A Holistic Strategy of Mother and Child Health Care to Improve the Coverage of Routine and Polio Immunization in Pakistan: Results from a Demonstration Project.

BACKGROUND: The eradication of poliovirus and improving routine immunization (RI) coverage rates present significant challenges in Pakistan. There is a need for interventions that focus on strengthening community engagement to improve routine immunization coverage. Our primary objective is to assess the impact of an integrated strategy designed to enhance community engagement and maternal and child health immunization campaigns on immunization coverage in Pakistan's high-risk union councils of polio-endemic districts. METHOD: We implemented an integrated approach for routine immunization and maternal and child health in the polio-endemic district of Pakistan. This approach involved setting up health camps and actively engaging and mobilizing the local community. An independent team conducted surveys at three key points: baseline, midline, and endline, to evaluate immunization coverage among children under the age of five. The primary outcome measures for the study were coverage of OPV, IPV, and changes in the proportion of unvaccinated and fully vaccinated children. To select clusters and eligible households in each cluster, we utilized a 30 × 15 cluster sampling technique. Multivariable associations between socio-demographic factors and changes in the proportion of fully vaccinated children at the UC level were assessed using hierarchical linear regression models. RESULTS: A total of 256,946 children under the age of five (122,950 at baseline and 133,996 at endline) were enrolled in the study. By the endline, full immunization coverage had increased to 60% or more in all three study areas compared to the baseline. Additionally, there was a significant increase in the coverage of both OPV and IPV across all three provinces at the endline. The full immunization rates were assessed on three levels of the framework: the distal, intermediate (access and environment), and proximal level (camp attendance and effectiveness). At the distal level, on multivariate analysis, family size was found to be a significant predictor of change in immunity within the families (ß = 0.68; p ≤ 0.0001). At the intermediate level, the likelihood of full immunization decreased with the decrease in knowledge about vaccination (ß = -0.38; p = 0.002), knowledge about polio vaccine (ß = -0.25; p = 0.011), and knowledge about IPV (ß = -0.06; p = 0.546). Perceived obstacles to vaccination were fear of adverse events (ß = -0.4; p ≤ 0.0001) and lack of education (ß = 0.23; p = 0.031), which were found to be significant in bivariate and multivariate analyses. At the proximal level, community mobilization (ß = 0.26; p = 0.008) and attendance at health camp (ß = 0.21; p ≤ 0.0001) were found to enhance full immunization coverage. On the other hand, the most prominent reason for not attending health camp included no need to attend the health camp as the child was not ill (ß = -0.13; p = 0.008). CONCLUSIONS: This study found that community mobilization and attendance at health camps significantly enhanced full immunization coverage. The findings highlight the importance of community engagement and targeted interventions in improving immunization coverage and addressing barriers to healthcare seeking.

Effect of the Children and Young People's Health Partnership model of paediatric integrated care on health service use and child health outcomes: a pragmatic two-arm cluster randomised controlled trial.

BACKGROUND: Paediatric health systems across high-income countries are facing avoidable adverse outcomes and increasing demands and costs. The aim of this study was to compare the effect of an enhanced usual care model with that of an integrated health-care model that offers local health clinics for general paediatric problems and early intervention and care for children and young people with tracer conditions. METHODS: In this pragmatic two-arm cluster randomised controlled trial, we compared the Children and Young People's Health Partnership (CYPHP) model of care versus enhanced usual care (EUC) among children registered at general practices in south London, UK. The CYPHP trial intervention was delivered between April 1, 2018, and June 30, 2021, and children younger than 16 years during the intervention period and registered at study practices on June 30, 2021, were included in the analysis. A restricted randomisation (1:1) following a computer-generated sequence was done by a masked independent statistician at the level of general practice cluster, stratified by borough (Lambeth or Southwark). Cluster allocation and data collection were masked, with unmasking of trial statisticians before analysis. The CYPHP model comprised all elements of EUC (electronic decision support, a primary care hotline, health checks, self-management support and health promotion, and resilience building and mental health first aid) plus local child health clinics delivered by paediatricians and general practitioners, and a nurse-led early intervention service for children with tracer conditions (asthma, eczema, and constipation). Primary outcomes were non-elective admissions (NELA; admissions coded as an emergency) among the whole trial population up to June 30, 2021, and paediatric quality of life (Pediatric Quality of Life Inventory [PedsQL]) among participants with tracer conditions at 6 months after recruitment. Secondary outcomes were primary and secondary care use, child mental health, parental wellbeing, standardised symptom scores for asthma, eczema, and constipation, health-care quality, and child absences from school and parent absences from work. The trial was registered on ClinicalTrials.gov, NCT03461848, and is complete. FINDINGS: The trial was conducted between April 1, 2018, and Dec 31, 2021. In total, 23 general practice clusters, consisting of 70 practices with 97 970 registered children, were randomised to CYPHP (n=11) or EUC (n=12). We found no effect, at the population level, of CYPHP versus EUC on non-elective admissions during the intervention period (adjusted mean incidence rate ratio [IRR] 1·00 [95% CI 0·91 to 1·10], p=0·99). Among children with tracer conditions, we found no difference in paediatric quality of life (PedsQL score) at 6 months (adjusted mean difference -0·033 [95% CI -0·122 to 0·055], p=0·46). As a secondary outcome, among children with tracer conditions and requiring care, NELA rates at 12 months did not differ between the CYPHP and EUC groups (66·1 per 1000 person-years vs 75·3 per 1000 person-years; adjusted mean IRR 0·87 [0·61-1·22], p=0·42). In children requiring care, a statistically significant improvement was observed in eczema symptoms at 6 months from baseline in the CYPHP group versus the EUC group (adjusted mean difference -1·370 [-2·630 to -0·122], p=0·032). Quality of asthma care significantly improved among children in the CYPHP group compared with children in the EUC group. No significant improvement was seen for all other secondary outcomes. INTERPRETATION: Although the CYPHP trial found a null effect for the primary outcomes, we found clinically important improvements in some secondary outcomes including care quality. Previous research has shown that large-scale system change requires time to observe a potential positive effect. FUNDING: Guy's and St Thomas Charity, the Lambeth and Southwark Clinical Commissioning Groups, and Evelina London Children's Hospital.

Infections and nutrient deficiencies during infancy predict impaired growth at 5 years: Findings from the MAL-ED study in Pakistan.

Background: Socio-economic, nutritional, and infectious factors have been associated with impaired infant growth, but how the presence of these factors during infancy affects growth around 5 years is not well understood. Methods: This secondary analysis of the MAL-ED cohort included 277 children from Pakistan for whom socio-demographic, breastfeeding, complementary foods, illness, nutritional biomarkers, stool pathogens and environmental enteropathy indicators between 0 and 11 months were recorded. We used linear regression models to analyze associations of these indicators with height-for-age (HAZ), weight-for-age (WAZ) and weight-for-height (WLZ) at 54-66 months (~5 years), and Poisson regression with robust standard errors to estimate risk ratios for stunting and underweight ~5 years, controlling for gender, first available weight, and income. Results: Among the 237 infants followed longitudinally and evaluated at about 5 years of age, exclusive breastfeeding was short (median = 14 days). Complementary feeding started before 6 months with rice, bread, noodles, or sugary foods. Roots, dairy products, fruits/vegetables, and animal-source foods were provided later than recommended (9-12 months). Anemia (70.9%), deficiencies in iron (22.0%), zinc (80.0%), vitamin A (53.4%) and iodine (13.3%) were common. Most infants (>90%) presented with diarrhea and respiratory infections in their first year. At ~5 years, low WAZ (mean-1.91 ± 0.06) and LAZ (-2.11 ± 0.06) resulted in high prevalence of stunting (55.5%) and underweight (44.4%) but a relatively low rate of wasting (5.5%). While 3.4% had concurrent stunting and wasting ~5 years, 37.8% of children had coexisting stunting and underweight. A higher income and receiving formula or dairy products during infancy were associated with a higher LAZ ~5 years, but infant's history of hospitalizations and more respiratory infections were associated with lower LAZ and higher risk of stunting ~5 years. Infants' intake of commercial baby foods and higher serum-transferrin receptors were associated with higher WAZ and lower risk of underweight ~5 years. Presence of Campylobacter and fecal neopterin >6.8 nmol/L in the first year were associated with increased risk of underweight ~5 years. Conclusion: Growth indicators ~5 years were associated with poverty, inappropriate complementary feeding, and infections during the first year of life, which supports the early start of public health interventions for preventing growth delay ~5 years.

Characteristics and birth outcomes of pregnant adolescents compared to older women: An analysis of individual level data from 140,000 mothers from 20 RCTs.

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

Multiple-micronutrient supplementation in pregnant adolescents in low- and middle-income countries: a systematic review and a meta-analysis of individual participant data.

CONTEXT: Approximately 7.3 million births occur annually among adolescents in low- and middle-income countries. Pregnant adolescents constitute a nutritionally vulnerable group that could benefit from intervention to mitigate the mortality and adverse birth outcomes associated with adolescent pregnancy. OBJECTIVE: The aim of this systematic review and meta-analysis was to assess the following: (1) the effect of multiple-micronutrient (MMN) supplementation vs iron and folic acid (IFA) supplementation among adolescents on maternal morbidity, birth outcomes, and mortality outcomes, (2) the effects of MMN supplementation in adolescents compared with the effects in adult women, and (3) the effect modification, if any, of MMN supplementation by baseline and geographic characteristics of adolescents. DATA SOURCES: MEDLINE and Cochrane databases were searched, along with the reference lists of relevant reviews. STUDY SELECTION: Multiple-micronutrient supplementation trials in pregnancy that were conducted in a low- or middle-income country and had included at least 100 adolescents (10-19 years of age) were eligible for inclusion. Two independent reviewers assessed study eligibility. DATA EXTRACTION: Thirteen randomized controlled trials conducted in Africa and Asia were identified from 1792 reviews and 1578 original trials. Individual-level data was shared by study collaborators and was checked for completeness and extreme values. One- and two-stage individual participant data meta-analyses were conducted using data from randomized controlled trials of MMN supplementation. RESULTS: A total of 15 283 adolescents and 44 499 adult women with singleton births were included in the individual participant data meta-analyses of MMN supplementation vs IFA supplementation. In adolescents, MMN supplementation reduced low birth weight (1-stage OR = 0.87, 95%CI 0.77-0.97; 2-stage OR = 0.81; 95%CI 0.74-0.88), preterm birth (1-stage OR = 0.88, 95%CI 0.80-0.98; 2-stage OR = 0.86, 95%CI 0.79-0.95), and small-for-gestational-age births (1-stage OR = 0.90, 95%CI 0.81-1.00; 2-stage OR = 0.86, 95%CI 0.79-0.95) when compared with IFA supplementation. The effects of MMN supplementation did not differ between adolescents and older women, although a potentially greater reduction in small-for-gestational-age births was observed among adolescents. Effect modification by baseline characteristics and geographic region was inconclusive. CONCLUSIONS: Multiple-micronutrient supplementation can improve birth outcomes among pregnant adolescents in low- and middle-income countries. Policy related to antenatal care in these settings should prioritize MMN supplementation over the currently recommended IFA supplementation for all pregnant women, especially adolescents.

Dietary diversity and social determinants of nutrition among late adolescent girls in rural Pakistan.

The conditions in which adolescent girls mature shape their health, development and nutrition. Nutrient requirements increase to support growth during adolescence, but gaps between consumption and requirements exist in low- and middle-income countries. We aimed to identify and quantify the relationship between dietary intake and diverse social determinants of nutrition (SDN) among a subset of adolescent girls 15-18.9 years (n = 390) enrolled within the Matiari emPowerment and Preconception Supplementation (MaPPS) Trial. The primary outcome, dietary diversity score (DDS), was derived by applying the Minimum Dietary Diversity for Women 10-item scale to 24-h dietary recall data collected three times per participant. To examine the associations between the SDN-related explanatory variables and DDS, we generated a hierarchical, causal model using mixed effects linear regression to account for the cluster-randomized trial design. Using all data, diets lacked diversity (DDS mean ± SD: 3.35 ± 1.03 [range: 1-7; n = 1170]), and the minimum cut-off for dietary diversity was infrequently achieved (13.5%; 95% CI: 11.6-15.6%). Consumption of starches was reported in all recalls, but micronutrient-rich food consumption was less common. Of the SDN considered, wealth quintile had the strongest association with DDS (P < 0.0001). The diets of the sampled Pakistani adolescent girls were insufficient to meet micronutrient requirements. Poverty was the most important predictor of a diet lacking in diversity, indicating limited purchasing power or access to nutritious foods. Dietary diversification and nutrition education strategies alone are unlikely to lead to improved diets without steps to tackle this barrier, for example, through fortification of staple foods and provision of supplements.

An Integrated eDiagnosis Approach (IeDA) versus standard IMCI for assessing and managing childhood illness in Burkina Faso: a stepped-wedge cluster randomised trial.

BACKGROUND: The Integrated eDiagnosis Approach (IeDA), centred on an electronic Clinical Decision Support System (eCDSS) developed in line with national Integrated Management of Childhood Illness (IMCI) guidelines, was implemented in primary health facilities of two regions of Burkina Faso. An evaluation was performed using a stepped-wedge cluster randomised design with the aim of determining whether the IeDA intervention increased Health Care Workers' (HCW) adherence to the IMCI guidelines. METHODS: Ten randomly selected facilities per district were visited at each step by two trained nurses: One observed under-five consultations and the second conducted a repeat consultation. The primary outcomes were: overall adherence to clinical assessment tasks; overall correct classification ignoring the severity of the classifications; and overall correct prescription according to HCWs' classifications. Statistical comparisons between trial arms were performed on cluster/step-level summaries. RESULTS: On average, 54 and 79% of clinical assessment tasks were observed to be completed by HCWs in the control and intervention districts respectively (cluster-level mean difference = 29.9%; P-value = 0.002). The proportion of children for whom the validation nurses and the HCWs recorded the same classifications (ignoring the severity) was 73 and 79% in the control and intervention districts respectively (cluster-level mean difference = 10.1%; P-value = 0.004). The proportion of children who received correct prescriptions in accordance with HCWs' classifications were similar across arms, 78% in the control arm and 77% in the intervention arm (cluster-level mean difference = - 1.1%; P-value = 0.788). CONCLUSION: The IeDA intervention improved substantially HCWs' adherence to IMCI's clinical assessment tasks, leading to some overall increase in correct classifications but to no overall improvement in correct prescriptions. The largest improvements tended to be observed for less common conditions. For more common conditions, HCWs in the control districts performed relatively well, thus limiting the scope to detect an overall impact. TRIAL REGISTRATION: ClinicalTrials.gov NCT02341469 ; First submitted August 272,014, posted January 19, 2015.

Review of the evidence regarding the use of antenatal multiple micronutrient supplementation in low- and middle-income countries.

Inadequate micronutrient intakes are relatively common in low- and middle-income countries (LMICs), especially among pregnant women, who have increased micronutrient requirements. This can lead to an increase in adverse pregnancy and birth outcomes. This review presents the conclusions of a task force that set out to assess the prevalence of inadequate micronutrient intakes and adverse birth outcomes in LMICs; the data from trials comparing multiple micronutrient supplements (MMS) that contain iron and folic acid (IFA) with IFA supplements alone; the risks of reaching the upper intake levels with MMS; and the cost-effectiveness of MMS compared with IFA. Recent meta-analyses demonstrate that MMS can reduce the risks of preterm birth, low birth weight, and small for gestational age in comparison with IFA alone. An individual-participant data meta-analysis also revealed even greater benefits for anemic and underweight women and female infants. Importantly, there was no increased risk of harm for the pregnant women or their infants with MMS. These data suggest that countries with inadequate micronutrient intakes should consider supplementing pregnant women with MMS as a cost-effective method to reduce the risk of adverse birth outcomes.

Associations between increased intervention coverage for mothers and newborns and the number and quality of contacts between families and health workers: An analysis of cluster level repeat cross sectional survey data in Ethiopia.

BACKGROUND: Survival of mothers and newborns depends on life-saving interventions reaching those in need. Recent evidence suggests that indicators of contact with health services are poor proxies for measures of coverage of life saving care and attention has shifted towards the quality of care provided during contacts. METHODS AND FINDINGS: Regression analysis using data from representative cluster-based household surveys and surveys of the frontline health workers and primary health facilities in four regions of Ethiopia in 2012 and 2015 was used to explore associations between increased numbers of contacts or improvements in quality and any change in the coverage of interventions (intervention coverage). In pregnancy, in multiple regression, an increase in the quality indicator 'focused ANC behaviours' was associated with a change in both the coverage of iron supplementation and syphilis prevention ((regression coefficients (95% CI)) 0·06 (0·01, 0·11); 0·07 (0·04, 0·10)). This equates to a 0.6% increase in the proportion of women taking iron supplementation and a 0.7% in women receiving syphilis prevention for a 10% increase in the quality indicator 'focused ANC behaviours'. At delivery, in multiple regression the quality indicator 'availability of uterotonic supplies amongst birth attendants' was associated with improved coverage of prophylactic uterotonics (0·72 (0·50, 0·94)). No evidence of any relationships between contacts, quality and intervention coverage were observed within the early postnatal period. CONCLUSIONS: Increases in both contacts and in quality of care are needed to increase the coverage of life saving interventions. For interventions that need to be delivered at multiple visits, such as antenatal vaccination, increasing the number of contacts had the strongest association with coverage. For those relying on a single point of contact, such as those delivered at birth, we found strong evidence to support current commitments to invest in both input and process quality.

Effect of provision of home-based curative health services by public sector health-care providers on neonatal survival: a community-based cluster-randomised trial in rural Pakistan.

BACKGROUND: Although the effectiveness of community mobilisation and promotive care delivered by community health workers in reducing perinatal and neonatal mortality is well established, evidence in support of home-based neonatal resuscitation and infection management is mixed. We assessed the effectiveness of adding training in neonatal bag and mask resuscitation and oral antibiotic therapy for suspected neonatal infections to a basic preventive and promotive interventions package delivered by public sector community-based lady health workers (LHWs) in rural Pakistan. METHODS: We did a cluster-randomised controlled trial in two subdistricts of Naushahro Feroze in rural Sindh, Pakistan, between April 15, 2009, and Dec 10, 2012. LHWs, trained in basic newborn resuscitation and in recognition and treatment (with oral amoxicillin) of suspected neonatal respiratory infections, were linked with traditional birth attendants and encouraged to attend home births. Control clusters received routine care through the existing national programme. The primary outcome was all-cause neonatal mortality. Independent data collection teams recorded data for all pregnancies and their outcomes, morbidity, mortality, and household practices related to maternal and newborn care. FINDINGS: Of the 27 randomised clusters with functional LHW programmes, 13 were allocated to the intervention group (n=242 749) and 14 to the control group (n=256 985). In the intervention group, LHWs did 80% of the planned community mobilisation sessions, but were able to attend only 1184 (14%) of 8425 deliveries and 4318 (25%) of 17 288 neonatal visits within 72 h of birth (p<0·0001 for both variables compared with the control group). The neonatal mortality rate was 42 deaths per 1000 livebirths in intervention clusters compared with 55 per 1000 in the control group (risk ratio 0·80, 95% CI 0·68-0·93; p=0·005). INTERPRETATION: The reduction in neonatal mortality in intervention clusters occurred against a background of improvements in domiciliary practices for maternal and newborn care. However, the poor reach of LHWs in accessing newborn infants at birth and in the early postnatal period underscores the limitations of tasking community health workers in public sector programmes working in similar circumstances with such complex interventions. Such community-based interventions in health systems should be accompanied by concerted efforts to improve quality of care in facilities and referral systems. FUNDING: Saving Newborn Lives, Save the Children USA.

Community engagement and integrated health and polio immunisation campaigns in conflict-affected areas of Pakistan: a cluster randomised controlled trial.

BACKGROUND: Pakistan faces huge challenges in eradicating polio due to widespread poliovirus transmission and security challenges. Innovative interventions are urgently needed to strengthen community buy-in, to increase the coverage of oral polio vaccine (OPV) and other routine immunisations, and to enhance immunity through the introduction of inactivated polio vaccine (IPV) in combination with OPV. We aimed to evaluate the acceptability and effect on immunisation coverage of an integrated strategy for community engagement and maternal and child health immunisation campaigns in insecure and conflict-affected polio-endemic districts of Pakistan. METHODS: We did a community-based three-arm cluster randomised trial in healthy children aged 1 month to 5 years that resided within the study sites in three districts of Pakistan at high risk of polio. Clusters were randomly assigned by a computer algorithm using restricted randomisation in blocks of 20 by an external statistician (1:1:1) to receive routine polio programme activities (control, arm A), additional interventions with community outreach and mobilisation using an enhanced communication package and provision of short-term preventive maternal and child health services and routine immunisation (health camps), including OPV (arm B), or all interventions of arm B with additional provision of IPV delivered at the maternal and child health camps (arm C). An independent team conducted surveys at baseline, endline, and after each round of supplementary immunisation activity for acceptability and effect. The primary outcome measures for the study were coverage of OPV, IPV, and routine extended programme on immunisation vaccines and changes in the proportion of unvaccinated and fully vaccinated children. This trial is registered with ClinicalTrials.gov, number NCT01908114. FINDINGS: Between June 4, 2013, and May 31, 2014, 387 clusters were randomised (131 to arm A, 127 to arm B, and 129 to arm C). At baseline, 28 760 children younger than 5 years were recorded in arm A, 30 098 in arm B, and 29 126 in arm C. 359 clusters remained in the trial until the end (116 in arm A, 120 in arm B, and 123 in arm C; with 23 334 children younger than 5 years in arm A, 26 110 in arm B, and 25 745 in arm C). The estimated OPV coverage was 75% in arm A compared with 82% in arm B (difference vs arm A 6·6%; 95% CI 4·8-8·3) and 84% in arm C (8·5%, 6·8-10·1; overall p<0·0001). The mean proportion of routine vaccine doses received by children younger than 24 months of age was 43% in arm A, 52% in arm B (9%, 7-11) and 54% in arm C (11%, 9-13; overall p<0·0001). No serious adverse events requiring hospitalisation were reported after immunisation. INTERPRETATION: Despite the challenges associated with the polio end-game in high-risk, conflict-affected areas of Pakistan, a strategy of community mobilisation and targeted community-based health and immunisation camps during polio immunisation campaigns was successful in increasing vaccine coverage, including polio vaccine coverage. FUNDING: Bill & Melinda Gates Foundation.

Evaluation of the uptake and impact of neonatal vitamin A supplementation delivered through the Lady Health Worker programme on neonatal and infant morbidity and mortality in rural Pakistan: an effectiveness trial.

BACKGROUND: Despite evidence for the benefits of vitamin A supplementation (VAS) among children 6 to 59 months of age, the feasibility of introduction and potential benefit of VAS in the neonatal period in public health programmes is uncertain. OBJECTIVE: The primary objective was to evaluate the feasibility and effectiveness of early neonatal VAS (single dose of 50 000 international units within 48-72 hours after birth) delivered through the public sector Lady Health Worker (LHW) programme in rural Pakistan and to document its association with a reduction in mortality at 6 months of age. METHODS: A community-based, cluster randomised, placebo-controlled trial was undertaken in two districts of rural Pakistan. LHWs dispensed vitamin A/placebo in identical capsules to newborn infants within 48-72 hours of birth. Follow-up visits were undertaken at 1 week of age and every 4 weeks thereafter until 6 months of age. RESULTS: Of a total of 15 433 consecutive pregnancies among eligible women of reproductive age, 13 225 pregnancies were registered, 12 218 live births identified and 11 028 newborn infants reached by LHWs. Of these, 5380 (49%) received neonatal VAS and 5648 (51%) placebo. The LHWs successfully delivered the capsules to 79% of newborns within 72 hours of birth with no significant adverse effects. Although the proportion of days observed with symptoms of fever, diarrhoea or rapid breathing were lower with neonatal VAS, these differences were not statistically significant. Mortality rates in the two groups were comparable at 6 months of age. CONCLUSIONS: While our study demonstrated that neonatal VAS was safe and could be feasibly delivered by LHWs in Pakistan as part of their early postnatal visits, the overall lack of benefit on neonatal and 6-month morbidity and mortality in our population suggests the need for further evaluation of this intervention in populations at risk. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00674089.

Is Beta Radiation Better than 5 Flurouracil as an Adjunct for Trabeculectomy Surgery When Combined with Cataract Surgery? A Randomised Controlled Trial.

INTRODUCTION: In an African setting surgery is generally accepted as the treatment of first choice for glaucoma. A problem with trabeculectomy surgery for the glaucomas is the frequent co-existence and exacerbation of cataract. We report a randomized controlled trial to compare the use of beta radiation with 5FU in combined cataract and glaucoma surgery. PARTICIPANTS AND METHODS: Consenting adults aged >40 years with glaucoma, an IOP>21mmHG and cataract were enrolled and randomised to receive either 1000cG ß radiation application or sub-conjunctival 5fluorouracil (5FU) at the time of combined trabeculectomy and phaco-emulsification with lens implant surgery. RESULTS: 385 individuals were eligible for inclusion of whom 301 consented to inclusion in the study (one eye per patient). 150 were randomised to the 5FU arm and 151 received ß radiation. In the 12 months following surgery there were 40 failures (IOP>21mmHg) in the 5FU arm and 34 failures in the beta arm. The hazard ratio for the beta radiation arm compared to the 5FU arm, adjusted for IOP at baseline, was 0.83 (95% c.i. 0.54 to 1.28; P = 0.40). The improvement from mean presenting visual acuities of 0.91 and 0.86 logMAR to 0.62 and 0.54 in the 5FU and beta arms respectively was comparable between groups (P = 0.4 adjusting for baseline VA). Incidence of complications did not differ between the two groups. DISCUSSION: This study highlights several important issues in the quest for a therapeutic strategy for the glaucomas in an African context. Firstly, there is no evidence of an important difference between the use of 5FU and beta radiation as an anti-metabolite in phacotrabeculectomy. Secondly phacotrabeculectomy is a successful operation that improves visual acuity as well as controlling IOP in a majority of patients. Although the success of trabeculectomy in lowering IOP is reduced when combined with phacoemulsification compared with trabeculectomy alone, this finding has to be set against the possible need for subsequent cataract surgery following trabeculectomy alone, which represents a second trip and expense for the patient and results in 10-61% failure of the trabeculectomy at one year post-cataract surgery. TRIAL REGISTRATION: ISRCTN Registry ISRCTN36436933.

A mixed methods protocol to evaluate the effect and cost-effectiveness of an Integrated electronic Diagnosis Approach (IeDA) for the management of childhood illnesses at primary health facilities in Burkina Faso.

BACKGROUND: Burkina Faso introduced the Integrated Management of Childhood Illnesses (IMCI) strategy in 2003. However, an evaluation conducted in 2013 found that only 28 % of children were assessed for three danger signs as recommended by IMCI, and only 15 % of children were correctly classified. About 30 % of children were correctly prescribed with an antibiotic for suspected pneumonia or oral rehydration salts (ORS) for diarrhoea, and 40 % were correctly referred. Recent advances in information and communication technologies (ICT) and use of electronic clinical protocols hold the potential to transform healthcare delivery in low-income countries. However, no evidence is available on the effect of ICT on adherence to IMCI. This paper describes the research protocol of a mixed methods study that aims to measure the effect of the Integrated electronic Diagnosis Approach innovation (an electronic IMCI protocol provided to nurses) in two regions of Burkina Faso. METHODS/DESIGN: The study combines a stepped-wedge trial, a realistic evaluation and an economic study in order to capture the effect of the innovation after its introduction on the level of adherence, cost and acceptability. DISCUSSION: The main challenge is to interconnect the three substudies. In integrating outcome, process and cost data, we focus on three key questions: (i) How does the effectiveness and the cost of the intervention vary by type of health worker and type of health centre? (ii) What is the impact of changes in the content, coverage and quality of the IeDA intervention on adherence and cost-effectiveness? (iii) What mechanisms of change (including costs) might explain the relationship between the IeDA intervention and adherence? TRIAL REGISTRATION: Clinicaltrials.gov, NCT02341469 .

Cost-effectiveness of strategies to improve the utilization and provision of maternal and newborn health care in low-income and lower-middle-income countries: a systematic review.

BACKGROUND: Each year almost 3 million newborns die within the first 28 days of life, 2.6 million babies are stillborn, and 287,000 women die from complications of pregnancy and childbirth worldwide. Effective and cost-effective interventions and behaviours for mothers and newborns exist, but their coverage remains inadequate in low- and middle-income countries, where the vast majority of deaths occur. Cost-effective strategies are needed to increase the coverage of life-saving maternal and newborn interventions and behaviours in resource-constrained settings. METHODS: A systematic review was undertaken on the cost-effectiveness of strategies to improve the demand and supply of maternal and newborn health care in low-income and lower-middle-income countries. Peer-reviewed and grey literature published since 1990 was searched using bibliographic databases, websites of selected organizations, and reference lists of relevant studies and reviews. Publications were eligible for inclusion if they report on a behavioural or health systems strategy that sought to improve the utilization or provision of care during pregnancy, childbirth or the neonatal period; report on its cost-effectiveness; and were set in one or more low-income or lower-middle-income countries. The quality of the publications was assessed using the Consolidated Health Economic Evaluation Reporting Standards statement. Incremental cost per life-year saved and per disability-adjusted life-year averted were compared to gross domestic product per capita. RESULTS: Forty-eight publications were identified, which reported on 43 separate studies. Sixteen were judged to be of high quality. Common themes were identified and the strategies were presented in relation to the continuum of care and the level of the health system. There was reasonably strong evidence for the cost-effectiveness of the use of women's groups, home-based newborn care using community health workers and traditional birth attendants, adding services to routine antenatal care, a facility-based quality improvement initiative to enhance compliance with care standards, and the promotion of breastfeeding in maternity hospitals. Other strategies reported cost-effectiveness measures that had limited comparability. CONCLUSION: Demand and supply-side strategies to improve maternal and newborn health care can be cost-effective, though the evidence is limited by the paucity of high quality studies and the use of disparate cost-effectiveness measures. TRIAL REGISTRATION: PROSPERO_ CRD42012003255.

Simplified antibiotic regimens for the management of clinically diagnosed severe infections in newborns and young infants in first-level facilities in Karachi, Pakistan: study design for an outpatient randomized controlled equivalence trial.

BACKGROUND: Infection in young infants is a major cause of morbidity and mortality in low-middle income countries, with high neonatal mortality rates. Timely case management is lifesaving, but the current standard of hospitalization for parenteral antibiotic therapy is not always feasible. Alternative, simpler antibiotic regimens that could be used in outpatient settings have the potential to save thousands of lives. METHODS: This trial aims to determine whether 2 simplified antibiotic regimens are equivalent to the reference therapy with 7 days of once-daily (OD) intramuscular (IM) procaine penicillin and gentamicin for outpatient management of young infants with clinically presumed systemic bacterial infection treated in primary health-care clinics in 5 communities in Karachi, Pakistan. The reference regimen is close to the current recommendation of the hospital-based intravenous ampicillin and gentamicin therapy for neonatal sepsis. The 2 comparison arms are (1) IM gentamicin OD and oral amoxicillin twice daily for 7 days; and (2) IM penicillin and gentamicin OD for 2 days, followed by oral amoxicillin twice daily for 5 days; 2250 "evaluable" infants will be enrolled. The primary outcome of this trial is treatment failure (death, deterioration or lack of improvement) within 7 days of enrollment. Results are expected by early 2014. DISCUSSION: This trial will determine whether simplified antibiotic regimens with fewer injections in combination with high-dose amoxicillin are equivalent to 7 days of IM procaine penicillin and gentamicin in young infants with clinical severe infection. Results will have program and policy implications in countries with limited access to hospital care and high burden of neonatal deaths.

Effect of provision of daily zinc and iron with several micronutrients on growth and morbidity among young children in Pakistan: a cluster-randomised trial.

BACKGROUND: Powders containing iron and other micronutrients are recommended as a strategy to prevent nutritional anaemia and other micronutrient deficiencies in children. We assessed the effects of provision of two micronutrient powder formulations, with or without zinc, to children in Pakistan. METHODS: We did a cluster randomised trial in urban and rural sites in Sindh, Pakistan. A baseline survey identified 256 clusters, which were randomly assigned (within urban and rural strata, by computer-generated random numbers) to one of three groups: non-supplemented control (group A), micronutrient powder without zinc (group B), or micronutrient powder with 10 mg zinc (group C). Children in the clusters aged 6 months were eligible for inclusion in the study. Powders were to be given daily between 6 and 18 months of age; follow-up was to age 2 years. Micronutrient powder sachets for groups B and C were identical except for colour; investigators and field and supervisory staff were masked to composition of the micronutrient powders until trial completion. Parents knew whether their child was receiving supplementation, but did not know whether the powder contained zinc. Primary outcomes were growth, episodes of diarrhoea, acute lower respiratory tract infection, fever, and incidence of admission to hospital. This trial is registered with ClinicalTrials.gov, number NCT00705445. RESULTS: The trial was done between Nov 1, 2008, and Dec 31, 2011. 947 children were enrolled in group A clusters, 910 in group B clusters, and 889 in group C clusters. Micronutrient powder administration was associated with lower risk of iron-deficiency anaemia at 18 months compared with the control group (odds ratio [OR] for micronutrient powder without zinc=0·20, 95% CI 0·11-0·36; OR for micronutrient powder with zinc=0·25, 95% CI 0·14-0·44). Compared with the control group, children in the group receiving micronutrient powder without zinc gained an extra 0·31 cm (95% CI 0·03-0·59) between 6 and 18 months of age and children receiving micronutrient powder with zinc an extra 0·56 cm (0·29-0·84). We recorded strong evidence of an increased proportion of days with diarrhoea (p=0·001) and increased incidence of bloody diarrhoea (p=0·003) between 6 and 18 months in the two micronutrient powder groups, and reported chest indrawing (p=0·03). Incidence of febrile episodes or admission to hospital for diarrhoea, respiratory problems, or febrile episodes did not differ between the three groups. INTERPRETATION: Use of micronutrient powders reduces iron-deficiency anaemia in young children. However, the excess burden of diarrhoea and respiratory morbidities associated with micronutrient powder use and the very small effect on growth recorded suggest that a careful assessment of risks and benefits must be done in populations with malnourished children and high diarrhoea burdens. FUNDING: Bill & Melinda Gates Foundation.

The effectiveness of birth plans in increasing use of skilled care at delivery and postnatal care in rural Tanzania: a cluster randomised trial.

OBJECTIVES: To determine the effectiveness of birth plans in increasing use of skilled care at delivery and in the postnatal period among antenatal care (ANC) attendees in a rural district with low occupancy of health units for delivery but high antenatal care uptake in northern Tanzania. METHODS: Cluster randomised trial in Ngorongoro district, Arusha region, involving 16 health units (8 per arm). Nine hundred and five pregnant women at 24 weeks of gestation and above (404 in the intervention arm) were recruited and followed up to at least 1 month postpartum. RESULTS: Skilled delivery care uptake was 16.8% higher in the intervention units than in the control [95% CI 2.6-31.0; P = 0.02]. Postnatal care utilisation in the first month of delivery was higher (difference in proportions: 30.0% [95% CI 1.3-47.7; P < 0.01]) and also initiated earlier (mean duration 6.6 ± 1.7 days vs. 20.9 ± 4.4 days, P < 0.01) in the intervention than in the control arm. Women's and providers' reports of care satisfaction (received or provided) did not differ greatly between the two arms of the study (difference in proportion: 12.1% [95% CI -6.3-30.5] P = 0.17 and 6.9% [95% CI -3.2-17.1] P = 0.15, respectively). CONCLUSION: Implementation of birth plans during ANC can increase the uptake of skilled delivery and post delivery care in the study district without negatively affecting women's and providers' satisfaction with available ANC services. Birth plans should be considered along with the range of other recommended interventions as a strategy to improve the uptake of maternal health services.

Topical application of chlorhexidine to neonatal umbilical cords for prevention of omphalitis and neonatal mortality in a rural district of Pakistan: a community-based, cluster-randomised trial.

BACKGROUND: Umbilical cord infection (omphalitis) is a risk factor for neonatal sepsis and mortality in low-resource settings where home deliveries are common. We aimed to assess the effect of umbilical-cord cleansing with 4% chlorhexidine (CHX) solution, with or without handwashing with antiseptic soap, on the incidence of omphalitis and neonatal mortality. METHODS: We did a two-by-two factorial, cluster-randomised trial in Dadu, a rural area of Sindh province, Pakistan. Clusters were defined as the population covered by a functional traditional birth attendant (TBA), and were randomly allocated to one of four groups (groups A to D) with a computer-generated random number sequence. Implementation and data collection teams were masked to allocation. Liveborn infants delivered by participating TBAs who received birth kits were eligible for enrolment in the study. One intervention comprised birth kits containing 4% CHX solution for application to the cord at birth by TBAs and once daily by family members for up to 14 days along with soap and educational messages promoting handwashing. One intervention was CHX solution only and another was handwashing only. Standard dry cord care was promoted in the control group. The primary outcomes were incidence of neonatal omphalitis and neonatal mortality. The trial is registered with ClinicalTrials.gov, number NCT00682006. FINDINGS: 187 clusters were randomly allocated to one of the four study groups. Of 9741 newborn babies delivered by participating TBAs, factorial analysis indicated a reduction in risk of omphalitis with CHX application (risk ratio [RR]=0·58, 95% CI 0·41-0·82; p=0·002) but no evidence of an effect of handwashing (RR=0·83, 0·61-1·13; p=0·24). We recorded strong evidence of a reduction in neonatal mortality in neonates who received CHX cleansing (RR=0·62, 95 % CI 0·45-0·85; p=0·003) but no evidence of an effect of handwashing promotion on neonatal mortality (RR=1·08, 0·79-1·48; p=0·62). We recorded no serious adverse events. INTERPRETATION: Application of 4% CHX to the umbilical cord was effective in reducing the risk of omphalitis and neonatal mortality in rural Pakistan. Provision of CHX in birth kits might be a useful strategy for the prevention of neonatal mortality in high-mortality settings. FUNDING: The United States Agency for International Development.