WHO Informal consultation on tetanus and voluntary medical male circumcision

10 January 2020

Key advice

For conventional surgical methods of male circumcision, the experts recommended that no modification be made to the advice provided in the 2015 report. The strategies used will depend on the country’s tetanus-toxoid-containing vaccine (TTCV) schedule and practices, and its tetanus burden. Ministries of health are advised to develop and phase in effective and practical delivery strategies for providing at least one dose of TTCV at the time of voluntary medical male circumcision (VMMC), unless an individual has documented evidence of protection through receipt of the necessary number of doses of TTCV.

For circumcision with a device method that requires that the foreskin remains in situ for several days before it is removed, the June 2016 consultation updated its previous advice. Circumcision with such a method should only be undertaken if the client is adequately protected against tetanus by immunization with TTCV. The manufacturer of the currently prequalified elastic collar compression device has updated the instructions for use and issued a Field Safety Notice (FSN-identifier: 002_2016) to reflect this advice, which supersedes the advice of the WHO 2015 report.

There is a need to strengthen efforts to better educate all male circumcision clients, their parents and care givers (in the case of adolescents), and communities and traditional healers on the importance of avoiding harmful wound-care practices. This applies to all male circumcision methods.

Key points

Twelve cases of tetanus, eight of which resulted in death, were reported through VMMC programmes in four countries of east and southern Africa between 2014 and May 2016. Over the same time period about 3 million medical male circumcisions were performed in these countries. Six of the tetanus cases occurred after use of the currently available elastic collar compression device method and six after conventional surgical circumcision.
In conventional surgical circumcision, application of traditional remedies with potentially tetanus-containing substances was reported and considered a predominant risk for tetanus. With the currently available elastic collar compression device method, the anaerobic environment identified during its use[1] increases the risk for Clostridium tetani growth.
The epidemiological evidence about these rare serious adverse events, supported by biological plausibility, was considered by the experts to be sufficient to conclude that the risk of tetanus with use of the currently available elastic collar compression device method differed from that assessed during earlier safety reviews[2,3] and was higher than that with conventional surgical circumcision.
The experts recommended revising the 2015 advice on tetanus and device circumcision; specifically, that circumcision with a device method where the foreskin is left in situ and is removed several days after device application should only be undertaken if the client is adequately protected against tetanus by immunization with TTCV that includes:

two TTCV doses at least 4 weeks apart, with the second dose at least 2 weeks before device placement; or
if a client has previously received three infant doses, or one dose during adolescence or adulthood, a booster at the time of device placement (this must be given at least 2 weeks before placement); or
a series of five doses of TTCV.

Although childhood immunization programmes are now reaching a high proportion of infants in many of the countries implementing VMMC programmes for HIV prevention, past coverage has been low and irregular. Thus, in the absence of documentation of previous vaccination with a sufficient number of TTCV doses, providers must presume that a client is not protected, and therefore must ensure that clients receive two TTCV doses as per a) above.
For conventional surgical methods in which the foreskin is removed at the time of the surgical procedure, the experts recommended that no modification be made to the 2015 advice. The strategies used will depend on the country’s TTCV schedule, practices and coverage, and its tetanus burden. Ministries of health are advised to develop and phase in TTCV delivery strategies to provide at least one dose of TTCV at the time of VMMC unless an individual has documented evidence of protection through receipt of the necessary number of doses of TTCV.
VMMC programmes must work closely with national immunization programmes to ensure that, in general, both males and females are protected against tetanus through vaccination.

There is a need to strengthen efforts to better educate male circumcision clients, their parents and care givers (in the case of adolescents), and communities and traditional healers on the importance of avoiding harmful wound-care practices. This applies to all male circumcision methods.

[1] Liu CM, Prodger JL, Tobian AAR, Serwadda D, Galiwango RM, Nalugoda F, et al. Genital anaerobic bacterial overgrowth and the PrePex male circumcision device, Rakai, Uganda. J Infect Dis. Advance access May 2016.

[2] Male circumcision for HIV prevention: WHO Technical Advisory Group on Innovations in Male Circumcision: evaluation of two adult devices, January 2013: meeting report. World Health Organization, 2013 (http://www.who.int/hiv/pub/malecircumcision/tag_devices/en/, accessed 30 June 2016).

[3] WHO Technical Advisory Group on Innovations in Male Circumcision, meeting report, 30 September – 2 October 2014, Geneva, Switzerland (http://www.who.int/hiv/pub/malecircumcision/innovations-mc/en/, accessed 30 June 2016).

Background

WHO and the Joint United Nations Programme on HIV/AIDS (UNAIDS) issued recommendations in March 2007 that male circumcision should be regarded as an additional method of HIV prevention. Since then, programmes have been implementing this partially protective prevention option in 14 priority countries in east and southern Africa with generalized HIV epidemics and low prevalence of male circumcision. By the end of 2015, a cumulative total of more than 11 million male circumcisions had been performed, most of which were undertaken using the forceps-guided and dorsal slit conventional surgical methods.

Innovative methods using male circumcision devices are being developed, and two devices are currently prequalified by WHO: an elastic collar compression device prequalified in 2013 and a collar clamp device prequalified in 2015. The goal of these innovative methods is to simplify the procedure and increase the acceptability of male circumcision while maintaining or improving safety. However, WHO has a recommended phase-in process for new methods that includes pilot studies and active post-market surveillance to identify potentially rare but serious adverse events as larger numbers of men are reached. Because of this process, only a limited number of procedures have been performed in Africa using the new device-based methods.

As part of the ongoing safety reviews of voluntary medical male circumcision (VMMC) procedures, in 2014 WHO requested data from VMMC programmes on serious and moderate adverse events that had occurred during 2013–2014. Over that period, nine cases of tetanus had been reported among a cumulative total of 9.1 million VMMCs at the end of 2014. Thus, WHO (through the Department of HIV, the Department of Essential Medicines and Health Products, and the Department of Immunization, Vaccines and Biologicals) convened a consultation on 9– 10 March 2015 to assess the potential risk of tetanus associated with medical male circumcision and to advise on risk management strategies[4]. Key points from that 2015 report included the following:

Tetanus is a severe and potentially fatal infection caused by the bacterium Clostridium tetani, spores of which are found in soil, dust, and faeces of animals and humans. These bacterial spores can germinate in the anaerobic conditions often found in wounds, and produce a powerful neurotoxin that impairs inhibition of motor neuron activity.
Wounds with devitalized tissue have been noted to provide the conditions for developing C. tetani infection and toxin production.
Possible risk factors for tetanus by circumcision method and its mechanism of action included:

for all circumcision methods—individual and environmental factors, such as personal hygiene, cleanliness of the home and environment, occupation and wound- care practices;
for the currently available elastic collar compression device method—the anaerobic environment between the necrotic foreskin and the healthy glans, and potentially in the junction between the healthy tissue and the elastic compression ring on the proximal side of the device; and
for the currently available collar clamp device method—tissue remnants distal to the device after placement and excision of the foreskin.

Surveillance and analysis of adverse events occurring in VMMC programmes should be improved; routine safety monitoring in all VMMC programmes, including notification of all suspected tetanus cases and deaths, should be reinforced; and the effect of revised instructions for use and hygienic interventions for all methods should be closely monitored, particularly in countries with a high background burden of tetanus.

[4] WHO informal consultation on tetanus and voluntary medical male circumcision: report of meeting convened in Geneva, Switzerland, 9–10 March 2015. World Health Organization, 2015 (http://apps.who.int/iris/bitstream/10665/181812/1/9789241509237_eng.pdf (accessed 30 June 2016).

Technical consultation

By May 2016, WHO had received reports through VMMC programmes on an additional six cases of tetanus since the previous consultation in March 2015. Thus, WHO convened a technical consultation by teleconference on 3 June 2016 to discuss these new tetanus cases. The consultation included members and observers of the WHO Technical Advisory Group on Innovations in Male Circumcision and other experts who had participated in the 2015 VMMC and tetanus consultation. Participants were reminded of the WHO requirement to declare potential interests related to the subject under discussion, and all interests were declared verbally at the start of the meeting. No declarations differed from those reported in 2015. Declared interests were managed as provided in Annex A.

Biological plausibility

The currently available elastic collar compression device causes ischaemic necrosis of the foreskin, which remains in situ for 7 days, raising concerns of anaerobic overgrowth. A study[5] conducted with the Rakai Health Sciences Program compared the subpreputial microbiome of 22 men 7 days after placement of an elastic collar compression device but before device removal, with that of 145 uncircumcised men, in Rakai, Uganda, using 16S rRNA gene-based real- time polymerase chain reaction (qPCR) and sequencing. The device users had increased absolute abundance of all bacteria (P=0.001), largely due to increased anaerobes: Porphyromonas (elastic collar compression device=5.2 × 107, uncircumcised men=1.1 × 106, P=0.002), Peptoniphilus (1.0 × 107 vs 1.8 × 106, P<0.05),>Anaerococcus (1.0 × 107 vs 1.1 × 106, P<0.001) and="">Campylobacter ureolyticus (1.6 × 107 vs 1.7 × 105, P<0.001). the="" authors="" of="" the="" study="" concluded="" that="" the="" increase="" in="" anaerobes="" associated="" with="" the="" device="" may="" account="" for="" unpleasant="" odour="" and="" a="" possible="" heightened="" risk="" of="" tetanus.="">

The microbiome with the use of a collar clamp type of device, where the foreskin is removed at the time of device placement, is currently being assessed.

Tetanus cases

A total of 15 tetanus cases were identified through VMMC programmes, including two cases from Zambia in 2012, which was before the active monitoring and reporting of tetanus cases. Of the 13 cases found through active monitoring and reporting, one case was considered to be inconsistent with a causal association with the circumcision procedure, but the remaining 12 cases were considered to be consistent with or of indeterminate association with the circumcision. Six of these cases have occurred since 2015, the most recent of which was in May 2016.

The 12 tetanus cases occurred in Kenya (2), Rwanda (4), Uganda (5) and the United Republic of Tanzania (1). Of these cases, six followed use of the currently available elastic collar compression device method and six followed conventional surgical circumcision. Four cases survived and eight died. Tetanus vaccination status was either not known or a single dose of tetanus-toxoid- containing vaccine (TTCV) had been given at the time of the circumcision procedure.

The six tetanus cases following surgery were among adolescents (mean age 14.5 years, range 11–19 years) and were associated with unhygienic living conditions or had a potentially C. tetani spore containing substance (e.g. “traditional medicine”, cow dung, “herbs” or “ash-like substance”) applied to the wound (five cases). Tetanus symptoms among these cases were first reported between 7 and 11 days post circumcision. Four cases died and two survived.

The six tetanus cases following the elastic collar compression device method were among adult farmers and a boda-boda (motorcycle taxi) driver (mean age 31.5 years, range 19–47 years). Two of the cases may have applied something to the wound, one did not, and in the remaining three cases it is not known whether anything was applied. For the most recent case following the elastic collar compression device method, the povidone-iodine skin preparation protocol recommended in 2015 was reportedly followed before device placement and removal, and a dose of TTCV was given at the time of device placement. Tetanus symptoms were first reported between 7 and 12 days from the day of device placement. Four cases died and two survived.

Tetanus incidence by method

In the four countries in which tetanus cases were reported, an estimated total of 3.04 million surgical circumcisions have been performed since 2014, giving an estimated incidence of 0.20 (95% confidence interval [CI]: 0.07–0.43) cases per 100 000 circumcisions. For the elastic collar compression device method, a total of 90 500 circumcisions have reportedly been performed with an estimated incidence of 6.63 (95% CI: 2.43–14.3) cases per 100 000 procedures. The estimated risk ratio is 33.6 (95% CI: 9.0–126).

Restricting analysis to Rwanda and Uganda, the only countries where tetanus cases following the currently available elastic collar compression device circumcision have been reported, results in estimated incidences of 0.17 (95% CI: 0.04–0.51) cases per 100 000 surgical circumcisions and 6.90 (95% CI: 2.53–15.0) cases per 100 000 elastic collar compression device procedures, or a risk ratio of 39.7 (95% CI: 8.49–245).

The only country for which an official reported estimate of background risk of tetanus outside the neonatal period is available is Uganda, where an annual inpatient incidence of 3.0 per 100 000 population was reported over the period 2012–2014[6]. Considering that the risk of tetanus following circumcision is restricted to an approximate 1-month period, comparison with the annual inpatient incidence rate should be based on 1 month. Thus, the equivalent incidence rate per month is three inpatient tetanus cases per 1 200 000 population per month, or 0.25 tetanus cases per 100 000 population per month. This is of the same order of magnitude as the estimated incidence of tetanus following conventional surgical circumcision.

[5] Liu CM, Prodger JL, Tobian AAR, Serwadda D, Galiwango RM, Nalugoda F, et al. Genital anaerobic bacterial overgrowth and the PrePex male circumcision device, Rakai, Uganda. J Infect Dis. Advance access May 2016.

[6] WHO informal consultation on tetanus and voluntary medical male circumcision: report of meeting convened in Geneva, Switzerland, 9–10 March 2015. World Health Organization, 2015 (http://apps.who.int/iris/bitstream/10665/181812/1/9789241509237_eng.pdf, accessed 30 June 2016).

Discussion and recommendation

Evidence

Since VMMC was performed as a public health intervention to prevent HIV infection rather than for any immediate medical reason, all cases consistent with or of indeterminate association with circumcision were included because of the clear sequence of events and timing of onset of symptoms. The experts discussed potential reasons for the observed incidence of tetanus following the currently available elastic collar compression device method compared with conventional surgical circumcision. There may have been some underreporting of tetanus cases following circumcision, particularly following surgical circumcision; however, differential underreporting was considered unlikely to account for the magnitude of the difference. Additionally, the symptoms of tetanus are quite specific, so misclassification or misdiagnosis of cases was considered unlikely.

The observation of strong odour reported by providers and some clients during the week after elastic collar compression device placement or at the time of device removal suggested an anaerobic environment. This observation has been confirmed by a study of the microbiome under the foreskin immediately before device removal[7]. An anaerobic environment is necessary for germination of C. tetani spores and growth of C. tetanibacteria.

Higher tetanus risk with the currently available elastic collar compression device method

The experts agreed that the evidence was sufficient to conclude that the risk of tetanus was different from that assessed during previous safety reviews by WHO [8,9] and was higher following the currently available elastic collar compression device method compared with conventional surgical circumcision. This elevated risk was supported by a plausible biological mechanism due to the anaerobic environment. This risk was in contrast to the low risk of tetanus following conventional surgical circumcision, because the method performed under aseptic conditions does not inherently create an anaerobic environment. In addition, for five of the six cases of tetanus following about 3 million surgical circumcisions, application of traditional remedies or potentially tetanus-containing substances was reported. The incidence of tetanus following conventional surgical circumcision did not appear to be higher than the background rate.

Mitigating tetanus risk with the currently available elastic collar compression device method

There was clear consensus on the need to mitigate the elevated risk of tetanus with use of the currently available elastic collar compression device method, particularly since the safer alternative of conventional surgical circumcision is available. The only reliable method of eliminating the risk of tetanus is to ensure that all clients on whom the device is placed are protected by vaccination. This requires a full series of five TTCV doses[10] or two TTCV doses at least 4 weeks apart, with the second dose at least 2 weeks before device placement. In a vaccine-naive individual, a single TTCV dose provides no protection and it must be complemented by a booster dose to give several months of protection. If a client has previously received three infant doses, or one dose during adolescence or adulthood, a booster at the time of device placement provides only limited protection as it takes 7–14 days for antibodies to rise to protective levels. Thus, a booster must be given at least 2 weeks before placement for adequate protection.

he challenge for programme managers and VMMC providers is that few clients will have documentation of past TTCV doses, and most will not recall their vaccination history, nor will their parents or care givers. In the absence of reliable documentation providers must assume that the client has received no TTCV doses and ensure that all clients who choose the elastic collar compression device method receive one TTCV dose at least 6 weeks before and a second TTCV dose 2 weeks before placement. Compared with current levels, the coverage rates for the three-dose diphtheria–tetanus–pertussis (DTP) series in infancy were much lower in past years, and even recent coverage levels are not uniform throughout the country. Hence, this advice also applies in countries with historical high TTCV coverage including boosters that would provide protection for men now coming for circumcision. For example, in settings with high current TTCV coverage and no or few reported tetanus cases in the general population, a small number of older adolescents and men—particularly from rural and hard to reach areas of the country—may never have received any TTCV vaccination. Such men would be potentially exposed to an unacceptably high risk of tetanus with the currently available elastic collar compression device method of circumcision. Good skin preparation, including genital cleaning and appropriate antiseptic (preferably povidone iodine) use at device placement, is necessary to prevent infection.

VMMC programmes must work closely with national immunization programmes to ensure adequate tetanus vaccination coverage before use of the currently available elastic collar compression device method.

Mitigating tetanus risk with surgical circumcision

The experts discussed whether there was a need to modify the vaccination recommendations, or other recommendations for conventional surgical circumcision. They noted that although it is simpler for programmes to implement a single approach to vaccination, this strategy could have a negative impact on VMMC uptake and increase the cost of circumcision if two TTCV doses were required before all circumcision methods. It was agreed that the advice from the 2015 consultation did not need revision. That advice included the following:

Ministries of health are advised to develop and phase in effective and practical delivery strategies for providing tetanus vaccination in the context of their programmes for VMMC for HIV prevention and vaccination. The most suitable schedule and delivery strategy would ideally be informed by reliable data on immunity levels in the community. However, because there is no herd immunity to tetanus, the individual’s documented personal vaccination history remains a critical consideration on the doses needed, together with the feasibility of different VMMC service delivery approaches.
The consultation advised that, unless an individual has documented evidence of receipt of a full five-dose to six-dose TTCV series, at a minimum, a single TTCV dose be administered before or at the time of male circumcision, recognizing that this dose will provide varying levels of protection, depending on the individual. In addition to infection prevention through rigorous surgical skin preparation (including improved device-specific protocols, and interventions to improve good wound care), VMMC programmes should work with Expanded Programme on Immunization (EPI) programmes to consider the phasing in of TTCV before or at the time of circumcision.

The tetanus cases to date suggest that tetanus risk after conventional surgical circumcision is predominantly linked to substances that potentially contain tetanus being applied to wounds. Such traditional wound-care practices (either by family members or traditional healers) bring a risk of infection, including tetanus, for all types of wounds. There must be stronger efforts to better educate circumcision clients, their parents and care givers (in the case of adolescents), and communities and traditional healers on the importance of avoiding harmful wound-care practices.

The tetanus cases occurring in association with VMMC have highlighted that fewer adolescent boys and men are immunologically protected against tetanus than women of comparable ages. This difference is primarily attributable to routine TTCV vaccination during pregnancy to reduce the risk of neonatal tetanus. TTCV vaccination is low cost and highly effective, and increasing coverage among males through routine immunization is an important public health action.

[7] Liu CM, Prodger JL, Tobian AAR, Serwadda D, Galiwango RM, Nalugoda F, et al. Genital anaerobic bacterial overgrowth and the PrePex male circumcision device, Rakai, Uganda. J Infect Dis. Advance access May 2016.

[8] Male circumcision for HIV prevention: WHO Technical Advisory Group on Innovations in Male Circumcision: evaluation of two adult devices, January 2013: meeting report. World Health Organization, 2013 (http://www.who.int/hiv/pub/malecircumcision/tag_devices/en/, accessed 30 June 2016).

[9] WHO Technical Advisory Group on Innovations in Male Circumcision, meeting report, 30 September – 2 October 2014, Geneva, Switzerland (http://www.who.int/hiv/pub/malecircumcision/innovations-mc/en/, accessed 30 June 2016).

[10] Three TTCV doses in infancy plus two boosters (one in second year of life or at school entry, and one in adolescence or adulthood based on WHO recommendations), WHO Weekly epidemiological record, No. 20, 19 May 2006, 197–208 (http://www.who.int/immunization/wer8120tetanus_May06_position_paper.pdf, accessed 30 June 2016).