2% and 51.7%; while specificity was reported to be 100% and 94.3% respectively in two included studies (very low-certainty evidence). One trial reported CBE coverage with a mean adherence of 67.07% for the first four screening rounds (low-certainty evidence). One trial reported follow-up suggesting that compliance rates for diagnostic confirmation following a positive CBE were 68.29%, 71.20%, 78.84% and 79.98% during the respective first four rounds of screening in the intervention group compared to 90.88%, 82.96%, 79.56% and 80.39% during the respective four rounds of screening in the control group. AUTHORS' CONCLUSIONS: Our review findings suggest some benefit of training health workers from LMICs in CBE on early detection of breast cancer. However, the evidence regarding mortality, accuracy of health worker-performed CBE, and completion of follow up is uncertain and requires further evaluation.

A century past the discovery of insulin: global progress and challenges for type 1 diabetes among children and adolescents in low-income and middle-income countries.

Type 1 diabetes is on the rise globally; however, the burden of mortality remains disproportionate in low-income and middle-income countries (LMICs). As 2021 marks 100 years since the discovery of insulin, we revisit progress, global burden of type 1 diabetes trends, and understanding of the pathogenesis and management practices related to the disease. Despite much progress, inequities in access and availability of insulin formulations persist and are reflected in differences in survival and morbidity patterns related to the disease. Some of these inequities have also been exacerbated by health-system challenges during the COVID-19 pandemic. There is a clear opportunity to improve access to insulin and related essential technologies for improved management of type 1 diabetes in LMICs, especially as a part of universal health coverage. These improvements will require concerted action and investments in human resources, community engagement, and education for the timely diagnosis and management of type 1 diabetes, as well as adequate health-care financing. Further research in LMICs, especially those in Africa, is needed to improve our understanding of the burden, risk factors, and implementation strategies for managing type 1 diabetes.

Effect of mass deworming with antihelminthics for soil-transmitted helminths during pregnancy.

BACKGROUND: Helminthiasis is an infestation of the human body with parasitic worms. It is estimated to affect 44 million pregnancies, globally, each year. Intestinal helminthiasis (hookworm infestation) is associated with blood loss and decreased supply of nutrients for erythropoiesis, resulting in iron-deficiency anaemia. Over 50% of the pregnant women in low- and middle-income countries (LMIC) suffer from iron-deficiency anaemia. Though iron-deficiency anaemia is multifactorial, hookworm infestation is a major contributory cause in women of reproductive age in endemic areas. Antihelminthics are highly efficacious, but evidence of their beneficial effect and safety when given during pregnancy has not been established. This is an update of a Cochrane Review last published in 2015. OBJECTIVES: To determine the effects of mass deworming with antihelminthics for soil-transmitted helminths (STH) during the second or third trimester of pregnancy on maternal and pregnancy outcomes. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (ICTRP) (8 March 2021) and reference lists of retrieved studies. SELECTION CRITERIA: We included all prospective randomised controlled trials evaluating the effect of administration of antihelminthics versus placebo or no treatment during the second or third trimester of pregnancy; both individual-randomised and cluster-randomised trials were eligible. We excluded quasi-randomised trials and studies that were only available as abstracts with insufficient information. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data, checked accuracy and assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included a total of six trials (24 reports) that randomised 7873 pregnant women. All of the included trials were conducted in antenatal clinics within hospitals in LMICs (Uganda, Nigeria, Peru, India, Sierra Leone and Tanzania). Among primary outcomes, five trials reported maternal anaemia, one trial reported preterm birth and three trials reported perinatal mortality. Among secondary outcomes, included trials reported maternal worm prevalence, low birthweight (LBW) and birthweight. None of the included studies reported maternal anthropometric measures or infant survival at six months. Overall, we judged the included trials to be generally at low risk of bias for most domains, while the certainty of evidence ranged from low to moderate. Analysis suggests that administration of a single dose of antihelminthics in the second trimester of pregnancy may reduce maternal anaemia by 15% (average risk ratio (RR) 0.85, 95% confidence interval (CI) 0.72 to 1.00; I²= 86%; 5 trials, 5745 participants; low-certainty evidence). We are uncertain of the effect of antihelminthics during pregnancy on preterm birth (RR 0.84, 95% CI 0.38 to 1.86; 1 trial, 1042 participants; low-certainty evidence) or perinatal mortality (RR 1.01, 95% CI 0.67 to 1.52; 3 trials, 3356 participants; low-certainty evidence). We are uncertain of the effect of antihelminthics during pregnancy on hookworm (average RR 0.31, 95% CI 0.05 to 1.93; Tau² = 1.76, I² = 99%; 2 trials, 2488 participants; low-certainty evidence). Among other secondary outcomes, findings suggest that administration of antihelminthics during pregnancy may reduce the prevalence of trichuris (average RR 0.68, 95% CI 0.48 to 0.98; I²=75%; 2 trials, 2488 participants; low-certainty evidence) and ascaris (RR 0.24, 95% CI 0.19 to 0.29; I²= 0%; 2 trials, 2488 participants; moderate-certainty evidence). Antihelminthics during pregnancy probably make little or no difference to LBW (RR 0.89, 95% CI 0.69 to 1.16; 3 trials, 2960 participants; moderate-certainty evidence) and birthweight (mean difference 0.00 kg, 95% CI -0.03 kg to 0.04 kg; 3 trials, 2960 participants; moderate-certainty evidence). AUTHORS' CONCLUSIONS: The evidence suggests that administration of a single dose of antihelminthics in the second trimester of pregnancy may reduce maternal anaemia and worm prevalence when used in settings with high prevalence of maternal helminthiasis. Further data is needed to establish the benefit of antihelminthic treatment on other maternal and pregnancy outcomes. Future research should focus on evaluating the effect of these antihelminthics among various subgroups in order to assess whether the effect varies. Future studies could also assess the effectiveness of co-interventions and health education along with antihelminthics for maternal and pregnancy outcomes.

Antibiotic therapy versus no antibiotic therapy for children aged 2 to 59 months with WHO-defined non-severe pneumonia and wheeze.

BACKGROUND: Worldwide, pneumonia is the leading cause of death amongst children under five years of age, and accounts for approximately two million deaths annually. Pneumonia can be classified according to the World Health Organization (WHO) guidelines. Classification includes assessment of certain clinical signs and symptoms, and the severity of the disease. Treatment is then tailored according to the classification. For non-severe pneumonia, the WHO recommends treatment with oral antibiotics. We used the 2014 WHO definition of non-severe pneumonia for this review: an acute episode of cough, or difficulty in breathing, combined with fast breathing and chest indrawing. The WHO recommends treating non-severe pneumonia with oral antibiotics. Pneumonia is more commonly caused by viruses that do not require antibiotic treatment, but pneumonia caused by bacteria needs management with antibiotics to avoid complications. There is no clear way to quickly distinguish between viral and bacterial pneumonia. It is considered safe to give antibiotics, however, this may lead to the development of antibiotic resistance, and thus, limit their use in future infections. Therefore, it is essential to explore the efficacy of antibiotics for children with WHO-defined non-severe pneumonia and wheeze. OBJECTIVES: To evaluate the efficacy of antibiotic therapy versus no antibiotic therapy for children aged 2 to 59 months with WHO-defined non-severe pneumonia and wheeze. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, four other databases, and two trial registers (December 2020). SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating the efficacy of antibiotic therapy versus no antibiotic therapy for children, aged 2 to 59 months, with non-severe pneumonia and wheeze. We defined non-severe pneumonia as 'a cough or difficulty in breathing, with rapid breathing (a respiratory rate of 50 breaths per minute or more for children aged 2 to 12 months, or a respiratory rate of 40 breaths per minute or more for children aged 12 to 59 months), chest indrawing and wheeze'. We excluded trials involving children with severe or very severe pneumonia, and non-RCTs. DATA COLLECTION AND ANALYSIS: Our primary outcomes were clinical cure and treatment failure; secondary outcomes were relapse, mortality, and treatment harms. We used standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of the evidence. Two review authors independently assessed the search results, extracted data, assessed risk of bias and the certainty of the evidence. We contacted the authors of two included trials and the author of the trial awaiting classification to obtain missing numerical outcome data. MAIN RESULTS: We included three trials involving 3256 children aged between 2 to 59 months, who exhibited features of non-severe pneumonia with wheeze. The included trials were multi-centre, double-blind, randomised, placebo-controlled trials carried out in Malawi, Pakistan, and India. The children were treated with a three-day course of amoxicillin or placebo, and were followed up for a total of two weeks. We assessed the included trials at overall low risk of bias for random sequence generation, allocation concealment, blinding, attrition bias, and selective reporting. Only one trial was assessed to be at high risk for blinding of outcome assessors. One trial is awaiting classification Antibiotic therapy may result in a reduction of treatment failure by 20% (risk ratio (RR) 0.80, 95% confidence interval (CI) 0.68 to 0.94; three trials; 3222 participants; low-certainty evidence). Antibiotic therapy probably results in little or no difference to clinical cure (RR 1.02, 95% CI 0.96 to 1.08; one trial; 456 participants; moderate-certainty evidence), and in little or no difference to relapse (RR 1.00, 95% CI 0.74 to 1.34; three trials; 2795 participants; low-certainty evidence), and treatment harms (RR 0.81, 95% CI 0.60 to 1.09; three trials, 3253 participants; low-certainty evidence). Two trials (2112 participants ) reported on mortality; no deaths occurred in either group. One trial reported cases of hospitalisation, diarrhoea (with and without dehydration), rash (without itch), tremors, mild nausea and vomiting. AUTHORS' CONCLUSIONS: We do not currently have enough evidence to support or challenge the continued use of antibiotics for the treatment of non-severe pneumonia. There is a clear need for RCTs to address this question in children aged 2 to 59 months with 2014 WHO-defined non-severe pneumonia and wheeze.

Vitamin C supplementation for prevention and treatment of pneumonia.

BACKGROUND: According to the Global Burden of Disease Study 2015, lower respiratory tract infection is the leading cause of infectious disease death, and the fifth most common cause of death overall. Vitamin C has a role in modulating resistance to infectious agents, therefore vitamin C supplementation may be important in preventing and treating pneumonia. OBJECTIVES: To assess the impact of vitamin C supplementation to prevent and treat pneumonia in children and adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, PubMed, CINAHL, LILACS, Web of Science, and two trials registers to 4 March 2020. We also checked references to identify additional studies. We did not apply any publication status or language filters. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs (studies using allocation methods that are not random, e.g. date of birth, medical record number) assessing the role of vitamin C supplementation in the prevention and treatment of pneumonia in children and adults compared to control or placebo. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included five studies in the review and identified two ongoing studies. The five included studies involved a total of 2655 participants; two studies were RCTs and three were quasi-RCTs. The included studies were conducted in one high-income country (USA) and three lower-middle-income countries (Bangladesh and Pakistan). Three studies were conducted in hospital inpatient settings, one in school, and one in a military training centre. Three studies included children under five years of age, one study included school-aged children, and one study included adult participants. Two studies assessed the effect of vitamin C supplementation for pneumonia prevention; and three studies assessed the effect of vitamin C supplementation as an adjunct to pneumonia treatment. For pneumonia prevention, the included studies provided supplementation in doses of 1 g daily for 14 weeks, 2 g daily for 8 weeks, and 2 g daily for 14 weeks. For pneumonia treatment, the included studies provided vitamin C supplementation in doses of 125 mg daily and 200 mg daily until the symptoms resolved or discharge, as an adjunct to the pneumonia treatment. Overall, the included studies were judged to be at either high or unclear risk of bias for random sequence generation, allocation concealment, and blinding; and the evidence certainty was very low. Two studies assessed the effect of vitamin C supplementation for pneumonia prevention; we judged the certainty of the evidence as very low. We are uncertain about the effect of vitamin C supplementation on pneumonia incidence and adverse events (urticaria). None of the included studies reported other primary outcomes (pneumonia prevalence and mortality) or any of the secondary outcomes. Three studies assessed the effect of vitamin C supplementation as an adjunct to pneumonia treatment; we judged the certainty of the evidence as very low. We are uncertain of the effect of vitamin C supplementation on duration of illness and hospitalisation. None of the included studies reported other primary or secondary outcomes. AUTHORS' CONCLUSIONS: Due to the small number of included studies and very low certainty of the existing evidence, we are uncertain of the effect of vitamin C supplementation for the prevention and treatment of pneumonia. Further good-quality studies are required to assess the role of vitamin C supplementation in the prevention and treatment of pneumonia.

Differences in pregnancy and perinatal outcomes among symptomatic versus asymptomatic COVID-19-infected pregnant women: a systematic review and meta-analysis.

BACKGROUND: There is dearth of information on COVID-19's impact on pregnant women. However, literature reported trends of COVID-19 differ, depending on the presence of clinical features upon presentation. OBJECTIVE: This systematic review aimed to assess differences in risk factors, management, complications, and pregnancy and perinatal outcomes in symptomatic vs. asymptomatic pregnant women with confirmed SARS-CoV-2 infection. METHODS: A search was run on electronic databases to identify studies reporting COVID-19 in pregnancy. Meta-analysis was performed and odds ratios and mean difference with 95% confidence intervals were calculated using Review Manager 5.4. Review Prospero registration number CRD42020204662. RESULTS: We included ten articles reporting data from 3158 pregnancies; with 1900 symptomatic and 1258 asymptomatic pregnant women. There was no significant difference in the mean age, gestational age, and body mass index between the two groups. The meta-analysis suggested that pregnant women who were obese (OR:1.37;95%CI:1.15 to 1.62), hypertensive (OR:2.07;95%CI:1.38 to 3.10) or had a respiratory disorder (OR:1.64;95%CI:1.25 to 2.16), were more likely to be symptomatic when infected with SARS-CoV-2. Pregnant women with Black (OR:1.48;95%CI:1.19 to 1.85) or Asian (OR:1.64;95%CI:1.23 to 2.18) ethnicity were more likely to be symptomatic while those with White ethnicity (OR:0.63;95%CI:0.52 to 0.76) were more likely to be asymptomatic. Cesarean-section delivery (OR:1.40;95%CI:1.17 to 1.67) was more likely amongst symptomatic pregnant women. The mean birthweight(g) (MD:240.51;95%CI:188.42 to 293.51), was significantly lower, while the odds of low birthweight (OR:1.85;95%CI:1.06 to 3.24) and preterm birth (< 37 weeks) (OR:2.10;95%CI:1.04 to 4.23) was higher amongst symptomatic pregnant women. Symptomatic pregnant women had a greater requirement for maternal ICU admission (OR:13.25;95%CI:5.60 to 31.34) and mechanical ventilation (OR:15.56;95%CI:2.96 to 81.70) while their neonates had a higher likelihood for Neonatal Intensive Care Unit admission (OR:1.96;95%CI:1.59 to 2.43). The management strategies in the included studies were poorly discussed, hence could not be analyzed. CONCLUSION: The evidence suggests that the presence of risk factors (co-morbidities and ethnicity) increased the likelihood of pregnant women being symptomatic. Higher odds of complications were also observed amongst symptomatic pregnant women. However, more adequately conducted studies with adjusted analysis and parallel comparison groups are required to reach conclusive findings.

Vitamin C supplementation for prevention and treatment of pneumonia.

BACKGROUND: According to the Global Burden of Disease Study 2015, lower respiratory tract infection is the leading cause of infectious disease death, and the fifth most common cause of death overall. Vitamin C has a role in modulating resistance to infectious agents, therefore vitamin C supplementation may be important in preventing and treating pneumonia. OBJECTIVES: To assess the impact of vitamin C supplementation to prevent and treat pneumonia in children and adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, PubMed, CINAHL, LILACS, Web of Science, and two trials registers to 4 March 2020. We also checked references to identify additional studies. We did not apply any publication status or language filters. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs (studies using allocation methods that are not random, e.g. date of birth, medical record number) assessing the role of vitamin C supplementation in the prevention and treatment of pneumonia in children and adults compared to control or placebo. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included seven studies in the review and identified two ongoing studies. The seven included studies involved a total of 2774 participants; five studies were RCTs and two were quasi-RCTs. The included studies were conducted in high-income countries (UK, USA and Chile) and lower-middle-income countries (Bangladesh and Pakistan). Four studies were conducted in hospital inpatient settings, two in schools, and one in a military training centre. Three studies included children under five years of age, two school-aged children, one adult participants, and one older participants aged 60 to 90 years. Two studies assessed the effect of vitamin C supplementation for pneumonia prevention; four studies assessed the effect of vitamin C supplementation as an adjunct to pneumonia treatment; and one study assessed the role of vitamin C for both prevention and treatment of pneumonia. For pneumonia prevention, the included studies provided supplementation in doses of 500 mg daily for 14 weeks, 2 g daily for 8 weeks, and 2 g daily for 12 weeks. For pneumonia treatment, the included studies provided vitamin C supplementation in doses of 125 mg daily (until discharge), 200 mg for 4 weeks, and 200 mg until discharge, as an adjunct to the pneumonia treatment. We assessed the included studies as at overall either high or unclear risk of bias for random sequence generation, allocation concealment, and blinding. We judged the quality of the evidence as very low. Three studies assessed the effect of vitamin C supplementation for pneumonia prevention; we judged the quality of the evidence as very low. We are uncertain about the effect of vitamin C supplementation on pneumonia incidence (risk ratio (RR) 0.46, 95% confidence interval (CI) 0.06 to 3.61; 2 studies, 736 participants; I² = 75%; very low-quality evidence) and adverse events (urticaria) (RR 3.11, 95% CI 0.13 to 76.03; 1 study, 674 participants; very low-quality evidence). No included studies reported our other primary outcomes (pneumonia prevalence and mortality) or any of our secondary outcomes. Five studies assessed the effect of vitamin C supplementation as an adjunct to pneumonia treatment; we judged the quality of the evidence as very low. One study reported a decrease in the duration of illness in the vitamin C supplementation group (3.4 days ± 2.54) compared to the control group (4.5 days ± 2.35), and one study reported a decrease in number of days required for improvement in oxygen saturation (1.03 days ± 0.16 versus 1.14 days ± 1.0) and respiratory rate (3.61 days ± 1.50 versus 4.04 days ± 1.62) in the vitamin C supplementation group compared to the control group. We are uncertain of the effect of vitamin C supplementation on mortality due to pneumonia (RR 0.21, 95% CI 0.03 to 1.66; 1 study, 57 participants; very low-quality evidence). One study reported that the mean duration of hospital stay was 6.75 days amongst children in the vitamin C supplementation group and 7.75 days in the control group; another study reported a lower mean duration of hospital stay in the vitamin C supplementation group compared to the control group (109.55 hours ± 27.89 versus 130.64 hours ± 41.76). AUTHORS' CONCLUSIONS: Due to the small number of included studies and very low quality of the existing evidence, we are uncertain of the effect of vitamin C supplementation for the prevention and treatment of pneumonia. Further good-quality studies are required to assess the role of vitamin C supplementation in the prevention and treatment of pneumonia.

Antenatal magnesium sulphate and adverse neonatal outcomes: A systematic review and meta-analysis.

BACKGROUND: There is widespread, increasing use of magnesium sulphate in obstetric practice for pre-eclampsia, eclampsia, and preterm fetal neuroprotection; benefit for preventing preterm labour and birth (tocolysis) is unproven. We conducted a systematic review and meta-analysis to assess whether antenatal magnesium sulphate is associated with unintended adverse neonatal outcomes. METHODS AND FINDINGS: CINAHL, Cochrane Library, LILACS, MEDLINE, Embase, TOXLINE, and Web of Science, were searched (inceptions to 3 September 2019). Randomised, quasi-randomised, and non-randomised trials, cohort and case-control studies, and case reports assessing antenatal magnesium sulphate for pre-eclampsia, eclampsia, fetal neuroprotection, or tocolysis, compared with placebo/no treatment or a different magnesium sulphate regimen, were included. The primary outcome was perinatal death. Secondary outcomes included pre-specified and non-pre-specified adverse neonatal outcomes. Two reviewers screened 5,890 articles, extracted data, and assessed risk of bias following Cochrane Handbook and RTI Item Bank guidance. For randomised trials, pooled risk ratios (RRs) or mean differences, with 95% confidence intervals (CIs), were calculated using fixed- or random-effects meta-analysis. Non-randomised data were tabulated and narratively summarised. We included 197 studies (40 randomised trials, 138 non-randomised studies, and 19 case reports), of mixed quality. The 40 trials (randomising 19,265 women and their babies) were conducted from 1987 to 2018 across high- (16 trials) and low/middle-income countries (23 trials) (1 mixed). Indications included pre-eclampsia/eclampsia (24 trials), fetal neuroprotection (7 trials), and tocolysis (9 trials); 18 trials compared magnesium sulphate with placebo/no treatment, and 22 compared different regimens. For perinatal death, no clear difference in randomised trials was observed between magnesium sulphate and placebo/no treatment (RR 1.01; 95% CI 0.92 to 1.10; 8 trials, 13,654 babies), nor between regimens. Eleven of 138 non-randomised studies reported on perinatal death. Only 1 cohort (127 babies; moderate to high risk of bias) observed an increased risk of perinatal death with >48 versus ≤48 grams magnesium sulphate exposure for tocolysis. No clear secondary adverse neonatal outcomes were observed in randomised trials, and a very limited number of possible adverse outcomes warranting further consideration were identified in non-randomised studies. Where non-randomised studies observed possible harms, often no or few confounders were controlled for (moderate to high risk of bias), samples were small (200 babies or fewer), and/or results were from subgroup analyses. Limitations include missing data for important outcomes across most studies, heterogeneity of included studies, and inclusion of published data only. CONCLUSIONS: Our findings do not support clear associations between antenatal magnesium sulphate for beneficial indications and adverse neonatal outcomes. Further large, high-quality studies (prospective cohorts or individual participant data meta-analyses) assessing specific outcomes, or the impact of regimen, pregnancy, or birth characteristics on these outcomes, would further inform safety recommendations. PROSPERO: CRD42013004451.

Preventive lipid-based nutrient supplements given with complementary foods to infants and young children 6 to 23 months of age for health, nutrition, and developmental outcomes.

BACKGROUND: One nutritional intervention advocated to prevent malnutrition among children is lipid-based nutrient supplements (LNS). LNS provide a range of vitamins and minerals, but unlike most other micronutrient supplements, LNS also provide energy, protein and essential fatty acids. Alternative recipes and formulations to LNS include fortified blended foods (FBF), which are foods fortified with vitamins and minerals, and micronutrient powders (MNP), which are a combination of vitamins and minerals, OBJECTIVES: To assess the effects and safety of preventive LNS given with complementary foods on health, nutrition and developmental outcomes of non-hospitalised infants and children six to 23 months of age, and whether or not they are more effective than other foods (including FBF or MNP).This review did not assess the effects of LNS as supplementary foods or therapeutic foods in the management of moderate and severe acute malnutrition. SEARCH METHODS: In October 2018, we searched CENTRAL, MEDLINE, Embase, 21 other databases and two trials registers for relevant studies. We also checked the reference lists of included studies and relevant reviews and contacted the authors of studies and other experts in the area for any ongoing and unpublished studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs that evaluated the impact of LNS plus complementary foods given at point-of-use (for any dose, frequency, duration) to non-hospitalised infants and young children aged six to 23 months in stable or emergency settings and compared to no intervention, other supplementary foods (i.e. FBF), nutrition counselling or multiple micronutrient supplements or powders for point-of-use fortification of complementary foods. DATA COLLECTION AND ANALYSIS: Two review authors independently screened studies for relevance and, for those studies included in the review, extracted data, assessed risk of bias and rated the quality of the evidence using the GRADE approach. We carried out statistical analysis using Review Manager software. We used a random-effects meta-analysis for combining data as the interventions differed significantly. We set out the main findings of the review in 'Summary of findings' tables,. MAIN RESULTS: Our search identified a total of 8124 records, from which we included 17 studies (54 papers) with 23,200 children in the review. The included studies reported on one or more of the pre-specified primary outcomes, and five studies included multiple comparison groups.Overall, the majority of trials were at low risk of bias for random sequence generation, allocation concealment, blinding of outcome assessment, incomplete outcome data, selective reporting and other sources of bias, but at high risk of bias for blinding of participants and personnel due to the nature of the intervention. Using the GRADE approach, we judged the quality of the evidence for most outcomes as low or moderate.LNS+complementary feeding compared with no intervention Thirteen studies compared LNS plus complementary feeding with no intervention. LNS plus complementary feeding reduced the prevalence of moderate stunting by 7% (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.88 to 0.98; nine studies, 13,372 participants; moderate-quality evidence), severe stunting by 15% (RR 0.85, 95% CI 0.74 to 0.98; five studies, 6151 participants; moderate-quality evidence), moderate wasting by 18% (RR 0.82, 95% CI 0.74 to 0.91; eight studies; 13,172 participants; moderate-quality evidence), moderate underweight by 15% (RR 0.85, 95% CI 0.80 to 0.91; eight studies, 13,073 participants; moderate-quality evidence), and anaemia by 21% (RR 0.79, 95% CI 0.69 to 0.90; five studies, 2332 participants; low-quality evidence). There was no impact of LNS plus complementary feeding on severe wasting (RR 1.27, 95% CI 0.66 to 2.46; three studies, 2329 participants) and severe underweight (RR 0.78, 95%CI 0.54 to 1.13; two studies, 1729 participants). Adverse effects did not differ between the groups (RR 0.86, 95% CI 0.74 to 1.01; three studies, 3382 participants).LNS+complementary feeding compared with FBF Five studies compared LNS plus complementary feeding with other FBF, including corn soy blend and UNIMIX. We pooled four of the five studies in meta-analyses and found that, when compared to other FBF, LNS plus complementary feeding significantly reduced the prevalence of moderate stunting (RR 0.89, 95% CI 0.82 to 0.97; three studies, 2828 participants; moderate-quality evidence), moderate wasting (RR 0.79, 95% CI 0.65 to 0.97; two studies, 2290 participants; moderate-quality evidence), and moderate underweight (RR 0.81, 95% CI 0.73 to 0.91; two studies, 2280 participants; moderate-quality evidence). We found no difference between LNS plus complementary feeding and FBF for severe stunting (RR 0.41, 95% CI 0.12 to 1.42; two studies, 729 participants; low-quality evidence), severe wasting (RR 0.64, 95% CI 0.19 to 2.81; two studies, 735 participants; moderate-quality evidence), and severe underweight (RR 1.23, 95% CI 0.67 to 2.25; one study, 173 participants; low-quality evidence).LNS+complementary feeding compared with MNP Four studies compared LNS plus complementary feeding with MNP. We pooled data from three of the four studies in meta-analyses and found that compared to MNP, LNS plus complementary feeding significantly reduced the prevalence of moderate underweight (RR 0.88, 95% CI 0.78 to 0.99; two studies, 2004 participants; moderate-quality evidence) and anaemia (RR 0.38, 95% CI 0.21 to 0.68; two studies, 557 participants; low-quality evidence). There was no difference between LNS plus complementary feeding and MNP for moderate stunting (RR 0.92, 95% CI 0.82 to 1.02; three studies, 2365 participants) and moderate wasting (RR 0.97, 95% CI 0.77 to 1.23; two studies, 2004 participants). AUTHORS' CONCLUSIONS: The findings of this review suggest that LNS plus complementary feeding compared to no intervention is effective at improving growth outcomes and anaemia without adverse effects among children aged six to 23 months in low- and middle-income countries (LMIC) in Asia and Africa, and more effective if provided over a longer duration of time (over 12 months). Limited evidence also suggests that LNS plus complementary feeding is more effective than FBF and MNP at improving growth outcomes.

Food fortification with multiple micronutrients: impact on health outcomes in general population.

BACKGROUND: Vitamins and minerals are essential for growth and maintenance of a healthy body, and have a role in the functioning of almost every organ. Multiple interventions have been designed to improve micronutrient deficiency, and food fortification is one of them. OBJECTIVES: To assess the impact of food fortification with multiple micronutrients on health outcomes in the general population, including men, women and children. SEARCH METHODS: We searched electronic databases up to 29 August 2018, including the Cochrane Central Register of Controlled Trial (CENTRAL), the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register and Cochrane Public Health Specialised Register; MEDLINE; Embase, and 20 other databases, including clinical trial registries. There were no date or language restrictions. We checked reference lists of included studies and relevant systematic reviews for additional papers to be considered for inclusion. SELECTION CRITERIA: We included randomised controlled trials (RCTs), cluster-RCTs, quasi-randomised trials, controlled before-after (CBA) studies and interrupted time series (ITS) studies that assessed the impact of food fortification with multiple micronutrients (MMNs). Primary outcomes included anaemia, micronutrient deficiencies, anthropometric measures, morbidity, all-cause mortality and cause-specific mortality. Secondary outcomes included potential adverse outcomes, serum concentration of specific micronutrients, serum haemoglobin levels and neurodevelopmental and cognitive outcomes. We included food fortification studies from both high-income and low- and middle-income countries (LMICs). DATA COLLECTION AND ANALYSIS: Two review authors independently screened, extracted and quality-appraised the data from eligible studies. We carried out statistical analysis using Review Manager 5 software. We used random-effects meta-analysis for combining data, as the characteristics of study participants and interventions differed significantly. We set out the main findings of the review in 'Summary of findings' tables, using the GRADE approach. MAIN RESULTS: We identified 127 studies as relevant through title/abstract screening, and included 43 studies (48 papers) with 19,585 participants (17,878 children) in the review. All the included studies except three compared MMN fortification with placebo/no intervention. Two studies compared MMN fortification versus iodised salt and one study compared MMN fortification versus calcium fortification alone. Thirty-six studies targeted children; 20 studies were conducted in LMICs. Food vehicles used included staple foods, such as rice and flour; dairy products, including milk and yogurt; non-dairy beverages; biscuits; spreads; and salt. Fourteen of the studies were fully commercially funded, 13 had partial-commercial funding, 14 had non-commercial funding and two studies did not specify the source of funding. We rated all the evidence as of low to very low quality due to study limitations, imprecision, high heterogeneity and small sample size. When compared with placebo/no intervention, MMN fortification may reduce anaemia by 32% (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.56 to 0.84; 11 studies, 3746 participants; low-quality evidence), iron deficiency anaemia by 72% (RR 0.28, 95% CI 0.19 to 0.39; 6 studies, 2189 participants; low-quality evidence), iron deficiency by 56% (RR 0.44, 95% CI 0.32 to 0.60; 11 studies, 3289 participants; low-quality evidence); vitamin A deficiency by 58% (RR 0.42, 95% CI 0.28 to 0.62; 6 studies, 1482 participants; low-quality evidence), vitamin B2 deficiency by 64% (RR 0.36, 95% CI 0.19 to 0.68; 1 study, 296 participants; low-quality evidence), vitamin B6 deficiency by 91% (RR 0.09, 95% CI 0.02 to 0.38; 2 studies, 301 participants; low-quality evidence), vitamin B12 deficiency by 58% (RR 0.42, 95% CI 0.25 to 0.71; 3 studies, 728 participants; low-quality evidence), weight-for-age z-scores (WAZ) (mean difference (MD) 0.1, 95% CI 0.02 to 0.17; 8 studies, 2889 participants; low-quality evidence) and weight-for-height/length z-score (WHZ/WLZ) (MD 0.1, 95% CI 0.02 to 0.18; 6 studies, 1758 participants; low-quality evidence). We are uncertain about the effect of MMN fortification on zinc deficiency (RR 0.84, 95% CI 0.65 to 1.08; 5 studies, 1490 participants; low-quality evidence) and height/length-for-age z-score (HAZ/LAZ) (MD 0.09, 95% CI 0.01 to 0.18; 8 studies, 2889 participants; low-quality evidence). Most of the studies in this comparison were conducted in children. Subgroup analyses of funding sources (commercial versus non-commercial) and duration of intervention did not demonstrate any difference in effects, although this was a relatively small number of studies and the possible association between commercial funding and increased effect estimates has been demonstrated in the wider health literature. We could not conduct subgroup analysis by food vehicle and funding; since there were too few studies in each subgroup to draw any meaningful conclusions. When we compared MMNs versus iodised salt, we are uncertain about the effect of MMN fortification on anaemia (R 0.86, 95% CI 0.37 to 2.01; 1 study, 88 participants; very low-quality evidence), iron deficiency anaemia (RR 0.40, 95% CI 0.09 to 1.83; 2 studies, 245 participants; very low-quality evidence), iron deficiency (RR 0.98, 95% CI 0.82 to 1.17; 1 study, 88 participants; very low-quality evidence) and vitamin A deficiency (RR 0.19, 95% CI 0.07 to 0.55; 2 studies, 363 participants; very low-quality evidence). Both of the studies were conducted in children. Only one study conducted in children compared MMN fortification versus calcium fortification. None of the primary outcomes were reported in the study. None of the included studies reported on morbidity, adverse events, all-cause or cause-specific mortality. AUTHORS' CONCLUSIONS: The evidence from this review suggests that MMN fortification when compared to placebo/no intervention may reduce anaemia, iron deficiency anaemia and micronutrient deficiencies (iron, vitamin A, vitamin B2 and vitamin B6). We are uncertain of the effect of MMN fortification on anthropometric measures (HAZ/LAZ, WAZ and WHZ/WLZ). There are no data to suggest possible adverse effects of MMN fortification, and we could not draw reliable conclusions from various subgroup analyses due to a limited number of studies in each subgroup. We remain cautious about the level of commercial funding in this field, and the possibility that this may be associated with higher effect estimates, although subgroup analysis in this review did not demonstrate any impact of commercial funding. These findings are subject to study limitations, imprecision, high heterogeneity and small sample sizes, and we rated most of the evidence low to very low quality. and hence no concrete conclusions could be drawn from the findings of this review.

Integrating nutrition into health systems: What the evidence advocates.

There is considerable evidence of positive health and nutrition outcomes resulting from integrating nutrition-specific interventions into health systems; however, current knowledge on establishing and sustaining effective integration of nutrition into health systems is limited. The objective of this review is to map the existing types of integration platforms and review the evidence on integrated health and nutrition programmes' impacts on specific nutrition outcomes. A literature search was conducted, and integrated nutrition programmes were examined through the lens of the six World Health Organization (WHO) building blocks, including the demand side. Forty-five studies were included in this review, outlining the integration of nutrition-specific interventions with various programmes, including integrated community case management and Integrated Management of Childhood Illness, Child Health Days, immunization, early child development, and cash transfers. Limited quantitative data were suggestive of some positive impact on nutrition and non-nutrition outcomes with no adverse effects on primary programme delivery. Through the lens of the six WHO building blocks, service delivery and health workforce were found to be well-integrated, but governance, information systems, finance and supplies and technology were less well-integrated. Integrating nutrition-specific interventions into health systems may ensure efficient service delivery while having an impact on nutrition outcomes. There is no single successful model of integration; it varies according to the context and demands of the particular setting in which integration occurs. There is a need for more well-planned programmes considering all the health systems building blocks to ensure compliance and sustainability.

Fly control to prevent diarrhoea in children.

BACKGROUND: Diarrhoeal disease accounts for millions of child deaths every year. Although the role of flies as vectors of infectious diarrhoea has been established, fly control is not often mentioned as an approach to decrease childhood diarrhoea. Theoretically, fly control for decreasing diarrhoea incidence can be achieved by intervening at four different levels: reduction or elimination of fly breeding sites; reduction of sources that attract houseflies; prevention of contact between flies and disease-causing organisms; and protection of people, food, and food utensils from contact with flies. OBJECTIVES: To assess the impact of various housefly control measures on the incidence of diarrhoea and its related morbidity and mortality in children under five years of age. SEARCH METHODS: We searched electronic databases including the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, CINAHL, and LILACS, from database inception to 24 May 2018. We also searched trial registries for relevant grey literature and ongoing trials. We checked the references of the identified studies and reviews. We did not apply any filters for language, publication status (published, unpublished, in press, and ongoing), or publication date. SELECTION CRITERIA: We planned to include randomized controlled trials (RCTs), quasi-RCTs, and controlled before-and-after studies that studied the effect of fly control on diarrhoea in children under five years of age. DATA COLLECTION AND ANALYSIS: Two review authors extracted the data and independently assessed the risk of bias in the included study. We planned to contact study authors for additional information, where necessary. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included one cluster-RCT (491 participants) conducted in Pakistan that evaluated insecticide spraying in the first two years and baited fly traps in the third year. Insecticide spraying reduced the fly population (house index) in the intervention group during the four months of the year when both flies and cases of diarrhoea were more common, but not at other times. On average, this was associated with a reduction in the incidence of diarrhoea in the first year (illustrative mean episodes per child-year in the intervention group was 6.3 while in the control group was 7.1) and second year of the intervention (illustrative mean episodes per child‒year in the intervention group was 4.4 while in the control group was 6.5; rate ratio (RaR) 0.77, 95% confidence interval (CI) 0.67 to 0.89, low-certainty evidence). In the third year of the intervention, the baited fly traps did not demonstrate an effect on the fly population or on diarrhoea incidence (RaR 1.15, 95% CI 0.90 to 1.47, low-certainty evidence). AUTHORS' CONCLUSIONS: The trial, conducted in a setting where there were clear seasonal peaks in fly numbers and associated diarrhoea, shows insecticide spraying may reduce diarrhoea in children. Further research on whether this finding is applicable to other setting is required, as well as work on other fly control methods, their effects, feasibility, costs, and acceptability.

Neonatal interventions for preventing cerebral palsy: an overview of Cochrane Systematic Reviews.

BACKGROUND: Cerebral palsy is an umbrella term that encompasses disorders of movement and posture attributed to non-progressive disturbances occurring in the developing foetal or infant brain. As there are diverse risk factors and aetiologies, no one strategy will prevent cerebral palsy. Therefore, there is a need to systematically consider all potentially relevant interventions for prevention. OBJECTIVES: PrimaryTo summarise the evidence from Cochrane Systematic Reviews regarding effects of neonatal interventions for preventing cerebral palsy (reducing cerebral palsy risk).SecondaryTo summarise the evidence from Cochrane Systematic Reviews regarding effects of neonatal interventions that may increase cerebral palsy risk. METHODS: We searched the Cochrane Database of Systematic Reviews (27 November 2016) for reviews of neonatal interventions reporting on cerebral palsy. Two review authors assessed reviews for inclusion, extracted data, and assessed review quality (using AMSTAR and ROBIS) and quality of the evidence (using the GRADE approach). Reviews were organised by topic; findings were summarised in text and were tabulated. Interventions were categorised as effective (high-quality evidence of effectiveness); possibly effective (moderate-quality evidence of effectiveness); ineffective (high-quality evidence of harm); probably ineffective (moderate-quality evidence of harm or lack of effectiveness); and no conclusions possible (low- to very low-quality evidence). MAIN RESULTS: Forty-three Cochrane Reviews were included. A further 102 reviews pre-specified the outcome cerebral palsy, but none of the included randomised controlled trials (RCTs) reported this outcome. Included reviews were generally of high quality and had low risk of bias, as determined by AMSTAR and ROBIS. These reviews involved 454 RCTs; data for cerebral palsy were available from 96 (21%) RCTs involving 15,885 children. Review authors considered interventions for neonates with perinatal asphyxia or with evidence of neonatal encephalopathy (3); interventions for neonates born preterm and/or at low or very low birthweight (33); and interventions for other specific groups of 'at risk' neonates (7). Quality of evidence (GRADE) ranged from very low to high.Interventions for neonates with perinatal asphyxia or with evidence of neonatal encephalopathyEffective interventions: high-quality evidence of effectivenessResearchers found a reduction in cerebral palsy following therapeutic hypothermia versus standard care for newborns with hypoxic ischaemic encephalopathy (risk ratio (RR) 0.66, 95% confidence interval (CI) 0.54 to 0.82; seven trials; 881 children).No conclusions possible: very low-quality evidenceOne review observed no clear differences in cerebral palsy following therapeutic hypothermia versus standard care.Interventions for neonates born preterm and/or at low or very low birthweightPossibly effective interventions: moderate-quality evidence of effectivenessResearchers found a reduction in cerebral palsy with prophylactic methylxanthines (caffeine) versus placebo for endotracheal extubation in preterm infants (RR 0.54, 95% CI 0.32 to 0.92; one trial; 644 children).Probably ineffective interventions: moderate-quality evidence of harmResearchers reported an increase in cerebral palsy (RR 1.45, 95% CI 1.06 to 1.98; 12 trials; 1452 children) and cerebral palsy in assessed survivors (RR 1.50, 95% CI 1.13 to 2.00; 12 trials; 959 children) following early (at less than eight days of age) postnatal corticosteroids versus placebo or no treatment for preventing chronic lung disease in preterm infants.Probably ineffective interventions: moderate-quality evidence of lack of effectivenessTrial results showed no clear differences in cerebral palsy following ethamsylate versus placebo for prevention of morbidity and mortality in preterm or very low birthweight infants (RR 1.13, 95% CI 0.64 to 2.00; three trials, 532 children); volume expansion versus no treatment (RR 0.76, 95% CI 0.48 to 1.20; one trial; 604 children); gelatin versus fresh frozen plasma (RR 0.94, 95% CI 0.52 to 1.69; one trial, 399 children) for prevention of morbidity and mortality in very preterm infants; prophylactic indomethacin versus placebo for preventing mortality and morbidity in preterm infants (RR 1.04, 95% CI 0.77 to 1.40; four trials; 1372 children); synthetic surfactant versus placebo for respiratory distress syndrome in preterm infants (RR 0.76, 95% CI 0.55 to 1.05; five trials; 1557 children); or prophylactic phototherapy versus standard care (starting phototherapy when serum bilirubin reached a pre-specified level) for preventing jaundice in preterm or low birthweight infants (RR 0.96, 95% CI 0.50 to 1.85; two trials; 756 children).No conclusions possible: low- to very low-quality evidenceNo clear differences in cerebral palsy were observed with interventions assessed in 21 reviews.Interventions for other specific groups of 'at risk' neonatesNo conclusions possible: low- to very low-quality evidenceReview authors observed no clear differences in cerebral palsy with interventions assessed in five reviews. AUTHORS' CONCLUSIONS: This overview summarises evidence from Cochrane Systematic Reviews regarding effects of neonatal interventions on cerebral palsy, and can be used by researchers, funding bodies, policy makers, clinicians, and consumers to aid decision-making and evidence translation. To formally assess other benefits and/or harms of included interventions, including impact on risk factors for cerebral palsy, review of the included Reviews is recommended.Therapeutic hypothermia versus standard care for newborns with hypoxic ischaemic encephalopathy can prevent cerebral palsy, and prophylactic methylxanthines (caffeine) versus placebo for endotracheal extubation in preterm infants may reduce cerebral palsy risk. Early (at less than eight days of age) postnatal corticosteroids versus placebo or no treatment for preventing chronic lung disease in preterm infants may increase cerebral palsy risk.Cerebral palsy is rarely identified at birth, has diverse risk factors and aetiologies, and is diagnosed in approximately one in 500 children. To date, only a small proportion of Cochrane Systematic Reviews assessing neonatal interventions have been able to report on this outcome. There is an urgent need for long-term follow-up of RCTs of such interventions addressing risk factors for cerebral palsy (through strategies such as data linkage with registries) and for consideration of the use of relatively new interim assessments (including the General Movements Assessment). Such RCTs must be rigorous in their design and must aim for consistency in cerebral palsy outcome measurement and reporting to facilitate pooling of data and thus to maximise research efforts focused on prevention.

Lipid-based nutrient supplements for maternal, birth, and infant developmental outcomes.

BACKGROUND: Ready-to-use lipid-based nutrient supplements (LNS) are a highly nutrient-dense supplement, which could be a good source of macro- and micronutrients for pregnant women who need to supplement their nutrient intake. OBJECTIVES: To assess the effects of LNS for maternal, birth and infant outcomes in pregnant women. Secondary objectives were to explore the most appropriate composition, frequency and duration of LNS administration. SEARCH METHODS: In May 2018, we searched CENTRAL, MEDLINE, Embase, 22 other databases and two trials registers for any published and ongoing studies. We also checked the reference lists of included studies and relevant reviews, and we contacted the authors of included studies and other experts in the field to identify any studies we may have missed, including any unpublished studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs that compared LNS given in pregnancy to no intervention, placebo, iron folic acid (IFA), multiple micronutrients (MMN) or nutritional counselling. DATA COLLECTION AND ANALYSIS: We used standard Cochrane procedures. MAIN RESULTS: We included four studies in 8018 pregnant women. All four studies took place in stable community settings in low- and middle-income countries: Bangladesh, Burkina Faso, Ghana and Malawi. None were in emergency settings. The oldest trial was published in 2009. Of the four included studies, one compared LNS to IFA, one compared LNS to MMN, and two compared LNS to both IFA and MMN.We considered the included studies to be of medium to high quality, and we rated the quality of the evidence as moderate using the GRADE approach.LNS versus IFAMaternal outcomes: there was no difference between the LNS and IFA groups as regards maternal gestational weight gain per week (standard mean difference (SMD) 0.46, 95% confidence interval (CI) -0.44 to 1.36; 2 studies, 3539 participants). One study (536 participants) showed a two-fold increase in the prevalence of maternal anaemia in the LNS group compared to the IFA group, but no difference between the groups as regards adverse effects. There was no difference between the two groups for maternal mortality (risk ratio (RR) 0.53, 95% CI 0.12 to 2.41; 3 studies, 5628 participants).Birth and infant outcomes: there was no difference between the LNS and IFA groups for low birth weight (LBW) (RR 0.87, 95% CI 0.72 to 1.05; 3 studies, 4826 participants), though newborns in the LNS group had a slightly higher mean birth weight (mean difference (MD) 53.28 g, 95% CI 28.22 to 78.33; 3 studies, 5077 participants) and birth length (cm) (MD 0.24 cm, 95% CI 0.11 to 0.36; 3 studies, 4986 participants). There was a reduction in the proportion of infants who were small for gestational age (SGA) (RR 0.94, 95% CI 0.89 to 0.99; 3 studies, 4823 participants) and had newborn stunting (RR 0.82, 95% CI 0.71 to 0.94; 2 studies, 4166 participants) in the LNS group, but no difference between the LNS and IFA groups for preterm delivery (RR 0.94, 95% CI 0.80 to 1.11; 4 studies, 4924 participants), stillbirth (RR 1.14; 95% CI 0.52 to 2.48; 3 studies, 5575 participants) or neonatal death (RR 0.96, 95% CI 0.14 to 6.51). The current evidence for child developmental outcomes is not sufficient to draw any firm conclusions.LNS versus MMNMaternal outcomes: one study (662 participants) showed no difference between the LNS and MMN groups as regards gestational weight gain per week or adverse effects. Another study (557 participants) showed an increased risk of maternal anaemia in the LNS group compared to the MMN group.Birth and infant outcomes: there was no difference between the LNS and MMN groups for LBW (RR 0.92, 95% CI 0.74 to 1.14; 3 studies, 2404 participants), birth weight (MD 23.67 g, 95% CI -10.53 to 57.86; 3 studies, 2573 participants), birth length (MD 0.20 cm, 95% CI -0.02 to 0.42; 3 studies, 2567 participants), SGA (RR 0.95, 95% CI 0.84 to 1.07; 3 studies, 2393 participants), preterm delivery (RR 1.15, 95% CI 0.93 to 1.42; 3 studies, 2630 participants), head circumference z score (MD 0.10, 95% CI -0.01 to 0.21; 2 studies, 1549 participants) or neonatal death (RR 0.88, 95% CI 0.36 to 2.15; 1 study, 1175 participants). AUTHORS' CONCLUSIONS: Findings from this review suggest that LNS supplementation has a slight, positive effect on weight at birth, length at birth, SGA and newborn stunting compared to IFA. LNS and MMN were comparable for all maternal, birth and infant outcomes. Both IFA and MMN were better at reducing maternal anaemia when compared to LNS. We did not find any trials for LNS given to pregnant women in emergency settings.Readers should interpret the beneficial findings of the review with caution since the evidence comes from a small number of trials, with one-large scale study (conducted in community settings in Bangladesh) driving most of the impact. In addition, effect sizes are too small to propose any concrete recommendation for practice.

Nutrition for the Next Generation: Older Children and Adolescents.

This paper reviews information on why the nutrition of older children (5-9 years) and adolescents (10-19 years) is important and the consequences that it can have over generations. Developing countries still face a high burden of undernutrition and anemia, while the burden of overweight and obesity is on the rise in both developing and developed countries. There are evidence-based interventions which can improve the nutritional status and these include interventions for a balanced and diverse diet and micronutrient supplementation, especially iron and multiple micronutrient supplementation where there is sufficient evidence to reduce anemia. There is mixed evidence for the effective strategies to prevent and control obesity and a dearth of evidence from developing countries. Adolescent pregnancy also poses greater challenges to the health of mother and child, and advocacy should be rampant to delay the age of marriage and pregnancy. Interventions targeted to improving the nutritional status among "pregnant adolescents" have shown improvement in birth weight and a reduction in low birth weight and preterm delivery. Traditional platforms including school-based and community-based approaches offer a mixed picture of effectiveness, but emerging avenues of mHealth and social media could also be channelized to reach this population. The population of this age group is on the rise globally, and failure to invest in improving the nutrition of older children and adolescents will further increase the number of dependents in coming generations and negatively influence the health of future generations and progress of nations.

Antenatal and intrapartum interventions for preventing cerebral palsy: an overview of Cochrane systematic reviews.

BACKGROUND: Cerebral palsy is an umbrella term encompassing disorders of movement and posture, attributed to non-progressive disturbances occurring in the developing fetal or infant brain. As there are diverse risk factors and causes, no one strategy will prevent all cerebral palsy. Therefore, there is a need to systematically consider all potentially relevant interventions for their contribution to prevention. OBJECTIVES: To summarise the evidence from Cochrane reviews regarding the effects of antenatal and intrapartum interventions for preventing cerebral palsy. METHODS: We searched the Cochrane Database of Systematic Reviews on 7 August 2016, for reviews of antenatal or intrapartum interventions reporting on cerebral palsy. Two authors assessed reviews for inclusion, extracted data, assessed review quality, using AMSTAR and ROBIS, and quality of the evidence, using the GRADE approach. We organised reviews by topic, and summarised findings in text and tables. We categorised interventions as effective (high-quality evidence of effectiveness); possibly effective (moderate-quality evidence of effectiveness); ineffective (high-quality evidence of harm or of lack of effectiveness); probably ineffective (moderate-quality evidence of harm or of lack of effectiveness); and no conclusions possible (low- to very low-quality evidence). MAIN RESULTS: We included 15 Cochrane reviews. A further 62 reviews pre-specified the outcome cerebral palsy in their methods, but none of the included randomised controlled trials (RCTs) reported this outcome. The included reviews were high quality and at low risk of bias. They included 279 RCTs; data for cerebral palsy were available from 27 (10%) RCTs, involving 32,490 children. They considered interventions for: treating mild to moderate hypertension (two) and pre-eclampsia (two); diagnosing and preventing fetal compromise in labour (one); preventing preterm birth (four); preterm fetal maturation or neuroprotection (five); and managing preterm fetal compromise (one). Quality of evidence ranged from very low to high. Effective interventions: high-quality evidence of effectiveness There was a reduction in cerebral palsy in children born to women at risk of preterm birth who received magnesium sulphate for neuroprotection of the fetus compared with placebo (risk ratio (RR) 0.68, 95% confidence interval (CI) 0.54 to 0.87; five RCTs; 6145 children). Probably ineffective interventions: moderate-quality evidence of harm There was an increase in cerebral palsy in children born to mothers in preterm labour with intact membranes who received any prophylactic antibiotics versus no antibiotics (RR 1.82, 95% CI 0.99 to 3.34; one RCT; 3173 children). There was an increase in cerebral palsy in children, who as preterm babies with suspected fetal compromise, were born immediately compared with those for whom birth was deferred (RR 5.88, 95% CI 1.33 to 26.02; one RCT; 507 children). Probably ineffective interventions: moderate-quality evidence of lack of effectiveness There was no clear difference in the presence of cerebral palsy in children born to women at risk of preterm birth who received repeat doses of corticosteroids compared with a single course (RR 1.03, 95% CI 0.71 to 1.50; four RCTs; 3800 children). No conclusions possible: low- to very low-quality evidence Low-quality evidence found there was a possible reduction in cerebral palsy for children born to women at risk of preterm birth who received antenatal corticosteroids for accelerating fetal lung maturation compared with placebo (RR 0.60, 95% CI 0.34 to 1.03; five RCTs; 904 children). There was no clear difference in the presence of cerebral palsy with interventionist care for severe pre-eclampsia versus expectant care (RR 6.01, 95% CI 0.75 to 48.14; one RCT; 262 children); magnesium sulphate for pre-eclampsia versus placebo (RR 0.34, 95% CI 0.09 to 1.26; one RCT; 2895 children); continuous cardiotocography for fetal assessment during labour versus intermittent auscultation (average RR 1.75, 95% CI 0.84 to 3.63; two RCTs; 13,252 children); prenatal progesterone for prevention of preterm birth versus placebo (RR 0.14, 95% CI 0.01 to 3.48; one RCT; 274 children); and betamimetics for inhibiting preterm labour versus placebo (RR 0.19, 95% CI 0.02 to 1.63; one RCT; 246 children).Very low-quality found no clear difference for the presence of cerebral palsy with any antihypertensive drug (oral beta-blockers) for treatment of mild to moderate hypertension versus placebo (RR 0.33, 95% CI 0.01 to 8.01; one RCT; 110 children); magnesium sulphate for prevention of preterm birth versus other tocolytic agents (RR 0.13, 95% CI 0.01 to 2.51; one RCT; 106 children); and vitamin K and phenobarbital prior to preterm birth for prevention of neonatal periventricular haemorrhage versus placebo (RR 0.77, 95% CI 0.33 to 1.76; one RCT; 299 children). AUTHORS' CONCLUSIONS: This overview summarises evidence from Cochrane reviews on the effects of antenatal and intrapartum interventions on cerebral palsy, and can be used by researchers, funding bodies, policy makers, clinicians and consumers to aid decision-making and evidence translation. We recommend that readers consult the included Cochrane reviews to formally assess other benefits or harms of included interventions, including impacts on risk factors for cerebral palsy (such as the reduction in intraventricular haemorrhage for preterm babies following exposure to antenatal corticosteroids).Magnesium sulphate for women at risk of preterm birth for fetal neuroprotection can prevent cerebral palsy. Prophylactic antibiotics for women in preterm labour with intact membranes, and immediate rather than deferred birth of preterm babies with suspected fetal compromise, may increase the risk of cerebral palsy. Repeat doses compared with a single course of antenatal corticosteroids for women at risk of preterm birth do not clearly impact the risk of cerebral palsy.Cerebral palsy is rarely diagnosed at birth, has diverse risk factors and causes, and is diagnosed in approximately one in 500 children. To date, only a small proportion of Cochrane reviews assessing antenatal and intrapartum interventions have been able to report on this outcome. There is an urgent need for long-term follow-up of RCTs of interventions addressing risk factors for cerebral palsy, and consideration of the use of relatively new interim assessments (including the General Movements Assessment). Such RCTs must be rigorous in their design, and aim for consistency in cerebral palsy outcome measurement and reporting to facilitate pooling of data, to focus research efforts on prevention.

Vitamin D supplementation for preventing infections in children under five years of age.

BACKGROUND: Vitamin D is a micronutrient important for bone growth and immune function. Deficiency can lead to rickets and has been linked to various infections, including respiratory infections. The evidence on the effects of supplementation on infections in children has not been assessed systematically. OBJECTIVES: To evaluate the role of vitamin D supplementation in preventing pneumonia, tuberculosis (TB), diarrhoea, and malaria in children under five years of age. This includes high-, middle-, and low-income countries. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library, MEDLINE, EMBASE, LILACS, the WHO International Clinical Trials Registry Platform (ICTRP; http://www.who.int/ictrp/en/) , ClinicalTrials.gov and the ISRCTN registry (http://www.isrctn.com/) up to 16 June 2016. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that evaluated preventive supplementation of vitamin D (versus placebo or no intervention) in children under five years of age. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the titles and abstracts, extracted the data, and assessed the risk of bias of included trials. MAIN RESULTS: Four trials met the inclusion criteria, with a total of 3198 children under five years of age, and were conducted in Afghanistan, Spain, and the USA. Prevalence of vitamin D deficiency varied widely in these populations (range: 73.1% in Afghanistan, 10 to 12% in USA, and 6.2% in Spain). The included trials evaluated mortality (two trials), pneumonia incidence (two trials), diarrhoea incidence (two trials), hospitalization (two trials), and mean serum vitamin D concentrations (four trials).We do not know whether vitamin D supplementation impacts on all-cause mortality because this outcome was underpowered due to few events (risk ratio (RR) 1.43, 95% confidence interval (CI) 0.54 to 3.74; one trial, 3046 participants, low quality evidence).For pneumonia, episodes of 'radiologically confirmed' first or only episode of pneumonia were little different in the supplemented and unsupplemented group (Rate Ratio: 1.06, 95% confidence interval (CI) 0.89 to 1.26; two trials, 3134 participants, moderate quality evidence), and similarly for children with confirmed or unconfirmed pneumonia (RR 0.95, 95% CI 0.87 to 1.04; one trial, 3046 participants). In these two trials there were no obvious differences between supplemented and unsupplemented children regarding episodes of diarrhoea.In the single large trial from Afghanistan, the trial authors reported that vitamin D supplementation was associated with an increase in repeat episodes of pneumonia confirmed by chest radiograph (RR 1.69, 95% CI 1.28 to 2.21; one trial, 3046 participants), but not reflected in the outcome of confirmed or unconfirmed pneumonia (RR 1.06, 95% CI 1.00 to 1.13; one trial, 3046 participants).For hospital admission measured in one small trial, there was no difference detected (RR 0.86, 95% CI 0.20 to 3.62; one trial, 88 participants; very low quality evidence).The mean serum vitamin D concentrations were higher in supplemented compared to unsupplemented children at the end of supplementation (MD 7.72 ng/mL, 95% CI 0.50 to 14.93; four trials, 266 participants, low quality evidence). These results were driven primarily by two smaller trials with large magnitudes of effect. In the other two bigger trials, serum vitamin D concentrations were elevated in the intervention group for most of the trial duration but not at the end of supplementation. This may be due to time elapsed at measurement from the last dose, incomplete compliance, or increased need of vitamin D with infant age.We did not find any trial that reported on the incidence of TB, malaria or febrile illness, duration of pneumonia, duration of diarrhoea, severity of infection, and cause-specific mortality (due to TB, diarrhoea, or malaria). AUTHORS' CONCLUSIONS: Evidence from one large trial did not demonstrate benefit of vitamin D supplementation on the incidence of pneumonia or diarrhoea in children under five years. To our knowledge, trials that evaluated supplementation for preventing other infections, including TB and malaria, have not been performed.

Potential for task-sharing to Lady Health Workers for identification and emergency management of pre-eclampsia at community level in Pakistan.

BACKGROUND: An estimated 276 Pakistani women die for every 100,000 live births; with eclampsia accounting for about 10 % of these deaths. Community health workers contribute to the existing health system in Pakistan under the banner of the Lady Health Worker (LHW) Programme and are responsible to provide a comprehensive package of antenatal services. However, there is a need to increase focus on early identification and prompt diagnosis of pre-eclampsia in community settings, since women with mild pre-eclampsia often present without symptoms. This study aims to explore the potential for task-sharing to LHWs for the community-level management of pre-eclampsia and eclampsia in Pakistan. METHODS: A qualitative exploratory study was undertaken February-July 2012 in two districts, Hyderabad and Matiari, in the southern province of Sindh, Pakistan. Altogether 33 focus group discussions (FGDs) were conducted and the LHW curriculum and training materials were also reviewed. The data was audio-recorded, then transcribed verbatim for thematic analysis using QSR NVivo-version10. RESULTS: Findings from the review of the LHW curriculum and training program describe that in the existing community delivery system, LHWs are responsible for identification of pregnant women, screening women for danger signs and referrals for antenatal care. They are the first point of contact for women in pregnancy and provide nutritional counselling along with distribution of iron and folic acid supplements. Findings from FGDs suggest that LHWs do not carry a blood pressure device or antihypertensive medications; they refer to the nearest public facility in the event of a pregnancy complication. Currently, they provide tetanus toxoid in pregnancy. The health advice provided by lady health workers is highly valued and accepted by pregnant women and their families. Many Supervisors of LHWs recognized the need for increased training regarding pre-eclampsia and eclampsia, with a focus on identifying women at high risk. The entire budget of the existing lady health worker Programme is provided by the Government of Pakistan, indicating a strong support by policy makers and the government for the tasks undertaken by these providers. CONCLUSION: There is a potential for training and task-sharing to LHWs for providing comprehensive antenatal care; specifically for the identification and management of pre-eclampsia in Pakistan. However, the implementation needs to be combined with appropriate training, equipment availability and supervision. TRIAL REGISTRATION: ClinicalTrial.gov, NCT01911494.