Pet ownership is associated with increased risk of non-atopic asthma and reduced risk of atopy in childhood: findings from a UK birth cohort.

BACKGROUND: Studies have shown an inverse association of pet ownership with allergy but inconclusive findings for asthma. OBJECTIVE: To investigate whether pet ownership during pregnancy and childhood was associated with asthma and atopy at the age of 7 in a UK population-based birth cohort. METHODS: Data from the Avon Longitudinal Study of Parents and Children (ALSPAC) were used to investigate associations of pet ownership at six time points from pregnancy to the age of 7 with asthma, atopy (grass, house dust mite, and cat skin prick test) and atopic vs. non-atopic asthma at the age of 7 using logistic regression models adjusted for child's sex, maternal history of asthma/atopy, maternal smoking during pregnancy, and family adversity. RESULTS: A total of 3768 children had complete data on pet ownership, asthma, and atopy. Compared with non-ownership, continuous ownership of any pet (before and after the age of 3) was associated with 52% lower odds of atopic asthma [odds ratio (OR) 0.48, 95% CI 0.34-0.68]. Pet ownership tended to be associated with increased risk of non-atopic asthma, particularly rabbits (OR 1.61, 1.04-2.51) and rodents (OR 1.86, 1.15-3.01), comparing continuous vs. non-ownership. Pet ownership was consistently associated with lower odds of sensitization to grass, house dust mite, and cat allergens, but rodent ownership was associated with higher odds of sensitization to rodent allergen. Differential effects of pet ownership on atopic vs. non-atopic asthma were evident for all pet types. CONCLUSIONS AND CLINICAL RELEVANCE: Pet ownership during pregnancy and childhood in this birth cohort was consistently associated with a reduced risk of aeroallergen sensitization and atopic asthma at the age of 7, but tended to be associated (particularly for rabbits and rodents) with an increased risk of non-atopic asthma. The opposing effects on atopy vs. non-atopic asthma might be considered by parents when they are deciding whether to acquire a pet.

Risk scores to facilitate preoperative prediction of transfusion and large volume blood transfusion associated with adult cardiac surgery.

BACKGROUND: The aim of this study was to develop two novel risk prediction scores for transfusion and bleeding that would be used to inform treatment decisions, quality assurance, and clinical trial design in cardiac surgery. METHODS: Clinical data prospectively collected from 26 UK cardiac surgical centres and a single European centre were used to develop two risk prediction models: one for any red blood cell (RBC) transfusion, and the other for large volume blood transfusion (≥4 RBC units; LVBT), an index of severe blood loss. 'Complete case' data were available for 24 749 patients. Multiple imputation was used for missing covariate data (typically <5% per variable), with the imputed data set containing 39 970 patients. Risk models were developed in the complete case data set, with internal validation using leave-one-centre-out cross-validation. The final selected models were fitted to the imputed data set. Final risk scores were then compared with the performance of three existing scores: the Transfusion Risk and Clinical Knowledge score (TRACK), the Transfusion Risk Understanding Scoring Tool (TRUST), and the Papworth Bleeding Risk Score (BRiSc). RESULTS: The area under the receiver operating characteristic curve (AUC) was 0.77 (95% confidence interval 0.77-0.77) for the any RBC transfusion score and AUC 0.80 (0.79-0.80) for the LVBT score in the imputed data set. The LVBT model also showed excellent discrimination (Hosmer-Lemeshow P=0.32). In the imputed data set, the AUCs for the TRACK and TRUST scores for any RBC transfusion were 0.71 and 0.71, respectively, and for LVBT the AUC for the BRiSc score was 0.69. CONCLUSIONS: Two new risk scores for any RBC transfusion or LVBT among cardiac surgery patients have excellent discrimination, and could inform clinical decision making.

Design and preliminary recruitment results of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP).

BACKGROUND: Screening for prostate cancer continues to generate controversy because of concerns about over-diagnosis and unnecessary treatment. We describe the rationale, design and recruitment of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP) trial, a UK-wide cluster randomised controlled trial investigating the effectiveness and cost-effectiveness of prostate-specific antigen (PSA) testing. METHODS: Seven hundred and eighty-five general practitioner (GP) practices in England and Wales were randomised to a population-based PSA testing or standard care and then approached for consent to participate. In the intervention arm, men aged 50-69 years were invited to undergo PSA testing, and those diagnosed with localised prostate cancer were invited into a treatment trial. Control arm practices undertook standard UK management. All men were flagged with the Health and Social Care Information Centre for deaths and cancer registrations. The primary outcome is prostate cancer mortality at a median 10-year-follow-up. RESULTS: Among randomised practices, 271 (68%) in the intervention arm (198,114 men) and 302 (78%) in the control arm (221,929 men) consented to participate, meeting pre-specified power requirements. There was little evidence of differences between trial arms in measured baseline characteristics of the consenting GP practices (or men within those practices). CONCLUSIONS: The CAP trial successfully met its recruitment targets and will make an important contribution to international understanding of PSA-based prostate cancer screening.

Breast-feeding and health consequences in early childhood: is there an impact of time-dependent confounding?

BACKGROUND: Estimated effects of breast-feeding on childhood health vary between studies, possibly due to confounding by baseline maternal and child characteristics. Possible time-dependent confounding has received little consideration. Our aim was to evaluate the impact of such confounding. METHODS: We estimated the relationship between cumulative exclusive breast-feeding up to 6 months and wheezing, rash and body mass index (BMI) at 12 months [in the Whistler cohort (n = 494) and PROBIT (n = 11,463)], and wheezing, rash, asthma, hay fever, eczema, allergy and BMI at age 6.5 years (PROBIT). We adjusted for time-dependent confounding by weight, length, rash, respiratory illness and day care attendance using marginal structural models (MSMs). RESULTS: Weight and day care attendance appeared potential time-dependent confounders, since these predicted breast-feeding status and were influenced by previous breast-feeding. However, adjustment for time-dependent confounders did not markedly change the estimated associations. For example, in PROBIT the adjusted increase in BMI at 12 months per 1-month increase in exclusive breast-feeding was 0.04 (95% CI -0.09 to 0.01) using logistic regression and -0.06 (95% CI -0.11 to -0.01) using MSM. In Whistler, these estimates were each -0.05 (95% CI -0.10 to 0.00). CONCLUSIONS: In two cohort studies, there was little evidence of time-dependent confounding by weight, length, rash, respiratory illness or day care attendance of the effects of breast-feeding on early childhood health.

Genome-wide association study of body mass index in 23 000 individuals with and without asthma.

BACKGROUND: Both asthma and obesity are complex disorders that are influenced by environmental and genetic factors. Shared genetic factors between asthma and obesity have been proposed to partly explain epidemiological findings of co-morbidity between these conditions. OBJECTIVE: To identify genetic variants that are associated with body mass index (BMI) in asthmatic children and adults, and to evaluate if there are differences between the genetics of BMI in asthmatics and healthy individuals. METHODS: In total, 19 studies contributed with genome-wide analysis study (GWAS) data from more than 23 000 individuals with predominantly European descent, of whom 8165 are asthmatics. RESULTS: We report associations between several DENND1B variants (P = 2.2 × 10(-7) for rs4915551) on chromosome 1q31 and BMI from a meta-analysis of GWAS data using 2691 asthmatic children (screening data). The top DENND1B single nucleotide polymorphisms(SNPs) were next evaluated in seven independent replication data sets comprising 2014 asthmatics, and rs4915551 was nominally replicated (P < 0.05) in two of the seven studies and of borderline significance in one (P = 0.059). However, strong evidence of effect heterogeneity was observed and overall, the association between rs4915551 and BMI was not significant in the total replication data set, P = 0.71. Using a random effects model, BMI was overall estimated to increase by 0.30 kg/m(2) (P = 0.01 for combined screening and replication data sets, N = 4705) per additional G allele of this DENND1BSNP. FTO was confirmed as an important gene for adult and childhood BMI regardless of asthma status. CONCLUSIONS AND CLINICAL RELEVANCE: DENND1B was recently identified as an asthma susceptibility gene in a GWAS on children, and here, we find evidence that DENND1B variants may also be associated with BMI in asthmatic children. However, the association was overall not replicated in the independent data sets and the heterogeneous effect of DENND1B points to complex associations with the studied diseases that deserve further study.

Methods for dealing with time-dependent confounding.

Longitudinal studies, where data are repeatedly collected on subjects over a period, are common in medical research. When estimating the effect of a time-varying treatment or exposure on an outcome of interest measured at a later time, standard methods fail to give consistent estimators in the presence of time-varying confounders if those confounders are themselves affected by the treatment. Robins and colleagues have proposed several alternative methods that, provided certain assumptions hold, avoid the problems associated with standard approaches. They include the g-computation formula, inverse probability weighted estimation of marginal structural models and g-estimation of structural nested models. In this tutorial, we give a description of each of these methods, exploring the links and differences between them and the reasons for choosing one over the others in different settings.

The effect of injecting drug use history on disease progression and death among HIV-positive individuals initiating combination antiretroviral therapy: collaborative cohort analysis.

BACKGROUND: We examined whether determinants of disease progression and causes of death differ between injecting drug users (IDUs) and non-IDUs who initiate combination antiretroviral therapy (cART). METHODS: The ART Cohort Collaboration combines data from participating cohort studies on cART-naïve adults from cART initiation. We used Cox models to estimate hazard ratios for death and AIDS among IDUs and non-IDUs. The cumulative incidence of specific causes of death was calculated and compared using methods that allow for competing risks. RESULTS: Data on 6269 IDUs and 37 774 non-IDUs were analysed. Compared with non-IDUs, a lower proportion of IDUs initiated cART with a CD4 cell count <200 cells/µL or had a prior diagnosis of AIDS. Mortality rates were higher in IDUs than in non-IDUs (2.08 vs. 1.04 per 100 person-years, respectively; P<0.001). Lower baseline CD4 cell count, higher baseline HIV viral load, clinical AIDS at baseline, and later year of cART initiation were associated with disease progression in both groups. However, the inverse association of baseline CD4 cell count with AIDS and death appeared stronger in non-IDUs than in IDUs. The risk of death from each specific cause was higher in IDUs than non-IDUs, with particularly marked increases in risk for liver-related deaths, and those from violence and non-AIDS infection. CONCLUSION: While liver-related deaths and deaths from direct effects of substance abuse appear to explain much of the excess mortality in IDUs, they are at increased risk for many other causes of death, which may relate to suboptimal management of HIV disease in these individuals.

Long-term trends in CD4 cell counts and impact of viral failure in individuals starting antiretroviral therapy: UK Collaborative HIV Cohort (CHIC) study.

OBJECTIVE: The aim of the study was to describe trends in CD4 cell counts in HIV-infected patients after initiation of combination antiretroviral therapy (cART), according to CD4 cell count at initiation (baseline), and to quantify the implications of virological failure for these trends. METHODS: Eligible participants from the UK Collaborative HIV Cohort (CHIC) were antiretroviralnaïve and started cART after 1997. Random effects were used to model CD4 cell count trends, accounting for multiple measurements within participants. We assessed whether CD4 cell count trends varied according to baseline CD4 cell count and separately in participants with and without post-cART virological failure. Effects of post-cART virological failure (>1000 HIV-1 RNA copies/mL) on subsequent CD4 cell counts were evaluated. FINDINGS: A total of 7069 participants were included in the analysis (median follow-up in all baseline CD4 cell count groups was ≥ 35 months). Among participants without virological failure ≥ 6 months after the start of cART, CD4 cell counts continued to increase up to 8 years, with little evidence that differences between baseline CD4 cell count groups diminished over time. Virological failure ≥ 6 months after the start of cART was associated with lower subsequent CD4 cell counts, with greater CD4 cell count reduction for more recent virological failure and higher viral load. CONCLUSIONS: Post-cART CD4 cell counts are strongly related to pre-cART CD4 cell counts. CD4 cell count recovery is greatest in individuals who can avoid viral loads >1000 copies/mL while on cART.

Association of secular trends in unemployment with suicide in Taiwan, 1959-2007: a time-series analysis.

OBJECTIVE: Despite the wealth of research investigating the association of unemployment with suicide in the West, few studies have investigated the association in non-Western countries. This study aimed to investigate the relationship between secular trends in unemployment and suicide in Taiwan. STUDY DESIGN: Time-series analysis. METHODS: Overall and age-specific suicide rates (1959-2007) for Taiwanese men and women aged 15 years or above were calculated from national population and mortality statistics. The association of secular trends in unemployment with suicide was investigated graphically and using time-series modelling (Prais-Winsten regression). RESULTS: Rises in unemployment were associated with an increase in male suicide rates, but evidence for an association in females was limited. In the model controlling for changes in gross domestic product (GDP) per capita, GDP growth, divorce and female labour force participation, for every 1% rise in unemployment, male suicide rates increased by 3.1 (95% confidence interval 1.4-4.8) per 100,000. There is no evidence for a difference in the strength of association between men of different ages. CONCLUSION: Trends in suicide, particularly for adult males, appear to be influenced by unemployment. The results have implications for suicide prevention, in particular for societies facing acute rises in unemployment during recessions.

Adjusting trial results for biases in meta-analysis: combining data-based evidence on bias with detailed trial assessment.

Flaws in the conduct of randomized trials can lead to biased estimation of the intervention effect. Methods for adjustment of within-trial biases in meta-analysis include the use of empirical evidence from an external collection of meta-analyses, and the use of expert opinion informed by the assessment of detailed trial information. Our aim is to present methods to combine these two approaches to gain the advantages of both. We make use of the risk of bias information that is routinely available in Cochrane reviews, by obtaining empirical distributions for the bias associated with particular bias profiles (combinations of risk of bias judgements). We propose three methods: a formal combination of empirical evidence and opinion in a Bayesian analysis; asking experts to give an opinion on bias informed by both summary trial information and a bias distribution from the empirical evidence, either numerically or by selecting areas of the empirical distribution. The methods are demonstrated through application to two example binary outcome meta-analyses. Bias distributions based on opinion informed by trial information alone were most dispersed on average, and those based on opinions obtained by selecting areas of the empirical distribution were narrowest. Although the three methods for combining empirical evidence with opinion vary in ease and speed of implementation, they yielded similar results in the two examples.

Associations of wheezing phenotypes in the first 6 years of life with atopy, lung function and airway responsiveness in mid-childhood.

BACKGROUND: Patterns of wheezing during early childhood may indicate differences in aetiology and prognosis of respiratory illnesses. Improved characterisation of wheezing phenotypes could lead to the identification of environmental influences on the development of asthma and airway diseases in predisposed individuals. METHODS: Data collected on wheezing at seven time points from birth to 7 years from 6265 children in a longitudinal birth cohort (the ALSPAC study) were analysed. Latent class analysis was used to assign phenotypes based on patterns of wheezing. Measures of atopy, airway function (forced expiratory volume in 1 s (FEV(1)), mid forced expiratory flow (FEF(25-75))) and bronchial responsiveness were made at 7-9 years of age. RESULTS: Six phenotypes were identified. The strongest associations with atopy and airway responsiveness were found for intermediate onset (18 months) wheezing (OR for atopy 8.36, 95% CI 5.2 to 13.4; mean difference in dose response to methacholine 1.76, 95% CI 1.41 to 2.12 %FEV(1) per mumol, compared with infrequent/never wheeze phenotype). Late onset wheezing (after 42 months) was also associated with atopy (OR 6.6, 95% CI 4.7 to 9.4) and airway responsiveness (mean difference 1.61, 95% CI 1.37 to 1.85 %FEV(1) per mumol). Transient and prolonged early wheeze were not associated with atopy but were weakly associated with increased airway responsiveness and persistent wheeze had intermediate associations with these outcomes. CONCLUSIONS: The wheezing phenotypes most strongly associated with atopy and airway responsiveness were characterised by onset after age 18 months. This has potential implications for the timing of environmental influences on the initiation of atopic wheezing in early childhood.

The association between mother and child MTHFR C677T polymorphisms, dietary folate intake and childhood atopy in a population-based, longitudinal birth cohort.

BACKGROUND: A recent study suggested a link between folate metabolism and atopy, based on a positive association between a common polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene and allergic sensitization in Danish adults. OBJECTIVE: We investigated the associations between MTHFR C677T and allergy or atopy in a large, population-based birth cohort of children and their mothers, the Avon Longitudinal Study of Parents and Children (ALSPAC). We also looked for evidence of a pre-natal effect of maternal folate metabolism on subsequent atopic disease in the offspring. METHODS: Mothers were recruited in pregnancy and the children followed from birth. Atopy in the child was assessed at 7-8 years of age by skin prick tests to common allergens. Asthma was defined as a physician diagnosis and current symptoms at 71/2 years of age. Asthma and allergy status of the mothers were obtained from self-completion questionnaires. RESULTS: Data on MTHFR C677T genotype and allergy were available for 5364 children and on allergy and/or asthma for 7356 mothers. In children, the prevalence of atopy was 20.0% and asthma 10.0% whereas in mothers, the prevalence of self-reported allergy was 42.7% and asthma 11.5%. Atopy in the child was associated with male gender (P<0.001), less tobacco smoke exposure and higher maternal education. MTHFR C677T genotype was not associated with social factors or dietary folate intake. We found no evidence of associations between the MTHFR C677T variant allele and atopy, allergy or asthma in mothers or children. There was no evidence to support an effect of maternal MTHFR C677T genotype on atopy in the offspring. CONCLUSION: The results of this study do not support the hypothesis that impaired folate metabolism is associated with allergy in adults or children in this population.

Epidemiological, social, diagnostic and economic evaluation of population screening for genital chlamydial infection.

OBJECTIVES: To investigate epidemiological, social, diagnostic and economic aspects of chlamydia screening in non-genitourinary medicine settings. METHODS: Linked studies around a cross-sectional population-based survey of adult men and women invited to collect urine and (for women) vulvovaginal swab specimens at home and mail these to a laboratory for testing for Chlamydia trachomatis. Specimens were used in laboratory evaluations of an amplified enzyme immunoassay (PCE EIA) and two nucleic acid amplification tests [Cobas polymerase chain reaction (PCR), Becton Dickinson strand displacement amplification (SDA)]. Chlamydia-positive cases and two negative controls completed a risk factor questionnaire. Chlamydia-positive cases were invited into a randomised controlled trial of partner notification strategies. Samples of individuals testing negative completed psychological questionnaires before and after screening. In-depth interviews were conducted at all stages of screening. Chlamydia transmission and cost-effectiveness of screening were investigated in a transmission dynamic model. SETTING AND PARTICIPANTS: General population in the Bristol and Birmingham areas of England. In total, 19,773 women and men aged 16-39 years were randomly selected from 27 general practice lists. RESULTS: Screening invitations reached 73% (14,382/19,773). Uptake (4731 participants), weighted for sampling, was 39.5% (95% CI 37.7, 40.8%) in women and 29.5% (95% CI 28.0, 31.0%) in men aged 16-39 years. Chlamydia prevalence (219 positive results) in 16-24 year olds was 6.2% (95% CI 4.9, 7.8%) in women and 5.3% (95% CI 4.4, 6.3%) in men. The case-control study did not identify any additional factors that would help target screening. Screening did not adversely affect anxiety, depression or self-esteem. Participants welcomed the convenience and privacy of home-sampling. The relative sensitivity of PCR on male urine specimens was 100% (95% CI 89.1, 100%). The combined relative sensitivities of PCR and SDA using female urine and vulvovaginal swabs were 91.8% (86.1, 95.7, 134/146) and 97.3% (93.1, 99.2%, 142/146). A total of 140 people (74% of eligible) participated in the randomised trial. Compared with referral to a genitourinary medicine clinic, partner notification by practice nurses resulted in 12.4% (95% CI -3.7, 28.6%) more patients with at least one partner treated and 22.0% (95% CI 6.1, 37.8%) more patients with all partners treated. The health service and patients costs (2005 prices) of home-based postal chlamydia screening were 21.47 pounds (95% CI 19.91 pounds, 25.99) per screening invitation and 28.56 pounds (95% CI 22.10 pounds, 30.43) per accepted offer. Preliminary modelling found an incremental cost-effectiveness ratio (2003 prices) comparing screening men and women annually to no screening in the base case of 27,000 pounds/major outcome averted at 8 years. If estimated screening uptake and pelvic inflammatory disease incidence were increased, the cost-effectiveness ratio fell to 3700 pounds/major outcome averted. CONCLUSIONS: Proactive screening for chlamydia in women and men using home-collected specimens was feasible and acceptable. Chlamydia prevalence rates in men and women in the general population are similar. Nucleic acid amplification tests can be used on first-catch urine specimens and vulvovaginal swabs. The administrative costs of proactive screening were similar to those for opportunistic screening. Using empirical estimates of screening uptake and incidence of complications, screening was not cost-effective.

Prognostic importance of initial response in HIV-1 infected patients starting potent antiretroviral therapy: analysis of prospective studies.

BACKGROUND: We examined whether the initial virological and immunological response to highly active antiretroviral treatment (HAART) is prognostic in patients with HIV-1 who start HAART. METHODS: We analysed 13 cohort studies from Europe and North America including 9323 adult treatment-naive patients who were starting HAART with a combination of at least three drugs. We modelled clinical progression from month 6 after starting HAART, taking into account CD4 count and HIV-1 RNA measured at baseline and 6 months. FINDINGS: During 13408 years of follow-up 152 patients died and 874 developed AIDS or died. Compared with patients who had a 6-month CD4 count of fewer than 25 cells/microL, adjusted hazard ratios for AIDS or death were 0.55 (95%CI 0.32-0.96) for 25-49 cells/microL, 0.62 (0.40-0.96) for 50-99 cells/microL, 0.42 (0.28-0.64) for 100-199 cells/microL, 0.25 (0.16-0.38) for 200-349 cells/microL, and 0.18 (0.11-0.29) for 350 or more cells/microL at 6 months. Compared with patients who had a 6-month HIV-1 RNA of 100000 copies/mL or greater, adjusted hazard ratios for AIDS or death were 0.59 (0.41-0.86) for 10000-99999 copies/mL, 0.42 (0.29-0.61) for 500-9999 copies/mL, and 0.29 (0.21-0.39) for 6-month HIV-1 RNA of 500 copies/mL or fewer. Baseline CD4 and HIV-1 RNA were not associated with progression after controlling for 6-month concentrations. The probability of progression at 3 years ranged from 2.4% in the patients in the lowest-risk stratum to 83% in patients in the highest-risk stratum. INTERPRETATION: At 6 months after starting HAART, the current CD4 cell count and viral load, but not values at baseline, are strongly associated with subsequent disease progression. Our findings should inform guidelines on when to modify HAART.

Vitamin A supplementation for reducing the risk of mother-to-child transmission of HIV infection.

BACKGROUND: Mother-to-child transmission (MTCT) of HIV is the dominant mode of acquisition of HIV infection for children, currently resulting in more than 2000 new paediatric HIV infections each day worldwide. OBJECTIVES: To assess the effects of antenatal and intrapartum vitamin A supplementation on the risk of MTCT of HIV infection and infant and maternal mortality and morbidity, and the tolerability of vitamin A supplementation. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials, PubMed, EMBASE, AIDSLINE, LILACS, AIDSTRIALS, and AIDSDRUGS, using standardised methodological filters for identifying trials. We also searched reference lists of identified articles, relevant editorials, expert opinions and letters to journal editors, and abstracts or proceedings of relevant conferences; and contacted subject experts, agencies, organisations, academic centres, and pharmaceutical companies. There were no language restrictions. SELECTION CRITERIA: Randomised trials comparing vitamin A supplementation with no vitamin A supplementation in known HIV infected pregnant women. Trials had to include an estimate of the effect of vitamin A supplementation on MTCT of HIV and or any other adverse pregnancy outcome to be included. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial eligibility and quality and extracted data. Effect measures (odds ratio [OR] for binary variables and weighted mean difference [WMD] for continuous variables) with their 95% confidence intervals (CI) were estimated for each study and combined using the fixed effect (Mantel-Haenszel) method, by intention to treat. Heterogeneity between studies was examined by graphical inspection of results followed by a chi-square test of homogeneity. MAIN RESULTS: Four trials, which enrolled 3,033 HIV-infected pregnant women, are included in this review. There was no evidence of an effect of vitamin A supplementation on MTCT of HIV infection (OR 1.14, 95% CI 0.93 to 1.38). There was evidence of heterogeneity between the three trials with information on MTCT of HIV (I(2) =75.7%, P=0.02). While the trials conducted in South Africa (OR 0.98, 95% CI 0.67 to 1.42 at three months) and Malawi (OR 0.78, 95% CI 0.53 to 1.15 at 24 months) did not find evidence that the effect of Vitamin A supplementation was different from that of placebo, the trial in Tanzania did find evidence that vitamin A supplementation increased the risk of MTCT of HIV (OR 1.53, 95% CI 1.15 to 2.04 at 24 months). Vitamin A supplementation significantly improved birth weight (WMD 89.78, 95% CI 84.73 to 94.83), but there was no evidence of an effect of vitamin A supplementation on stillbirths (OR 0.99, 95% CI 0.67 to 1.46), preterm births (OR 0.89, 95% CI 0.71 to 1.11), death by 24 months among live births (OR 1.11, 95% CI 0.88 to 1.40), postpartum CD4 levels (WMD -4.00, 95% CI -51.06 to 43.06), and maternal death (OR 0.49, 95%CI 0.04 to 5.40). IMPLICATIONS FOR PRACTICE: Currently available evidence do not support the use of vitamin A supplementation of HIV-infected pregnant women to reduce MTCT of HIV, though there is an indication that vitamin A supplementation improves birth weight. IMPLICATIONS FOR RESEARCH: The awaited publication of data from a large trial involving 4,495 HIV infected pregnant women in Harare (Zimbabwe Vitamin A for Mothers and Babies Project), will further clarify the effect of vitamin A supplementation on MTCT of HIV. The current review will be updated as soon as the trial is published.

Vaginal disinfection for preventing mother-to-child transmission of HIV infection.

BACKGROUND: Mother-to-child transmission (MTCT) of HIV infection is one of the most tragic consequences of the HIV epidemic, especially in resource-limited countries, resulting in about 650 000 new paediatric HIV infections each year worldwide. The paediatric HIV epidemic threatens to seriously undermine decade-old child survival programmes. OBJECTIVES: To estimate the effect of vaginal disinfection on the risk of MTCT of HIV and infant and maternal mortality and morbidity, as well as tolerability of vaginal disinfection in HIV-infected women. SEARCH STRATEGY: We searched the Cochrane Controlled Trials Register, Cochrane Pregnancy and Childbirth Register, PubMed, EMBASE, AIDSLINE, LILACS, AIDSTRIALS, and AIDSDRUGS, using standardised methodological filters for identifying trials. We also searched reference lists of identified articles, relevant editorials, expert opinions and letters to journal editors, and abstracts and proceedings of relevant conferences, and contacted subject experts and pharmaceutical companies. There were no language restrictions. SELECTION CRITERIA: Randomised trials or clinical trials comparing vaginal disinfection during labour with placebo or no treatment, in known HIV-infected pregnant women. Trials had to include an estimate of the effect of vaginal disinfection on MTCT of HIV and or infant and maternal mortality and morbidity. DATA COLLECTION AND ANALYSIS: Three authors independently assessed trial eligibility and quality, and extracted data. Meta-analysis was performed using the Yusuf-Peto modification of Mantel-Haenszel's fixed effect method. MAIN RESULTS: Only two trials that included 708 patients met the inclusion criteria. The effect of vaginal disinfection on the risk of MTCT of HIV (OR 0.93, 95% CI 0.65 to 1.33), neonatal death (OR 1.38, 95% CI 0.30 to 6.33), and death after the neonatal period (OR 1.45, 95% CI 0.47 to 4.45) is uncertain. There was no evidence that vaginal disinfection increased adverse effects in mothers (OR 1.15, 95% CI 0.41 to 3.22), and evidence from one trial showed that adverse effects decreased in neonates (OR 0.14, 95% CI 0.07 to 0.31). AUTHORS' CONCLUSIONS: Currently, there is no evidence of an effect of vaginal disinfection on the risk of MTCT of HIV. Given its simplicity and low cost, there is need for a large well-designed and well-conducted randomised controlled trial to assess the additive effect of vaginal disinfection on the risk of MTCT of HIV in antiretroviral treated women.

Comparison of methods for analysing cluster randomized trials: an example involving a factorial design.

BACKGROUND: Studies involving clustering effects are common, but there is little consistency in their analysis. Various analytical methods were compared for a factorial cluster randomized trial (CRT) of two primary care-based interventions designed to increase breast screening attendance. METHODS: Three cluster-level and five individual-level options were compared in respect of log odds ratios of attendance and their standard errors (SE), for the two intervention effects and their interaction. Cluster-level analyses comprised: (C1) unweighted regression of practice log odds; (C2) regression of log odds weighted by their inverse variance; (C3) random-effects meta-regression of log odds with practice as a random effect. Individual-level analyses comprised: (I1) standard logistic regression ignoring clustering; (I2) robust SE; (I3) generalized estimating equations; (I4) random-effects logistic regression; (I5) Bayesian random-effects logistic regression. Adjustments for stratification and baseline variables were investigated. RESULTS: As expected, method I1 was highly anti-conservative. The other, valid, methods exhibited considerable differences in parameter estimates and standard errors, even between the various random-effects methods based on the same statistical model. Method I4 was particularly sensitive to between-cluster variation and was computationally stable only after controlling for baseline uptake. CONCLUSIONS: Commonly used methods for the analysis of CRT can give divergent results. Simulation studies are needed to compare results from different methods in situations typical of cluster trials but when the true model parameters are known.