IMPORTANCE: Previous meta-analyses suggest that fluoride exposure is adversely associated with children's IQ scores. An individual's total fluoride exposure comes primarily from fluoride in drinking water, food, and beverages. OBJECTIVE: To perform a systematic review and meta-analysis of epidemiological studies investigating children's IQ scores and prenatal or postnatal fluoride exposure. DATA SOURCES: BIOSIS, Embase, PsycInfo, PubMed, Scopus, Web of Science, CNKI, and Wanfang, searched through October 2023. STUDY SELECTION: Studies reporting children's IQ scores, fluoride exposure, and effect sizes. DATA EXTRACTION AND SYNTHESIS: Data were extracted into the Health Assessment Workplace Collaborative system. Study quality was evaluated using the OHAT risk-of-bias tool. Pooled standardized mean differences (SMDs) and regression coefficients were estimated with random-effects models. MAIN OUTCOMES AND MEASURES: Children's IQ scores. RESULTS: Of 74 studies included (64 cross-sectional and 10 cohort studies), most were conducted in China (n = 45)
other locations included Canada (n = 3), Denmark (n = 1), India (n = 12), Iran (n = 4), Mexico (n = 4), New Zealand (n = 1), Pakistan (n = 2), Spain (n = 1), and Taiwan (n = 1). Fifty-two studies were rated high risk of bias and 22 were rated low risk of bias. Sixty-four studies reported inverse associations between fluoride exposure measures and children's IQ. Analysis of 59 studies with group-level measures of fluoride in drinking water, dental fluorosis, or other measures of fluoride exposure (47 high risk of bias, 12 low risk of bias
n = 20 932 children) showed an inverse association between fluoride exposure and IQ (pooled SMD, -0.45
95% CI, -0.57 to -0.33
P <
.002). In 31 studies reporting fluoride measured in drinking water, a dose-response association was found between exposed and reference groups (SMD, -0.15
95% CI, -0.20 to -0.11
P <
.002), and associations remained inverse when exposed groups were restricted to less than 4 mg/L and less than 2 mg/L
however, the association was null at less than 1.5 mg/L. In analyses restricted to low risk-of-bias studies, the association remained inverse when exposure was restricted to less than 4 mg/L, less than 2 mg/L, and less than 1.5 mg/L fluoride in drinking water. In 20 studies reporting fluoride measured in urine, there was an inverse dose-response association (SMD, -0.15
95% CI, -0.23 to -0.07
P <
.002). Associations remained inverse when exposed groups were restricted to less than 4 mg/L, less than 2 mg/L, and less than 1.5 mg/L fluoride in urine
the associations held in analyses restricted to the low risk-of-bias studies. Analysis of 13 studies with individual-level measures found an IQ score decrease of 1.63 points (95% CI, -2.33 to -0.93
P <
.002) per 1-mg/L increase in urinary fluoride. Among low risk-of-bias studies, there was an IQ score decrease of 1.14 points (95% CI, -1.68 to -0.61
P <
.002). Associations remained inverse when stratified by risk of bias, sex, age, outcome assessment type, country, exposure timing, and exposure matrix. CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis found inverse associations and a dose-response association between fluoride measurements in urine and drinking water and children's IQ across the large multicountry epidemiological literature. There were limited data and uncertainty in the dose-response association between fluoride exposure and children's IQ when fluoride exposure was estimated by drinking water alone at concentrations less than 1.5 mg/L. These findings may inform future comprehensive public health risk-benefit assessments of fluoride exposures.