Jake H. Waskett

A 'snip' in time: what is the best age to circumcise?

BackgroundCircumcision is a common procedure, but regional and societal attitudes differ on whether there is a need for a male to be circumcised and, if so, at what age. This is an important issue for many parents, but also pediatricians, other doctors, policy makers, public health authorities, medical bodies, and males themselves.DiscussionWe show here that infancy is an optimal time for clinical circumcision because an infants low mobility facilitates the use of local anesthesia, sutures are not required, healing is quick, cosmetic outcome is usually excellent, costs are minimal, and complications are uncommon. The benefits of infant circumcision include prevention of urinary tract infections (a cause of renal scarring), reduction in risk of inflammatory foreskin conditions such as balanoposthitis, foreskin injuries, phimosis and paraphimosis. When the boy later becomes sexually active he has substantial protection against risk of HIV and other viral sexually transmitted infections such as genital herpes and oncogenic human papillomavirus, as well as penile cancer. The risk of cervical cancer in his female partner(s) is also reduced. Circumcision in adolescence or adulthood may evoke a fear of pain, penile damage or reduced sexual pleasure, even though unfounded. Time off work or school will be needed, cost is much greater, as are risks of complications, healing is slower, and stitches or tissue glue must be used.SummaryInfant circumcision is safe, simple, convenient and cost-effective. The available evidence strongly supports infancy as the optimal time for circumcision.

The Strong Protective Effect of Circumcision against Cancer of the Penis

Male circumcision protects against cancer of the penis, the invasive form of which is a devastating disease confined almost exclusively to uncircumcised men. Major etiological factors are phimosis, balanitis, and high-risk types of human papillomavirus (HPV), which are more prevalent in the glans penis and coronal sulcus covered by the foreskin, as well as on the penile shaft, of uncircumcised men. Circumcised men clear HPV infections more quickly. Phimosis (a constricted foreskin opening impeding the passage of urine) is confined to uncircumcised men, in whom balanitis (affecting 10%) is more common than in circumcised men. Each is strongly associated with risk of penile cancer. These findings have led to calls for promotion of male circumcision, especially in infancy, to help reduce the global burden of penile cancer. Even more relevant globally is protection from cervical cancer, which is 10-times more common, being much higher in women with uncircumcised male partners. Male circumcision also provides indirect protection against various other infections in women, along with direct protection for men from a number of genital tract infections, including HIV. Given that adverse consequences of medical male circumcision, especially when performed in infancy, are rare, this simple prophylactic procedure should be promoted.

Review: a critical evaluation of arguments opposing male circumcision for HIV prevention in developed countries.

Abstract A potential impediment to evidence-based policy development on medical male circumcision (MC) for HIV prevention in all countries worldwide is the uncritical acceptance by some of arguments used by opponents of this procedure. Here we evaluate recent opinion-pieces of 13 individuals opposed to MC. We find that these statements misrepresent good studies, selectively cite references, some containing fallacious information, and draw erroneous conclusions. In marked contrast, the scientific evidence shows MC to be a simple, low-risk procedure with very little or no adverse long-term effect on sexual function, sensitivity, sensation during arousal or overall satisfaction. Unscientific arguments have been recently used to drive ballot measures aimed at banning MC of minors in the USA, eliminate insurance coverage for medical MC for low-income families, and threaten large fines and incarceration for health care providers. Medical MC is a preventative health measure akin to immunisation, given its protective effect against HIV infection, genital cancers and various other conditions. Protection afforded by neonatal MC against a diversity of common medical conditions starts in infancy with urinary tract infections and extends throughout life. Besides protection in adulthood against acquiring HIV, MC also reduces morbidity and mortality from multiple other sexually transmitted infections (STIs) and genital cancers in men and their female sexual partners. It is estimated that over their lifetime one-third of uncircumcised males will suffer at least one foreskin-related medical condition. The scientific evidence indicates that medical MC is safe and effective. Its favourable risk/benefit ratio and cost/benefit support the advantages of medical MC.

CASE NUMBER AND THE FINANCIAL IMPACT OF CIRCUMCISION IN REDUCING PROSTATE CANCER

Prostate cancer risk is influenced by genetic and other factors, such as a diet high in red meat (1.3-fold increase in risk). As highlighted in various publications, including the BJU International recently [1], the risk also correlates with a history sexually transmitted infections (STIs), most consistently gonorrhoea, but also syphilis, human papillomavirus, and the recently discovered Molony murine leukaemia virus homologue XMRV. Such infections might establish in the prostate a state of chronic active inflammation, which is associated with various cancers. STIs are more common in uncircumcised men, three times more in a recent longitudinal study in New Zealand [2], which could explain why uncircumcised men have been reported to have 1.6–2.0 times the incidence of prostate cancer [3–6].

Does sexual function survey in Denmark offer any support for male circumcision having an adverse effect

In the current issue of International Journal of Epidemiology Frisch et al. extend previous research that showed ‘11% of sexually active Danish men and women fulfilled rather stringent criteria for having at least one sexual dysfunction’.1 Their new survey examined associations with male circumcision (MC).2 Of 5395 men invited to participate, 48% accepted, and 1893 uncircumcised and 203 circumcised men were interviewed, as were 40% of the 5521 female partners invited. The survey involved 12 questions related to sexual activity and function. The findings for uncircumcised and circumcised participants were largely similar, there being no difference in age at first intercourse, perceived importance of a good sex life, sexual activity with partner in the past year, frequency of sex, sexual function overall, premature ejaculation, erectile difficulties or dyspareunia (painful intercourse). The only differences found were (i) that circumcised men had a greater ‘number of sex partners since age 15’ and (ii) under ‘orgasm difficulties’ (where the options were ‘no’, ‘occasional’ or ‘frequent’), 10 of the 95 circumcised men reported ‘frequent’. The authors stated that most men, circumcised or otherwise, reported no or only occasional difficulties. A note of caution is, however, needed in interpretation of these new findings. Before explaining our reservation, it may be worth noting that under ‘Conflicts of interest’ Frisch declares his active involvement in opposition to MC. The tone of the paper accords with such a stance. The low participation rates are concerning as these can lead to self-selection bias. The statistics merit particular scrutiny. The large number of predictors in their statistical model versus the relatively small number of circumcised men with ‘frequent orgasm difficulties’ (10 circumcised) and women with ‘dyspareunia’ (n = 8) is problematic, and may indicate overfitting and, consequently, instability in the model. The study also did not correct for multiple testing. Another concern is that their use of odds ratios (ORs) as a measure of association is inappropriate if the outcome of interest is common (>10%). The prevalence risk ratio is the more appropriate measure.3,4 As an example, the authors report an odds ratio of 3.26 [95% confidence interval (95% CI) 1.15–9.27] for ‘frequent sexual function difficulties’ in women with circumcised partners (31%) compared with uncircumcised partners (22%), whereas the prevalence risk ratio is 1.41. All of the odds ratios for frequent outcomes are similarly biased, and this exaggerates the apparent associations. Without evidence, Frisch et al. argue for reduced penile sensitivity as being responsible for their findings. However, this explanation is questionable since medical MC in Denmark is only partial (CH Anderson, personal communication) and the foreskin is not removed as it is for MC in most other countries such as the USA. Thus, the men who self-reported that they were ‘circumcised’ may still have had residual foreskin tissue and its associated nerve endings. The only exception would have been the 4% who were Muslim and 2% Jewish who had religious circumcisions. In all, 89% of the circumcised men were Lutheran or not religious, i.e. were typical of a traditional Danish population. Moreover, the fact that 85% had their ‘circumcision’ after infancy is consistent with it having been performed for treatment of foreskin pathology such as phimosis (which affects ~10%—not 1%—of boys by their late teens5). Moreover, virtually all credible research,5 including clinical measurements and large randomized controlled trials (RCTs),6,7 that the authors disparage, show no difference in sensation or sensitivity during arousal as a result of MC. Their claim that ‘reduced penile sensitivity [of the circumcised penis is] supported by recent neurophysiological studies’ uses as support a flawed study funded NOCIRC in which a subsequent proper statistical analysis of the data revealed no difference.8 One of the large RCTs, moreover, found that ‘circumcised men reported increased penile sensitivity and enhanced ease of reaching orgasm’.6 If their ‘frequent orgasm difficulties’ finding were valid, a possible reason could be that the data emanate from a population in which very few men are circumcised (here 5%). Psychological factors can affect sexual function. In this regard, Frisch et al. admit that their study had limited statistical power to address ‘whether the observed associations with sexual difficulties applied particularly to neonatal circumcisions or operations performed after infancy’. A study in Sydney of men who have sex with men (MSM) noted some associations between MC and sexual difficulties only among those men who had been circumcised after infancy.9 Because of their foreskin problems and associated penile pain and/or difficulties, these men had already acquired behavioural aversions and sexual practices that meant they engaged in less penetrative sex than men who had never had penile problems. Since most of the Danish circumcised men were likely circumcised post-infancy for a medical reason, the majority of the ‘circumcised’ men in the Frisch study would likely have been previously uncircumcised men who had had a lingering medical problem that one might suspect of causing them distress. If true, as is likely, the findings argue in favour of circumcision in infancy as a prophylactic measure to prevent later medical, and associated sexual and thus psychological, problems that then require medical intervention. Research in China has, moreover, found that men with redundant prepuce or phimosis have poor mental health.10 Psychological factors were also implicated in a Swedish study that reported slight shyness in the school changing-room in 9% of boys after circumcision for medical reasons.11 Could it be that, being aware that their penis looks different from that of most other Danish men, some may suffer anxiety during sex with a fellow countrywoman unused to a circumcised penis? The findings for women are at odds with a survey in Mexico of women who had experienced sexual intercourse with the same partner before and 2 months after his circumcision.12 That study found no difference in general sexual satisfaction, pain during vaginal penetration, desire and vaginal orgasm. The findings are also at odds with data from a large RCT of MC for HIV prevention in healthy men.13 Like the men, their wives had experienced intercourse both before and after the procedure, meaning they could compare what it was like with the same man over time. The women reported either no change (57%) or improved (40%) sexual satisfaction after their male partners had been circumcised. One reason was improved genital hygiene of their male partners. The authors of the RCT concluded that MC has no deleterious effect on female sexual satisfaction, and that it might, moreover, have social benefits in addition to the established health benefits. Frisch et al. fail to point out that ‘dyspareunia’ can be due to psychological causes. This is likely to be an important factor in the context of a society in which 95% of the men are uncircumcised. So could a type of penis that the women are unused to explain in part the report of dyspareunia by 8 of the 68 (11.8%) female participants when having sexual intercourse with ‘circumcised’ men? In contrast to statements to the contrary by Frisch et al. in their paper, rather than ‘a widespread belief’, there is now strong evidence from a large meta-analysis and RCTs, as well as biological support, that indeed ‘circumcision provides superior penile hygiene and protects against urinary tract infections, phimosis, paraphimosis, balanoposthitis, venereal [sic] diseases and [genital] cancer’.5 Their claim that ‘reduced risks of balanoposthitis, sexually transmitted infections and penile cancer, can be achieved without tissue loss through the maintenance of good penile hygiene combined with proper use of condoms’ has limited or no research support. For example, phimosis, the biggest risk factor for penile cancer (OR = 12),14 is only eliminated by MC, hygiene does not reduce penile cancer risk15 and condoms offer only partial protection against oncogenic human papillomavirus,14 whereas RCT data show MC reduces HPV-related flat penile lesions by 98%.16 ‘HIV transmission in industrialized parts of the world’ is mostly from receptive anal intercourse among MSM and contaminated needles, although for heterosexual men MC offers similar protection during intercourse with an infected woman in the USA as in sub-Saharan Africa.5 Moreover, in contrast to the selectively cited outlier studies, data from multiple large populations and a meta-analysis17 suggest female partners of circumcised men may be at lower risk of HIV. The paper ends with a plea to the WHO to consider the ‘possible sexual consequences of circumcision’. The Danish study, however, provides no convincing evidence of sexual dysfunction in circumcised men given the potential self-selection bias due to low participation rates, the potential confounding by indication among the majority of men who were circumcised at older ages, and the inappropriate statistical analyses. We therefore consider that the WHO and other bodies such as the Centers for Disease Control and Prevention should have no qualms in supporting MC as a safe, effective procedure whose benefits far outweigh any immediate risks,5 and where considerable research has failed to provide convincing evidence for any adverse long-term effects on sexual function.

Errors in meta-analysis by Van Howe

Caesarean section was performed at week 38, when maternal CD4 count was 787 (25%) cells/mL and viral load undetectable. The newborn was healthy with HIV RNA below 50 copies at birth and six months later. At delivery, maternal plasma darunavir was 4350 ng/mL. The darunavir concentration in the umbilical cord was 1370 ng/mL (child-to-mother ratio: 31.5%). Generally, PIs can cross the placenta at a low level. When umbilical cord/maternal blood ratios has been performed, the ratios varied from 0% to 25% for several PIs commonly used in pregnancy. – 10 The reason for such a low transfer probably lies in their high protein-binding capacity and their large molecular size. Darunavir is 95% bound to plasma proteins (mostly a1-acid glycoprotein). The extent to which a low, but still detectable, PI plasma concentration can provide a direct protection for the newborn is uncertain, although a low level of placental passage may prevent toxic effects in the fetus. The DRV levels measured in our two umbilical cords were substantially higher than the median EC50 for wild-type virus (i.e. 0.7–5.0 ng/mL, increased by a median factor of 5.4 in the presence of human serum), although we should bear in mind that this option is considered for patients harbouring PI-resistant virus. Both our newborns were healthy and tested HIV RNA negative six months after delivery. Safety and efficacy of DRV/r in pregnancy remains undefined (Food and Drug Administration pregnancy category C), but our information can be of help in the case of women with child-bearing potential or willing to get pregnant in the presence of MDR virus and limited treatment options.

MEDICAID COVERAGE OF NEWBORN CIRCUMCISION: A HEALTH PARITY RIGHT OF THE POOR

We applaud Leibowitz et al. for describing the adverse impact on public health of the withdrawal by 16 states of Medicaid coverage for male circumcision.1 However, we are alarmed by a subsequent letter by anticircumcision lobbyists, in which the evidence regarding circumcision is thoroughly misrepresented.2 Their claims flatly contradict the bulk of the legitimate medical literature demonstrating that male circumcision protects against urinary tract infections, HIV, HSV-2, syphilis, chancroid, thrush, bacterial accumulation, human papillomavirus, penile (and possibly prostate) cancer, local inflammation (balanitis), phimosis, paraphimosis, sexual problems with age, and, in female partners, human papillomavirus, cervical cancer, HSV-2, chlamydia, and bacterial vaginosis.3 The evidence for several of these conditions now includes data from randomized controlled trials and rigorous meta-analyses. Two recent randomized controlled trials also show no adverse effect on sensitivity, sexual function, or satisfaction.4 Risks associated with medical circumcision of infants are extremely low (0.3%–0.6%) and the majority of complications are minor and easily treated.3 Moreover, this procedure remains as popular as ever in the United States, with the majority of male infants being circumcised. Green et al. display a disturbing lack of understanding of basic epidemiology. A valid test of whether circumcision protects against HIV infection or penile cancer is not by comparing rates between different countries! Moreover, the flaws in their arguments denying circumcisions protection against HIV infection have been exposed previously in a detailed 48-author commentary.5 In contrast to their claim about applicability of data from Africa to the United States, the degree of protection that circumcision affords against heterosexual HIV infection confirmed in 3 large randomized controlled trials is now observed in heterosexual men in the United States.6 This protection probably extends, moreover, to insertive anal intercourse.7 Circumcision also protects against urinary tract infections throughout life.8 The accumulated lifetime prevalence in US men is up to 14%.9 But the highest rate (1%–4%) is during infancy, where circumcision affords a 10-fold protective effect.3 This is observed consistently in the literature. Properly conducted cost-benefit analyses have indicated that, over a mans lifetime, infant circumcision provides a positive cost benefit, especially when diseases and medical problems in female partners are also considered.10 In this new political era in the United States, with its hope for better health care generally, Medicaid coverage for circumcision is a health care parity right of the poor. It must be retained by the majority of states, and must be reinstated by those states that have previously withdrawn it.

Exposé of misleading claims that male circumcision will increase HIV infections in Africa

Despite over two decades of extensive research showing that male circumcision protects against heterosexual acquisition of HIV in men, and that includes findings from large randomized controlled trials leading to acceptance by the WHO/UNAIDS and the Cochrane Committee, opponents of circumcision continue to generate specious arguments to the contrary. In a recent issue of the Journal of Public Health in Africa, Van Howe and Storms claim that male circumcision will increase HIV infections in Africa. Here we review the statements they use in support of their thesis and show that there is no scientific basis to such an assertion. We also evaluate the statistics used and show that when these data are properly analyzed the results lead to a contrary conclusion affirming the major role of male circumcision in protecting against HIV infection in Africa. Researchers, policy makers and the wider community should rely on balanced scholarship when assessing scientific evidence. We trust that our assessment may help refute the claims by Van Howe and Storms, and provide reassurance on the importance of circumcision for HIV prevention.

Re: ‘RS Van Howe, FM Hodges. The carcinogenicity of smegma: debunking a myth.’ An example of myth and mythchief making?

Editor This ‘Review’ and re-analysis of published data misrepresents sources, is statistically dubious, has fallacious reasoning, is inconsistent and contains biased statements that make it fatally flawed. The authors claim that smegma contains immunologically active compounds, but their sources largely discuss gland secretions in general, not smegma nor the prepuce. A study (their ref. 9) cited to support ‘Lytic materials, such as lysozyme,’ being present did not mention lysozyme, and the presence in smegma of ‘prostate and seminal vesicle’ secretions is speculative. The preputial mucosa is ‘completely free of lanugo hair follicles, sweat and sebaceous glands,’ and there is ‘no evidence of any glandular tissue in the subpreputial region of the penis’. Moreover, subpreputial wetness is associated with increased human immunodeficiency virus infection and balanitis. In discussing data from human studies, errors abound. For example, the number of smegma cases in their ref. 43 is 25, not 24, meaning odds ratio should be 11 (95% confidence interval, 3.7–33). By incorrectly calculating one missing data extreme for this study, they get an odds ratio of 1.6, when it is really 2.5 (95% confidence interval, 1.2–5.4). Thus, the association of penile cancer with smegma is significant, in sharp contradiction to their conclusion that it is not. Furthermore, their adjustment for phimosis by logistic regression for 95 samples that include only 29 cases is questionable. Incidentally, their expression of P-values and 95% confidence intervals to 4 or 5 significant figures when n-values of source data extend to only 1 or 2 shows statistical naïvety. The authors dismiss Maden’s findings by describing the participants as ‘poor, alcoholic, uneducated smokers with substandard and unhealthy hygienic and lifestyle practices and a history of venereal disease’ when the source provides no evidence for this being the case. Curiously, however, Van Howe and Hodges unquestioningly accept claims by O’Hara and O’Hara (their ref. 18), failing to mention that this survey admits to being comprised mostly of anti-circumcision proponents! The authors refer on six occasions to ‘pro-circumcision’ articles, ‘circumcision zealots’, and other variations. These appear to be examples of either ad hominem or special pleading. Nor are the authors neutral: one discussion of the debate notes that Van Howe ‘preferred to describe it as male genital mutilation, claiming that, just as in the female equivalent, the simple term “circumcision” did not do full descriptive justice to the horror of the procedure.’ In discussing animal studies of the carcinogenicity of smegma, the authors criticize Mayo Clinic urologists for relying upon ‘an opinion piece written by a well-known circumcision advocate’, claiming that the primary sources ‘do not exist’. In fact, the article they refer to cites Plaut and Kohn-Speyer’s 1947 study, which not only exists, but is the authors’ ref. 32. These are but some of the errors. Space limitations preclude a full list. Van Howe is, moreover, renowned for use of statistical games and misleading arguments to support his agenda. Clearly, an objective and careful literature review is required before meaningful conclusions can be drawn on this issue.