Critical evaluation of arguments opposing male circumcision: A systematic review

Abstract Objective To systematically evaluate evidence against male circumcision (MC). Methods We searched PubMed, Google Scholar, EMBASE and Cochrane databases. Results Database searches retrieved 297 publications for inclusion. Bibliographies of these yielded 101 more. After evaluation we found: Claims that MC carries high risk were contradicted by low frequency of adverse events that were virtually all minor and easily treated with complete resolution. Claims that MC causes psychological harm were contradicted by studies finding no such harm. Claims that MC impairs sexual function and pleasure were contradicted by high‐quality studies finding no adverse effect. Claims disputing the medical benefits of MC were contradicted by a large body of high‐quality evidence indicating protection against a wide range of infections, dermatological conditions, and genital cancers in males and the female sexual partners of men. Risk‐benefit analyses reported that benefits exceed risks by 100‐200 to 1. To maximize benefits and minimize risks, the evidence supported early infant MC rather than arguments that the procedure should be delayed until males are old enough to decide for themselves. Claims that MC of minors is unethical were contradicted by balanced evaluations of ethical issues supporting the rights of children to be provided with low‐risk, high‐benefit interventions such as MC for better health. Expert evaluations of case‐law supported the legality of MC of minors. Other data demonstrated that early infant MC is cost‐saving to health systems. Conclusions Arguments opposing MC are supported mostly by low‐quality evidence and opinion, and are contradicted by strong scientific evidence.

The VMMC Experience Project*** * Policy is currently in the process of being updated. ** Only recommends nontherapeutic MC for "boys in high-risk populations and circumstances." *** Opposition by this group is directed at MC irrespective of age, with a particular focus on the voluntary medical male circumcision (VMMC) programs currently underway in sub-Saharan Africa.
Various individuals, certain small professional organizations and lay lobby groups (Table 1) actively discourage nontherapeutic circumcision of boys. Members adopt various tactics, including the use of social media, to influence parents, physicians, academics and others regarding MC. [8][9][10][11][12] Contradicting the AAP and CDC policy recommendations, opponents have lobbied to have MC of minors banned in the United States 13 and Scandinavian countries, although to date such efforts have not been successful. [14][15][16][17] Arguments opposing nontherapeutic MC, especially in minors, appear to start with the premise that MC has no benefits, only harms, or that any benefits only apply later in life when the male can make his own decision to get circumcised. [18][19][20][21] In this "posttruth" era, vocal minority groups consider that their opinions count more than those of medical and scientific experts. 22 These attitudes fit with a pattern of radical individualism, devaluation of scientific evidence, and promotion of autonomy, in which life-saving childhood vaccines, for example, may be refused by parents, as is their legal right, which must be respected, except when parents are not in agreement.
To help provide clarity to this vexing issue, especially given the adverse consequences to global public health and individual well-being of getting MC policy wrong, the aim of the present systematic review was to evaluate the arguments made against nontherapeutic MC (summarized in Table 2), as well as assertions by MC opponents of purported functions of the foreskin that are lost to circumcision (listed in Table 3). In particular, we examine the extent to which arguments used to oppose nontherapeutic MC are supported by current scientific evidence. In our article, benefits (and harms) of nontherapeutic MC (hereinafter referred to simply as "MC" and "EIMC") are judged according to the difference in prevalence of an adverse medical condition in those who have received MC compared with those who have not.

TA B L E 2 Common arguments used in opposing nontherapeutic MC of minors
• MC for prevention of urinary tract infections in infancy is unnecessary as these are rare, of minor consequence, and easily treated with oral antibiotics • MC causes physical harm, including a high rate of surgical complications, numerous deaths, disrupts breastfeeding, commonly results in meatal stenosis and glans keratinization • MC "pain" can result in permanent brain damage, autism, alexithymia, and post-traumatic stess disorder  with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). 24

Articles retrieved and included
PubMed searches for 2005 through 2018 yielded 12 754 "hits" (Supporting Information), with 73 more "hits" to 31 Figure 2 summarizes the search strategy in accord with the PRISMA statement. 24 Two "in press" articles by the first author were also included. In order to address a comment by one of the reviewers, four publications on vaccination were included.

Urinary tract infection
The most recent meta-analysis reported UTI incidence as 10 times lower in circumcised versus uncircumcised infant males. 25 Cumulative incidence was 0.1% versus 1%, respectively. Infant UTI has been regarded by some as rare, 19,26 although pediatric urologists consider it to be a common problem. 27  In summary, EIMC reduces the substantial risk of UTI in infancy and beyond.

Terminology
MC has been termed, "male genital mutilation," 13 a term adopted from "female genital mutilation," which has no medical benefits and is often harmful. Mutilation means damage or disfigurement. Below we examine whether this applies to MC. MC has also been referred to as "amputation," a term used in the medical literature when referring to removal of a limb, digit, or the entire penis. A belief in physical harm underlies arguments that MC presents, "intractable moral, child abuse, human rights, and ethical problems," 50 the veracity of which will be addressed in the section on ethical issues.

Immediate complications of MC and their frequency
A 2014 study by CDC researchers of 1.4 million circumcisions in the United States, based on inpatient data as well as data from more than 870 000 unique outpatient medical providers, found frequency of adverse events associated with EIMC was 0.4%. 51 Adverse events were 20 times more frequent in boys aged 1-9 years, and were 10 times higher for males aged ≥10 years in this study. Adverse events were 0.5% in neonates and 18.5 times higher in nonneonates in a recent large California study. 52 The AAP's 2012 policy statement 1 reported figures of 0.19% 53 and 0.22% 31 from two large US studies, and 0.34% from a large Israeli study. 54 The most common complications were: hemorrhage (0.08-0.18%), infection (0.06%), and injury to the penis (0.01-0.04%). 51 ." Other studies found no deaths. 59 The authors noted one death from an "at home" procedure in records of the New York City

Deaths from EIMC
Health Department in 1953, 60 but there were no deaths after 500 000 EIMCs in the United States in 1982. 61 In the mid-1940s in England, deaths during MC of boys aged 0-4 years were mostly from the types of general anesthetics used at the time. 62 In Canada, where approximately half of males are circumcised, only three deaths were attributed to EIMC 63 and three to vaccination over the period 1992-2004. 64 The report also documented 38 cases of anaphylaxis, 37 cases of convulsions, and 4 brain infections attributable to vaccination. Like EIMC, benefits of childhood vaccination greatly outweigh the risks. In comparison to deaths from EIMC, in Canada there were 43 deaths from penile cancer, 65 3708 annual deaths from prostate cancer and 443 from cervical cancer. 65 The evidence, discussed below, shows EIMC reduces risk of each of these diseases.

Breastfeeding outcomes
A longitudinal study in New Zealand found that, over the course of 4 months, there was no difference in initiation of, duration of, or stopping of breastfeeding in circumcised versus uncircumcised males. 66 Similar findings were obtained for infants from discharge to 2 weeks in a large retrospective San Diego study. 67 No significant differences in 43 mother-infant interactions during breastfeeding were found between neonatally circumcised and uncircumcised infants in a Missouri study. 68 Outcomes associated with breastfeeding, such as being less prone to gastrointestinal problems and asthma, were also unaffected. 66

Meatal stenosis (MS)
MS has been said to be a common complication of circumcision. 69 Often quoted by opponents is a prevalence of 20% reported in a small study of neonatally circumcised boys at age 5-10 years attending a pediatric clinic in Iran for other problems, the incidental MS diagnosed being asymptomatic. 70 MS data from a large Danish study 71 were further evaluated by critics, revealing a MS prevalence of 0.099% in Muslim (circumcised) males and 0.12% in non-Muslim (uncircumcised) males, of all ages combined (0-60+ years), making the condition uncommon. 72 A small US study that reported a figure of 7% in circumcised boys, that was not significantly higher than in uncircumcised boys, 73 was strongly criticized by a former chair of the AAP's infant MC policy committee. 74 In the Danish study, prevalence of other urethral stricture disease was 0.55% in Muslim and 0.82% in non-Muslim males. 71,72 In elderly men prevalence of MS was 1.9 times higher in the uncircumcised. 71 Each condition was higher in younger ethnic Danish men circumcised for medical problems compared with uncircumcised Danish men. 71 Rather than being a long-term complication of MC, 75 onset was found to occur in the first 2 months after neonatal MC, 76 but diagnosis is generally much later. 77 A recent meta-analysis of all published data from 27 studies (representing 350 MS cases amongst 1 498 536 males) found an overall summary risk estimate of 0.66% for MS in circumcised males. 78 In uncircumcised males MS gradually increases in prevalence with age, mostly as a result of penile inflammation caused by lichen sclerosis, which is much more common in uncircumcised males. 71,72,78 MS in uncircumcised males is likely underreported. 78 Correct diagnosis can, moreover, present challenges. 79 While more studies are warranted, the current data do not support MS being a major adverse effect of MC.

Glans keratinization
An argument that over time the glans of a circumcised penis becomes thickened, hardened and cornified is contradicted by histological studies comparing glans skin of circumcised and uncircumcised men. 80,81 A difference in rete ridges/pegs was, however, found in a small study, 81 but the finding could have been confounded by age. Further research is therefore needed to clarify whether there is any effect of MC on rete ridges.

"False beliefs"
In a recent survey of 902 US men by MC opponents, a satisfaction score of 3.5-3.9 out of 5 amongst 732 circumcised men was found, compared to lower scores among 170 uncircumcised men. 82 Rather than accepting the findings at face value, the authors then asserted that circumcised men held, "false beliefs concerning circumcision and the foreskin," and that, "These findings provide tentative support for the hypothesis that the lack-of-harm reported by many circumcised men ….
may be related to holding inaccurate beliefs concerning unaltered genitalia and the consequences of childhood genital modification." 82

Pain
It has been argued that pain associated with EIMC causes permanent, harmful, neurological changes in the brain. 83 As support, a small study by Taddio et al found neonatally circumcised infants exhibited a stronger pain response to vaccination at 4 or 6 months than did uncircumcised infants. 84 This finding was, however, confined to infants circumcised without anesthetic. Infants circumcised with topical local anesthesia (EMLA cream) had significantly lower pain scores at later vaccination than those circumcised without anesthetic. 84  An "after-hours" MRI brain scan of a single infant before and after circumcision without anesthesia was reported to reveal changes in parts of the brain associated with reasoning, perception, and emotion. 86 Ethical approval, logistics, and compliance with procedural guidelines were not stated. The mother was strongly opposed to MC, leading critics to question her approval for this experiment and an assertion that the online report, by an MC opponent, was a fabrication. 87 A study of 20 Jewish males in Dresden, Germany found that MC did not alter long-term limbic-hypothalamic-pituitary-adrenal axis activity, subjective stress perception, anxiety, depressiveness, physical complaints, sense of coherence, and resilience. 88 Rather, the study found that an increase in the glucocorticoid levels indicated a healthy lifestyle and appropriate functioning, concluding that the study provided evidence that MC does not promote psychological trauma. An MC opponent commented that the study was underpowered. 89 A larger confirmation study would help address this.

Cognitive ability later in life
A New Zealand longitudinal study comparing boys circumcised in 1977 or left uncircumcised found no adverse effect on cognitive ability (IQ at age 8-9 years and scholastic ability at age 13). 66 Similarly, a Swedish study of schoolboys found no adverse psychological effect of MC. 90 A longitudinal study in the United Kingdom, beginning in 1946, of more than 5000 individuals followed from birth to age 27, found no difference in developmental and behavioral indices between circumcised and uncircumcised males. 91 Taken together, these consistent findings in different populations support an absence of an effect of MC on cognitive ability.

Satisfaction and body image of boys
A study of boys aged 9-11 in San Francisco found that circumcised boys had higher satisfaction scores, in contrast to general body image, which was no different. 92

Autism spectrum disorder (ASD)
Analysis of a Danish national medical records databank led to a finding that "circumcision pain" causes ASD and hyperkinetic disorder in a study of boys aged 0-9 years circumcised before the age of 2 years. 93 Critics exposed numerous flaws in the study, pointing out that the number of cases was small, statistical significance was marginal, association was stronger in Muslim boys which might suggest a need for consideration of genetic or cultural influences, association with ASD of painful conditions more prevalent in uncircumcised boys (such as cystitis) was not examined, association with ASD diagnosis was found in boys under the age of 4 years, but not in boys aged 5-9 years, which is relevant to alternative explanations such as neuronal damage caused by analgesic usage on immature brains. 94 General anesthesia, sometimes advocated for infant MC, 95 is neurotoxic and associated with later cognitive impairment. 96 It has generally been disavowed in favor of local anesthesia. 1,97 Medications for post-EIMC analgesia-specifically, the use of acetaminophen (paracetamol), found in 1994 to be effective for management of post-EIMC pain, 98 led the AAP to recommend it. 99 In support of acetaminophen use, rather than EIMC, being responsible for the association, a US study by Bauer et al found no association of EIMC with ASD prior to 1995. 100 Unlike in older individuals, acetaminophen metabolism in immature brains generates neurotoxic by-products. Bauer criticized the Danish ASD study for falsely suggesting that her group's findings applied to EIMC. 101

Alexithymia
Alexithymia is an idiopathic personality trait characterized by difficulty identifying and describing an individual's own, or other peoples' emotions. Like many personality traits, a complex interaction of genetics and environment is generally postulated to be responsible.
It has been argued that early trauma, such as pain from EIMC (presumably when performed contrary to recommendations to use local anesthesia), affects the brain, leading to alexithymia. 108 Research support for the hypothesis was provided in a study involving subjects recruited by advertisements on an anti-MC website. 108 Psychiatric problems appeared to be more common in men unhappy at having been circumcised. 109 Body dysmorphic disorder has been linked to alexithymia. 110 Consistent with bias in the small self-selected sample, the overall rate of alexithymia was over 3 times higher than seen in the general population. 111 There was, moreover, no association between TA B L E 4 Quality rating 23 of published studies that have shown negligible physical and psychological effects of MC and studies claiming a detrimental effect

Rating
Detrimental effect

2-
Frisch et al, 135 Frisch & Simonsen, 71  There is strong empirical support for alexithymia being a stable personality trait rather than simply a consequence of psychological distress. 113 A large survey evaluating a comprehensive array of emotional problems in preschool 114 and in 6-to 16-year-old 115 children from 24 different societies found differences in severity of these between countries, irrespective of MC prevalence in each. While some, but not all, 116 studies have shown that men exhibit higher alexithymia scores than women, the difference is seen in countries with divergent MC rates. 111

Psychological trauma
An unpublished study in 2000 claimed MC was associated with posttraumatic stress disorder. 117 This was contradicted by the survey above. 108 We found no studies to support other MC trauma-related claims. 118

Conclusion
Studies listed in Table 4 reporting negligible adverse effect of MC on physical or psychological outcomes compare favorably with those reporting an adverse effect.

Sexual function
All systematic reviews of relevant research studies rated by quality found no harmful effect. [119][120][121][122] One systematic review included data from 19 542 uncircumcised and 20 931 circumcised men. 119 The key finding was that MC had no adverse effect on sexual function, including erectile function, premature ejaculation, ejaculatory latency, orgasm difficulties, and pain during penetration. Evaluations by researchers in China 120,121 and Denmark, 122 where MC is uncommon, found the same. The findings were, moreover, supported by meta-analyses of each sexual dysfunction. 120,121 The most recent of these found pain during intercourse was 64% more common in uncircumcised males, and that that erectile dysfunction was significantly less common in circumcised men. 121 A UK study of 6293 men and 8869 women added further support. 123 A case-control study in Kenya found that circumcised men reported less pain during sexual intercourse than uncircumcised control men during 2 years of follow-up. 124 Other aspects of sexual function did not differ between circumcised and uncircumcised men. Included in each review were 2 RCTs, 125,126 which are regarded as high-quality evidence. 23 Each RCT found no adverse effect on any aspect of sexual function by the 2-year post-MC follow-up point. Coital injuries were significantly lower in circumcised men. [127][128][129] Sexual dysfunction is common in men. 130 There is now strong evidence that MC is not responsible, as we will present below.

Sexual pleasure
Several studies concluded that MC diminishes sexual pleasure for men and their female sexual partners. [131][132][133][134][135][136][137] Evaluation of these identified multiple flaws. 119,[138][139][140][141][142][143][144] Other studies, [145][146][147][148] including RCTs, [125][126][127]149 found MC had no adverse effect. In fact, the RCTs found a net increase in sexual pleasure in men and their female partners. The reasons given by women for favoring MC were also esthetics, vaginal penetration, hygiene, and reduced infection risk. 149 A systematic review of all 29 relevant publications found the same, 150 as did a smaller systematic review. 151 A list of "16 functions of the foreskin" 152 (Table 3) compiled by opponents, and widely circulated on the Internet will now be evaluated in relation to data, when available, there being no evidence to assess the veracity of some of the claims.
It has been argued that the foreskin contains "10 000" or "20 000" nerve endings essential for sexual pleasure. The "10 000" figure (specif- age. 158 Amongst these were 2 fine-touch receptors, but no genital corpuscles that have been invoked as the nerve endings responsible for erogenous sensations. 143 To arrive at "20 000," 212 would need to be multiplied by 94 160 Those measurements showed that foreskin size is highly variable, very much more so than penis length. 161 Darwin noted, "An organ, when rendered useless, may well be variable, for its variations cannot be checked by natural selection." 162 We could find no evidence to support the claim of pheromones being present in the foreskin. 163 It has been postulated that, "In heterosexual intercourse, the nonabrasive gliding of the [uncircumcised] penis in and out of itself within the vagina facilitates smooth and pleasurable intercourse for both partners," meaning easier penetration, nerve stimulation and prevention of loss of vaginal lubricant. 164 No gliding would, however, occur for men with short foreskins. We could find no studies investigating this proposed phenomenon in men or their sexual partners. The purported lubrication provided by "gliding" should reduce pain during intercourse (dyspareunia). However, most studies reported either no difference or less pain in circumcised men, [119][120][121][122][124][125][126][127]165 and their female sexual partners 149,150 (Table 5). Contrary claims appeared to be based on speculation, anecdotes, or low-quality studies. 166,167 Further information addressing the "16 functions" is available. 168

Data from high-quality studies
Two high-quality studies, a RCT in Kenya 126 and a cohort study in the Caribbean, 127 found that most sexually experienced men reported improved sexual pleasure and function after circumcision. A meticulously conducted systematic review of all studies found that, over-all, MC had no adverse effect on penile sensitivity, sexual arousal, sexual sensation, or pleasure. 119 Criticisms of that study 137 were shown to lack merit. 142 The findings were consistent with a systematic review of histological correlates of sexual sensation showing that the sensory receptors responsible for sexual pleasure (genital corpuscles) reside in the glans, not the foreskin, meaning loss of the foreskin by MC should not diminish sexual pleasure. 143 By exposing the glans, as often occurs in an uncircumcised man during erection, MC was proposed to increase sexual pleasure. 143 The foreskin, just as other skin on the body, contains sensory receptors that respond to touch, temperature and pain. Since the density of Meissner's corpuscles in the foreskin diminishes at puberty when male sexual activity is increasing, these touch receptors are unlikely to be involved in sexual sensation. 143 Moreover, free nerve endings (that respond to touch) showed no correlation with sexual response. Sensitivity of the glans to touch decreased with sexual arousal, so further diminishing a role for touch receptors in sexual sensation. 169 Sensitivity of the penis to vibration, which is able to elicit arousal and ejaculation, is not related to MC status. 143

"Foreskin restoration"
This undertaking involves stretching the skin on the shaft of the circumcised penis using weights. Various psychological disorders 170,171 were found to be more prevalent in circumcised men preoccupied with their absent foreskin. 109 Such men were more likely to undertake "foreskin restoration," which was found to occasionally require subsequent "re-circumcision" 172,173 or medical attention for resulting genital mutilation. 172,174

Conclusion
As summarized in Table 6, high-quality research shows that MC has no adverse effect on sexual function, sensitivity, or pleasure. This finding contradicts arguments based on low-quality evidence.  120 Nordstrom et al, 124 Kigozi et al, 125,149 Krieger et al 126

HIV infection in women
Based on data from two studies, 243,244 it was argued that MC increases women's HIV infection risk. In the Rwanda study, women with higher HIV-positivity were from higher socioeconomic groups 243 in which MC is more common, as is promiscuity. Cross-infection from unhygienic traditional MC may also have contributed. 245 The Uganda study found that 17 women in the intervention group (18%) and 8 (12%) in the control group acquired HIV during follow-up (P = .04). The marginally higher HIV infection in the female partners of men who had been circumcised was limited to women whose male partner disobeyed medical advice and resumed sexual intercourse prior to the end of the 6-week post-MC wound-healing period. 244 254 Detailed evaluation of that article revealed serious flaws in statistical analyses, as well as obfuscation and misrepresentation of data. 255 The author, Robert Van Howe, has a history of analyses of MC and other STIs 254,256-258 that have been shown to contain serious analytical and evidential flaws. 255,259,260 The following summarizes the high-quality evidence addressing the role of MC in protecting against various specific STIs.

Oncogenic human papillomavirus (HPV) genotypes
A recent meta-analysis of 30 studies found MC was strongly associated with reduced odds of genital HPV prevalence (OR 0.68; 95% CI 0.56-0.82). 261 That meta-analysis treated all study types equally. Risk reduction was 53-65% in 2 earlier meta-analyses and 40% in 6 RCTs. [262][263][264][265][266][267] (See also recent risk-benefit analyses 268 MC also protects against low-risk (nononcogenic) HPV types responsible for genital warts. 272 These HPV types infect the shaft and genital area generally, whereas high-risk types mostly infect the foreskin and underlying glans. 272 274 The metaanalysis cited above conceded that, "sampling sites also played an important role in the final results" and that, "selection bias in our meta-analysis" (ie, not taking into account penile sites used for sampling) affected the conclusions. 261 Use of a single combined sample for the penis and scrotum was the likely explanation for a negative result in one study. 275 Foreskin HPV infection is significantly higher in men with phimosis. 276 In summary, MC reduces penile infection by, and increases clearance of, high-risk HPV genotypes.

Protection of men against other STIs
As documented in a critical review, 255 RCTs and other studies have found MC affords protection against Trichomonas vaginalis (50%), 282 Mycoplasma genitalium (40%), 283 Treponema pallidum (syphilis) (33-50%), 281,284,285 chancroid (50%), 281 and genital ulcer disease (50%). 286,287 Genital ulcers in uncircumcised men contain a higher prevalence of anaerobic bacteria. RCT data showed that MC reduces total bacterial load and microbiota biodiversity. 49 A RCT found no syphilis infections in the 24 months after MC compared with 9.6% in men who remained uncircumcised (P = .09). 232 Although RCT data by Tobian et al failed to find a reduction in syphilis, this might have reflected lack of statistical power due to the small number of syphilis infections identified on follow-up testing. 288 Tobian, in an editorial covering another large study that found 42% lower syphilis in circumcised men, 284 acknowledged that MC does reduce syphilis risk. 289 Arguments disputing the use of MC for syphilis risk reduction 290 have been criticized as flawed. 219 Data show that MC does not protect men against sexually transmitted urethritis. 260

Protection against STIs in women
Findings on the impact of MC on STIs in women are mixed. At the very least, it should be obvious that any measure that reduces risk to the male partner of being infected should reduce STI prevalence in women.
Below we summarize available data.
In women, high-risk HPV infection may cause cervical dysplasia that can progress to cervical cancer. High-risk HPV also contributes to other genital cancers and to oropharyngeal cancers. Over her lifetime, a woman may have sexual partners of either MC status, potentially confounding associations between male partner MC status and a woman's HPV risk. This issue was addressed in a large multinational study, in which confounding was minimized by restricting the analysis to 1420 men whose female partner reported having had only a single sexual partner. 270 The men were rated for their "sexual-behavior risk  297 Similarly, a RCT found 2-fold higher HSV-2 infection over 12 months in 783 wives of uncircumcised men. 298 Secondary data from another RCT found HSV-2 was the primary pathogen in 96% of the 67% of genital ulcers in the female partners in whom an etiological agent had been identified. 299 Most participants had been infected with HSV-2 prior to commencement of the trial and HSV-2 detected in these women represented mostly reactivation of preexisting infection.
Chlamydia trachomatis seropositivity in a large, multinational study was 5.6-fold higher in women with an uncircumcised male partner. 300 The finding also applied to women who had only had one sexual part- HIV, high-risk HPV, nonspecific genital ulcers, trichomonas, and vaginal discharge that rendered the latter low consistency. More information was presented in an editorial. 303 Another recent systematic review identified 82 studies of MC and STI in women, leading to similar conclusions. 248 Clearly, reduced population prevalence of STIs in men will translate into lower risk of STI exposure in women.

Protection against other STIs in MSM
A study in 2012 found that MC provided 57% protection against the major oncogenic HPV type, HPV16, in Australian MSM who practiced predominantly insertive anal intercourse. 304

Conclusion
As summarized in Table 7, high-quality data show that MC protects against risk of HIV and various other STIs.

Condoms for protection against STIs
It has been argued that condoms afford complete protection against HIV and other STIs, so obviating the need for MC. 69 194 Bailey et al, 195 Gray et al, 196 Siegfried et al 198 1+ Weiss et al, 197 Morris et al, 221 Lei et al, 225 Sharma et al, 226 Freeman et al, 233 Weiss et al, 246 Wiysonge et al, 250 Yuan et al 251 2++ Morris et al, 220 Gray et al, 232 Boily et al 223,234

Rating
Studies disputing the protective effect of MC 2-Van Howe 175,191,192 Other STIs

2-Van Howe 254,256-258
results" for HIV prevention. 309 That study did, however, find that condoms were 42% effective in prevention of syphilis infection. 309 Unlike condoms, MC is a one-off procedure that does not require future compliance each time a man has sexual intercourse. In this respect MC can be compared with vaccination. However, besides the hepatitis B vaccine, the only vaccines currently in widespread use (in early high school females and increasingly in males) for STI prevention are those that protect against certain HPV genotypes. MC and condom use each provide a reasonable degree of protection against STIs. When both are in place protection is higher. 56

Delay of MC until males become sexually active
It has been argued that MC be delayed to allow the male to decide if he wishes to reduce his risk by choosing to get circumcised when he is old enough to be sexually active. 310,311 Substantial problems with this argument have been enunciated 312 (Table 8). First, MC has other benefits besides STI prevention and these benefits start early in life (see UTIs section above and inflammatory skin conditions and physical problems sections below). The benefit-to-risk ratio from EIMC is high and has increased over the years as more evidence has accumulated 268,269,[312][313][314][315][316] (Table 9). Second, EIMC is simpler, quicker, less expensive, with lower risk of complications, 51 healing is faster, and the scar can be almost invisible. 312 Third, there are substantial barriers to later circumcision. 312 These barriers include the decision process, peer pressure, affordability, slower healing, pain during nocturnal erections, the need to abstain from sexual activity for ∼6 weeks, and a visible scar afterwards. The sexual abstinence period is often cited by men as a significant barrier, so favoring EIMC as the preferred time. 317 Because these barriers deter many men from getting circumcised a much higher uptake of MC can be achieved for EIMC. 318 An argument that infant MC should be banned, discouraged, or at least delayed until the boy is old enough to decide for himself [18][19][20]319,320 was refuted by authorities in ethics, who have presented sound reasons why such reasoning is flawed. [321][322][323][324][325][326][327] . It was argued that being circumcised boosts autonomy more than constraining it. 328 The AAP recommended that prior to or early in a pregnancy the medical practitioner should provide parents with unbiased education about risks and benefits of EIMC so they have adequate opportunity to choose what is in their child's best interests should they have a boy. 1 Furthermore, MC later in life is not only associated with a 10-to 20-fold higher risk of adverse events, 51 but, as explained above, having MC performed later poses significant barriers to adolescent boys and men that usually mean MC will not happen, except for a medical reason. 312

Penile inflammatory conditions and treatment
There has been a trend away from MC and toward use of steroid creams for treatment of phimosis and penile inflammation. 329 This approach is not ideal. 330,331 Commitment is needed for regular application, there is a risk of side effects from long-term use of steroids, and effectiveness of 2 (range 1-23) months' treatment was only 35% during 4 (range 1.5-60) months' follow-up in a recent meta-analysis of the very serious foreskin-related inflammatory condition, lichen sclerosus. 331 In contrast, MC is close to 100% effective. 332 Preputioplasty can also be used, but is less effective as a cure than MC, and serves to accommodate the wishes of those patients who want to preserve their foreskin. 333 Phimosis, balanitis, and candidiasis can occur alone, or can cooccur. A meta-analysis found 68% lower balanitis rates in circumcised males. 334 Penile candidiasis was reported in 7.7% of uncircumcised men versus 4.9% of circumcised men in a large Australian survey. 335 In boys aged 8 months to 18 years (mean 6.4 years), the prevalence of fungal infection was 44% in uncircumcised boys versus 18% in circumcised boys. 336 The fungal species were, in order of decreasing prevalence: Malassezia globosa, M. furfur, M. slooffiae, C. albicans, C. tropicalis, and C. parapsilosis. Each was present in uncircumcised infants, but none were present in circumcised infants. A gradual accumulation with age occurred, by age 18 years reaching 62.5% in uncircumcised boys versus 37.5% in circumcised boys. Recently, a strong direct link has been found between C. albicans antibodies and schizophrenia in men, independent of potential confounders. 337

Penile cancer
Despite strong evidence for MC, especially EIMC, conferring protection against penile cancer, contrary arguments have been presented. 26,338,339 Those arguments have been criticized. [340][341][342] For example, it has been stated that because penile cancer diagnosis in men is 1 in 100 000 the disease is very rare. This figure is, however, an approximation of the annual incidence. The more relevant figure is lifetime risk, which is approximately 1 in 1000 for an uncircumcised man. 343 This would make penile cancer uncommon, but not rare. Its prevalence in circumcised men, of 1 in 50 000 to 1 in 12 000 000, 344,345 might be considered rare. A California study found that uncircumcised men had a 22-fold higher risk. 346 The reason why uncircumcised men are at elevated risk stems from foreskin-related conditions, most prominently phimosis, which was shown in a meta-analysis to increase the risk 12-fold. 334 EIMC eliminates lifetime risk of phimosis. Metaanalyses found that balanitis increases penile cancer risk 3.8-fold and smegma (a whitish film that accumulates under the foreskin of men and that comprises dead and decomposing exfoliated skin cells, bacteria, and other microorganisms) increases penile cancer risk 3.0-fold. 334 Penile inflammatory conditions are much more common in uncircumcised men. 330 A meta-analysis found 47% of penile cancers are positive for high-risk HPV genotypes. 347 Since HPV genotypes prevented by current HPV vaccines constitute approximately 70% of population prevalence of all high-risk HPV genotypes, one might predict that HPV vaccination would offer the potential to reduce penile cancer by up to 47 × 0.7 = 33%. This level of risk reduction is similar to that conferred by MC in a meta-analysis 261 and RCTs. [262][263][264][265][266][267] An early concern was that, over time, nonvaccine HPV genotypes might replace vaccine genotypes. 348 There is now evidence for this. Eight years after introduction of the HPV vaccination program for girls in Australia, prevalence of HPV 16 and 18 decreased in heterosexual men from 13% to 3% (P < .0001). 349 But there was no decrease in HPV genotypes overall, and, "prevalence of nonvaccine-targeted genotypes" increased from 16% to 22% (P < .0001). 349 A combination of public health measures is normally advocated for disease prevention.

Prostate cancer
Prostate cancer affects ≥10% of men over the lifetime. A 2015 metaanalysis found that, after reducing heterogeneity by removing outlier studies, prostate cancer risk was significantly lower in circumcised men, especially in the post-PSA testing era (P = .01). 350 In men of African descent, large US 351 and Canadian 352 studies showed risk reductions of up to 36% (95% CI 8-61) and 60% (95% CI 0.19-0.86), respectively. MC prevalence worldwide is inversely correlated with prostate cancer incidence. 353 Countries with high MC prevalence have lower prostate cancer-related mortality, corrected for potential confounding factors. 354 The risk reduction associated with MC is on a par with other commonly recognized factors associated with decreased prostate cancer risk. 355,356

Ethical and legal issues
Legal, human rights and other arguments (presented below) have been invoked in opposing EIMC. 26 Scholarly assessments concluded that MC of minors is ethical. 321,323,324,326,327,371,381 Given the wide-ranging protection against multiple medical conditions and infections in infancy and childhood, including STIs in adolescents who become sexually active, it was argued that it would be unethical to leave boys uncircumcised. 323,371 It was argued that Article 24 (3)  It has been pointed out that, unlike EIMC, it is not the practice to routinely cut off ear lobes and breast buds to prevent future cancers or to remove the appendix to prevent appendicitis. 21 The fallacy of false equivalence was invoked in disputing the argument. 385,386 It was pointed out that the breast is a body part with an important function.
In contrast to MC, none of the other proposed prophylactic interventions would come close to the outcome of risk-benefit (Table 9) or costbenefit analyses obtained for EIMC.
Another example we found was associating MC with female genital cutting/mutilation, the more extreme forms of which cause severe harm. The closest female equivalent of MC, clitoral hoodectomy, was introduced in the 1950s for women with an excessive or phimotic clitoral foreskin. 387,388 In a sexual dysfunction clinic in Boston, severity of clitoral phimosis was associated with increased likelihood of anorgasmia. 389 We could find no recent evidence for clitoral hoodectomy to treat anorgasmia, but did find a recent study for treatment of severe clitoral phimosis and lichen sclerosus, that resulted in a significant increase in the patients' Female Sexual Function Index Score. 390 There is no scientific reason to equate the strong arguments favoring MC because of its multiple medical benefits with female genital mutilation or other genital procedures devoid of proven medical benefits, which would include labioplasty in high-income countries to improve cosmesis.

Genetic fallacy
Historical anecdotes, such as a belief by some in Victorian times that MC could be used to cure masturbation, have been used by opponents to dismiss MC. 391 It has been suggested that irritation from balanitis, smegma, and infections could cause an uncircumcised boy to touch his penis, leading to stimulation and masturbation, behaviors frowned on in Victorian times. 392,393 A major 1913 textbook that expressed disdain for masturbation, made no mention of MC as a "cure." 394 MC is an ancient practice. 395,396 Evidence of MC in Europe during the Upper Paleolithic era (38 000-11 000 BCE) was found in portable art and rock art at that time. 395 It was suggested that the practice of MC may have accompanied the radiation of Homo sapiens out of Africa 396 ∼220 000 years ago. 397 It has further been suggested that privation and other forces explain why MC subsequently ceased in some cultures. 396 In Victorian times, health benefits, such as protection against syphilis, 398 balanitis, inferior hygiene, and phimosis, 399,400 have been used to explain why MC became popular in Anglophone countries. 396 MC is common in diverse cultures globally. 401 Ancient practices such as MC and hand-washing may have stemmed from disease prevention measures. Over time these may have been subsumed into religious custom. 396 The reasons humans might have had for MC hundreds or thousands of years ago can nevertheless be separated from the reasons for medical MC in contemporary society, the latter being based on sound scientific evidence described above, this being independent of earlier reasons.

Cost effectiveness
In the United States, a downturn in MC prevalence has been attributed to weak pediatric policy statements prior to 2012, increased immigration from countries in which MC is less common, a reduction in access and affordability, and lobbying by organizations opposed to MC. 316  States. US studies show that, in the long-term, costs will be substantially higher because of the need for later, more expensive, medically indicated MC, 240,[402][403][404][405] which carries a 10-to 20-fold higher risk of an adverse event, 51 and for treatment of a wide array of conditions that EIMC protects against. 240,370,[402][403][404][405][406][407]

US and non-US policies
Affirmative MC statements arose from reviews by the AAP 2012 1,2 and CDC. 3 Although the Canadian Pediatric Society (CPS) produced a position statement in 2015, it only recommended MC for males in high-risk situations. 7 Its recommendations stemmed from a faulty risk-benefit analysis that was subsequently performed correctly by critics. 268 The CPS responded to the criticisms, 63 but their response was also seriously flawed. 414 Current policies in other countries are negative and out-of-date.

Limitations
A limitation of this study is that many arguments opposing MC are absent from the scientific literature, but are popular on anti-MC TA B L E 1 0 PRISMA-required summary of the key publications on each topic cited in this systematic review

CPS policy on EIMC
Sorokan et al 2015 7 Morris et al 2016 268 Robinson et al 2017 63 Morris et al 2017 414 websites and social media. Searching only publication databases will miss these. We addressed this limitation to some extent by examining the "16 functions of the foreskin" meme (Table 3), which is particularly popular, as an Internet search will show. Some others are mentioned where they are relevant to published claims. But others will, inevitably, be overlooked as our review gave priority to published claims, these being the ones more likely to be influential to health care professionals.
Not being in the peer-reviewed scientific literature necessarily reduces the credibility of certain claims. It is to be hoped that health care professionals at least should be wary of claims that are not supported by scientific evidence published in reputable journals.
Another limitation is that the degree of benefit over the long-term may be higher than evident from age-restricted or short-term studies.
For example, early studies of UTIs in infancy found MC conferred a 10-fold risk reduction, but only 1% of uncircumcised males were diagnosed with a UTI in the first year of life, whereas inclusion of data for older children and men found the ongoing risk reduction conferred by MC meant overall lifetime risk reduction was 4-fold, but the proportion of uncircumcised males experiencing a UTI over their lifetime was 32% compared with 8.8% for circumcised males. 25 Long-term follow-up of the three MC and VMMC RCTs have shown a continuation of level of effectiveness of approximately 60% in two of these, 203,425 and an increase in effectiveness in another RCT to 73%. 426 Thus, with larger and wider studies we expect the data will continue to consolidate and may show an increase in the strength of the protective effect conferred by MC.
The specific focus of our evaluation is another potential limitation. The purpose of our systematic review was to assess the scientific and medical data, including data on sexual function. We did not address psychosocial, religious, or emotional arguments that might be posed. Nor did we address local or regional factors, MC practice in developed countries versus developing countries, or Muslims versus others.

CONCLUSIONS AND IMPLICATIONS
The present systematic review has contrasted evidence used to argue against MC with evidence from RCTs, systematic reviews, and metaanalyses, in particular, that has demonstrated the multiple medical and health benefits and low risk of MC to males 269,316,427 and their female sexual partners. 249,303 The key publications forming the framework of the present systematic review are provided in Table 10, as required by PRISMA guidelines. We find that, based on the evidence rated by quality, MC, especially when performed in early infancy, is favored.
One should be aware of confirmation bias and asymmetric The present systematic review should help prioritize the best scientific evidence when it comes to MC, especially EIMC, as an important public health issue worldwide. It should also provide a useful resource for those confronted with contrary information.

ADDENDUM
The authors wish to draw the attention of readers to a recent critique of Hammond and Carmack 431 by Bailis and co-workers. 432

AUTHOR CONTRIBUTIONS
BM, SM, and JK contributed equally to the work. BM conceptualized and designed the review. BM and SM carried out the analysis. BM drafted the initial manuscript. SM and JK further evaluated the data and made substantial contributions to successive drafts. All authors reviewed and approved the final manuscript as submitted.

CONFLICTS OF INTEREST
The first author is a member of the Circumcision Academy of Australia, a not-for-profit, government registered, medical association that provides evidence-based information on male circumcision to parents, practitioners and others, as well as contact details of doctors who perform the procedure. The second author is an editor for CircFacts.org.
The third author provided advice and supported the legal help to University of Washington for the patenting of a circumcision device. He did not receive any income from this. The authors have no religious or other affiliations that might influence the topic of MC.