Concentrations, Number of Doses, and Formulations of Aluminium Adjuvants in Vaccines: A Systematic Review with Meta-Analysis and Trial Sequential Analysis of Randomized Clinical Trials.

Aluminium adjuvants are commonly used in vaccines to boost the effects of vaccination. Here, we assessed the benefits and harms of different aluminium adjuvants vs. other aluminium adjuvants or vs. the same aluminium adjuvant at other concentrations, administered a different number of doses, or at different particle sizes used in vaccines or vaccine excipients. We conducted a systematic review with meta-analysis and Trial Sequential Analysis to assess the certainty of evidence with Grading of Recommendations Assessment, Development and Evaluation (GRADE). We obtained data from major medical databases until 20 January 2023 and included 10 randomized clinical trials of healthy volunteers. The comparisons assessed higher vs. lower aluminium adjuvant concentrations; higher vs. lower number of doses of aluminium adjuvant; and aluminium phosphate adjuvant vs. aluminium hydroxide adjuvant. For all three comparisons, meta-analyses showed no evidence of a difference on all-cause mortality, serious adverse events, and adverse events considered non-serious. The certainty of evidence was low to very low. None of the included trials reported on quality of life or proportion of participants who developed the disease being vaccinated against. The benefits and harms of different types of aluminium adjuvants, different aluminium concentrations, different number of doses, or different particle sizes, therefore, remain uncertain.

Was amorphous aluminium hydroxyphosphate sulfate adequately evaluated before authorisation in Europe?

The Merck Sharp & Dohme Corp aluminium adjuvant 'amorphous aluminium hydroxyphosphate sulfate' (AAHS), primarily used in the Gardasil vaccines against human papilloma virus, has been criticised for lack of evidence for its safety. Documentation from Danish authorities and answers from the European Medicines Agency (EMA) suggest that AAHS may not have been sufficiently evaluated. Documentation from the Danish Medicines Agency shows discrepancies in the trial documents of two prelicensure clinical trials with Gardasil in 2002 and 2003. For both trials, the Agency seems to have authorised potassium aluminium sulfate as the adjuvant and not AAHS. In addition, the participants in the trial launched in 2002 were informed that the comparator was saline, even though the comparator was AAHS in an expedient consisting of L-histidine, polysorbate-80, sodium borate and sodium chloride. According to the EMA, AAHS was first introduced in Europe in 2004 as the adjuvant in Procomvax, a vaccine against the hepatitis B virus and Haemophilus influenza type b. The EMA reports that AAHS was introduced without any prelicensure safety evaluation. The adjuvant is described by the company to be both physically and functionally distinct from all other previously used aluminium adjuvants. There is a need for rigorous evaluation of benefits and harms of the adjuvant AAHS.

Predicted vitamin D status during pregnancy in relation to offspring forearm fractures in childhood: a study from the Danish National Birth Cohort.

In a prospective cohort study, the association between maternal vitamin D status during pregnancy and offspring forearm fractures during childhood and adolescence was analysed in 30 132 mother and child pairs recruited to the Danish National Birth Cohort between 1996 and 2002. Data on characteristics, dietary factors and lifestyle factors were collected on several occasions during pregnancy. We analysed the association between predicted vitamin D status, based on a subsample with 25-hydroxyvitamin D (25(OH)D) biomarker measurements (n 1497) from gestation week 25, and first-time forearm fractures among offspring between birth and end of follow-up. Diagnoses were extracted from the Danish National Patient Register. Multivariable Cox regression models using age as the underlying time scale indicated no overall association between predicted vitamin D status (based on smoking, season, dietary and supplementary vitamin D intake, tanning bed use and outdoor physical activity) in pregnancy and offspring forearm fractures. Likewise, measured 25(OH)D, tanning bed use and dietary vitamin D intake were not associated with offspring forearm fractures. In mid-pregnancy, 91 % of the women reported intake of vitamin D from dietary supplements. Offspring of women who took >10 µg/d in mid-pregnancy had a significantly increased risk for fractures compared with the reference level of zero intake (hazard ratios (HR) 1·31; 95% CI 1·06, 1·62), but this was solely among girls (HR 1·48; 95% CI 1·10, 2·00). Supplement use in the peri-conceptional period exhibited similar pattern, although not statistically significant. In conclusion, our data indicated no protective effect of maternal vitamin D status with respect to offspring forearm fractures.

Maternal dietary patterns during pregnancy in relation to offspring forearm fractures: prospective study from the Danish National Birth Cohort.

Limited evidence exists for an association between maternal diet during pregnancy and offspring bone health. In a prospective study, we examined the association between dietary patterns in mid-pregnancy and offspring forearm fractures. In total, 101,042 pregnancies were recruited to the Danish National Birth Cohort (DNBC) during 1996-2002. Maternal diet was collected by a food frequency questionnaire. Associations were analyzed between seven dietary patterns extracted by principal component analysis and offspring first occurrence of any forearm fracture diagnosis, extracted from the Danish National Patient Register, between time of birth and end of follow-up (< 16 year) (n = 53,922). In multivariable Cox regression models, offspring of mothers in the fourth vs. first quintile of the Western pattern had a significant increased risk (Hazard ratio, 95% confidence interval: 1.11, 1.01-1.23) of fractures, and there was a borderline significant positive trend (p = 0.06). The other dietary patterns showed no associations and neither did supplementary analyses of macro- and micronutrients or single food groups, except for the intake of artificially sweetened soft drinks, which was positively associated with offspring forearm fractures (p = 0.02). In the large prospective DNBC high mid-pregnancy consumption of Western diet and artificially sweetened soft drinks, respectively, indicated positive associations with offspring forearm fractures, which provides interesting hypotheses for future research.

Possibilities and considerations when merging dietary data from the world's two largest pregnancy cohorts: the Danish National Birth Cohort and the Norwegian Mother and Child Cohort Study.

OBJECTIVES: To elucidate the research possibilities when merging data on maternal diet from the Danish National Birth Cohort (DNBC) and the Norwegian Mother and Child Cohort Study (MoBa), through comparison of (i) the methodology used for dietary assessment and (ii) the estimated intake of selected food groups in the two cohorts. DESIGN: Qualitative and quantitative comparison of the two dietary databases. SETTING: Two national prospective pregnancy cohorts. POPULATION: Denmark, Norway. METHODS: Comparison of food intake using food frequency questionnaires (FFQs). RESULTS: The FFQs had overlapping time windows and a majority of the questions in the two FFQs were comparable. Calculation principles shared similar features, including the software used and use of global questions to calibrate intakes of different food groups. A total of 63 food groups were defined that could be compared across the two cohorts; these were further aggregated down to 31 broader groups. A comparison of food intakes (grams/d) showed 39, 74 and 141% lower daily intakes of fish, potatoes and rice, respectively, in DNBC vs. MoBa and 39, 54 and 65% higher daily intakes of milk, butter and potatoes in DNBC vs. MoBa. For most other food groups, differences in consumption data were below 20%. CONCLUSIONS: The two FFQs are to a large extent compatible and substantial differences in dietary habits were observed between the two cohorts. This may strengthen studies using pooled analysis to examine diet-disease relations. This is a conclusion of great importance given the colossal and costly task involved to establish each of these two cohorts.

Sociodemographic characteristics and food habits of organic consumers--a study from the Danish National Birth Cohort.

OBJECTIVE: To develop a basis for building models that can examine the impact of organic food (OF) choices on maternal and offspring health, including identification of factors associated with OF consumption and underlying dietary patterns. DESIGN: Dietary intake was collected for the preceding month from an FFQ in mid-pregnancy and information on sociodemographic characteristics was collected from telephone interviews during pregnancy. From a question about OF consumption in the FFQ, including six food categories, an OF preference index was calculated. Latent variables that captured the variability in OF choices in relation to dietary intake were defined. SETTING: The Danish National Birth Cohort (DNBC), 1996-2002. SUBJECTS: Pregnant women from DNBC (n 60,773). RESULTS: We found that frequent OF use was highly associated with age, occupational status, urbanization, smoking and vegetarianism. By principal components analysis we identified two eating patterns, a 'Western dietary pattern' and a 'Prudent dietary pattern', that explained 14.2% of the variability in data. Frequent OF users consumed a more 'prudent' diet compared with non-users and had significantly higher intakes of vegetables (167%), fibre (113%) and n-3 fatty acids (111%) and less saturated fat (28%). CONCLUSIONS: Frequent OF users seemed to have a healthier lifestyle than non-users. These findings highlight a major challenge in observational studies examining the impact of OF consumption on health due to potentially irremediable confounding factors.

Peanut and tree nut consumption during pregnancy and allergic disease in children-should mothers decrease their intake? Longitudinal evidence from the Danish National Birth Cohort.

BACKGROUND: The relation between maternal peanut intake during pregnancy and allergic disease development in children has been controversial. OBJECTIVE: We used data from the Danish National Birth Cohort to examine associations between maternal peanut and tree nut intake during pregnancy and allergic outcomes in children at 18 months and 7 years of age. METHODS: We estimated maternal peanut and tree nut intake (n = 61,908) using a validated midpregnancy food frequency questionnaire. At 18 months, we used parental report of childhood asthma diagnosis, wheeze symptoms, and recurrent wheeze (>3 episodes). We defined current asthma at 7 years as doctor-diagnosed asthma plus wheeze in the past 12 months and allergic rhinitis as a self-reported doctor's diagnosis. We also used alternative classifications based on registry-based International Classification of Diseases, Tenth Revision, codes and drug dispensary data. We report here odds ratios (ORs) comparing intake of 1 or more times per week versus no intake. RESULTS: We found that maternal intake of peanuts (OR, 0.79; 95% CI, 0.65-0.97) and tree nuts (OR, 0.75; 95% CI, 0.67-0.84) was inversely associated with asthma in children at 18 months of age. Compared with mothers consuming no peanuts, children whose mothers reported eating peanuts 1 or more times per week were 0.66 (95% CI, 0.44-0.98) and 0.83 (95% CI, 0.70-1.00) times as likely to have a registry-based and medication-related asthma diagnosis, respectively. Higher tree nut intake was inversely associated with a medication-related asthma diagnosis (OR, 0.81; 95% CI, 0.73-0.90) and self-reported allergic rhinitis (OR, 0.80; 95% CI, 0.64-1.01). CONCLUSIONS: Our results do not suggest that women should decrease peanut and tree nut intake during pregnancy; instead, consumption of peanuts and tree nuts during pregnancy might even decrease the risk of allergic disease development in children.

Sources and determinants of vitamin D intake in Danish pregnant women.

Vitamin D deficiency during pregnancy has been associated with the development of several adverse health outcomes, e.g., pre-eclampsia, gestational diabetes mellitus, preterm delivery, low birth weight, birth length, and bone mineral content. The aims of the present study were to estimate the intake and sources of vitamin D in Danish pregnant women and to examine potential determinants of vitamin D intake of the recommended level (10 µg per day). In 68,447 Danish pregnant women the mean ± SD for vitamin D intake was 9.23 ± 5.60 µg per day (diet: 3.56 ± 2.05 µg per day, supplements: 5.67 ± 5.20 µg per day). 67.6% of the women reported use of vitamin D supplements but only 36.9% reported use of vitamin D supplements of at least 10 µg. Supplements were the primary source of vitamin D for the two higher quartiles of total vitamin D intake, with diet being the primary source for the two lower quartiles. Determinants of sufficient total vitamin D intake were: high maternal age, nulliparity, non-smoking, and filling out of the Food Frequency Questionnaire (FFQ) during summer or fall. We propose that clinicians encourage vitamin D supplementation among pregnant women, with special focus on vulnerable groups such as the young, smokers and multiparous women, in order to improve maternal and fetal health both during and after pregnancy.

Intake of artificially sweetened soft drinks and risk of preterm delivery: a prospective cohort study in 59,334 Danish pregnant women.

BACKGROUND: Sugar-sweetened soft drinks have been linked to a number of adverse health outcomes such as high weight gain. Therefore, artificially sweetened soft drinks are often promoted as an alternative. However, the safety of artificial sweeteners has been disputed, and consequences of high intakes of artificial sweeteners for pregnant women have been minimally addressed. OBJECTIVE: We examined the association between intakes of sugar-sweetened and artificially sweetened soft drinks and preterm delivery. DESIGN: We conducted prospective cohort analyses of 59,334 women from the Danish National Birth Cohort (1996-2002). Soft drink intake was assessed in midpregnancy by using a food-frequency questionnaire. Preterm delivery ( lt 37 wk) was the primary outcome measure. Covariate information was assessed by telephone interviews. RESULTS: There was an association between intake of artificially sweetened carbonated and noncarbonated soft drinks and an increased risk of preterm delivery (P for trend: le 0.001, both variables). In comparison with women with no intake of artificially sweetened carbonated soft drinks, the adjusted odds ratio for women who consumed ge 1 serving of artificially sweetened carbonated soft drinks/d was 1.38 (95% CI: 1.15, 1.65). The corresponding odds ratio for women who consumed ge 4 servings of artificially sweetened carbonated soft drinks/d was 1.78 (95% CI: 1.19, 2.66). The association was observed for normal-weight and overweight women. A stronger increase in risk was observed for early preterm and moderately preterm delivery than with late-preterm delivery. No association was observed for sugar-sweetened carbonated soft drinks (P for trend: 0.29) or for sugar-sweetened noncarbonated soft drinks (P for trend: 0.93). CONCLUSIONS: Daily intake of artificially sweetened soft drinks may increase the risk of preterm delivery. Further studies are needed to reject or confirm these findings.