On 2015 Apr 15, Ann Z Bauer commented:

We commend Frisch and Simonsen on their high quality prospective cohort analysis on ritual circumcision and the risk of autism spectrum disorder (ASD) in young boys. As the authors acknowledge, and we are pleased to see, our ecologic analysis was part of the motivation behind the performance of this study. The finding in this cohort of 342,877 boys born between 1994 and 2003, that circumcised boys were more likely than intact boys to develop ASD before age 10 (HR=1.46, 95% CI: 1.11 -1.93) concurs with our study findings.Bauer AZ, 2013 It is, however, important to note that in our study we did not focus on the psychological consequences of the circumcision procedure as the causal ASD mechanism, rather we were using circumcision exposure as a proxy for the potential paracetamol (APAP, acetaminophen) exposure that may occur with the procedure. Our study aim was to explore at a population level the hypothesis of a relationship between paracetamol exposure and ASD. The authors of this study did point out that they did not have the individual data to explore this but in light of temporal rationale and new research we believe that confounding by paracetamol exposure is a plausible explanation for the observed associations and should be part of the discussion of these findings.

Temporal Rationale: The origins of circumcision predate recorded history, yet autism is considered a relatively new phenomenon, first recognized in 1943 and escalating in incidence, beginning in the 1980’s. History CDC.gov Volkmar FR, 2014 Assuming a significant portion of the recent increase in autism incidence is real, and not strictly a function of greater recognition, something about circumcision would have to have changed during this time period for it to be a significant causal factor in autism. It is difficult to contend that the psychological stress and physical pain related to circumcision has only occurred during the past 35 years. It can, however, be demonstrated that the techniques to manage this pain and stress have changed during this time period. Research beginning in the 1980’s documented the negative consequences associated with inadequate treatment of pain in children. Anand KJ, 1987 Mather L, 1983 Schechter NL, 2008 Prior to the 1990’s many procedures, including circumcision, were generally performed without analgesics. A 1994 study by Howard et al. found that when paracetamol was given regularly for at least the first 24-hour circumcision postoperative period, infants demonstrated decreased response to pain. Howard CR, 1994 This lead to the development of circumcision pain management guidelines by the American Academy of Pediatrics in 1999 suggesting procedures including the use of paracetamol. Anonymous, 1999 The International Evidence Based Group for Neonatal Pain, which included Danish researchers, published their consensus statement on newborn pain management in 2001. This statement suggests the use of paracetamol for postoperative pain including circumcision. Anand KJ, 2001 A perplexing finding in this Frisch and Simonsen Danish study is a statistically significant association between circumcision and the development of autism in the cohort of boys ages 0-4 (hazard ratio (HR)= 1.80, 95% CI 1.25-2.60) while only a very weak association for the boys ages 5-9 (HR=1.15, 95% CI 0.75-1.77). This finding can be explained by the paracetamol hypothesis. The boys that were 5-9 years of age would have been born in 1999 or prior and, based on the timing of guideline development, would likely not have been exposed to paracetamol with the procedure, while the younger boys would likely have received analgesia.

Paracetamol Research: Three prospective cohort studies have found an association between prenatal exposure to paracetamol and adverse neurodevelopment. Brandlistuen RE, 2013 Liew Z, 2014 Thompson JM, 2014 In addition, recent animal data has shown that cognition and behavior may be altered following exposure to therapeutic doses of paracetamol during early development. A recent review by de Fays et al. summaries these finding. de Fays L, 2015

To date, most neurodevelopmental research has focused on prenatal exposure. These findings by Frisch and Simonsen and research identifying time sensitive developmental periods surrounding birth suggest the potential importance of neonate exposure. Wang SS, 2014 Although the evidence presented here is far from conclusive, paracetamol administered along with the circumcision procedure is a plausible causal mechanism for ASD that should not be dismissed and is deserving of further investigation.

On 2015 Apr 15, Ann Z Bauer commented:

We commend Frisch and Simonsen on their high quality prospective cohort analysis on ritual circumcision and the risk of autism spectrum disorder (ASD) in young boys. As the authors acknowledge, and we are pleased to see, our ecologic analysis was part of the motivation behind the performance of this study. The finding in this cohort of 342,877 boys born between 1994 and 2003, that circumcised boys were more likely than intact boys to develop ASD before age 10 (HR=1.46, 95% CI: 1.11 -1.93) concurs with our study findings.Bauer AZ, 2013 It is, however, important to note that in our study we did not focus on the psychological consequences of the circumcision procedure as the causal ASD mechanism, rather we were using circumcision exposure as a proxy for the potential paracetamol (APAP, acetaminophen) exposure that may occur with the procedure. Our study aim was to explore at a population level the hypothesis of a relationship between paracetamol exposure and ASD. The authors of this study did point out that they did not have the individual data to explore this but in light of temporal rationale and new research we believe that confounding by paracetamol exposure is a plausible explanation for the observed associations and should be part of the discussion of these findings.

Temporal Rationale: The origins of circumcision predate recorded history, yet autism is considered a relatively new phenomenon, first recognized in 1943 and escalating in incidence, beginning in the 1980’s. History CDC.gov Volkmar FR, 2014 Assuming a significant portion of the recent increase in autism incidence is real, and not strictly a function of greater recognition, something about circumcision would have to have changed during this time period for it to be a significant causal factor in autism. It is difficult to contend that the psychological stress and physical pain related to circumcision has only occurred during the past 35 years. It can, however, be demonstrated that the techniques to manage this pain and stress have changed during this time period. Research beginning in the 1980’s documented the negative consequences associated with inadequate treatment of pain in children. Anand KJ, 1987 Mather L, 1983 Schechter NL, 2008 Prior to the 1990’s many procedures, including circumcision, were generally performed without analgesics. A 1994 study by Howard et al. found that when paracetamol was given regularly for at least the first 24-hour circumcision postoperative period, infants demonstrated decreased response to pain. Howard CR, 1994 This lead to the development of circumcision pain management guidelines by the American Academy of Pediatrics in 1999 suggesting procedures including the use of paracetamol. Anonymous, 1999 The International Evidence Based Group for Neonatal Pain, which included Danish researchers, published their consensus statement on newborn pain management in 2001. This statement suggests the use of paracetamol for postoperative pain including circumcision. Anand KJ, 2001 A perplexing finding in this Frisch and Simonsen Danish study is a statistically significant association between circumcision and the development of autism in the cohort of boys ages 0-4 (hazard ratio (HR)= 1.80, 95% CI 1.25-2.60) while only a very weak association for the boys ages 5-9 (HR=1.15, 95% CI 0.75-1.77). This finding can be explained by the paracetamol hypothesis. The boys that were 5-9 years of age would have been born in 1999 or prior and, based on the timing of guideline development, would likely not have been exposed to paracetamol with the procedure, while the younger boys would likely have received analgesia.

Paracetamol Research: Three prospective cohort studies have found an association between prenatal exposure to paracetamol and adverse neurodevelopment. Brandlistuen RE, 2013 Liew Z, 2014 Thompson JM, 2014 In addition, recent animal data has shown that cognition and behavior may be altered following exposure to therapeutic doses of paracetamol during early development. A recent review by de Fays et al. summaries these finding. de Fays L, 2015

To date, most neurodevelopmental research has focused on prenatal exposure. These findings by Frisch and Simonsen and research identifying time sensitive developmental periods surrounding birth suggest the potential importance of neonate exposure. Wang SS, 2014 Although the evidence presented here is far from conclusive, paracetamol administered along with the circumcision procedure is a plausible causal mechanism for ASD that should not be dismissed and is deserving of further investigation.