Prevalence and Risk Factors for Iron Deficiency Anemia among Children under Five and Women of Reproductive Age in Pakistan: Findings from the National Nutrition Survey 2018.

INTRODUCTION: Anemia remains a global public health problem, especially in developing countries. It affects primarily children under five (CU5), women of reproductive age (WRA), and pregnant women due to their higher need for iron. The most common form of anemia is iron-deficiency anemia (IDA). IDA is estimated to cause half of all anemia cases and one million deaths per year worldwide. However, there remains a lack of well-documented and biochemically assessed prevalence of IDA based on the representative population-based samples globally and regionally. In this study, we aimed to assess the National Nutrition Survey (NNS) 2018 to identify the prevalence and risk factors of IDA in Pakistani CU5 and WRA. METHODS: Secondary analysis was conducted on the NNS 2018, a cross-sectional survey, which collected data on dietary practices, malnutrition, and food insecurity. Anemia was defined as hemoglobin levels < 11.0 g/dL in children and 12.0 g/dL in women. IDA was defined as low hemoglobin and low ferritin (<12 ng/mL) levels, adjusted for inflammation using AGP and CRP biomarkers in CU5 and WRA. Univariate and multivariable logistic regressions were conducted using Stata statistical software (version 16). We also compared the IDA rates of NNS 2018 and 2011. RESULTS: A total of 17,814 CU5 and 22,114 WRA were included in the analysis. Of the CU5, 28.9% had IDA, while 18.4% of WRA reported to experience IDA. Among the CU5, IDA was most prevalent among male children aged 6-23 months living in rural areas and with the presence of diarrhea and fevers in the last 2 weeks. Children whose mothers had no education, were aged 20-34 years, and employed, had a higher prevalence of IDA. Married WRA, who are employed, living in rural areas, and with no education, had a higher prevalence of IDA. In the multivariable logistic regression, children aged 6-23 months (AOR = 1.19, 95% CI [1.08-1.33], p < 0.001) and with the presence of diarrhea in the last 2 weeks (AOR = 1.32, 95% CI [1.13-1.54], p < 0.001) or fever (AOR = 1.16, 95% CI [1.02-1.32], p = 0.02) had higher odds of IDA. At the household level, the odds of IDA among CU5 were higher in the poorest households (AOR = 1.27, 95% CI [1.08-1.50], p = 0.005), with ≥5 CU5 (AOR = 1.99, 95% CI [1.28-3.11], p = 0.002), and with no access to improved sanitation facilities (AOR = 1.17, 95% CI [1.02-1.34], p = 0.026). For WRA, the multivariable logistic regression found that the odds of IDA were higher among women with vitamin A deficiency (Severe: AOR = 1.26, 95% CI [1.05-1.52], p = 0.013; Mild: AOR = 1.36, 95% CI [1.23-1.51], p < 0.001), zinc deficiency (AOR = 1.42, 95% CI [1.28-1.57], p < 0.001), no education (AOR = 1.53, 95% CI [1.30-1.81], p < 0.001), and from severely food insecure households (AOR = 1.20, 95% CI [1.07-1.34], p = 0.001). The odds of IDA were lower among women whose body mass index was overweight (AOR = 0.77, 95% CI [0.69-0.86], p < 0.001) or obese (AOR = 0.71, 95% CI [0.62-0.81], p < 0.001). CONCLUSIONS: The child's age, presence of diarrhea or fever, place of residence, household size, wealth status, and access to sanitation facilities were significantly associated with IDA among CU5 in Pakistan. For WRA, education, body mass index, vitamin A and zinc status, household food security status, wealth status, and access to sanitation facilities were significantly associated with IDA. Large, well-established, government-funded programmes focused on micronutrient supplementation, food fortification, the diversification of food supplies, and the treatment and prevention of infectious and parasitic diseases are needed to prevent IDA and all forms of anemia among children and women in Pakistan.

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.

Effectiveness of unconditional cash transfers combined with lipid-based nutrient supplement and/or behavior change communication to prevent stunting among children in Pakistan: a cluster randomized controlled trial.

BACKGROUND: In Pakistan, the prevalence of stunting among children younger than 5 y has remained above WHO critical thresholds (≥30%) over the past 2 decades. OBJECTIVES: We hypothesized that an unconditional cash transfer (UCT) combined with lipid-based nutrient supplement (LNS) and/or social and behavior change communication (SBCC) will prevent stunting among children 6-23 mo of age. METHODS: This was a 4-arm, community-based cluster randomized controlled trial conducted in the district of Rahim Yar Khan, Pakistan. A total of 1729 children (UCT, n = 434; UCT + SBCC, n = 433; UCT + LNS, n = 430; and UCT + LNS + SBCC, n = 432) were enrolled at 6 mo of age and measured monthly for 18 mo until the age of 24 mo. RESULTS: At 24 mo of age, children who received UCT + LNS [rate ratio (RR): 0.85; 95% CI: 0.74, 0.97; P = 0.015) and UCT + LNS + SBCC (RR: 0.86; 95% CI: 0.77, 0.96; P = 0.007) had a significantly lower risk of being stunted compared with the UCT arm. No significant difference was noted among children who received UCT + SBCC (RR: 1.03; 95% CI: 0.91, 1.16; P = 0.675) in the risk of being stunted compared with the UCT arm. The pooled prevalence of stunting among children aged 6-23 mo was 41.7%, 44.8%, 38.5%, and 39.3% in UCT, UCT + SBCC, UCT + LNS, and UCT + LNS + SBCC, respectively. In pairwise comparisons, a significant impact on stunting among children in UCT + LNS (P = 0.029) and UCT + LNS + SBCC (P = <0.001) was noted compared with the UCT arm. CONCLUSIONS: UCT combined with LNS and UCT + LNS + SBCC were effective in reducing the prevalence of stunting among children aged 6-23 mo in marginalized populations. UCT + SBCC was not effective in reducing the child stunting prevalence. This trial was registered at clinicaltrials.gov as NCT03299218.

Effectiveness of Transcutaneous Bilirubin Measurement in High-Risk Neonates and to Evaluate Validity of Transcutaneous Bilirubin With Total Serum Bilirubin Levels in Both Low and High-Risk Neonates at a Tertiary Care Center in a Developing Country.

Objectives To evaluate the usefulness of transcutaneous bilirubin (TcBR) nomogram in high-risk neonates and to identify the validity of TcBR and total serum bilirubin (TsBR) in both low and high-risk neonates to guide management in under-resourced settings. Methodology A cross-sectional study was conducted at the well-baby nursery of a tertiary care center in Karachi, Pakistan. All neonates admitted in the well-baby nursery with jaundice were stratified into high and low-risk groups. Eighty-seven neonates were included in the low-risk group and 121 neonates in the high-risk group. The usefulness of the TcBR nomogram in high-risk neonates and the validity of TcBR and TsBR in both low and high-risk neonates were determined through sensitivity and specificity analysis. Results The correlation coefficients (r) were found to be comparable in the high-risk group (r = 0.82, p < 0.001) and the low-risk group (r = 0.87, p < 0.001). The specificity of cutaneous bilirubin measurement based on bilirubin levels in the high-risk group was higher (93.0%) than that of the low-risk group (90.1%). However, the sensitivity was found to be lower (60.0%) in the high-risk group compared to the low-risk group (68.8%). The mean value of TsBR was equal in both groups. The mean TcBR in the high-risk group was 10 ± 2.3 compared to 11 ± 2.1 in the low-risk group. Phototherapy was given in 67.0% of the high-risk cases and 41.4% of the low-risk cases. Bland Altman analysis was also performed to depict the relationship between TcBR and TsBR measurements. Conclusion The TcBR nomogram was effective in high-risk neonates and also had validity in both high and low-risk neonates. A phototherapy-driven protocol based on TcBR would be a cost-effective and useful tool in the identification and management of neonatal jaundice in both high and low-risk groups in developing countries like Pakistan.

Impact evaluation of the efficacy of different doses of vitamin D supplementation during pregnancy on pregnancy and birth outcomes: a randomised, controlled, dose comparison trial in Pakistan.

BACKGROUND: Vitamin D deficiency during pregnancy is a public health problem in Pakistan and is prevalent among most women of reproductive age in the country. Vitamin D supplementation during pregnancy is suggested to prevent adverse pregnancy outcomes and vitamin D deficiency in both the mother and her newborn. METHODS: We conducted a double-blinded, randomised controlled trial in Karachi, Pakistan to evaluate the effect of different doses of vitamin D supplementation during pregnancy on biochemical markers (serum 25(OH)D, calcium, phosphorus and alkaline phosphatase) in women and neonates, and on pregnancy and birth outcomes (gestational diabetes, pre-eclampsia, low birth weight, preterm births and stillbirths). RESULTS: Pregnant women (N=350) in their first trimester were recruited and randomised to three treatment groups of vitamin D supplementation: 4000 IU/day (group A, n=120), 2000 IU/day (group B, n=115) or 400 IU/day (group C, n=115). Women and their newborn in group A had the lowest vitamin D deficiency at endline (endline: 75.9%; neonatal: 64.9%), followed by group B (endline: 84.9%; neonatal: 73.7%) and then the control group (endline: 90.2%; neonatal: 91.8%). Vitamin D deficiency was significantly lower in group A than in group C (p=0.006) among women at endline and lower in both groups A and B than in the control group (p=0.001) in neonates. Within groups, serum 25(OH)D was significantly higher between baseline and endline in group A and between maternal baseline and neonatal levels in groups A and B. Participant serum 25(OH)D levels at the end of the trial were positively correlated with those in intervention group A (4000 IU/day) (ß=4.16, 95% CI 1.6 to 6.7, p=0.002), with food group consumption (ß=0.95, 95% CI 0.01 to 1.89, p=0.047) and with baseline levels of serum 25(OH)D (ß=0.43, 95% CI 0.29 to 0.58, p<0.0001). CONCLUSION: The evidence provided in our study indicates that vitamin D supplementation of 4000 IU/day was more effective in reducing vitamin D deficiency among pregnant women and in improving serum 25(OH)D levels in mothers and their neonates compared with 2000 IU/day and 400 IU/day. Trial registration number NCT02215213.

Effectiveness of wheat soya blend supplementation during pregnancy and lactation on pregnancy outcomes and nutritional status of their infants at 6 months of age in Thatta and Sujawal districts of Sindh, Pakistan: a cluster randomized-controlled trial.

PURPOSE: We aimed to assess the effectiveness of wheat soya blend plus (WSBP) provided during pregnancy and lactation on weight gain during pregnancy, reduction of low birthweight (LBW), and improvement in nutritional status in infants at 6 months of age in Thatta and Sujawal districts of Sindh, Pakistan. METHODS: A cluster randomized-controlled trial was conducted in Thatta and Sujawal districts in Pakistan from August 2014 to December 2016. A total of 2030 pregnant women were enrolled in the study. These women and their infants were followed during pregnancy and first 6 months of life. Pregnant women received a monthly ration of 5 kg (i.e., 165 g/day) of WSB + during pregnancy and the first 6 months of their lactation period. RESULTS: There was no difference in weight gain during pregnancy between the intervention and control groups (n = 496, 326.7 g/week 95% CI 315.2-338.1 vs. (n = 507, 306.9 g/week, 95% CI 279.9-333.9 P = 0.192), after adjustment with different factors. The reduction in the prevalence of LBW was not different between intervention and control groups (n = 325, 34.0%, 95% CI 31.7-36.4, vs. (n = 127, 34.3%, 95% CI 27.2-41.5, P = 0.932). Significant reductions in risk of stunting (n = 1319 RR 0.85, 95% CI 0.73-0.99, P = 0.041), wasting (n = 1330 RR 0.77, 95% CI 0.65-0.91, P = 0.003), and underweight (n = 1295 RR 0.77, 95% CI 0.69-0.87, P < 0.001) were observed in infants at 6 months of age in the intervention as compared to the control group. However, no difference was noted on reduction in the risk of stunting among infants at 6 months of age in the intervention and control group (n = 1318 RR 0.91, 95% CI 0.78-1.07, P = 0.253) after adjustment. A significant reduction in anemia was noted (n = 1328 RR 0.94, 95% CI 0.91-0.98, P = 0.002) in infants at 6 months of age in the intervention as compared to the control group in adjusted analysis. CONCLUSIONS: Provision of WSB + during pregnancy and the first 6 months of lactation is effective in reducing the risk of under nutrition and anemia in infants at 6 months of age. This study can potentially guide the government and donor agencies in investing in nutritional programmes, especially for pregnant and lactating women living in vulnerable settings.

Effect of lipid-based nutrient supplement-Medium quantity on reduction of stunting in children 6-23 months of age in Sindh, Pakistan: A cluster randomized controlled trial.

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

Impact of Treatment with RUTF on Plasma Lipid Profiles of Severely Malnourished Pakistani Children.

(1) Background: Little is known on impacts of ready-to-use therapeutic food (RUTF) treatment on lipid metabolism in children with severe acute malnutrition (SAM). (2) Methods: We analyzed glycerophospholipid fatty acids (FA) and polar lipids in plasma of 41 Pakistani children with SAM before and after 3 months of RUTF treatment using gas chromatography and flow-injection analysis tandem mass spectrometry, respectively. Statistical analysis was performed using univariate, multivariate tests and evaluated for the impact of age, sex, breastfeeding status, hemoglobin, and anthropometry. (3) Results: Essential fatty acid (EFA) depletion at baseline was corrected by RUTF treatment which increased EFA. In addition, long-chain polyunsaturated fatty acids (LC-PUFA) and the ratio of arachidonic acid (AA)/linoleic acid increased reflecting greater EFA conversion to LC-PUFA, whereas Mead acid/AA decreased. Among phospholipids, lysophosphatidylcholines (lyso.PC) were most impacted by treatment; in particular, saturated lyso.PC decreased. Higher child age and breastfeeding were associated with great decrease in total saturated FA (ΣSFA) and lesser decrease in monounsaturated FA and total phosphatidylcholines (ΣPC). Conclusions: RUTF treatment improves EFA deficiency in SAM, appears to enhance EFA conversion to biologically active LC-PUFA, and reduces lipolysis reflected in decreased ΣSFA and saturated lyso.PC. Child age and breastfeeding modify treatment-induced changes in ΣSFA and ΣPC.

Exchangeable Zinc Pool Size at Birth in Pakistani Small for Gestational Age and Appropriate for Gestational Age Infants Do Not Differ But Are Lower Than in US Infants.

OBJECTIVES: Small for gestational age (SGA) infants are more susceptible to infectious morbidity and growth faltering compared to their appropriate for gestational age (AGA) counterparts. Zinc supplementation of SGA infants may be beneficial but the underlying susceptibility to zinc deficiency of SGA infants has not been examined. METHODS: In a community-based, observational, longitudinal study in a peri-urban settlement of Karachi, Pakistan, we compared the size of the exchangeable zinc pools (EZPs) in term SGA and AGA infants at birth and at 6 months of age, hypothesizing that the EZP would be lower in the SGA group. To measure EZP size, a zinc stable isotope was intravenously administered within 48 hours of birth (n = 17 and 22) at 6 months (n = 11 and 14) in SGA and AGA infants, respectively. Isotopic enrichment in urine was used to determine EZP. RESULTS: No significant difference was detected in the mean (±standard deviation) EZP between SGA and AGA infants at birth, with values of 9.8 ±â€Š3.5 and 10.1 ±â€Š4.1 mg/kg, respectively (P = 0.86), or at 6 months. Longitudinal EZP measurements demonstrated a significant decline in EZP relative to body weight in both groups at 6 months (P < 0.001). Mean EZP (adjusted for body weight) size at birth for the combined Pakistani groups was significantly lower than AGA infants at birth in the United States (P = 0.017). CONCLUSIONS: These results did not support a difference in zinc endowment between SGA and AGA Pakistani infants. They, however, do suggest lower in utero zinc transfer to the fetus in a setting where poor maternal nutritional status may confer a high susceptibility to postnatal zinc deficiency.

Modifiers of the effect of maternal multiple micronutrient supplementation on stillbirth, birth outcomes, and infant mortality: a meta-analysis of individual patient data from 17 randomised trials in low-income and middle-income countries.

BACKGROUND: Micronutrient deficiencies are common among women in low-income and middle-income countries. Data from randomised trials suggest that maternal multiple micronutrient supplementation decreases the risk of low birthweight and potentially improves other infant health outcomes. However, heterogeneity across studies suggests influence from effect modifiers. We aimed to identify individual-level modifiers of the effect of multiple micronutrient supplements on stillbirth, birth outcomes, and infant mortality in low-income and middle-income countries. METHODS: This two-stage meta-analysis of individual patient included data from 17 randomised controlled trials done in 14 low-income and middle-income countries, which compared multiple micronutrient supplements containing iron-folic acid versus iron-folic acid alone in 112 953 pregnant women. We generated study-specific estimates and pooled subgroup estimates using fixed-effects models and assessed heterogeneity between subgroups with the χ2 test for heterogeneity. We did sensitivity analyses using random-effects models, stratifying by iron-folic acid dose, and exploring individual study effect. FINDINGS: Multiple micronutrient supplements containing iron-folic acid provided significantly greater reductions in neonatal mortality for female neonates compared with male neonates than did iron-folic acid supplementation alone (RR 0·85, 95% CI 0·75-0·96 vs 1·06, 0·95-1·17; p value for interaction 0·007). Multiple micronutrient supplements resulted in greater reductions in low birthweight (RR 0·81, 95% CI 0·74-0·89; p value for interaction 0·049), small-for-gestational-age births (0·92, 0·87-0·97; p=0·03), and 6-month mortality (0·71, 0·60-0·86; p=0·04) in anaemic pregnant women (haemoglobin <110g/L) as compared with non-anaemic pregnant women. Multiple micronutrient supplements also had a greater effect on preterm births among underweight pregnant women (BMI <18·5 kg/m2; RR 0·84, 95% CI 0·78-0·91; p=0·01). Initiation of multiple micronutrient supplements before 20 weeks gestation provided greater reductions in preterm birth (RR 0·89, 95% CI 0·85-0·93; p=0·03). Generally, the survival and birth outcome effects of multiple micronutrient supplementation were greater with high adherence (≥95%) to supplementation. Multiple micronutrient supplements did not significantly increase the risk of stillbirth or neonatal, 6-month, or infant mortality, neither overall or in any of the 26 examined subgroups. INTERPRETATION: Antenatal multiple micronutrient supplements improved survival for female neonates and provided greater birth-outcome benefits for infants born to undernourished and anaemic pregnant women. Early initiation in pregnancy and high adherence to multiple micronutrient supplements also provided greater overall benefits. Studies should now aim to elucidate the mechanisms accounting for differences in the effect of antenatal multiple micronutrient supplements on infant health by maternal nutrition status and sex. FUNDING: None.

Comparison of enteral versus intravenous potassium supplementation in hypokalaemia in paediatric patients in intensive care post cardiac surgery: open-label randomised equivalence trial (EIPS).

OBJECTIVES: The primary objective was to compare the efficacy of enteral potassium replacement (EPR) and intravenous potassium replacement (IVPR) as first-line therapy. Secondary objectives included comparison of adverse effects and number of doses required to resolve the episode of hypokalaemia. TRIAL DESIGN: The EIPS trial is designed as a randomised, equivalence trial between two treatment arms. STUDY SETTING: The study was conducted at the paediatric cardiac intensive care unit (PCICU) at Aga Khan University Hospital, Karachi. PARTICIPANTS: 41 patients (aged 1 month to 15 years) who were admitted to PCICU post cardiac surgery were recruited (23 IVPR arm and 18 EPR arm). INTERVENTION: Intervention arms were block randomised on alternate weeks for IVPR and EPR. OUTCOME MEASURE: Change in serum potassium levels in (mmol/L) and percentage change after each event of potassium replacement by the intravenous or enteral route. RESULTS: Both groups (41 patients) had similar baseline characteristics. Mean age was 4.7 (SD±4) years while the most common surgical procedure was ventricular septal defect repair (12 patients, 29.3%). No mortality was observed in either arm. Four episodes of vomiting and one arrhythmia were seen in the EPR group. After adjusting for age, potassium level at the beginning of the episode, average urine output, inotropic score and diuretic dose, it was found that there was no statistically significant difference in change in potassium levels after EPR and IVPR: 0.86 mmol/L (±0.8) and 0.82 mmol/L (±0.7) respectively (p=0.86, 95% CI -0.08 to 1.10), or percentage change in potassium level after enteral and intravenous replacement: 26% (±30) and 24% (±20) (95% CI -3.42 to 4.03, p=0.87). CONCLUSION: EPR may be an equally efficacious alternative first-line therapy in treating hypokalaemia after surgery in selective patients with congenital heart disease. ETHICS AND DISSEMINATION: This study has been approved by Ethics Review Committee at AKU. TRIAL REGISTRATION NUMBER: NCT02015962.

Effect of integrated responsive stimulation and nutrition interventions in the Lady Health Worker programme in Pakistan on child development, growth, and health outcomes: a cluster-randomised factorial effectiveness trial.

BACKGROUND: Stimulation and nutrition delivered through health programmes at a large scale could potentially benefit more than 200 million young children worldwide who are not meeting their developmental potential. We investigated the feasibility and effectiveness of the integration of interventions to enhance child development and growth outcomes in the Lady Health Worker (LHW) programme in Sindh, Pakistan. METHODS: We implemented a community-based cluster-randomised effectiveness trial through the LHW programme in rural Sindh, Pakistan, with a 2 × 2 factorial design. We randomly allocated 80 clusters (LHW catchments) of children to receive routine health and nutrition services (controls; n=368), nutrition education and multiple micronutrient powders (enhanced nutrition; n=364), responsive stimulation (responsive stimulation; n=383), or a combination of both enriched interventions (n=374). The allocation ratio was 1:20 (ie, 20 clusters per intervention group). The data collection team were masked to the allocated intervention. All children born in the study area between April, 2009, and March, 2010, were eligible for enrolment if they were up to 2·5 months old without signs of severe impairments. Interventions were delivered by LHWs to families with children up to 24 months of age in routine monthly group sessions and home visits. The primary endpoints were child development at 12 and 24 months of age (assessed with the Bayley Scales of Infant and Toddler Development, Third Edition) and growth at 24 months of age. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT007159636. FINDINGS: 1489 mother-infant dyads were enrolled into the study, of whom 1411 (93%) were followed up until the children were 24 months old. Children who received responsive stimulation had significantly higher development scores on the cognitive, language, and motor scales at 12 and 24 months of age, and on the social-emotional scale at 12 months of age, than did those who did not receive the intervention. Children who received enhanced nutrition had significantly higher development scores on the cognitive, language, and social-emotional scales at 12 months of age than those who did not receive this intervention, but at 24 months of age only the language scores remained significantly higher. We did not record any additive benefits when responsive stimulation was combined with nutrition interventions. Responsive stimulation effect sizes (Cohen's d) were 0·6 for cognition, 0·7 for language, and 0·5 for motor development at 24 months of age; these effect sizes were slightly smaller for the combined intervention group and were low to moderate for the enhanced nutrition intervention alone. Children exposed to enhanced nutrition had significantly better height-for-age Z scores at 6 months (p<0·0001) and 18 months (p=0·02) than did children not exposed to enhanced nutrition. Longitudinal analysis showed a small benefit to linear growth from enrolment to 24 months (p=0·026) in the children who received the enhanced nutrition intervention. INTERPRETATION: The responsive stimulation intervention can be delivered effectively by LHWs and positively affects development outcomes. The absence of a major effect of the enhanced nutrition intervention on growth shows the need for further analysis of mediating variables (eg, household food security status) that will help to optimise future nutrition implementation design. FUNDING: UNICEF.

Evidence-based interventions for improvement of maternal and child nutrition: what can be done and at what cost?

Maternal undernutrition contributes to 800,000 neonatal deaths annually through small for gestational age births; stunting, wasting, and micronutrient deficiencies are estimated to underlie nearly 3·1 million child deaths annually. Progress has been made with many interventions implemented at scale and the evidence for effectiveness of nutrition interventions and delivery strategies has grown since The Lancet Series on Maternal and Child Undernutrition in 2008. We did a comprehensive update of interventions to address undernutrition and micronutrient deficiencies in women and children and used standard methods to assess emerging new evidence for delivery platforms. We modelled the effect on lives saved and cost of these interventions in the 34 countries that have 90% of the world's children with stunted growth. We also examined the effect of various delivery platforms and delivery options using community health workers to engage poor populations and promote behaviour change, access and uptake of interventions. Our analysis suggests the current total of deaths in children younger than 5 years can be reduced by 15% if populations can access ten evidence-based nutrition interventions at 90% coverage. Additionally, access to and uptake of iodised salt can alleviate iodine deficiency and improve health outcomes. Accelerated gains are possible and about a fifth of the existing burden of stunting can be averted using these approaches, if access is improved in this way. The estimated total additional annual cost involved for scaling up access to these ten direct nutrition interventions in the 34 focus countries is Int$9·6 billion per year. Continued investments in nutrition-specific interventions to avert maternal and child undernutrition and micronutrient deficiencies through community engagement and delivery strategies that can reach poor segments of the population at greatest risk can make a great difference. If this improved access is linked to nutrition-sensitive approaches--ie, women's empowerment, agriculture, food systems, education, employment, social protection, and safety nets--they can greatly accelerate progress in countries with the highest burden of maternal and child undernutrition and mortality.

Stillbirths: what difference can we make and at what cost?

Worldwide, 2·65 million (uncertainty range 2·08 million to 3·79 million) stillbirths occur yearly, of which 98% occur in countries of low and middle income. Despite the fact that more than 45% of the global burden of stillbirths occur intrapartum, the perception is that little is known about effective interventions, especially those that can be implemented in low-resource settings. We undertook a systematic review of randomised trials and observational studies of interventions which could reduce the burden of stillbirths, particularly in low-income and middle-income countries. We identified several interventions with sufficient evidence to recommend implementation in health systems, including periconceptional folic acid supplementation or fortification, prevention of malaria, and improved detection and management of syphilis during pregnancy in endemic areas. Basic and comprehensive emergency obstetric care were identified as key effective interventions to reduce intrapartum stillbirths. Broad-scale implementation of intervention packages across 68 countries listed as priorities in the Countdown to 2015 report could avert up to 45% of stillbirths according to a model generated from the Lives Saved Tool. The overall costs for these interventions are within the general estimates of cost-effective interventions for maternal care, especially in view of the effects on outcomes across maternal, fetal, and neonatal health.

Treatment response to iron and folic acid alone is the same as with multivitamins and/or anthelminthics in severely anemic 6- to 24-month-old children.

We assessed the effectiveness of iron+folic acid for the treatment of severe anemia [hemoglobin (Hb) <70 g/L] and the efficacy of added multivitamins and/or anthelminthics among children aged 6-24 mo in periurban Karachi, Pakistan. The study design was a double blind, placebo-controlled, randomized trial of currently recommended daily iron (25 mg) and folic acid (100 microg) for 90 d with daily multivitamins [vitamin A (300 microg, as retinol palmitate), vitamin E (6 mg tocopherol equivalents), vitamin B-12 (0.9 microg), vitamin C (15 mg), riboflavin (0.5 mg)] and/or anthelminthics (100 mg mebendazole twice daily for 3 d) compared with placebos. Treatment response was defined as reaching a Hb concentration > or =100 g/L at the end of 90 d. The prevalence of severe anemia in the 9518 children screened was 5.7% and a total of 462 severely anemic children were enrolled in the study. Adherence to treatment was approximately 70% for iron+folic acid, approximately 80% for multivitamins, and almost 100% for mebendazole. Children receiving iron+folic acid alone had a response rate of 38.7% at 90 d. The additional treatment with mebendazole or multivitamins did not significantly improve cure rates or change the Hb concentration over and above iron+folic acid treatment alone. Adherence to iron+folic acid of higher than the median resulted in a better treatment response rate of 50%. High-dose daily iron+folic acid performed as well as iron+folic acid with anthelminthics and multivitamins in the treatment of severe anemia in this setting. Higher adherence may be important in enhancing treatment impact.

Treatment response to standard of care for severe anemia in pregnant women and effect of multivitamins and enhanced anthelminthics.

BACKGROUND: Severe anemia (hemoglobin < 70 g/L) in pregnancy may increase the risk of maternal and perinatal mortality. OBJECTIVES: We assessed response to standard treatment with high-dose iron-folic acid for 90 d and single-dose (500 mg) mebendazole among severely anemic pregnant women in periurban Karachi, Pakistan. In addition, we evaluated the efficacy of 2 enhanced treatment regimens. DESIGN: We screened pregnant women (n = 6288) for severe anemia and provided them all with the standard treatment. To test the efficacy of 2 additional treatments, women were randomly assigned to standard treatment alone (control) or with 100 mg mebendazole twice daily for 3 d or 90 d of daily multivitamins or both using a 2 x 2 factorial design. RESULTS: Prevalence of severe anemia was high (10.5%) during pregnancy. Prevalence of geohelminths and malaria was low. Treatment response was defined as hemoglobin > 100 g/L at the 90-d or > or = 25 g/L at the 60-d follow-up visit. The standard-of-care treatment resulted in a response rate of 49% at follow-up, although an adherence of > or = 85% elicited a higher response (67%). The effect of the additional treatments was weak. Although response was higher in the enhanced groups than for the standard treatment at the final assessment, the differences were not statistically significant. However, hemoglobin concentration increased significantly in all groups and was higher in the enhanced mebendazole group compared with the standard group (P < 0.05). CONCLUSIONS: Iron deficiency was high in this population, and the standard-of-care treatment resulted in a treatment response of 50%, although better treatment adherence showed a higher response. Multivitamins and the enhanced mebendazole regimen had a modest benefit over and above the standard treatment.

A comparative evaluation of multiple micronutrient and iron-folic acid supplementation during pregnancy in Pakistan: impact on pregnancy outcomes.

BACKGROUND: Maternal micronutrient deficiencies are widespread in Pakistan and are potentially associated with maternal undernutrition and intrauterine growth retardation. Intervention strategies largely consist of administration of iron-folic acid supplements during pregnancy. OBJECTIVE: We evaluated the acceptability of multiple micronutrient supplementation and its potential benefits on pregnancy outcomes and maternal micronutrient status in a cohort of pregnant women in rural and urban Sindh through a cluster-randomized design. METHODS: We randomly assigned 2378 pregnant women to receive either iron-folic acid or multiple micronutrient supplements. The supplements were administered fortnightly by community health workers who performed home visits to assess tolerance and observe the mothers. RESULTS: The women in both groups consumed about 75% of the supplements provided, and few reported adverse effects such as vomiting, abdominal pain, etc. There was a small (70 g) but significant increase in birthweight among infants of mothers receiving multiple micronutrients as compared with infants of mothers receiving iron-folic acid supplements (2.95 +/- 0.6 vs. 2.88 +/- 0.5 kg, p = .01). This translated into a 10% reduction (p < 0.17) in the proportion of low-birthweight infants among infants of mothers receiving multiple micronutrients. Although stillbirth rates were comparable in the two groups, the early neonatal mortality rate in the group receiving multiple micronutrients was higher, although not significantly, than that in the group receiving iron-folic acid (43.2 vs. 23.5 deaths per 1000 live births; RR = 1.64; 95% CI, 0.94 to 2.87). Comparable reductions in anemia (hemoglobin < 11 g/dL) were observed, although the proportion with low iron stores (assessed by serum ferritin) was lower in the iron-folic acid group in the postnatal period. Although the proportion of women with subclinical vitamin A deficiency after supplementation did not differ between the two groups, the iron-folic acid group had a higher proportion with lower serum zinc levels in the immediate postpartum period. CONCLUSIONS: These data suggest that multiple micronutrient supplements are well tolerated during pregnancy, but the effect on birthweight is modest. The observed effect on early neonatal mortality suggests the need for further studies and careful assessment of the intervention in health system settings.