Are birthweight and postnatal weight gain in childhood associated with blood pressure in early adolescence? Results from a Ugandan birth cohort.

BACKGROUND: In Africa, where low birthweight (LBW), malnutrition and high blood pressure (BP) are prevalent, the relationships between birthweight (BW), weight gain and BP later in life remain uncertain. We examined the effects of early life growth on BP among Ugandan adolescents. METHODS: Data were collected prenatally from women and their offspring were followed from birth, with BP measured following standard protocols in early adolescence. Weight-for-age Z-scores (WAZ) were computed using World Health Organization references. Linear regression was used to relate BW, and changes in WAZ between birth and 5 years, to adolescents' BP, adjusting for confounders. RESULTS: Among 2345 live offspring, BP was measured in 1119 (47.7%) adolescents, with mean systolic BP 105.9 mmHg and mean diastolic BP 65.2 mmHg. There was little evidence of association between BW and systolic [regression coefficient ß = 0.14, 95% confidence interval (CI) (-1.00, 1.27)] or diastolic [ß = 0.43, 95% CI (-0.57, 1.43)] BP. Accelerated weight gain between birth and 5 years was associated with increased BP: systolic ß = 1.17, 95% CI (0.69, 1.66) and diastolic ß = 1.03, 95% CI (0.59, 1.47). Between birth and 6 months of age, effects of accelerated weight gain on adolescent BP were strongest among the LBW (both premature and small-for-gestational-age) children [BW < 2.5 kg: ß = 2.64, 95% CI (0.91, 4.37), BW≥2.5 kg: ß = 0.58, 95% CI (0.01, 1.14), interaction P-value = 0.024]. CONCLUSIONS: Findings from this large tropical birth cohort in Uganda suggest that postnatal weight gain rather than BW is important in the developmental programming of BP, with fast-growing LBW children at particular risk. Efforts to control BP should adopt a life course approach.

Determinants of Gammaherpesvirus Shedding in Saliva Among Ugandan Children and Their Mothers.

Background: Epstein-Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV) are transmitted via saliva, but factors associated with salivary shedding are unknown. Methods: We measured the DNA load of both viruses in saliva specimens collected from approximately 500 Ugandan mothers and their 6-year-old children, testing all participants for EBV and KSHV-seropositive individuals for KSHV. Results: EBV and KSHV were shed by 72% and 22% of mothers, respectively, and by 85% and 40% of children, respectively; boys were more likely than girls to shed KSHV (48% vs 30%) but were equally likely to shed EBV. Children shed more KSHV and EBV than mothers, but salivary loads of EBV and KSHV were similar. KSHV shedding increased with increasing anti-KSHV (K8.1) antibodies in mothers and with decreasing antimalarial antibodies both in mothers and children. Among mothers, 40% of KSHV shedders also shed EBV, compared with 75% of KSHV nonshedders; among children, EBV was shed by 65% and 83%, respectively. Conclusions: In summary, in this population, individuals were more likely to shed EBV than KSHV in saliva. We identified several factors, including child's sex, that influence KSHV shedding, and we detected an inverse relationship between EBV and KSHV shedding, suggesting a direct or indirect interaction between the two viruses.

The role of the home environment in neurocognitive development of children living in extreme poverty and with frequent illnesses: a cross-sectional study.

Background: The home environment is reported to contribute significantly to children's developing cognitive skills. However, it is not yet evident whether this role prevails in the context of extreme poverty and frequent ill-health. We therefore investigated the role of the home environment in Ugandan children taking into account the frequent infections and extreme poverty in which they lived. Methods: Cognitive abilities of 163 5-year-old children were assessed. Home environments of these children, their health status and family socioeconomic status (SES) were assessed respectively using the EC-HOME, anthropometry and illnesses, and traditional SES measures. Structural equation analyses compared five models on the influence of the home environment, SES, and child health on the cognitive scores. Results: The model in which the home environment mediates the combined influence of SES and child health on cognitive performance showed a particularly good fit to the data compared with the four alternative models, i.e. those in which the HOME, SES and health independently influence cognitive performance. Conclusions: Home environments providing cognitive stimulation can enable children to overcome effects of major adverse life experiences on cognitive development.

Effects of treating helminths during pregnancy and early childhood on risk of allergy-related outcomes: Follow-up of a randomized controlled trial.

BACKGROUND: Helminth infections, common in low-income countries, may protect against allergy-related disease. Early exposure may be a key. In the Entebbe Mother and Baby Study, treating helminths during pregnancy resulted in increased eczema rates in early childhood. We followed the cohort to determine whether this translated to increased asthma rates at school age. METHODS: This randomized, double-blind, placebo-controlled trial, conducted in Entebbe, Uganda, had three interventions. During pregnancy, women were randomized, simultaneously, to albendazole vs placebo and to praziquantel vs placebo. Their children were independently randomized to quarterly albendazole vs placebo from age 15 months to 5 years. We here report follow-up to age 9 years. Primary outcomes at 9 years were recent reported wheeze, skin prick test positivity (SPT) to common allergens and allergen-specific IgE positivity to dust mite or cockroach. Secondary outcomes were doctor-diagnosed asthma and eczema rates between 5 and 9 years, recent eczema, rhinitis and urticaria at 9 years, and SPT and IgE responses to individual allergens. RESULTS: 2507 pregnant women were enrolled; 1215 children were seen at age nine, of whom 1188 are included in this analysis. Reported wheeze was rare at 9 years (3.7%) while SPT positivity (25.0%) and IgE positivity (44.1%) were common. There was no evidence of a treatment effect for any of the three interventions on any of the primary outcomes. CONCLUSIONS: Prenatal and early-life treatment of helminths, in the absence of change in other exposures, is unlikely to increase the risk of atopic diseases later in childhood in this tropical, low-income setting.

Life-course of atopy and allergy-related disease events in tropical sub-Saharan Africa: A birth cohort study.

BACKGROUND: In high-income countries, allergy-related diseases (ARDs) follow a typical sequence, the 'Atopic March'. Little is known about the life-course of ARDs in the markedly different, low-income, tropical environment. We describe ARDs in a tropical, African birth cohort. METHODS: Ugandan children were followed from birth to 9 years. ISAAC questionnaires were completed at intervals; doctor-diagnosed ARDs were recorded throughout follow-up. Skin prick tests (SPTs) were performed at 3 and 9 years. Atopy was defined as ≥1 positive SPT. RESULTS: Of the 2345 live-born children, 1214 (52%) were seen at 9 years. Wheeze and eczema were common in infancy, but by 9 years, only 4% reported recent wheeze, 5% eczema and 5% rhinitis. Between 3 and 9 years, atopy prevalence increased from 19% to 25%. Atopy at 3 or 9 years was associated with reported ARD events at 9 years, for example OR = 5.2 (95% CI 2.9-10.7) for atopy and recent wheeze at 9 years. Reported or doctor-diagnosed ARD events in early childhood were associated with the same events in later childhood, for example OR = 4.4 (2.3-8.4) for the association between reported wheeze before 3 years with reported recent wheeze at 9 years, but progression from early eczema to later rhinitis or asthma was not observed. CONCLUSION: Allergen sensitization started early in childhood and increased with age. Eczema and wheeze were common in infancy and declined with age. Atopy was strongly associated with ARD among the few affected children. The typical Atopic March did not occur. Environmental exposures during childhood may dissociate atopy and ARD.

Schistosoma mansoni and HIV infection in a Ugandan population with high HIV and helminth prevalence.

OBJECTIVES: Recent reports suggest that Schistosoma infection may increase the risk of acquiring human immunodeficiency virus (HIV). We used data from a large cross-sectional study to investigate whether Schistosoma mansoni infection is associated with increased HIV prevalence. METHODS: We conducted a household survey of residents in island fishing communities in Mukono district, Uganda, between October 2012 and July 2013. HIV status was assessed using rapid test kits. Kato-Katz (KK) stool tests and urine-circulating cathodic antigen (CCA) were used to test for Schistosoma infection. Multivariable logistic regression, allowing for the survey design, was used to investigate the association between S. mansoni infection and HIV infection. RESULTS: Data from 1412 participants aged 13 years and older were analysed (mean age 30.3 years, 45% female). The prevalence of HIV was 17.3%. Using the stool Kato-Katz technique on a single sample, S. mansoni infection was detected in 57.2% (719/1257) of participants; urine CCA was positive in 73.8% (478/650) of those tested. S. mansoni infection was not associated with HIV infection. [KK (aOR = 1.04; 95% CI: 0.74-1.47, P = 0.81), CCA (aOR = 1.53; 95% CI: 0.78-3.00, P = 0.19)]. The median S. mansoni egg count per gram was lower in the HIV-positive participants (P = 0.005). CONCLUSIONS: These results add to the evidence that S. mansoni has little effect on HIV transmission, but may influence egg excretion.

The Lake Victoria Island Intervention Study on Worms and Allergy-related diseases (LaVIISWA): study protocol for a randomised controlled trial.

BACKGROUND: The Hygiene Hypothesis proposes that infection exposure protects against inflammatory conditions. Helminths possess allergen-like molecules and may specifically modulate allergy-related immunological pathways to inhibit responses which protect against them. Mass drug administration is recommended for helminth-endemic communities to control helminth-induced pathology, but may also result in increased rates of inflammation-mediated diseases in resource-poor settings. Immunological studies integrated with implementation of helminth control measures may elucidate how helminth elimination contributes to ongoing epidemics of inflammatory diseases. We present the design of the Lake Victoria Island Intervention Study on Worms and Allergy-related diseases (LaVIISWA), a cluster-randomised trial evaluating the risks and benefits of intensive versus standard anthelminthic treatment for allergy-related diseases and other health outcomes. METHODS/DESIGN: The setting is comprised of island fishing communities in Mukono district, Uganda. Twenty-six communities have been randomised in a 1:1 ratio to receive standard or intensive anthelminthic intervention for a three-year period. Baseline characteristics were collected immediately prior to intervention rollout, commenced in February 2013. Primary outcomes are reported wheeze in the past 12 months and atopy (skin prick test response and allergen-specific immunoglobulin (asIg) E concentration). Secondary outcomes are visible flexural dermatitis, helminth infections, haemoglobin, growth parameters, hepatosplenomegaly, and responses to vaccine antigens. The trial provides a platform for in-depth analysis of clinical and immunological consequences of the contrasting interventions. DISCUSSION: The baseline survey has been completed successfully in a challenging environment. Baseline characteristics were balanced between trial arms. Prevalence of Schistosoma mansoni, hookworm, Strongyloides stercoralis and Trichuris trichiura was 52%, 23%, 13%, and 12%, respectively; 31% of Schistosoma mansoni infections were heavy (>400 eggs/gram). The prevalence of reported wheeze and positive skin prick test to any allergen was 5% and 20%, respectively. Respectively, 77% and 87% of participants had Dermatophagoides- and German cockroach-specific IgE above 0.35 kUA/L. These characteristics suggest that the LaVIISWA study will provide an excellent framework for investigating beneficial and detrimental effects of worms and their treatment, and the mechanisms of such effects. TRIAL REGISTRATION: This trial was registered with Current Controlled Trials (identifier: ISRCTN47196031) on 7 September 2012.

Factors associated with tuberculosis infection, and with anti-mycobacterial immune responses, among five year olds BCG-immunised at birth in Entebbe, Uganda.

BACKGROUND: BCG is used widely as the sole licensed vaccine against tuberculosis, but it has variable efficacy and the reasons for this are still unclear. No reliable biomarkers to predict future protection against, or acquisition of, TB infection following immunisation have been identified. Lessons from BCG could be valuable in the development of effective tuberculosis vaccines. OBJECTIVES: Within the Entebbe Mother and Baby Study birth cohort in Uganda, infants received BCG at birth. We investigated factors associated with latent tuberculosis infection (LTBI) and with cytokine response to mycobacterial antigen at age five years. We also investigated whether cytokine responses at one year were associated with LTBI at five years of age. METHODS: Blood samples from age one and five years were stimulated using crude culture filtrates of Mycobacterium tuberculosis in a six-day whole blood assay. IFN-γ, IL-5, IL-13 and IL-10 production was measured. LTBI at five years was determined using T-SPOT.TB(®) assay. Associations with LTBI at five years were assessed using multivariable logistic regression. Multiple linear regression with bootstrapping was used to determine factors associated with cytokine responses at age five years. RESULTS: LTBI prevalence was 9% at age five years. Only urban residence and history of TB contact/disease were positively associated with LTBI. BCG vaccine strain, LTBI, HIV infection, asymptomatic malaria, growth z-scores, childhood anthelminthic treatment and maternal BCG scar were associated with cytokine responses at age five. Cytokine responses at one year were not associated with acquisition of LTBI by five years of age. CONCLUSION: Although multiple factors influenced anti-myocbacterial immune responses at age five, factors likely to be associated with exposure to infectious cases (history of household contact, and urban residence) dominated the risk of LTBI.

Assessing the external validity of a randomized controlled trial of anthelminthics in mothers and their children in Entebbe, Uganda.

BACKGROUND: The 'external validity' of randomized controlled trials is an important measure of quality, but is often not formally assessed. Trials concerning mass drug administration for helminth control are likely to guide public health policy and careful interpretation of their context is needed. We aimed to determine how representative participants in one such trial were of their community. We explore implications for trial interpretation and resulting public health recommendations. METHODS: The trial assessed was the Entebbe Mother and Baby Study (EMaBS), a trial of anthelminthic treatment during pregnancy and early childhood. In a novel approach for assessing external validity, we conducted a two-stage cluster sample community survey within the trial catchment area and compared characteristics of potentially-eligible community children with characteristics of children participating in the trial. RESULTS: A total of 173 children aged three to five-years-old were surveyed from 480 households. Of children surveyed, we estimated that mothers of 60% would have been eligible for recruitment, and of these, 31% had actually been enrolled. Children surveyed were compared to 199 trial children in the same age group reviewed at annual trial visits during the same time period. There were significant differences in ethnicity between the trial participants and the community children, and in socioeconomic status, with those in the trial having, on average, more educated parents and higher maternal employment. Trial children were less likely to have barefoot exposure and more likely to use insecticide-treated bed nets. There were no significant differences in numbers of reported illness events over the last year. CONCLUSIONS: The trial had not enrolled all eligible participants, and those enrolled were of higher socioeconomic status, and had lower risk of exposure to the parasitic infections targeted by the trial interventions. It is possible the trial may have underestimated the absolute effects of anthelminthic treatment during pregnancy and early childhood, although the fact that there were no differences in reported incidence of common infectious diseases (one of the primary outcomes of EMaBS) between the two groups provides reassurance. Concurrent community surveys may be an effective way to test the external validity of trials. EMABS TRIAL REGISTRATION: ISRCTN32849447, registered 22 July 2005.

Maternal hookworm modifies risk factors for childhood eczema: results from a birth cohort in Uganda.

BACKGROUND: Worms may protect against allergy. Early-life worm exposure may be critical, but this has not been fully investigated. OBJECTIVES: To investigate whether worms in pregnancy and in early childhood are associated with childhood eczema incidence. METHODS: The Entebbe Mother and Baby Study, an anthelminthic treatment trial, enrolled pregnant women between 2003 and 2005 in Uganda. Mothers were investigated for worms during pregnancy and children annually. Eczema was doctor-diagnosed from birth to age five years. A planned observational analysis was conducted within the trial cohort to investigate associations between worms and eczema. RESULTS: Data for 2345 live-born children were analysed. Hookworm was the most prevalent maternal worm (45%). Childhood worms were less prevalent. Eczema incidence was 4.68/100 person-years. Maternal hookworm was associated with reduced eczema incidence [adjusted hazard ratio (95% confidence interval), p-value: 0.71(0.51-0.99), 0.04] and modified effects of known risk factors for eczema: Dermatophagoides-specific IgE in children was positively associated with eczema incidence if the mother had no hookworm [2.72(1.11-6.63), 0.03], but not if the mother had hookworm [0.41(0.10-1.69), 0.22], interaction p-value = 0.03. Similar interactions were seen for maternal history of eczema {[2.87(1.31-6.27, 0.008) vs. [0.73(0.23-2.30), 0.60], interaction p-value = 0.05}, female gender {[1.82(1.22-2.73), 0.004 vs. [0.96(0.60-1.53), 0.87], interaction p-value = 0.04} and allergen-specific IgE. Childhood Trichuris trichiura and hookworm were inversely associated with eczema. CONCLUSIONS: Maternal hookworm modifies effects of known risk factors for eczema. Mechanisms by which early-life worm exposures influence allergy need investigation. Worms or worm products, and intervention during pregnancy have potential for primary prevention of allergy.

Associations between maternal helminth and malaria infections in pregnancy and clinical malaria in the offspring: a birth cohort in entebbe, Uganda.

BACKGROUND: Helminth and malaria coinfections are common in the tropics. We investigated the hypothesis that prenatal exposure to these parasites might influence susceptibility to malaria in childhood. METHODS: In a birth cohort of 2345 mother-child pairs in Uganda, maternal helminth and malaria infection status was determined during pregnancy, and childhood malaria episodes were recorded from birth to age 5 years. We examined associations between maternal infections and malaria in the offspring. RESULTS: Common maternal infections were hookworm (45%), Mansonella perstans (21%), Schistosoma mansoni (18%), and Plasmodium falciparum (11%). At age 5 years, 69% of the children were still under follow-up. The incidence of malaria was 34 episodes per 100 child-years, and the mean prevalence of asymptomatic malaria at annual visits was 5.4%. Maternal hookworm and M. perstans infections were associated with an increased rate of childhood clinical malaria (adjusted hazard ratio [aHR], 1.24, 95% confidence interval [CI], 1.10-1.41; aHR, 1.20, 95% CI, 1.05-1.38, respectively). S. mansoni infection had no consistent association with childhood malaria. CONCLUSIONS: This is the first report of an association between helminth infections in pregnancy and malaria in the offspring and indicates that helminth infections in pregnancy may increase the burden of childhood malaria morbidity.

Factors affecting the infant antibody response to measles immunisation in Entebbe-Uganda.

BACKGROUND: Vaccine failure is an important concern in the tropics with many contributing elements. Among them, it has been suggested that exposure to natural infections might contribute to vaccine failure and recurrent disease outbreaks. We tested this hypothesis by examining the influence of co-infections on maternal and infant measles-specific IgG levels. METHODS: We conducted an observational analysis using samples and data that had been collected during a larger randomised controlled trial, the Entebbe Mother and Baby Study (ISRCTN32849447). For the present study, 711 pregnant women and their offspring were considered. Helminth infections including hookworm, Schistosoma mansoni and Mansonella perstans, along with HIV, malaria, and other potential confounding factors were determined in mothers during pregnancy and in their infants at age one year. Infants received their measles immunisation at age nine months. Levels of total IgG against measles were measured in mothers during pregnancy and at delivery, as well as in cord blood and from infants at age one year. RESULTS: Among the 711 pregnant women studied, 66% had at least one helminth infection at enrolment, 41% had hookworm, 20% M. perstans and 19% S. mansoni. Asymptomatic malaria and HIV prevalence was 8% and 10% respectively. At enrolment, 96% of the women had measles-specific IgG levels considered protective (median 4274 mIU/ml (IQR 1784, 7767)). IgG levels in cord blood were positively correlated to maternal measles-specific IgG levels at delivery (r = 0.81, p < 0.0001). Among the infants at one year of age, median measles-specific IgG levels were markedly lower than in maternal and cord blood (median 370 mIU/ml (IQR 198, 656) p < 0.0001). In addition, only 75% of the infants had measles-specific IgG levels considered to be protective. In a multivariate regression analysis, factors associated with reduced measles-specific antibody levels in infancy were maternal malaria infection, infant malaria parasitaemia, infant HIV and infant wasting. There was no association with maternal helminth infection. CONCLUSION: Malaria and HIV infection in mothers during pregnancy, and in their infants, along with infant malnutrition, may result in reduction of the antibody response to measles immunisation in infancy. This re-emphasises the importance of malaria and HIV control, and support for infant nutrition, as these interventions may have benefits for vaccine efficacy in tropical settings.

Maternal HIV infection and other factors associated with growth outcomes of HIV-uninfected infants in Entebbe, Uganda.

OBJECTIVE: To assess the associations between maternal HIV infection and growth outcomes of HIV-exposed but uninfected infants and to identify other predictors for poor growth among this population. DESIGN: Within a trial of de-worming during pregnancy, the cohort of offspring was followed from birth. HIV status of the mothers and their children was investigated and growth data for children were obtained at age 1 year. Length-for-age, weight-for-age and weight-for-length Z-scores were calculated for each child; Z-scores ,22 were defined as stunting, underweight and wasting, respectively. SETTING: The study was conducted in Entebbe municipality and Katabi subcounty, Uganda. SUBJECTS: The sample consisted of 1502 children aged 1 year: HIV-unexposed (n 1380) and HIV-exposed not infected (n 122). RESULTS: Prevalence of stunting, underweight and wasting was 14.2%, 8.0% and 3.9%, respectively. There was evidence for an association between maternal HIV infection and odds of being underweight (adjusted OR52.32; 95% CI 1.32, 4.09; P=0.006) but no evidence for an association with stunting or with wasting. Young maternal age, low maternal education, low birth weight, early weaning and experiencing a higher number of episodes of malaria during infancy were independent predictors for stunting and underweight. A higher number of living children in the family was associated with wasting. CONCLUSIONS: Maternal HIV infection was associated with being underweight in HIV-exposed uninfected infants. The success of programmes for prevention of mother-to-child HIV transmission means that an increasing number of infants will be born to HIV-infected women without acquiring HIV. Therefore, viable nutritional interventions need to be identified for this population.

Risk factors for seropositivity to Kaposi sarcoma-associated herpesvirus among children in Uganda.

BACKGROUND: Determinants of Kaposi sarcoma-associated herpesvirus (KSHV) seropositivity among children living in sub-Saharan African populations where infection is endemic are not well understood. Local environmental factors, including other infectious agents, may be key. METHODS: Within the context of a well-characterized birth cohort, we examined associations between various factors and antibodies against KSHV, measured in stored plasma samples from 1823 mother-child pairs in Entebbe, Uganda. RESULTS: Seroprevalence increased with increasing age of the child (P = 0.0003) and was higher among those with KSHV seropositive mothers than in those without (12% vs 9%; odds ratio: 1.4, 95% confidence interval: 1.1 to 2.0). It was also higher among children with HIV infection (29% vs 10%; odds ratio: 3.1, 95% confidence interval: 1.2 to 8.3) or malaria parasitemia (30% vs 10%; odds ratio: 4.1, 95% confidence interval: 2.4 to 7.0) than in children without. These associations were not explained by socioeconomic status. CONCLUSIONS: The finding that KSHV serostatus is associated with malaria parasitemia in children is novel. In a country endemic for KSHV, malaria may be a cofactor for KSHV infection or reactivation among children.

Impact of anthelminthic treatment in pregnancy and childhood on immunisations, infections and eczema in childhood: a randomised controlled trial.

BACKGROUND: Helminth infections may modulate immune responses to unrelated pathogens and allergens; these effects may commence prenatally. We addressed the hypothesis that anthelminthic treatment in pregnancy and early childhood would improve responses to immunisation and modulate disease incidence in early childhood with both beneficial and detrimental effects. METHODS AND FINDINGS: A randomised, double-blind, placebo-controlled trial was conducted in Entebbe, Uganda [ISRCTN32849447]. In three independent randomisations, 2507 pregnant women were allocated to receive single-dose albendazole or placebo, and praziquantel or placebo; 2016 of their offspring were randomised to receive quarterly single-dose albendazole or placebo from age 15 months to 5 years. Primary outcomes were post-immunisation recall responses to BCG and tetanus antigens, and incidence of malaria, diarrhoea, and pneumonia; incidence of eczema was an important secondary outcome. Analysis was by intention-to-treat. Of 2345 live births, 1622 (69%) children remained in follow-up at age 5 years. 68% of mothers at enrolment, and 11% of five-year-olds, had helminth infections. Maternal hookworm and Schistosoma mansoni were effectively treated by albendazole and praziquantel, respectively; and childhood hookworm and Ascaris by quarterly albendazole. Incidence rates of malaria, diarrhoea, pneumonia, and eczema were 34, 65, 10 and 5 per 100 py, respectively. Albendazole during pregnancy caused an increased rate of eczema in the children (HR 1.58 (95% CI 1.15-2.17), p = 0.005). Quarterly albendazole during childhood was associated with reduced incidence of clinical malaria (HR 0.85 (95% CI 0.73-0.98), p = 0.03). There were no consistent effects of the interventions on any other outcome. CONCLUSIONS: Routine use of albendazole in pregnancy may not always be beneficial, even in tropical developing countries. By contrast, regular albendazole treatment in preschool children may have an additional benefit for malaria control where helminths and malaria are co-endemic. Given the low helminth prevalence in our children, the effect of albendazole on malaria is likely to be direct. TRIAL REGISTRATION: Current Controlled Trials ISRCTN32849447.

Effects of maternal worm infections and anthelminthic treatment during pregnancy on infant motor and neurocognitive functioning.

We tested the hypothesis that maternal worm infections in pregnancy affect infant motor and neurocognitive development, and that anthelminthic treatment during pregnancy can reverse these effects. We used measures which examine infant motor, cognitive and executive function, including inhibition. We assessed 983 Ugandan infants aged 15 months, using locally appropriate measures within the Entebbe Mother and Baby Study, a trial of anthelminthic treatment during pregnancy. Key exposures were maternal worm infections and anthelminthic treatment during pregnancy. Effects of other health and social factors were controlled for statistically. Of the five major worm species found in the pregnant women, two had influences on the developmental measures: Maternal Mansonella perstans and Strongyloides stercoralis infections showed negative associations with the A-not B-task, and Language, respectively. Performance on other psychomotor and cognitive measures was associated with illnesses during infancy and infants' behavior during assessment, but not with maternal worm infections. There were no positive effects of maternal anthelminthic treatment on infant abilities. Mansonella perstans and Strongyloides stercoralis infection during pregnancy seem associated with impaired early executive function and language, respectively, but single-dose anthelminthic treatment during pregnancy was not beneficial. The biological mechanisms that could underlie these neurocognitive effects are discussed.

Determining Mycobacterium tuberculosis infection among BCG-immunised Ugandan children by T-SPOT.TB and tuberculin skin testing.

BACKGROUND: Children with latent tuberculosis infection (LTBI) represent a huge reservoir for future disease. We wished to determine Mycobacterium tuberculosis (M.tb) infection prevalence among BCG-immunised five-year-old children in Entebbe, Uganda, but there are limited data on the performance of immunoassays for diagnosis of tuberculosis infection in children in endemic settings. We therefore evaluated agreement between a commercial interferon gamma release assay (T-SPOT.TB) and the tuberculin skin test (TST; 2 units RT-23 tuberculin; positive defined as diameter ≥10 mm), along with the reproducibility of T-SPOT.TB on short-term follow-up, in this population. METHODOLOGY/PRINCIPAL FINDINGS: We recruited 907 children of which 56 were household contacts of TB patients. They were tested with T-SPOT.TB at age five years and then re-examined with T-SPOT.TB (n = 405) and TST (n = 319) approximately three weeks later. The principal outcome measures were T-SPOT.TB and TST positivity. At five years, 88 (9.7%) children tested positive by T-SPOT.TB. More than half of those that were T-SPOT.TB positive at five years were negative at follow-up, whereas 96% of baseline negatives were consistently negative. We observed somewhat better agreement between initial and follow-up T-SPOT.TB results among household TB contacts (κ = 0.77) than among non-contacts (κ = 0.39). Agreement between T-SPOT.TB and TST was weak (κ = 0.28 and κ = 0.40 for T-SPOT.TB at 5 years and follow-up, respectively). Of 28 children who were positive on both T-SPOT.TB tests, 14 (50%) had a negative TST. Analysis of spot counts showed high levels of instability in responses between baseline and follow-up, indicating variability in circulating numbers of T cells specific for certain M.tb antigens. CONCLUSIONS/SIGNIFICANCE: We found that T-SPOT.TB positives are unstable over a three-week follow-up interval, and that TST compares poorly with T-SPOT.TB, making the categorisation of children as TB-infected or TB-uninfected difficult. Existing tools for the diagnosis of TB infection are unsatisfactory in determining infection among children in this setting.

Maternal recall of birthweight and birth size in Entebbe, Uganda.

OBJECTIVES: To assess the reliability of maternally recalled birthweight and size in Entebbe, Uganda. METHODS: The study population comprised 404 mothers, who were participants in the Entebbe Mother and Baby Study (EMaBS). Mothers were recruited to EMaBS during antenatal care, maternal characteristics were recorded during pregnancy, and birthweight was recorded at delivery. Four to seven years after delivery, mothers were asked to recall the child's birthweight and size. Their responses were compared with the birthweight recorded in the EMaBS database. RESULTS: Of 404 interviewed mothers, 303 (75%) were able to give an estimate of birthweight and for 265 of these EMaBS data on recorded birthweights were available. Women who were educated and whose children had low birth order were more likely to be able to give an estimate: 37 (14%) recalled the exact recorded birthweight; a further 52 (20%) were accurate to within 0.1 kg of the recorded weight. On average, mothers overestimated birthweight by 0.06 kg (95% CI: 0.00-0.13 kg, P = 0.04). Recalled and recorded birthweights showed moderate agreement with an intraclass correlation coefficient of 0.64. Four hundered mothers gave an estimate of birth size: the sensitivity and specificity of recalled birth size for classifying low birthweight were 76% (95% CI: 50-93%) and 70% (95% CI: 65-75%), respectively. CONCLUSIONS: Mothers' recall of birthweight was not precise but in absence of other data, recall of birthweight and size may have some value in epidemiological studies in these settings.

The effect of anthelmintic treatment during pregnancy on HIV plasma viral load: results from a randomized, double-blind, placebo-controlled trial in Uganda.

BACKGROUND: To investigate the effect of helminth infections and their treatment during pregnancy on HIV load, we conducted a 2 × 2 factorial randomized controlled trial of albendazole versus placebo and praziquantel versus placebo in pregnant women in Entebbe, Uganda. METHODS: Two hundred sixty-four HIV-infected pregnant women from the Entebbe Mother and Baby Study (ISRCTN 32849447) were included in this analysis. Women were tested for helminth infections at enrollment, and mean HIV load was compared between infected and uninfected groups. The effect of anthelmintic treatment on HIV load was evaluated at 6 weeks after treatment and at delivery using linear regression and adjusting for enrollment viral load. RESULTS: Hookworm and Trichuris infections were associated with higher mean viral load at enrollment [adjusted mean difference 0.24 log10 copies/mL, 95% confidence interval (CI): 0.01 to 0.47, P = 0.03, and 0.37 log(10) copies/mL, 95% CI: 0.00 to 0.74, P = 0.05, respectively]. There were no associations between viral load and other helminth species. There was some evidence that albendazole reduced viral load at 6 weeks after treatment (adjusted mean difference -0.17, 95% CI: -0.36 to 0.01, P = 0.07); however, this effect did not differ according to mother's hookworm infection status and had diminished at delivery (adjusted mean difference -0.11, 95% CI: -0.28 to 0.07, P = 0.23). There was no effect of praziquantel treatment on HIV load at any time point. CONCLUSIONS: Infection with some soil-transmitted helminth species is associated with increased HIV load in pregnancy. Treatment with albendazole causes a small decrease in HIV load; however, this may not represent a direct effect of worm removal.

Parasite infection is associated with Kaposi's sarcoma associated herpesvirus (KSHV) in Ugandan women.

BACKGROUND: Immune modulation by parasites may influence susceptibility to bacteria and viruses. We examined the association between current parasite infections, HIV and syphilis (measured in blood or stool samples using standard methods) and antibodies against Kaposi's sarcoma herpesvirus (KSHV), measured by ELISA, in 1915 stored plasma samples from pregnant women in Entebbe, Uganda. RESULTS: Seroprevalence of KSHV was higher in women with malaria parasitaemia (73% vs 60% p = 0.01), hookworm (67% vs 56% p = 0.001) and Mansonella perstans (69% vs 59% p = 0.05); seroprevalence increased with increasing intensity of hookworm infection (p < 0.001[trend]). No associations were found for HIV, five other parasites or active syphilis. These effects were not explained by socioeconomic status or education. CONCLUSIONS: Specific parasite infections are associated with presence of antibodies against KSHV, perhaps mediated via their effect on immune function.