Biomarkers of systemic inflammation and growth in early infancy are associated with stunting in young Tanzanian children

Stunting can afflict up to one-third of children in resource-constrained countries. We hypothesized that low-grade systemic inflammation (defined as elevations in serum C-reactive protein or alpha-1-acid glycoprotein) in infancy suppresses the growth hormone–insulin-like growth factor (IGF) axis and is associated with subsequent stunting. Blood samples of 590 children from periurban Dar es Salaam, Tanzania, were obtained at 6 weeks and 6 months of age as part of a randomized controlled trial. Primary outcomes were stunting, underweight, and wasting (defined as length-for-age, weight-for-age and weight-for-length z-scores < −2) between randomization and endline (18 months after randomization). Cox proportional hazards models were constructed to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of time to first stunting, underweight, and wasting as outcomes, with measures of systemic inflammation, insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding protein-3 (IGFBP-3) as exposures, adjusting for numerous demographic and clinical variables. The incidences of subsequent stunting, underweight, and wasting were 26%, 20%, and 18%, respectively. In multivariate analyses, systemic inflammation at 6 weeks of age was significantly associated with stunting (HR: 2.14, 95% CI: 1.23, 3.72; p = 0.002). Children with higher levels of IGF-1 at 6 weeks were less likely to become stunted (HR: 0.58, 95% CI: 0.37, 0.93; p for trend = 0.019); a similar trend was noted in children with higher levels of IGF-1 at 6 months of age (HR: 0.50, 95% CI: 0.22, 1.12; p for trend = 0.07). Systemic inflammation occurs as early as 6 weeks of age and is associated with the risk of future stunting among Tanzanian children.This research was funded by the National Institutes of Health (R01 HD048969, 2P30 DK040561, K24 DK104676-Dr. Duggan) and the Bill and Melinda Gates Foundation (OPP1066203-Dr. Duggan). (R01 HD048969 - National Institutes of Health; 2P30 DK040561 - National Institutes of Health; K24 DK104676 - National Institutes of Health; OPP1066203 - Bill and Melinda Gates Foundation)Accepted manuscrip

Dyslipidemia in an HIV-Positive Antiretroviral Treatment-Naive Population in Dar es Salaam, Tanzania.

Limited data are available on dyslipidemia in HIV-infected patients in resource-limited settings. We performed a cross-sectional analysis in antiretroviral therapy (ART)-naive, non-fasting HIV-infected patients in Tanzania between November 2004 to June 2008. Robust linear regression modeling was performed. Lipid parameters were assessed in 12,513 patients [65% women; median (interquartile range) age, 36 (30-42) years; CD4 count, 143 (51-290) cells/mm]. Low high-density lipoprotein was prevalent in 67% and increased triglyceride in 28%. High triglyceride and low high-density lipoprotein levels were associated with low CD4 counts (P < 0.001). In this ART-naive Tanzanian population, dyslipidemia was highly prevalent and associated with advanced disease. The impact of ART on these changes requires further exploration

Multivitamin Supplementation Improves Haematologic Status in Children Born to HIV-positive women in Tanzania.

Anaemia is prevalent among children born to HIV-positive women, and it is associated with adverse effects on cognitive and motor development, growth, and increased risks of morbidity and mortality. To examine the effect of daily multivitamin supplementation on haematologic status and mother-to-child transmission (MTCT) of HIV through breastfeeding. A total of 2387 infants born to HIV-positive women from Dar es Salaam, Tanzania were enrolled in a randomized, double-blind, placebo-controlled trial, and provided a daily oral supplement of multivitamins (vitamin B complex, C and E) or placebo at age 6 weeks for 24 months. Among them, 2008 infants provided blood samples and had haemoglobin concentrations measured at baseline and during a follow-up period. Anaemia was defined as haemoglobin concentrations <11 g/dL and severe anaemia <8.5 g/dL. Haemoglobin concentrations among children in the treatment group were significantly higher than those in the placebo group at 12 (9.77 vs. 9.64 g/dL, p=0.03), 18 (9.76 vs. 9.57 g/dL, p=0.004), and 24 months (9.93 vs. 9.75 g/dL, p=0.02) of follow-up. Compared to those in the placebo group, children in the treatment group had a 12% lower risk of anaemia (hazard ratio (HR): 0.88; 95% CI: 0.79-0.99; p=0.03). The treatment was associated with a 28% reduced risk of severe anaemia among children born to women without anaemia (HR: 0.72; 95% CI: 0.56-0.92; p=0.008), but not among those born to women with anaemia (HR: 1.10; 95% CI: 0.79-1.54; p=0.57; p for interaction=0.007). One thousand seven hundred fifty three infants who tested HIV-negative at baseline and had HIV testing during follow-up were included in the analysis for MTCT of HIV. No association was found between multivitamin supplements and MTCT of HIV. Multivitamin supplements improve haematologic status among children born to HIV-positive women. Further trials focusing on anaemia among HIV-exposed children are warranted in the context of antiretroviral therapy

Maternal hyperglycemia and adverse pregnancy outcomes in Dar es Salaam, Tanzania

Objective To evaluate maternal glucose levels during pregnancy as a predictor of adverse perinatal outcomes in Dar es Salaam, Tanzania. Methods Random blood glucose measurements were analyzed from 3833 pregnant women enrolled in a randomized trial to assess the impact of multivitamins on pregnancy outcomes in Dar es Salaam between August 2001 and July 2004. Information on maternal and neonatal morbidity was recorded at monthly study visits, delivery, and 6 weeks postpartum. Generalized estimating equations specified with a binomial distribution and log-link function were used to determine the relationship between elevated glucose (>7.8 mmol/L) and pregnancy outcomes. Results In total, 25 women had elevated glucose (0.7%). Hyperglycemia was associated with an increased risk of delivery before 37 weeks [relative risk (RR), 2.11; 95% confidence interval [CI], 1.07–4.13; P=0.03), delivery before 34 weeks (RR, 4.15; 95% CI, 1.43–12.03, P=0.009), incident gestational hypertension (RR, 2.90; 95% CI, 1.24–6.76; P=0.01), low birth weight (RR, 2.87; 95% CI, 1.18–6.99; P=0.02), reduced newborn head circumference (mean difference, –1.53; 95% CI, –2.51 to –0.62; P=0.001), and stillbirth (RR, 3.38; 95% CI, 1.13–10.08; P=0.03). Conclusion Maternal hyperglycemia is uncommon among pregnant Tanzanian women, but nonetheless seems to increase the risk of several adverse perinatal outcomes

Suboptimal gestational weight gain and neonatal outcomes in low and middle income countries: individual participant data meta-analysis

OBJECTIVE: To estimate the associations between gestational weight gain (GWG) during pregnancy and neonatal outcomes in low and middle income countries. DESIGN: Individual participant data meta-analysis. SETTING: Prospective pregnancy studies from 24 low and middle income countries. MAIN OUTCOME MEASURES: Nine neonatal outcomes related to timing (preterm birth) and anthropometry (weight, length, and head circumference) at birth, stillbirths, and neonatal death. ANALYSIS METHODS: A systematic search was conducted in PubMed, Embase, and Web of Science which identified 53 prospective pregnancy studies published after the year 2000 with data on GWG, timing and anthropometry at birth, and neonatal mortality. GWG adequacy was defined as the ratio of the observed maternal weight gain over the recommended weight gain based on the Institute of Medicine body mass index specific guidelines, which are derived from data in high income settings, and the INTERGROWTH-21st GWG standards. Study specific estimates, adjusted for confounders, were generated and then pooled using random effects meta-analysis models. Maternal age and body mass index before pregnancy were examined as potential modifiers of the associations between GWG adequacy and neonatal outcomes. RESULTS: Overall, 55% of participants had severely inadequate (<70%) or moderately inadequate (70% to <90%) GWG, 22% had adequate GWG (90-125%), and 23% had excessive GWG (≥125%). Severely inadequate GWG was associated with a higher risk of low birthweight (adjusted relative risk 1.62, 95% confidence interval 1.51 to 1.72; 48 studies, 93 337 participants; τ2=0.006), small for gestational age (1.44, 1.36 to 1.54; 51 studies, 93 191 participants; τ2=0.016), short for gestational age (1.47, 1.29 to 1.69; 40 studies, 83 827 participants; τ2=0.074), and microcephaly (1.57, 1.31 to 1.88; 31 studies, 80 046 participants; τ2=0.145) compared with adequate GWG. Excessive GWG was associated with a higher risk of preterm birth (1.22, 1.13 to 1.31; 48 studies, 103 762 participants; τ2=0.008), large for gestational age (1.44, 1.33 to 1.57; 47 studies, 90 044 participants; τ2=0.009), and macrosomia (1.52, 1.33 to 1.73; 29 studies, 68 138 participants; τ2=0) compared with adequate GWG. The direction and magnitude of the associations between GWG adequacy and several neonatal outcomes were modified by maternal age and body mass index before pregnancy. CONCLUSIONS: Inadequate and excessive GWG are associated with a higher risk of adverse neonatal outcomes across settings. Interventions to promote optimal GWG during pregnancy are likely to reduce the burden of adverse neonatal outcomes, however further research is needed to assess optimal ranges of GWG based on data from low and middle income countries

Effect of Zinc Supplementation on Growth Outcomes in Children under 5 Years of Age

(1) Background: The effects of zinc supplementation on child growth, and prior reviews of these studies, have shown mixed results. We aim to systematically review and meta-analyze randomized controlled trials evaluating effects of preventive zinc supplementation for 3 months or longer during pregnancy or in children up to age 5 years on pregnancy outcomes and child growth; (2) Methods: We searched PubMed, EMBASE, Cochrane Library, Web of Science, and trial registries for eligible trials up to October 10, 2017. Inclusion selection and data extractions were performed independently and in duplicate. Study quality was evaluated by the Cochrane Risk of Bias tool. Findings were pooled using random effects meta-analysis, with heterogeneity assessed by I2 and τ2 statistic, stratified analyses, and meta-regression, and publication bias by Egger’s and Begg’s tests; (3) Results: Seventy-eight trials with 34,352 unique participants were identified, including 24 during pregnancy and 54 in infancy/childhood. Maternal zinc supplementation did not significantly increase birth weight (weighted mean difference (WMD) = 0.08 kg, 95%CI: −0.05, 0.22) or decrease the risk of low birth weight (RR = 0.76, 95%CI: 0.52–1.11). Zinc supplementation after birth increased height (WMD = 0.23 cm, 95%CI: 0.09–0.38), weight (WMD = 0.14 kg, 95%CI: 0.07–0.21), and weight-for-age Z-score (WMD = 0.04, 95%CI: 0.001–0.087), but not height-for-age Z-score (WMD = 0.02, 95%CI: −0.01–0.06) or weight-for-height Z score (WMD = 0.02, 95%CI: −0.03–0.06). Child age at zinc supplementation appeared to modify the effects on height (P-interaction = 0.002) and HAZ (P-interaction = 0.06), with larger effects of supplementation starting at age ≥2 years (WMD for height = 1.37 cm, 95%CI: 0.50–2.25; WMD for HAZ = 0.12, 95%CI: 0.05–0.19). No significant effects of supplementation were found on the risk of stunting, underweight or wasting; (4) Conclusion: Although the possibility of publication bias and small study effect could not be excluded, the current meta-analysis indicates that zinc supplementation in infants and early childhood, but not pregnancy, increases specific growth outcomes, with evidence for a potentially stronger effect after 2 years of age. These findings inform recommendation and policy development for zinc supplementation to improve growth among young children

Angiogenic Proteins, Placental Weight and Perinatal Outcomes Among Pregnant Women in Tanzania

Introduction Placental vascular development, and ultimately placental weight, is essential to healthy fetal development. Here, we examined placental weight in a cohort of Tanzanian women in association with angiogenic proteins known to regulate placental vascular development and perinatal outcomes. Methods A total of n = 6579 women with recorded placental weight were included in this study. The relative risk of adverse perinatal outcomes (Apgar score, death, asphyxia, respiratory distress, seizures, pneumonia and sepsis) was compared between placental weight in the bottom and top 10th percentiles. We quantified angiogenic mediators (Ang-1, Ang-2, VEGF, PGF and sFlt-1) in plasma samples (n = 901) collected between 12 to 27 weeks of pregnancy using ELISA and assessed the relative risk of placental weight in the bottom and top 10th percentiles by protein levels in quartiles. Results Women with Ang-2 levels in the highest quartile had an increased relative risk of placental weight in the bottom 10th percentile (RR = 1.45 (1.10, 1.91), p = 0.01). Women with VEGF-A (RR = 0.73 (0.56, 0.96), p = 0.05) and PGF (RR = 0.58 (0.44, 0.72), p = 0.002) in the highest quartile had a reduced relative risk of placental weight in the bottom 10th percentile. Low placental weight (in bottom 10th percentile) was associated with an increased relative risk of Apgar score of <7 at 1 minute (RR = 2.31 (1.70, 3.13), p = 0.001), at 5 minutes (RR = 3.53 (2.34, 5.33), p = 0.001), neonatal death (RR = 5.02 (3.61, 7.00), p = 0.001), respiratory distress (RR = 4.80(1.71, 13.45), p = 0.001), and seizures (RR = 4.18 (1.16, 15.02), p = 0.03). Discussion The association between low placental weight and risk of adverse perinatal outcomes in this cohort suggests that placental weight could serve as a useful indicator, providing additional insight into high-risk pregnancies and identifying neonates that may require additional monitoring and follow-up

Enteral Multiple Micronutrient Supplementation in Preterm and Low Birth Weight Infants: A Systematic Review and Meta-analysis

OBJECTIVES To assess effects of supplementation with 3 or more micronutrients (multiple micronutrients; MMN) compared to no MMN in human milk-fed preterm and low birth weight (LBW) infants. RESULTS Data on a subgroup of 414 preterm or LBW infants from 2 randomized controlled trials (4 reports) were included. The certainty of evidence ranged from low to very low. For growth outcomes in the MMN compared to the non-MMN group, there was a small increase in weight-for-age (2 trials, 383 participants) and height-for-age z-scores (2 trials, 372 participants); a small decrease in wasting (2 trials, 398 participants); small increases in stunting (2 trials, 399 participants); and an increase in underweight (2 trials, 396 participants). For neurodevelopment outcomes at 78 weeks, we found small increases in Bayley Scales of Infant Development, Version III (BISD-III), scores (cognition, receptive language, expressive language, fine motor, gross motor) in the MMN compared to the non-MMN group (1 trial, 27 participants). There were no studies examining dose or timing of supplementation. CONCLUSIONS Evidence is insufficient to determine whether enteral MMN supplementation to preterm or LBW infants who are fed mother's own milk is associated with benefit or harm. More trials are needed to generate evidence on mortality, morbidity, growth, and neurodevelopment.publishedVersio

Tuberculosis incidence rate and risk factors among HIV-infected adults with access to antiretroviral therapy

OBJECTIVE: The objective of this study is to determine the incidence rate and risk factors of tuberculosis (TB) among HIV-infected adults accessing antiretroviral therapy (ART) in Tanzania. DESIGN: A prospective observational study among HIV-infected adults attending HIV clinics in Dar es Salaam. METHODS: We estimated TB incidence rates among HIV-infected patients prior to and after ART initiation. We used Cox proportional hazard regressions to determine the predictors of incident TB among HIV-infected adults enrolled in the HIV care and treatment programme. RESULTS: We assessed 67 686 patients for a median follow-up period of 24 (interquartile range: 8-49) months; 7602 patients were diagnosed with active TB. The TB incidence rate was 7.9 [95% confidence interval (95% CI), 7.6-8.2] per 100 person-years prior to ART initiation, and 4.4 (95% CI, 4.2-4.4) per 100 person-years for patients receiving ART. In multivariate analyses, patients on ART in the first 3 months had a 57% higher risk of TB (hazard ratio: 1.57, 95% CI, 1.47-1.68) than those not on ART, but the risk significantly decreased with increasing duration of ART. Risk factors for incident TB included being male, having low BMI or middle upper arm circumference, lower CD4 cell count and advanced WHO disease stage. There was seasonal variation for incident TB, with higher risk observed following the rainy seasons (May, June and November). CONCLUSION: In TB endemic regions, HIV-infected patients initiating ART, particularly men and those with poor nutritional status, should be closely monitored for active TB at ART initiation. In addition to increasing the access to ART, interventions should be considered to improve nutritional status among HIV-infected patients

Prevalence of Hypertension and Its Associated Risk Factors among 34,111 HAART Naïve HIV-Infected Adults in Dar es Salaam, Tanzania

Background:. Elevated blood pressure has been reported among treatment naïve HIV-infected patients. We investigated prevalence of hypertension and its associated risk factors in a HAART naïve HIV-infected population in Dar es Salaam, Tanzania. Methods. A cross-sectional analysis was conducted among HAART naïve HIV-infected patients. Hypertension was defined as systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg. Overweight and obesity were defined as body mass index (BMI) between 25.0–29.9 kg/m2 and ≥30 kg/m2, respectively. We used relative risks to examine factors associated with hypertension. Results. Prevalence of hypertension was found to be 12.5%. After adjusting for possible confounders, risk of hypertension was 10% more in male than female patients. Patients aged ≥50 years had more than 2-fold increased risk for hypertension compared to 30–39-years-old patients. Overweight and obesity were associated with 51% and 94% increased risk for hypertension compared to normal weight patients. Low CD4+ T-cell count, advanced WHO clinical disease stage, and history of TB were associated with 10%, 42%, and 14% decreased risk for hypertension. Conclusions. Older age, male gender, and overweight/obesity were associated with hypertension. Immune suppression and history of TB were associated with lower risk for hypertension. HIV treatment programs should screen and manage hypertension even in HAART naïve individuals