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. 2013 May 9;12:41.
doi: 10.1186/1476-069X-12-41.

Prenatal and Perinatal Analgesic Exposure and Autism: An Ecological Link

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Free PMC article

Prenatal and Perinatal Analgesic Exposure and Autism: An Ecological Link

Ann Z Bauer et al. Environ Health. .
Free PMC article

Abstract

Background: Autism and Autism Spectrum Disorder (ASD) are complex neurodevelopmental disorders. Susceptibility is believed to be the interaction of genetic heritability and environmental factors. The synchronous rises in autism/ASD prevalence and paracetamol (acetaminophen) use, as well as biologic plausibility have led to the hypothesis that paracetamol exposure may increase autism/ASD risk.

Methods: To explore the relationship of antenatal paracetamol exposure to ASD, population weighted average autism prevalence rates and paracetamol usage rates were compared. To explore the relationship of early neonatal paracetamol exposure to autism/ASD, population weighted average male autism prevalence rates for all available countries and U.S. states were compared to male circumcision rates - a procedure for which paracetamol has been widely prescribed since the mid-1990s. Prevalence studies were extracted from the U.S. Centers for Disease Control and Prevention Summary of Autism/ASD Prevalence Studies database. Maternal paracetamol usage and circumcision rates were identified by searches on Pub Med.

Results: Using all available country-level data (n = 8) for the period 1984 to 2005, prenatal use of paracetamol was correlated with autism/ASD prevalence (r = 0.80). For studies including boys born after 1995, there was a strong correlation between country-level (n = 9) autism/ASD prevalence in males and a country's circumcision rate (r = 0.98). A very similar pattern was seen among U.S. states and when comparing the 3 main racial/ethnic groups in the U.S. The country-level correlation between autism/ASD prevalence in males and paracetamol was considerably weaker before 1995 when the drug became widely used during circumcision.

Conclusions: This ecological analysis identified country-level correlations between indicators of prenatal and perinatal paracetamol exposure and autism/ASD. State level correlation was also identified for the indicator of perinatal paracetamol exposure and autism/ASD. Like all ecological analyses, these data cannot provide strong evidence of causality. However, biologic plausibility is provided by a growing body of experimental and clinical evidence linking paracetamol metabolism to pathways shown to be important in autism and related developmental abnormalities. Taken together, these ecological findings and mechanistic evidence suggest the need for formal study of the role of paracetamol in autism.

Figures

Figure 1
Figure 1
Graph of country-level data on Autism/ASD prevalence and average prenatal paracetamol usage. The Autism/ASD prevalence and the prenatal paracetamol usage rates are both population weighted averages of all the respective studies for a country. (See Additional files 2 and 5).
Figure 2
Figure 2
Graph of country and U.S. state- level data on Autism/ASD and circumcision prevalence rates. All studies in which at least some cohort members were born after 1995. This graph includes country-level studies with the U.S. stratified to state-level studies for the post-1995 cohort (no overall U.S. data point). The assumption is that, due to changes in neonate prescribing practices in the mid-1990s, some cohort members in each study would likely be exposed to paracetamol at the time of circumcision. Autism rates are population weighted averages of all studies for a country or U.S. state. (See Additional files 1, 3, 4 and 5).
Figure 3
Figure 3
Graph of country-level data on Autism/ASD and circumcision prevalence rates. All studies in which all cohort members were born before 1995. The assumption is that all of the cohort members in each study would not likely be exposed to paracetamol at the time of circumcision. U.S. state level data was not available for this pre-1995 cohort. Autism rates are population weighted averages of all studies for a country. (See Additional files 1 and 3).
Figure 4
Figure 4
Comparison of U.S. demographic characteristics. Comparison of U.S. autism prevalence rates, circumcision rate and prenatal paracetamol usage rates by maternal race, education level and age.
Figure 5
Figure 5
Metabolic pathway model for paracetamol.

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