Tuesday, April 21, 2009

Does male circumcision protect against syphilis?

Circumcision has been shown to reduce the risk of men contracting several sexually transmitted infections (STIs). Three randomized controlled trials (RCTs) published over the last few years have demonstrated that removing the foreskin of adult men diminished the risk of HIV infection by at least 50%. An article by Tobian and colleagues in last week's issue of the New England Journal of Medicine revealed a weak protective effect of circumcision against two other infections, herpes simplex virus 2 (HSV-2) and human papilloma virus (HPV), which cause genital herpes and penile warts, respectively. The same study showed no effect of circumcision on acquisition of Treponema pallidum, the agent of syphilis. You can find a nice critical analysis of the study here. Because I am interested in diseases caused by spirochetes, I will focus on the syphilis data.

Tobian et al. conducted two RCTs with similar designs. When the data were combined, they found that 50 of 2083 (2.4%) male adolescents and adults in Uganda who underwent circumcision became infected with T. pallidum over the following 24 month period. Similarly, 45 of 2143 (2.1%) control subjects became infected within the same time period, suggesting that circumcision had no effect on contracting T. pallidum. An editorial in the same journal issue points out that the study may have been underpowered to detect a protective effect (i.e., not enough subjects in the study).

Since the Tobian et al. study failed to give a simple answer to the question, I thought it would be illuminating to look at the older observational studies that examined the effects of male circumcision on syphilis transmission. Fortunately, I found a meta-analysis that compiled data from 14 research papers, most of which described cross-sectional studies.

The meta-analysis presented by Weiss and colleagues revealed a slight protective effect of male circumcision. The relative risks (RRs) along with the 95% confidence intervals (CI) are plotted in the graph. The RR in 11 of the 14 studies were adjusted for potential confounding factors such as age. The summary statistics listed at the bottom of the graph indicate a small protective effect (summary RR, 0.67; 95% CI, 0.54-0.83).

Ideally, all studies included in a meta-analysis would have similar RRs. However, if you look carefully at the graph, you will notice a wide variation in the RRs with some of the 95% confidence intervals failing to overlap. Using standard statistical calculations, the investigators determined that it was unlikely that the variation of the RR among the studies was due to chance (P = 0.01). In other words, differences in how the studies were designed and conducted led to significant variation in the outcomes. Consequently, the authors declared that there was significant heterogeneity among the studies and warned that the summary RR "should be interpreted cautiously."

The authors described one potential source of the heterogeneity. Looking at the plots again, you will note that the Cook and Parker studies demonstrated the largest statistically significant protective effect of male circumcision. Those two studies were conducted in the United States and Australia, respectively, where males are circumcised as infants. In contrast, the two largest studies, authored by Gray and Urassa, showed no effect of circumcision on the risk of becoming infected with T. pallidum. Those studies were conducted in Uganda and Tanzania, respectively, where males are not circumcised until they are adolescents or young adults. Many of the circumcised males examined in the two African studies, which were cross-sectional and case-control studies, could have contracted syphilis before being circumcised. Weiss et al. excluded subjects who were circumcised after their first sexual intercourse or after age eleven, but this information was not available for all studies. This would lead to an underestimate of the protective effects of circumcision.

You may look at the large protective effects of infant circumcision observed in the U.S. and Australian studies (RR = 0.25 and 0.19, respectively) and conclude that mass infant circumcision would be beneficial (at least for protection against syphilis). However, both studies involved men visiting STD clinics, and the results may not apply to the general population in those countries.


Tobian, A.A.R., Serwadda, D., Quinn, T.C., Kigozi, G., Gravitt, P.E., Laeyendecker, O., Charvat, B., Ssempijja, V., Riedesel, M., Oliver, A.E., Nowak, R.G., Moulton, L.H., Chen M.Z., Reynolds, S.J., Wawer, M.J., Gray, R.H. (2009). Male circumcision for the prevention of HSV-2 and HPV infections and syphilis. The New England Journal of Medicine 360(13):1298-1309.

Golden M.R. and Wasserheit, J.N. (2009) Prevention of viral sexually transmitted infections--foreskin at the forefront (Editorial). The New England Journal of Medicine 360(13):1349-1350.

Weiss, H.A., Thomas, S.L., Munabi, S.K., and Hayes, R.J. (2006). Male circumcision and risk of syphilis, chancroid, and genital herpes: a systematic review and meta-analysis. Sexually Transmitted Infections 82(2):101-109.

1 comment:

  1. Is Neonatal Circumcision Clinically Beneficial? Argument Against

    Robert S. Van Howe

    Nat Clin Pract Urol. 2009;6(2):74-75. ©2009 Nature Publishing Group
    Posted 03/26/2009

    Clinical benefit is only one facet of clinical decision making; medical risks and financial costs also need to be considered. For example, many of the benefits espoused by advocates of circumcision would be more effectively achieved by penectomy, which has the additional benefit of preventing unwanted pregnancies. Of course, penectomy is too invasive, and is not a practical solution. Many of the "clinical benefits" lauded by advocates of circumcision include reduced risk of phimosis, balanitis, urinary tract infections (UTIs), genital cancer and sexually transmitted infections (STIs); however, evidence for these benefits are weak or nonexistent, and several alternatives to circumcision are available that are more effective, less invasive, and less expensive.

    Phimosis is as common in circumcised newborns as it is in boys who are not circumcised. Topical steroids are effective in approximately 85% of patients,[1] and could eliminate the need for newborn circumcision to avoid phimosis. Balanitis is more common in circumcised than uncircumcised boys under age 3 years, but may be more common in uncircumcised older boys. The only published adult study of balanitis showed that a referral bias occurred among circumcised men: the control group had a 47.8% circumcision rate,[2] but the participants were from the UK, where the circumcision rate is around 21%. Balanitis can typically be treated with topical antimicrobials.

    Newborn boys are more likely to have urinary tract abnormalities compared with girls, particularly in the first 6 months of life; however, many boys later outgrow these abnormalities. Observational studies have found that uncircumcised boys are at increased risk of UTIs during the first 6 months, but this finding might be a result of differential rates of prematurity, urine collection, false-positive urine specimens, and the frequency at which health care is sought.[3] In the absence of anatomic defects, UTIs do not require surgery and can be treated with oral antibiotics. The risk of UTI resulting in chronic renal disease is remote.

    Of the 16 studies that assessed whether an association exists between circumcision status and the risk of cervical cancer in female partners, only 1 study found a significant association: a positive association in 1 study out of 16 studies is what would be expected by chance alone. Furthermore, a newly available vaccine against human papillomavirus (HPV) could prevent most cases of cervical cancer. With regard to a reduced prostate cancer risk after circumcision, the medical evidence that supports this association is weak.[4] The incidence of penile cancer is rare (0.8 cases per 100,000); two case–control studies in the US found that, when adjusted for phimosis, newborn circumcision was not associated with penile cancer.[5,6] The association between phimosis and penile cancer might explain why only half of patients with penile cancers are positive for HPV DNA, whereas nearly all patients with cervical cancer have HPV DNA. The other half of patients with penile cancer are probably associated with balanitis xerotica obliterans, the leading cause of true phimosis. Countries with very low circumcision rates, such as Japan, Norway, Finland and Denmark, have a lower age-adjusted incidence of penile cancer than the US. Low-risk sexual practices combined with screening and treatment of HPV infection and phimosis may be more effective and less invasive than universal circumcision.

    The effect of circumcision on STIs is varied. Circumcision status has no consistent association with herpes simplex virus 2, HPV, gonorrhea, or chlamydia.[7-9] Men who are not circumcised, particularly in Africa, are at a slightly greater risk of syphilis and genital ulcerative disease, but have a lower risk of genital discharge syndrome compared with circumcised men.[7-9] As genital discharge syndrome is more common than genital ulcers, the overall rate of STIs is greater in circumcised men. STIs can be prevented and/or treated more effectively, less invasively, and less expensively with condoms and antibiotics than with circumcision.

    Randomized controlled trials in Africa have shown some efficacy for circumcision in preventing HIV infection; however, these trials have bias for both participants and researchers (e.g. selection, lead time, expectation, attrition, intervention and length), improper randomization and early study termination, which amplified the lead-time bias. Each type of bias contributed towards overestimating the treatment effect. Advocates for circumcision believe that data from these randomized controlled trials, which recruited motivated, self-selected, well-compensated, high-risk adults, can be extrapolated to the general population in Africa and to infants; however, no studies have shown an association between HIV and neonatal circumcision. On the contrary, in a study of 52,143 heterosexual men attending a sexual health clinic, circumcised men had a greater risk of HIV infection than uncircumcised men.[10] Among developed nations, the US has the highest rates of heterosexually transmitted HIV and newborn circumcision. Condoms, when used consistently, provide 99% protection. HIV infections can also be prevented by choosing sexual partners responsibly and by treating STIs. For the cost of every circumcision performed in Africa, 3,500 condoms can be purchased. As condoms can provide nearly complete protection from HIV infection, circumcision adds little value.

    Circumcision removes a complex, pentilaminar, specialized, junctional structure that contains nearly all the penis' fine-touch neuroreceptors. Not surprisingly, the foreskin is the most sensitive portion of the penis. Circumcision can reduce the sensitivity of the glans to fine-touch and vibration.[11,12] No wonder adults who undergo circumcision report less-satisfying sex, reduced sensitivity and erectile function, difficulty with intromission, and increased premature ejaculation.[13] Other commonly reported complications of circumcision include infection (1–3%), excessive bleeding (1–9%), meatitis (20%), meatal stenosis (5–8%), subcutaneous granuloma (5%), balanitis (16%), coronal adhesions (30%), skin bridges (2%), and phimosis (1–2%). Parents also request a repeat circumcision for cosmetic reasons in 2% of cases. Furthermore, circumcised newborn boys are 12 times more likely to acquire community-associated methicillin-resistant Staphylococcus aureus infections than uncircumcised newborns.[14] Other less-common complications of circumcision include septicemia, meningitis, Fournier gangrene, staphylococcal scalded skin syndrome, osteomyelitis, septic arthritis, tetanus, herpes simplex infection, empyema, pubic hair strangulation, denudation of the penis, glans amputation, urethral fistula, penile edema, pyogenic granulomas, acute urinary retention with acute renal failure, ruptured bladder, UTI or urine advancing in subcutaneous fascial plains, penile ischemia, pneumothorax, pseudoparaphimosis, pulmonary embolism, unilateral leg cyanosis, gastric rupture, myocardial injury and erythema multiforme.

    Circumcision has no medical indication during the newborn period, and it is not the first-line preventive for any illness. Very few adult men choose to be circumcised, full disclosure is a rarity, and parental proxy consent for newborn circumcision is not valid.[15] No reason exists that can justify why circumcision cannot wait until the infant is old enough to choose for himself. As a public health measure, newborn circumcision in the US has failed to show a benefit in protecting against cervical cancer, penile cancer, STIs, and HIV.

    CLICK HERE for subscription information about this journal.

    Ashfield JE et al. (2003) Treatment of phimosis with topical steroids in 194 children. J Urol 169: 1106–1108
    Mallon E et al. (2000) Circumcision and genital dermatoses. Arch Dermatol 136: 350–354
    Van Howe RS (2005) Effect of confounding in the association between circumcision status and urinary tract infection. J Infect 51: 59–68
    Van Howe RS (2007) Case number and the financial impact of circumcision in reducing prostate cancer. BJU Int 100: 1193–1194
    Daling JR et al. (2005) Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease. Int J Cancer 116: 606–616
    Tseng HF et al. (2001) Risk factors for penile cancer: results of a population-based case–control study in Los Angeles County (United States). Cancer Causes Control 12: 267–277
    Weiss HA et al. (2006) Male circumcision and risk of syphilis, chancroid, and genital herpes: a systematic review and meta-analysis. Sex Transm Infect 82: 101–109
    Van Howe RS (2007) Genital ulcerative disease and sexually transmitted urethritis and circumcision: a meta-analysis. Int J STD AIDS 18: 799–809
    Van Howe RS (2007) Human papillomavirus and circumcision: a meta-analysis. J Infect 54: 490–496
    Mor Z et al. (2007) Declining rates in male circumcision amidst increasing evidence of its public health benefit. PLoS ONE 2: e861
    Sorrells ML et al. (2007) Fine-touch pressure thresholds in the adult penis. BJU Int 99: 864–869
    Yang DM et al. (2008) Circumcision affects glans penis vibration perception threshold [Chinese]. Zhonghua Nan Ke Xue 14: 328–330
    Fink KS et al. (2002) Adult circumcision outcomes study: effect on erectile function, penile sensitivity, sexual activity and satisfaction. J Urol 167: 2113–2116
    Nguyen DM et al. (2007) Risk factors for neonatal methicillin-resistant Staphylococcus aureus infection in a well-infant nursery. Infect Control Hosp Epidemiol 28: 406–411
    Svoboda JS et al. (2000) Informed consent for neonatal circumcision: an ethical and legal conundrum. J Contemp Health Law Policy 17: 61–133

    Reprint Address

    Department of Pediatrics and Human Development Michigan State University College of Human Medicine, 1414 West Fair Avenue Suite 226, Marquette, MI 49855, USA; E-mail: rsvanhowe@mgh.org

    Robert S. Van Howe, Clinical Professor in the Department of Pediatrics and Human Development, Michigan State University College of Human Medicine, Marquette, MI, USA.

    Disclosure: The author declared no competing interests