Discussion

Ritual circumcision among Danish boys is linked to an overall 46–62% increase in ASD risk in the first 10 years of life, with the upper risk estimate obtained after restriction to the period with the most complete data. More strikingly, risk was 80–83% increased in the first 0–4 years of life, an increase that was restricted to infantile autism. Non-therapeutic circumcision is uncommon in Denmark outside Jewish and Muslim communities, but due to our study’s national coverage over two decades (1994–2013), findings were based on fairly solid numbers, and a series of robustness analyses confirmed the main findings. To our knowledge, there is no prior evidence to suggest a link between circumcision and hyperactivity disorder, so our finding of an increased risk of this common neurobehavioral disorder among circumcised boys in non-Muslim families was unexpected and needs cautious interpretation. As expected, risk of asthma was independent of the boys’ foreskin status, which is in accordance with prior findings for asthma in the first years of life.24

National register-based cohort studies have a number of advantages over other study designs. Our study relied on unselected national data that have been used extensively for a multitude of research purposes. 41 We constructed a cohort of all children born in Denmark 1994–2003, and we used national data on hospital contacts and public subsidies paid to private practitioners to identify cohort members undergoing ritual circumcision in a doctor’s office or in a hospital department. We used national hospital data for ASD, hyperkinetic disorder and asthma, as well as national data on pregnancy complications and birth characteristics to evaluate potential confounding factors. Methodologically, the stratified proportional hazards regression analysis, and our ability to censor boys undergoing foreskin surgery other than ritual circumcision, ensured that our data were analysed in a prospective manner and that HRs of ASD, hyperkinetic disorder and asthma represented appropriate comparisons of risks among ritually circumcised and intact boys of same age, birth year and cultural background.

Weaknesses

Limitations with respect to the exposure variable, ritual circumcision, need careful consideration. Operations by religious circumcisers and non-Danish doctors were not covered due to lacking public surveillance of such procedures. According to Muslim authorities, circumcisions in Danish boys with Muslim parents are often done by doctors,35 and to the extent such operations took place in public hospitals or in private clinics as part of the public healthcare system in Denmark, they were included in our study. It is unknown to what extent Danish boys in families with a Muslim cultural background actually undergo ritual circumcision, but our estimate that only 10.9% of these boys were circumcised by Danish doctors before their 10th birthday appears low. Recently, Muslim authorities in Denmark explained to the National Board of Health that Muslim circumcisions are often made by private practitioners in their clinics or in the boys’ homes. One possible explanation for the apparent low overall circumcision rate in boys with a Muslim family background is that when payment occurs directly between parents and doctor, no public record will be available. The extent to which such arrangements take place, or similar ones involving non-Danish doctors or non-medical circumcisers, will determine the degree to which our 10.9% figure is an underestimate.

Among the much smaller group of Jews, the Chief Rabbi of Denmark reportedly performs all the approximately 15 orthodox Jewish circumcisions per year among boys with Jewish mothers.35 Virtually all other Jewish circumcisions in Denmark are performed by doctors and are therefore most likely included in our data.

Importantly, any influence on our HR estimates arising from this kind of misclassification of cohort member’s foreskin status, a type of misclassification that cannot plausibly depend on the boys’ future risk of ASD, will most likely be towards the null. The statistically significant associations between ritual circumcision and ASD risk emerged despite the fact that some unknown proportion of circumcised boys were incorrectly considered to be genitally intact throughout follow-up. Our HR estimates for ASD are therefore most likely conservative.

In our main analysis, we followed the cohort of boys until April 2013, although we had no data on ritual circumcisions performed by Danish doctors after 2003. As with the missing circumcisions performed by religious circumcisers, such non-differential exposure misclassification will most likely produce conservative estimates of any real difference in ASD risk between circumcised and intact boys. Reassuringly, our robustness analysis in which we restricted the observation period to 1994–2003, when ritual circumcisions and ASD outcomes were covered, revealed a stronger association of ritual circumcision with ASD risk (HR = 1.62) than in the main analysis (HR = 1.46).

Ritual circumcisions in private practitioners’ clinics were available only since 1996. Thus, boys who were circumcised in private clinics in 1994 or 1995 were inaccurately considered intact throughout follow-up. Again, any impact of such exposure misclassification would likely be non-differential, thus contributing to a conservative assessment of the link between circumcision and ASD risk. The observed 80–83% increase in ASD risk among 0- to 4-year-old circumcised boys is therefore unlikely to be an overestimate.

Limitations with respect to the outcome variables (ASD, hyperactivity disorder and asthma) also need consideration. To the extent outcomes were inaccurately or incompletely recorded in the national health registers, we might have missed some true cases, or wrongly included some irrelevant cases, as outcomes in the cohort. If outcomes were differentially under- or over-ascertained among either circumcised or intact boys within strata of cultural background, we cannot exclude the possibility of spurious results. However, we can think of no plausible mechanism through which culturally comparable boys with ASD, hyperactivity disorder or asthma would be systematically less or more likely to have their diagnoses recorded, or recorded correctly, in a manner depending on their foreskin status. Consequently, we consider potential under- or over-ascertainment problems for the outcomes likely to be non-differential, which tend to produce unaffected or conservative HR estimates. Reassuringly, 486 out of 499 ASD diagnoses (97%) in children born 1990–1999 and recorded in the Danish Psychiatric Central Register, the source of psychiatric data in the National Patient Register, were confirmed upon medical chart review.42

We lacked information about ASD and hyperkinetic disorder in the first year of life among cohort members born in 1994, because psychiatric data were only included in the National Patient Register from January 1995. However, this is an entirely theoretical concern, because the youngest case of ASD among the 57 circumcised boys with ASD was diagnosed at age 16 months, and hyperkinetic disorder is not a disease of infants either.

The way we dealt with cultural factors also needs comment. Most ritual circumcisions were in boys from Muslim families. To reduce any possible influence of cultural factors unrelated to the practice of ritual circumcision, we stratified all analyses on cultural background, using an algorithm capturing cohort members with at least one parent or grandparent born in a predominantly Muslim country. This algorithm categorised 7.8% of children in our cohort as having a likely Muslim cultural background. Applying the same algorithm to the entire Danish population on 1 January 2013, we identified a total of 243,175 Danish citizens (4.4%) as having a likely Muslim cultural background, which is in excellent agreement with the estimate of approximately 240,000 Danish Muslims calculated in a recent report by the Pew Research Center.36 Therefore, it is likely that our cultural background variable categorised most children with a Muslim family background correctly, except those exceedingly few children whose Danish-born parents converted to Islam. Consequently, by stratifying on cultural background, we controlled for unmeasured cultural factors that might otherwise have produced spurious associations between circumcision and the outcomes studied.

An additional attempt was made to examine for possible unmeasured family factors that might explain the observed excess of ASD in circumcised boys. We studied ASD risk in sisters of boys undergoing ritual circumcision, assuming that any circumcision-unrelated family factor, whether cultural or genetic, would be equally associated with ASD risk in boys and girls. ASD risk was inconspicuous in sisters of ritually circumcised boys, suggesting that family factors other than circumcision per se would not explain the observed link with ASD risk in boys.

While no firm conclusions should be drawn at this point, several lines of evidence are compatible with a possible causal role of circumcision trauma in some cases of ASD. Recently, a strong positive correlation was reported between rates of infant male circumcision and ASD prevalence, with high rates of ASD in circumcising nations such as the United States and considerably lower rates in non-circumcising countries of Western Europe.31 If circumcision-related pain and discomfort are sufficiently traumatic in some boys to be causally involved, then one would expect a lower average age at onset of ASD in countries with widespread neonatal circumcision than in countries where this practice is rare. In a study from the United Kingdom where infant circumcision is uncommon the estimated mean age at ASD diagnosis was 66 months.43 This is considerably older than the corresponding average age of 39 months in Israel where most boys are circumcised on the eighth day according to Jewish tradition.44

Recently, a hypothesis linking prolonged paracetamol exposure in utero and early life to an increased risk of ASD development has received some attention.45 So far, however, it has obtained only limited empirical support. The abovementioned study by Bauer and Kriebel, which demonstrated a strong, positive correlation between rates of neonatal circumcision and ASD, was actually carried out in an attempt to indirectly address the possible impact of paracetamol exposure in early life on ASD risk, under the questionable assumption that boys undergoing circumcision always receive paracetamol to curb the procedural or postoperative pain. Regardless of the authors’ underlying thoughts, however, the study provided clear ecological support for a link between male circumcision in early life and ASD risk.31 Unfortunately, we had no data available on analgesics or possible local anaesthetics used during ritual circumcisions in our cohort, so we were unable to address the paracetamol hypothesis directly.

A number of studies have linked obstetrical hazards to increased risk of ASD.46 Based on national register data, our findings support the likely role of such early traumatic life experiences on ASD risk. Specifically, in univariate analyses, we observed increased rates of ASD in children with low birth weight, those born before 37 weeks of gestation, those with low Apgar scores, and those born by caesarean section, all of which are associated with elevated levels of neonatal stress. Of note, however, the robustness analysis with the most parsimonious statistical model that left all birth and perinatal characteristics out of the equation, produced HRs similar to those of the main model. The observed association of foreskin status with ASD risk therefore appears to be independent of already established birth and perinatal risk factors for ASD.

Possible mechanisms linking early life pain and stress to an increased risk of neurodevelopmental, behavioral or psychological problems later in life remain incompletely conceptualised. Circumcision was found in one preliminary report to be associated with increased risk of alexithymia in adult men,47 a personality construct with reduced ability to identify and describe feelings,48 and our findings suggest that circumcision may somehow trigger the development of ASD in a small fraction of young boys. These findings obviously do not prove the suggested associations. However, in combination with recent animal studies showing lifelong deficits in stress responses following exposure to just one single neonatal insult,25 the observed strong correlation between circumcision and ASD prevalence,31 and clinical observations of long-term changes in pain perception in circumcised infants,4 our population-based findings should prompt other researchers to examine the possibility that circumcision trauma in infancy or early childhood might carry an increased risk of serious, yet hitherto unappreciated negative neurodevelopmental and psychological consequences.