The Lancet, Volume 1: Pages 598-599, 18 March 1989.
JAN WINBERG1, INGELA BOLLGREN2, LEIF GOTHEFORS3, MARIA HERTHELIUS1, KJELL TULLUS4
1Department of Paediatrics, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden
2Department of Paediatrics, Sach's Childrens Hospital, Karolinska Institutet, Stockholm,
3Department of Paediatrics, Umea University, Umea, and
4Department of Paediatrics, Danderyds Hospital, Stockholm
Summary Retrospective studies suggest that circumcision of newborn boys will reduce the frequency of male early infantile urinary tract infection by about 90% If they are correct, this will be the first known instance of a common potentially lethal disease being preventable by extirpation of a piece of normal tissue. To reconcile the phenomenon with existing views of evolution and biology, it is suggested that the effects of one unphysiological intervention are counterbalancing those of another - ie, colonisation of the babies gastrointestinal tract and genitals in maternity units by Escherichia coli strains of non-maternal origin, to which the baby has no passive immunity. As an alternative to circumcision to prevent early infantile male UTI, more natural colonisation could be promoted by strict rooming in of mother and baby or by active colonisation of the baby with his mother's anaerobic gut flora.
CIRCUMCISION in the neonatal period may reduce the frequency of male urinary tract infection (UTI) by some 90%. These sensational findings are reported by Wiswell et al1-3 in studies of more than 200 000 babies. Although retrospective, the evidence is persuasive. Moreover, Ginsburg and McCracken4 report that 95% of male infantile UTI occurred in uncircumcised boys. With a circumcision rate of about 80%, this distribution between circumcised and non-circumcised boys could not be random. In addition, in the international reflux study5 comprising about 600 cases with UTI, there are 9.9 males in the American link but 22.7% males in the European link (Olbing H, personal communication). Since circumcision in the newborn period is rare in Europe but common in the USA, this is further evidence for the role of theprepuce in the pathogenesis of neonatal UTI.
These data are of immediate importance in the USA, general circumcision might prevent 20 000 attacks of pyelonephritis in male infants per year.5 They are also of interest from other points of view. Firstly, they could bring to an end the old controversy concerning the infection route in neonatal UTI. The studies by Wiswell et al suggest that even neonatal infections are often ascending and not blood-borne. Secondly they indicate that, as in girls, the external genitals of boys are important in the pathogenesis of UTI. Thirdly, this is the first demonstration of effective prevention of UTI by means other than long-term administration of antibiotics. Fourthly, the findings raise questions of general biological interest since they indicate that a common potentially lethal disease, early infantile male UTI,6,10 can be prevented by extirpation of a piece of normal, healthy tissue of universal occurrence in males.11 It would not be easy to find a parallel in medicine or biology. That the prepuce is a mistake of Nature seems improbable, and we offer here an alternative explanation.
We propose that one unphysiological intervention (circumcision) is counterbalancing the effect of another unphysiological state of affairs--namely, exposure to the microbiological environment of a modern maternity unit. The hypothesis is based on four observations.
Firstly, in biologically natural settings mothers often defaecate during delivery and this colonise the baby their own aerobic and anaerobic intestinal flora. Together with this gift they provide specific protection--immunoglobulins transferred before delivery though the placenta and later transferred through breast milk. The transferred anaerobic flora12 might also contribute to protection by controlling the growth of the gram-negative anaerobic flora. In contrast, when babies are born and cared for in hospital the Escherichia coli strains that colonise the intestine tend to be acquired from the environment.13-15 Further evidence of disturbed intestinal ecology is the anaerobic bacteria of the gut in breastfed babies born and cared for in modern maternity units is often not dominated by bifidobacteria (as in babies born under village conditions) but by other strains.16,17
Secondly, with the gastrointestinal tract as the probable source, the male prepuce becomes heavily colonised with E. coli during the first few days of life.18
Thirdly, this colonisation seems to arise from the fact that E coli--p-fimbriated uropathogenic strains thereof - bind avidly to the inside of the prepuce.19 This tissue may thus play a key role in events leading to UTI by increasing the risk for colonisation of the urethra, and from there ascent of uripathogenic bacteria in the urinary tract. Extirpation of the prepuce may break an important link in this chain. In fact, Wiswell et al5 have shown that circumcision reduces not only the periurethral but also the urethral E coli flora. Similar findings are reported for proteus.20
Fourthly, infantile pyelonephritis is in 80-90% of cases due to P-imfimbriated E coli,21 often belonging to special uropathogenic clones.22,23 These attach to the mucous membranes of the lower urinary tract and can ascend the urinary pathways even in the absence of vesicouteral reflux. Pathogenic clones can be efficient colonisers also of the gut,24 and sometimes spread among patients and staff of neonatal wards, causing outbreaks of pyelonephritis.25,26 Under such circumstances extirpation of the prepuce could be especially effective as a preventative measure.
In monkeys, vaccination experiments show that antibody from the mother increases the resistance of offspring to UTI caused by P-fimbriated E coli strains.27
If our hypothesis is true it raises vital questions. On mucous membranes not already occupied by by bacteria, there is a "race for the surface",28 and those bacteria appearing first tend to persist.29 If the composition of the normal flora is as important as many think it is,30 the colonisation of newborn babies may be too serious a matter to be left to chance in environments--the modern obstetric hospital or the neonatal intensive care unit--which from a biological point of view are unphysiological and possibly hazardous.
Would deliberate application of a more physiological bacterial flora on certain mucous membranes (and skin?) during the newborn period abolish or diminish the risk of colonisation with potentially dangerous bacteria? In a classic study performed 25 years age active colonisation of the umbilicus and the nasal mucosa were shown to stop epidemics of virulent Staphylococcus aureus infections.31 Florey32 summarised such attempts in the preantibiotic era. There is a long way to go in research before such a prevention programme can be offered, but much work is underway. For example, we already know that elimination of the indigenous vaginal flora increases the risk of colonisation with a uropathogenic E coli strain,33 and that inoculation of the indigenous normal flora eliminates the pathogens. (Herthelius M, Gorbach SL, Mollby R, Nord CE, Petterson L, Winberg J, unpublished). In the USA, the American Academy of Pediatrics is under pressure to revise its 1975 pronouncement that there are no medical benefits to be gained from routine circumcision: an increased circumcision program is proposed with the aim of preventing some 20 000 cases of neonatal UTI a year.34 Similar proposals may soon be heard in Europe. Before we embark on such a programme further thought should be given to the physiology of neonatal bacterial colonisation and its possible clinical importance. Attempts to manipulate the faecal flora might in the long run be a more physiological approach than to remove the prepuce from all newborn boys. Pending further research strict rooming-in might increase the likelihood of the baby being colonised by the maternal strains.35
This work was supported by a grant from the Swedish Medical Research Council.
Correspondence should be addressed to J. W., Department of Paediatrics, Karolinska Hospital, 104 01 Stockholm, Sweden.
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