By Jake Scott, MD
Synopsis: A large Danish cohort study of 1.2 million children found no association between cumulative aluminum exposure from childhood vaccines and increased risk for autoimmune, atopic/allergic, or neurodevelopmental disorders, adding to nearly a century of safety data for aluminum adjuvants, although the study’s findings have been the subject of public debate about interpretation of secondary analyses.
Source: Andersson NW, Bech Svalgaard I, Hoffmann SS, Hviid A. Aluminum-adsorbed vaccines and chronic diseases in childhood: A nationwide cohort study. Ann Intern Med. 2025;Jul 15. doi:10.7326/ANNALS-25-00997. [Online ahead of print].
Andersson and colleagues conducted a nationwide cohort study leveraging Denmark’s comprehensive health registries to evaluate the association between cumulative aluminum exposure from childhood vaccines and chronic diseases.1 The study included 1,224,176 children born between 1997 and 2018 who were alive and residing in Denmark at age 2 years. The researchers exploited natural variations in aluminum content of vaccines used in Denmark’s childhood vaccination program over time, which changed because of policy updates and vaccine substitutions, creating a quasi-experimental framework where exposure varied at the population level independent of individual characteristics.
Children were followed from age 2 to 5 years (with secondary analyses extending to age 8 years) for 50 conditions across three categories: autoimmune (36 disorders), atopic/allergic (nine disorders), and neurodevelopmental (five disorders). The median cumulative aluminum exposure through vaccination by age 2 years was 3 mg (interquartile range [IQR], 2.8 mg to 3.4 mg), ranging from 0 mg to 4.5 mg. Only 1.2% of children (15,237) received no aluminum-containing vaccines.
For the primary analysis, the researchers found no association between cumulative aluminum exposure and any of the combined outcome groups. The adjusted hazard ratios per 1-mg increase in aluminum exposure were 0.98 (95% confidence interval [CI], 0.94-1.02) for any autoimmune disorder, 0.99 (CI, 0.98-1.01) for any atopic/allergic disorder, and 0.93 (CI, 0.90-0.97) for any neurodevelopmental disorder. For most individually analyzed outcomes, the upper bounds of the 95% CIs were incompatible, with relative increases greater than 10% or 30%.
Notably, for asthma — the most common outcome, with 28,346 cases — the hazard ratio was 0.96 (CI, 0.94-0.98) per mg of aluminum exposure. For autism spectrum disorder (4,806 cases) and attention deficit/hyperactivity disorder (1,580 cases), the hazard ratios were 0.93 (CI, 0.89-0.97) and 0.90 (CI, 0.84-0.96), respectively.
The robustness of these findings was tested through multiple secondary analyses, including stratification by sex and birth cohort, extension of follow-up to age 8 years, and various exposure categorizations. Results remained consistent across these analyses.
Commentary
Aluminum salts have been used safely as vaccine adjuvants since the 1930s, enhancing immune responses and allowing for reduced antigen doses.2 Despite this extensive track record, concerns about aluminum safety emerged in the mid-2000s, largely driven by observations that high aluminum levels can cause osteomalacia, anemia, or encephalopathy — although these occur almost exclusively in preterm infants with compromised renal function receiving high doses from multiple sources.3 This Danish study provides the largest and most comprehensive evaluation to date of aluminum exposure from childhood vaccines and chronic disease risk.
The Danish setting offers unique advantages: universal healthcare with complete capture of vaccinations and diagnoses, minimal loss to follow-up, and natural variation in vaccine aluminum content over time that approximates randomization at the population level. These findings align with previous safety assessments, including a systematic review showing no association between aluminum-containing vaccines and serious adverse events, and studies demonstrating that vaccinated children maintain serum aluminum levels well below toxic ranges.4-7
Karwowski and colleagues previously evaluated 85 children aged 9-13 months, finding no correlation between blood or hair aluminum concentrations and vaccine history, nor between aluminum levels and developmental status.8 The current Danish study extends these findings across a vastly larger population and longer follow-up period.
The study’s findings have generated significant public discussion, particularly after criticism from a U.S. government official regarding the interpretation of secondary analyses. Some observers have pointed to Supplement Figure 4, which shows a statistically significant hazard ratio (HR) of 1.67 (95% CI, 1.01-2.77) for Asperger syndrome in the 2007-2018 birth cohort. However, several important contextual factors must be considered when interpreting this finding.
First, this represents one of only two statistically significant findings among 50 outcomes tested in subgroup analyses — a pattern consistent with chance findings when multiple comparisons are performed. Second, the confidence interval barely excludes 1.0 and extends to 2.77, indicating substantial imprecision. Third, the earlier birth cohort (1997-2006), which had longer follow-up and more cases (124 vs. 51), showed no association (HR, 0.99; CI, 0.76-1.29). If a true causal relationship existed, one would expect consistency across cohorts, particularly in the larger cohort with longer observation.
Critics also have highlighted risk difference analyses from Supplement Figure 11, noting 9.7 additional neurodevelopmental disorder cases per 10,000 children when comparing moderate to highest aluminum exposure groups. However, this selective citation obscures important context: The comparison between lowest and highest exposure groups — which should show the strongest signal if aluminum were harmful — actually showed 11.05 more cases per 10,000 in the lowest exposure group (although not statistically significant). This absence of a dose-response relationship, combined with the primary analysis showing lower risk with higher aluminum exposure (HR 0.93 for neurodevelopmental disorders), argues against a causal association.
The study has several strengths beyond its size and setting. The researchers adjusted for numerous potential confounders, including socioeconomic factors, maternal health conditions, and healthcare use patterns. They also conducted extensive sensitivity analyses that consistently supported the null findings. The quasi-experimental design, leveraging policy-driven changes in vaccine formulations, provides stronger causal inference than traditional observational studies.
Some limitations merit consideration. The study relied on registry diagnoses rather than clinical validation, although Danish registries have demonstrated good validity for most conditions studied. Follow-up was relatively short for conditions that may manifest later in childhood, although extension to age 8 years did not alter findings. The study also could not address individual susceptibility factors or gene-environment interactions.
As Mitkus and colleagues previously demonstrated, aluminum levels from vaccines remain well below minimal risk thresholds.2 The theoretical concerns about aluminum neurotoxicity, largely extrapolated from high-dose parenteral exposure in specific medical contexts or animal studies, do not appear to translate to the much lower exposures from childhood vaccines.
For clinicians counseling vaccine-hesitant families, this study offers high-quality evidence from more than 1 million children that aluminum-containing vaccines do not increase risk for chronic conditions. The absence of association across multiple disorders, consistency across various analytical approaches, and biological plausibility given the low exposure levels all support vaccine safety. While no study can definitively rule out tiny effect sizes or effects in rare susceptible subpopulations, this research substantially narrows any remaining uncertainty about aluminum adjuvant safety in routine childhood vaccination.
Jake Scott, MD, is Clinical Associate Professor, Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Antimicrobial Stewardship Program Medical Director, Stanford Health Care Tri-Valley.
References
1. Andersson NW, Bech Svalgaard I, Hoffmann SS, Hviid A. Aluminum-adsorbed vaccines and chronic diseases in childhood : A nationwide cohort study. Ann Intern Med. 2025;Jul 15. doi:10.7326/ANNALS-25-00997. [Online ahead of print].
2. Mitkus RJ, King DB, Hess MA, et al. Updated aluminum pharmacokinetics following infant exposures through diet and vaccination. Vaccine. 2011;29(51):9538-9543.
3. Bishop NJ, Morley R, Day JP, Lucas A. Aluminum neurotoxicity in preterm infants receiving intravenous-feeding solutions. N Engl J Med. 1997;336(22):1557-1561.
4. Jefferson T, Rudin M, Di Pietrantonj C. Adverse events after immunisation with aluminium-containing DTP vaccines: Systematic review of the evidence. Lancet Infect Dis. 2004;4(2):84-90.
5. Baylor NW, Egan W, Richman P. Aluminum salts in vaccines — US perspective. Vaccine. 2002;20 (Suppl 3):S18-S23.
6. [No authors listed]. Aluminum toxicity in infants and children. American Academy of Pediatrics, Committee on Nutrition. Pediatrics.1996;97(3):413-416.
7. Keith LS, Jones DE, Chou CHSJ. Aluminum toxicokinetics regarding infant diet and vaccinations. Vaccine. 2002;20 (Suppl 3):S13-S17.
8. Karwowski MP, Stamoulis C, Wenren LM, et al. Blood and hair aluminum levels, vaccine history, and early infant development: A cross-sectional study. Acad Pediatr. 2018;18(2):161-165.
9. Klein NP, Edwards KM, Sparks RC, Dekker CL; Clinical Immunization Safety Assessment (CISA) Network. Recurrent sterile abscesses following aluminium adjuvant-containing vaccines. BMJ Case Rep. 2009;2009:bcr09.2008.0951.
10. Bergfors E, Trollfors B, Inerot A, Gente Lidholm A. Contact allergy to aluminium induced by commonly used pediatric vaccines. Clin Transl Med. 2017;6(1):4.
A large Danish cohort study of 1.2 million children found no association between cumulative aluminum exposure from childhood vaccines and increased risk for autoimmune, atopic/allergic, or neurodevelopmental disorders, adding to nearly a century of safety data for aluminum adjuvants, although the study’s findings have been the subject of public debate about interpretation of secondary analyses.
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