Acta Paediatrica Scandinavia, Volume 93, Issue 2: Pages 164-168, February 2004.
S Mårild, S Hansson, U Jodal, A OdÉn1 and K Svedberg
Department of Paediatrics, The Queen Silvia Children's Hospital, Sahlgrenska University Hospital, Göteborg, Sweden; Romelanda1, Sweden
Aim: To assess the possible protective effect of exclusive breastfeeding against first-time febrileurinary tract infection (UTI) in children.
Methods: Two children's hospitals and local child health centres in the Goteborg area, Sweden, participated in a prospective case-control study. In total, 200 consecutive cases (89M, 111F), aged 0-6y, presenting with first-time febrile UTI were enrolled. The mean +/- SD age was 0.98 +/- 1.15 y. As control subjects, 336 children (147M, 189F) were recruited from the child health centre of the case, matched for age and gender and included consecutively for each case during the first days after diagnosis. The duration of exclusive breastfeeding was obtained from the case and controls by a standardized procedure.
Results: Ongoing exclusive breastfeeding gave a significantly lower risk of infection. A longer duration of breastfeeding gave a lower risk of infection after weaning, indicating a long-term mechanism. The protective role of breastfeeding was strongest directly after birth, then decreased until 7 mo of age, after which age no effect was demonstrated.
Conclusion: A protective role of breastfeeding against UTI was demonstrated. The study provides statistical support to the view that breast milk is a part of the natural defence against UTI.
Key words: Breastfeeding, infant, urinary tract infection
S Mårild, Department of Paediatrics, The Queen Silvia Children’s Hospital/Sahlgrenska University Hospital, SE-416 85 Göteborg, Sweden (Fax. +46 31 843653, e-mail. firstname.lastname@example.org)
This file does not include table one, figures one and two, and the statistical appendix.
A previous case–control study indicated that cases with urinary tract infection (UTI) had a shorter duration of breastfeeding than controls (1). In a similar study, breastfeeding was shown to occur significantly less often at the time when a urinary infection was diagnosed compared with age-matched control subjects (2). It was suggested that the antiadhesive properties of breast milk could explain the protection offered by human milk (3).
The aim of the present study was to investigate the relationship between breastfeeding and the risk of firsttime febrile UTI and to assess the relation in girls and boys between the duration of breastfeeding and the momentary risk of acquiring an infection. The intention was also to illustrate the findings by determining the probability of acquiring a urinary infection in a population with a known incidence rate.
Eligible were children 0–6 y of age with a first-time symptomatic UTI attending the Paediatric Departments at the Hospital of Mölndal and the Queen Silvia Children’s Hospital, Göteborg, Sweden. The inclusion criteria were: fever of >38.5°C within 24 h of diagnosis together with bacteriuria, defined by one of the following: for suprapubic aspirates, growth of any number of colony-forming units (cfu) per millilitre, one strain; for midstream samples, growth >100000 cfu ml-1, one strain; for bag urine, two separate specimens with growth of >100000 cfu ml-1, one and the same strain in both specimens. The children also had to be living in the uptake area of the two hospitals.
Controls were recruited among infants or children registered at the Child Health Centre of the case. They had no history of previous UTI or of urinary tract anomalies. The selection aimed at two control subjects per case, matched for gender and age.
The following were excluded: families with language difficulties or other obstacles for participation; those who had not answered interview questions within the required time limit (see below); children with concomitant serious diseases or other major health impairment; those who declined to participate; and other reasons, e.g. maternal disease or missing records.
Background population data
During a 2 y period (1993–1995) the diagnostic rate of first-time symptomatic UTI in children below 2 y of age in the area was calculated to be 2.5% for girls and 2.5% for boys (4). The present study included a total of 300 girls, 111 cases and 189 control subjects, and 236 boys, 89 cases and 147 control subjects. None of the boys was circumcised.
Exclusive breastfeeding Exclusive breastfeeding was defined as proposed by the World Health Organization (WHO) and according to the Swedish National Board of Health and Welfare Official statistics at the time of the start of the study, as complete nutrition with full meals of breast milk. Ingestion of small amounts of other food, one spoonful a day at most, to familiarize the child with the taste was accepted, but not a larger quantity (5, 6).
An experienced and specially trained paediatric nurse performed all the interviews (KS). Only mothers were questioned. Immediately after the identification of a new case, the nurse initiated recruitment of the corresponding controls. A questionnaire was sent to the case and its controls simultaneously before an interview by telephone. The answers had to be obtained within 1 mo for infants below 1 y of age and within 2 mo for older children. The mean number of days until the interview was completed was 20.6 for cases and 23.6 for controls.
Fisher’s non-parametric permutation test (7) was used to compare differences in variables characterizing cases and controls. A p-value >0.05 was considered significant. The effect of gender, age and duration of exclusive breastfeeding on the risk of having UTI was studied as a hazard function of UTI by the use of Poisson regression models (8). The hazard functions were assumed to be of the form exp(β0 + β1x1 + β2x2 +…).
The probability of UTI was calculated from the hazard function determined by the Poisson regression analysis. The general relationship between survival and hazard function was applied. Adjustment for the enrichment in the study population of children with UTI was performed.
A full description of the statistical analysis is given in the appendix. Three Poisson models were applied to elucidate different aspects of the relation between breastfeeding and the risk of UTI. First, the general relationship was studied to show whether there was any preventive effect of breastfeeding on the risk of UTI (see Appendix, Table A1). Then, a second model was used to study gender differences with respect to the preventive effect (see Appendix, Table A2). Finally, to illustrate the importance of the duration of breastfeeding, a third model was used (see Appendix, Table A3). This last model was also applied repeatedly for various ages to obtain coordinates for the figuresillustrating the risk patterns.
The Research Ethics Committee of Göteborg University approved the study (official record no. 158-91).
Cases and control subjects
In total, 265 cases and 400 controls met the inclusion criteria, whereas 65 cases and 64 controls were excluded. In 25 cases and 28 controls there were language difficulties, in 26 and 27 there were missing answers, or answers were received too late, in 7 and 3 a serious concomitant disease was present, and in 7 and 6 maternal disease made questioning impossible. A final number of 200 cases (89M, 111F) and 336 controls (147M, 189F) was available for evaluation. One of the cases had no matching control and 47 of the controls had no matching case. Gender was successfully matched between cases and controls. The mean ± SD age of cases was 0.98 ± 1.15 y and that of controls was 0.97 ± 1.15 y (ns).
Duration of exclusive breastfeeding
The mean duration of exclusive breastfeeding in girls at the time of the interview was 16 wk in cases and 18 wk in controls (Table 1). Corresponding figures for boys were 11 and 12 wk. Girls had ongoing breastfeeding at the time of the infection in 8 (7.5%) cases and 23 (12.5%) control subjects, and boys in 36 (40%) and 52 (35%), respectively. The gender-dependent difference reflects the higher age of girls at the diagnosis of firsttime UTI (Table 1).
Urinary tract infection in relation to ongoing breastfeeding
By the first Poisson regression model the impact of breastfeeding on the risk of UTI was estimated by a hazard ratio, non-breastfeeding versus breastfeeding, equal to 2.30, 95% confidence interval 1.56–3.39 (see Appendix, Table A1). The ratio was significantly larger than 1 (p > 0.001). This finding means that there was a significantly higher risk of UTI for babies who were not breastfed compared with babies of similar age with ongoing breastfeeding.
In the second model (see Table A2), the interaction between gender and breastfeeding for the risk of UTI was studied. There was a general significant effect of gender (p = 0.0491). For girls the hazard ratio was 3.78, indicating an almost fourfold higher momentary risk, while it was 1.63 for boys, or a 63% increase for UTI for not breastfeeding.
The hazard function of the third model was used to calculate the risk of acquiring a UTI in girls during the first 2 y of life in relation to age at weaning. In Fig. 1. this is illustrated for two theoretical examples where exclusive breastfeeding is discontinued at 2 and 7 mo of age, respectively. If breastfeeding is ended at 2 mo of age, the risk of UTI is found to increase rapidly. After this, the risk is reduced, but remains at a higher level than in those discontinuing at 7 mo of age. In the latter case there is a momentary increase in the risk directly after weaning, followed by a lower risk of an infection until 2 y of age.
Urinary tract infection in relation to duration of breastfeeding
Using the hazard function determined by the Poisson regression analysis (see Table A3) and data from the incidence study (4), the probability of acquiring UTI during the first 2 y of life could be calculated. The third model was used here to elucidate temporal aspects of breastfeeding in relation to the risk of UTI. The duration of breastfeeding has an impact on the risk of UTI at any moment, both while ongoing and after weaning until 2 y of age. The functions for girls and boys in the model were permutated repeatedly to obtain coordinates for Fig. 2. Thus, a longer duration of exclusive breastfeeding in girls significantly reduced the probability of UTI. This effect was seen for breastfeeding up to 7 mo of age and thereafter no additional protection could be shown. For boys, there was a trend in the same direction, but less marked, and a constant decrease with age throughout infancy.
In 1971 Winberg and Wessner presented a study suggesting a protective effect of breastfeeding against septic infection in newborns. The evidence was based on a case–control study showing a significantly higher consumption of breast milk in healthy controls than in the group of septic patients (9). In studies from developing countries infection-related morbidity and mortality were shown to be lower in infants with longer duration of breastfeeding than in those with early weaning (10, 11). Lactating infants have been shown to be protected against diarrhoea (12, 13), infantile respiratory infections (14), otitis media (15) and other bacterial infections (16).
To optimize the information about breastfeeding, emphasis was placed on the details in the interview technique. Thus, only mothers were contacted, a single nurse conducted all interviews, the timing was matched between cases and controls, and a standard protocol was used. In addition, there was social matching between cases and controls. Therefore, the authors believe that the breastfeeding data are valid.
A protective effect of ongoing breastfeeding against UTI in infants was demonstrated in this study, in accordance with the previous pilot study (1). In this study, it appeared that breastfeeding was more beneficial in girls, although there was a similar effect in boys. Furthermore, breastfeeding also had a protective effect after weaning, with long-term protectionuntil 2 y of age.
Population-based studies show the highest incidence of UTI in infancy, most often affecting males the first 6 mo of life, followed in older children by a female predominance (4, 17, 18). The difference in mean age at diagnosis of UTI between boys and girls in this study is in accordance with this knowledge. Since the majority of infants with first-time UTI have a normal anatomy of the urinary tract, functional immaturity with residual urine, combined with insufficient function of the immune system, are likely to be important pathogenic factors in both genders. For girls, the short distance from the bladder to the periurethral flora is an important factor in ascending infections. Closeness to the bacterial reservoir may explain the more pronounced and longer lasting benefit from breastfeeding in girls, through effects on the intestinal flora. In infant boys, the preputial flora has been shown to play a pathogenic role (19). Exclusive breastfeeding may provide protection by favouring colonization in the prepuce of bacteria with low virulence (20).
Several mechanisms have been suggested to explain the preventive effect of breastfeeding against infections (21–23). In the case of UTIs, there are several possibilities. A reduction in the risk of an ascending infection in breastfed babies has been associated with the presence of antiadhesive oligosaccharides in breast milk (3), contributing to the selection of and intestinal colonization by low-virulence bacteria (24). If left undisturbed by antibiotic treatment, the intestinal flora is quite constant and can provide long-term protection, which may explain the long-term effects found in this study. In addition, lactoferrin, with powerful unspecific antibacterial effects, is present in the urine of breastfed infants (25). Secretory immunoglobulin A antibodies are also present in the urine of breastfed babies, offering specific protection against the bacterial antigens characterizing the intestinal flora shared by the child and the mother (26).
Acknowledgements.–This study was supported by the Swedish Research Council and research grants from Frimurare-Barnhusfonden, Göteborg University and Bohuslandstinget, Sweden.
Received Sept. 9, 2002; revisions received Mar. 27, 2003 and Sept. 15, 2003; accepted Oct. 6, 2003
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