Prenatal iodine supplementation and early childhood neurodevelopment: the PoppiE trial - study protocol for a multicentre randomised controlled trial.

INTRODUCTION: Observational studies suggest both low and high iodine intakes in pregnancy are associated with poorer neurodevelopmental outcomes in children. This raises concern that current universal iodine supplement recommendations for pregnant women in populations considered to be iodine sufficient may negatively impact child neurodevelopment. We aim to determine the effect of reducing iodine intake from supplements for women who have adequate iodine intake from food on the cognitive development of children at 24 months of age. METHODS AND ANALYSIS: A multicentre, randomised, controlled, clinician, researcher and participant blinded trial with two parallel groups. Using a hybrid decentralised clinical trial model, 754 women (377 per group) less than 13 weeks' gestation with an iodine intake of ≥165 µg/day from food will be randomised to receive either a low iodine (20 µg/day) multivitamin and mineral supplement or an identical supplement containing 200) µg/day (amount commonly used in prenatal supplements in Australia), from enrolment until delivery. The primary outcome is the developmental quotient of infants at 24 months of age assessed with the Cognitive Scale of the Bayley Scales of Infant Development, fourth edition. Secondary outcomes include infant language and motor development; behavioural and emotional development; maternal and infant clinical outcomes and health service utilisation of children. Cognitive scores will be compared between groups using linear regression, with adjustment for location of enrolment and the treatment effect described as a mean difference with 95% CI. ETHICS AND DISSEMINATION: Ethical approval has been granted from the Women's and Children's Health Network Research Ethics Committee (HREC/17/WCHN/187). The results of this trial will be presented at scientific conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04586348.

No dose-dependent increase in fracture risk after long-term exposure to high doses of retinol or beta-carotene.

UNLABELLED: Uncertainty remains over whether or not high intakes of retinol or vitamin A consumed through food or supplements may increase fracture risk. This intervention study found no increase in fracture risk among 2,322 adults who took a controlled, high-dose retinol supplement (25,000 IU retinyl palmitate/day) for as long as 16 years. There was some evidence that beta-carotene supplementation decreased fracture risk in men. INTRODUCTION: There is conflicting epidemiological evidence regarding high intakes of dietary or supplemental retinol and an increased risk for bone fracture. We examined fracture risk in a study administering high doses of retinol and beta-carotene (BC) between 1990 and 2007. METHODS: The Vitamin A Program was designed to test the efficacy of retinol and BC supplements in preventing malignancies in persons previously exposed to blue asbestos. Participants were initially randomised to 7.5 mg retinol equivalents (RE)/day as retinyl palmitate, 30 mg/day BC or 0.75 mg/day BC from 1990 to 1996; after which, all participants received 7.5 mg RE/day. Fractures were identified by questionnaire and hospital admission data up until 2006. Risk of any fracture or osteoporotic fracture according to cumulative dose of retinol and BC supplementation was examined using conditional logistic regression models adjusting for age, sex, smoking, body mass index, medication use and previous fracture. RESULTS: Supplementation periods ranged from 1 to 16 years. Of the 2,322 (664 females and 1,658 males) participants, 187 experienced 237 fractures. No associations were observed between cumulative dose of retinol and risk for any fracture (OR per 10 g RE=0.83; 95% CI, 0.63-1.08) or osteoporotic fracture (OR per 10 g RE=0.95; 95% CI 0.64-1.40). Among men, cumulative dose of BC was associated with a slightly reduced risk of any fracture (OR per 10 g=0.89; 95% CI 0.81-0.98) and osteoporotic fracture (OR per 10 g=0.84; 95% CI 0.72-0.97). CONCLUSIONS: This study observed no increases in fracture risk after long-term supplementation with high doses of retinol and/or beta-carotene.

Fruit, vegetable, vitamin A intakes, and prostate cancer risk.

Prostate cancer risk was examined in relation to intakes of fruit, vegetables, beta-carotene and retinol. Subjects were a cohort of 1985 men previously to asbestos who participated in a cancer prevention programme of beta-carotene and retinol supplements that commenced in July 1990. Diet was assessed at entry to the programme. Ninety-seven cases of prostate cancer were identified during follow-up until the end of 2004. A decreased prostate cancer risk was observed with increasing intakes of vitamin C-rich vegetables, including bell peppers and broccoli. Fruit, other vegetables and vitamin A intakes did not appear to be strong factors in the development of prostate cancer in this study.

The prevalence of anaemia depends on the definition: an example from the Aboriginal Birth Cohort Study.

OBJECTIVE: The cutoffs defining anaemia based on haemoglobin and haematocrit recommended by the World Health Organization (WHO) and the United States (US) are different. We compared the prevalences resulting from these definitions and explored the reasons for the variation observed. DESIGN: A cross-sectional survey within a cohort study of children recruited at birth at Royal Darwin Hospital. SETTING: Subjects were interviewed in their homes or other convenient location and had a blood sample drawn. SUBJECTS: Five hundred and seventeen Australian Aboriginal children aged 9-13 years inclusive. RESULTS: Depending on the criterion used, the prevalence of anaemia in the total group ranged between 6% (95% confidence interval: 4.1-8.4%) and 24.4% (20.7-28.3). Using the WHO criteria, girls aged 12-13 years were identified as a target group, having a two- to-six fold higher prevalence than the other groups. When compared to the US criteria, boys aged 12-13 years had the highest prevalence of anaemia, although this was not significant. Simulations show that the WHO cutoffs are based on inconsistent centiles of the age-sex haemoglobin and haematocrit distributions, and that this largely explains the discrepant results. CONCLUSIONS: This variability in definition could lead to inappropriate identification of target groups for intervention programmes.

Monitoring the 'Strong Women, Strong Babies, Strong Culture Program': the first eight years.

OBJECTIVE: To assess improvements in perinatal health following the introduction of the Strong Women, Strong Babies, Strong Culture (SWSBSC) Program in two groups of Aboriginal communities in the Northern Territory. METHODS: A comparison of pre and post birthweights in intervention and control communities in rural and remote regions in the Top End of the Northern Territory was performed. RESULTS: Significant improvements in birthweight were observed for Group 1 communities with no significant change in Group 2. CONCLUSION: There is a need to better understand how the intervention differed in the two groups of communities.

Comparison of an Australian food-frequency questionnaire with diet records: implications for nutrition surveillance.

OBJECTIVES: To compare a widely used Australian food-frequency questionnaire (FFQ) with diet records and consider the results in relation to its use in nutrition surveillance. DESIGN: Inter-method reliability study. SETTING: A randomised trial in subjects with past asbestos exposure. SUBJECTS: Seventy-two adults living in Western Australia. METHODS: A semi-quantitative FFQ developed by the Commonwealth Scientific Industrial Research Organisation in South Australia was administered after the completion of four 7-day diet records (DRs). RESULTS: Mean agreement between methods was not significantly different from 100% for many nutrients, but the limits of agreement indicated that, at the individual level, the FFQ over- or underestimated the DR by at least 50%. Mean agreement between methods decreased significantly with increasing intakes for the majority of nutrients. Pearson's correlation coefficients were less informative indicators of agreement compared with the limits of agreement. CONCLUSIONS: These results indicate poor agreement between the FFQ and DR when estimating absolute intakes. Therefore, comparing intakes collected using this FFQ with specific cut-off points such as Recommended Dietary Intakes for nutrition surveillance may lead to seriously flawed conclusions about population intakes.

Birthweight changes in the pilot phase of the Strong Women Strong Babies Strong Culture Program in the Northern Territory.

OBJECTIVE: The Strong Women Strong Babies Strong Culture Program had specific goals to increase infant birthweights by earlier attendance for antenatal care and improved maternal weight status. Starting in August 1993, Aboriginal women in three pilot communities worked with pregnant women in a program that emphasised both traditional practices and Western medicine. METHOD: Two sources of data were used to examine different aspects of program effects. RESULTS: Data from the NT Midwives Collection shows that the mean birthweight of infants of Aboriginal women increased by 171 g between 1990/91 and 1994/95 in the pilot communities and by 92 g in the surrounding three rural regions. Data extracted from clinic records in the pilot communities found that changes in maternal weight were associated with change in birthweight over time. CONCLUSION: Changes in birthweight coincide with the commencement of the program and are larger than the secular trend in surrounding communities. IMPLICATIONS: Ongoing evaluation of the expanded program will help to determine the extent to which the change in birthweight can be attributed to the program and whether the effects can be replicated.

Comparison of two frequency questionnaires for quantifying fruit and vegetable intake.

OBJECTIVE: The effect on individual rankings and total intakes of nutrients of correcting total fruit and vegetable frequencies from a long food frequency questionnaire (FFQ) using the responses to two summary questions was examined in a group of women. METHODS: The performance of a self-administered FFQ in ranking individual levels of intake and estimating absolute levels of nutrient and energy intake was compared with the performance of the questionnaire when it was corrected for fruit and vegetable intake reported using the Block summary questions. SUBJECTS: The study population included 123 women, aged between 18 and 54 years, who were recruited from the Family Planning Association Colposcopy Clinic in Sydney. RESULTS: Substantial and significant differences (P < 0.001) were found in fruit and vegetable intakes between the FFQ and the summary questions. Intake frequency by the FFQ was more than double that by the summary questions. When the FFQ was corrected for fruit and vegetable intakes using the summary questions, the intakes of beta-carotene, vitamins A and C, and dietary fibre were more than 20% lower (p < 0.001) than the uncorrected results. However, this had little effect on ranking individuals. This study also examined seasonal differences in vegetable intakes and differences in nutrient intakes when either summer or winter vegetable consumption was substituted for seasonal vegetable intake in the FFQ. Although there were seasonal differences for some foods, the substitution had little effect on intake of nutrients. CONCLUSION: These results indicate that important differences in intakes are observed when two methods, which appear to yield the same results, are used. Further work is needed to determine which, if either, of the two methods yields intakes that can be compared quantitatively with national references for assessing the adequacy of population intakes.

Agreement between a brief food frequency questionnaire and diet records using two statistical methods.

OBJECTIVE: To compare intra- and inter-method reliability of a semi-quantitative food frequency questionnaire (FFQ) designed specifically to measure beta carotene (BC) and retinol intake, using two methods - the limits of agreement (LOA) and the correlation coefficient. DESIGN: A cross-sectional study of dietary intake. SETTING: A randomized trial of vitamin A supplements in 2769 subjects with past asbestos exposure. SUBJECTS: Data from 57 men and 26 women, aged 28-72 years, living in Western Australia. METHODS: The FFQ was administered at baseline (FFQ1) and repeated 1 year later (FFQ2). Four 1-week diet records (DRs) were completed during the year. RESULTS: Mean agreement between FFQ2 and FFQ1 was 120% for BC and 98% for retinol. LOA were 47-306% and 21-459%, respectively. Mean agreement between FFQ2 and the DR was 149% for BC and 63% for retinol; LOA were 50-447% and 11-349%, respectively. Mean agreement and LOA varied across energy intakes. Between the DR and FFQ2, correlation coefficients were 0.36 for BC and 0.51 for retinol. These varied considerably across age, gender and energy intakes and were not in accordance with limits of agreement findings. CONCLUSION: Although correlation coefficients were positive and significant, there was less than ideal intra-method and inter-method reliability shown by the limits of agreement method. Bias was uneven across the range of intakes, the LOA were wide and, compared with the DR, the FFQ significantly over-estimated BC and under-estimated retinol. This shows the limitations of calculating correlation coefficients alone, for assessing reliability and validity.

Size for gestation in Aboriginal babies: a comparison of two papers.

OBJECTIVE: Two recent papers examining low birthweight in Aboriginal infants came to different conclusions about the role of size for gestation and preterm delivery in influencing the low birthweight proportion. As the two studies used different methods to estimate the infants' gestational age and to analyse the data, the results cannot be compared directly. This analysis combines the methods of both earlier studies. METHOD: Data collected in 6 Top End communities were analysed to calculate the proportion of infants who were small for gestational age. RESULTS: Despite the high overall prevalence of preterm delivery from the midwives' estimates, 31.4% of infants fell below the 10th centile of weight for gestational age and sex. The majority of these infants were not low birthweight. CONCLUSIONS: The earlier report from the Top End of high proportions of small-for-gestational age infants cannot be dismissed as an artefact due to the method of estimating gestational age. IMPLICATIONS: Intervention programs to improve birth weights in Aboriginal infants need to address both conditions--small size for gestational age and preterm delivery--and need to target the whole population rather than high risk pregnancies.

Vitamin E for intermittent claudication.

BACKGROUND: It is thought that vitamin E may improve tolerance to intermittent claudication (i.e. pain caused by ischaemia in the muscles of the leg during exercise), thereby relieving the pain, through a variety of mechanisms. OBJECTIVES: The objective of this review was to determine the effects of vitamin E on people with intermittent claudication. SEARCH STRATEGY: The reviewers searched the Cochrane Peripheral Vascular Diseases Group trials register, reference lists of relevant articles and a library specialising in literature on vitamins. SELECTION CRITERIA: Controlled trials comparing vitamin E with placebo, or other interventions, in patients with intermittent claudication. DATA COLLECTION AND ANALYSIS: Both reviewers extracted data and assessed study quality independently. MAIN RESULTS: Five eligible studies were found with a total of 265, predominantly male, participants. The average age was 57 years. The follow-up varied from 12 weeks to 18 months. The trials were small and generally of poor quality. The people studied were reasonably homogeneous but five different doses of vitamin E were used and four different physical outcomes were measured. No trials were identified that compared vitamin E with treatments other than placebo. All trials showed positive effects on one of their main outcomes. No serious adverse effects of vitamin E were reported. Two trials that lasted approximately eight months and used similar doses reported patients' subjective evaluation of the treatment. The relative risk for the combined results of these two trials using a random effects model was 0.57 with a 95% confidence interval of 0.28 to 1.15. REVIEWER'S CONCLUSIONS: While vitamin E - which is inexpensive and has had no serious side effects reported with its use - may have beneficial effects, there is insufficient evidence to determine whether it is an effective treatment for intermittent claudication.

Randomized double-blind trial of beta-carotene and vitamin C in women with minor cervical abnormalities.

A double-blind, placebo-controlled, randomized, factorial study using a daily oral administration of 30 mg beta-carotene and/or 500 mg vitamin C was conducted in 141 women with colposcopically and histologically confirmed minor squamous atypia or cervical intra-epithelial neoplasia (CIN) I. Over approximately 2 years of follow-up, 43 lesions regressed to normal and 13 progressed to CIN II. The regression rate was slightly higher, but not significantly so, in those randomized to beta-carotene compared to no beta-carotene (hazard ratio = 1.58, 95% CI: 0.86-2.93, P = 0.14) and slightly lower, but not statistically significant, for those randomized to vitamin C compared to no vitamin C (hazard ratio = 0.65, 95% CI: 0.35-1.21, P = 0.17). In a model with no interaction, the progression rate was slightly higher in those randomized to beta-carotene (hazard ratio = 1.75, 95% CI: 0.57-5.36, P = 0.32) and also in those randomized to vitamin C (hazard ratio = 2.40, 95% CI: 0.74-7.80, P = 0.13). Neither of these were statistically significant. However, there was some evidence of an interaction effect of the two compounds on the progression rate (P = 0.052), with seven of the progressed lesions occurring in those randomized to both vitamins compared to a total of six in the three other groups. The currently available evidence from this and other trials suggests that high doses of these compounds are unlikely to increase the regression or decrease the progression of minor atypia and CIN I.

First- and second-year effects in trials of calcium supplementation on the loss of bone density in postmenopausal women.

The analysis of clinical trials investigating the effect of calcium on the loss of bone mass or density has been based on the assumption that the effects are the same for all years of follow-up. Hence the average annual rate of loss is calculated and compared in the calcium and control groups. In this metaanalysis, we investigated this assumption and found that it is not tenable in the groups randomized to calcium for most sites that have been measured. The rate of bone loss was significantly less in the first year after randomization than in the second year. By contrast, the rate of loss in the control groups was less in the second year than the first, although this was not significant. At the spine, femoral neck, trochanter, intertrochanter, midtibia, and ultratibia, the effect of calcium in reducing bone loss was statistically significant compared with control only in the first year after randomization; there was no difference in rates between the groups in the second year. The effect of calcium compared to control in two arm sites and Ward's triangle was of a similar magnitude but was not statistically significant. We recommend that analysis and metaanalysis of trials should always consider the effects on a year-by-year basis.

Energy adjustment: the concepts underlying the debate.

The similarities and differences in four methods for adjusting nutrient intake for energy intake are discussed. The situation for macronutrients, as exemplified by fat intake, is compared to the situation for micronutrients such as vitamin C, with the conclusion that different methods are appropriate for the two situations. The categorization of data in analyses is identified as a source of potential misinterpretation of study results.

The traditional humoral food habits of pregnant Vietnamese-Australian women and their effect on birth weight.

Vietnamese-Australian women have infants with lower birth weight than Australian-born women. Traditional humoral food habits, based on ancient Chinese medicine, are more likely to be followed during life changes like pregnancy. These food habits may influence maternal energy intake, weight gain and therefore infant birth weight. This study determined the proportion of pregnant Vietnamese women in southwestern Sydney who practise traditional humoral food habits, and their effect on birth weight. A cohort of 113 pregnant Vietnamese-born women were questioned on smoking status, height, weight, parity, food practices and demographics. Dietary intake was measured in each trimester. Known risk factors and infant birth weights were collected from medical records for participants and nonresponders. Fifty-seven per cent practised the traditional food habits. There were no differences in energy intake or weight gain between the two groups. After adjusting for confounders, birth weight was estimated to be 3257 g (95 per cent confidence interval (CI) 3205 to 3309) and 3272 g (CI 3211 to 3333) for the infants of traditional and nontraditional women respectively. Following humoral food habits does not appear to affect birth weight. Women who choose to follow these traditions should not be discouraged from doing so.

Fourier transform infrared spectroscopy of dysplastic, papillomavirus-positive cervicovaginal lavage specimens.

To assess the utility of a new, rapid, economical procedure that may prove valuable in cervical screening, Fourier transform infrared (ir) spectroscopy was performed on 25 cervicovaginal lavage specimens from women referred for colposcopy on the basis of a cytological abnormality detected on their Pap smear and whose lavage specimen was positive for human papillomavirus. Of the 18 classed as CIN I or less by histopathology, 11 showed band frequencies that deviated only slightly from spectra that characterize normal cervical cells and 3 of 5 "atypia" specimens had spectra identical to normal. Two of 3 classed as CIN II had spectra only slightly more abnormal to these 11. In the case of 2 graded as CIN I, several bands were similarly altered in the direction of the pattern seen for 4 CIN III specimens. A further CIN I sample gave a spectrum that was even further shifted toward the latter and the remaining CIN I sample had a pattern that matched the 4 CIN IIIs. The most obvious change in each of the CIN IIIs was an additional peak at 972 cm-1 and this has been suggested as a key indicator for malignancy. One of the 3 CIN IIs had this peak. Other characteristic spectral changes were seen as well in the CIN III samples. High-risk HPV18 was present in 3 of the CIN III samples, as well as in one specimen classed as atypia, but having an abnormal ir spectrum. Low-risk HPV 6 or 11 was seen along in samples with a normal or slightly abnormal ir spectrum, but never in those that showed an ir pattern that was abnormal. The current study has therefore shown complete concordance between ir spectral findings and histopathology result in the case of CIN III specimens, but less precise matching for other grades of CIN. The spectral differences revealed by ir spectroscopy are likely to characterize molecular abnormalities in cervical cells during progression to cancer and may therefore have potential in assisting with clinical decision making. More studies will, however, be required to establish the place of this technique in cervical screening.