From the *Department of Epidemiology, The German Centre for Research on Ageing, Heidelberg, Germany; and the †Department of Internal Medicine I, University of Ulm, Ulm, Germany.
Submitted 14 June 2005; accepted 4 October 2005.
Supported by grants from the German Research Foundation (BR 1704/3-1, BR 1704/3-2, and BR 1704/3-3).
Correspondence: Hermann Brenner, Department of Epidemiology, The German Centre for Research on Ageing, Bergheimer Str. 20, D-69115 Heidelberg, Germany. E-mail: email@example.com.
Background: To further elucidate the intrafamilial transmission of Helicobacter pylori infection, we investigated the occurrence of infection by parental infection status in a large community-based birth cohort of children from Germany.
Methods: Parental infection (at birth) and children's infection (at age 3 years) were determined by 13C-urea breath test and by monoclonal antigen stool test.
Results: Twenty of 834 children (2.4%) were found to be infected. The odds ratio for H. pylori infection of the child was 12.9 (95% confidence interval = 3.2–52.5) if the mother was infected and 1.4 (0.4–4.6) if the father was infected, after adjustment for infection status of the other parent and for nationality. The number of older siblings was not a risk factor for H. pylori infection of the child.
Conclusions: This longitudinal study suggests that infected mothers are the main source of H. pylori infection of their children.
Approximately half of the world's population has been estimated to carry the gastric bacterium Helicobacter pylori.1 It is now considered to be a major, if not the most important, risk factor for a variety of gastrointestinal diseases, including gastric cancer.2–5
Current knowledge suggests that acquisition of H. pylori occurs predominantly in early childhood.6–9 Although a major role of intrafamilial spread is now beyond controversy, one of the most elusive questions in H. pylori research is who in the family is the main source of infection.
Some studies conducted in high-prevalence countries have suggested a major role of siblings in the transmission of H. pylori infection to the child,10,11 whereas several independent population-based, cross-sectional studies12–14 in southern Germany have consistently shown that the parents, and especially the mother, may play a key role in transmitting H. pylori to the child. There have been no longitudinal studies with employment of adequate methods to define infection status in small children in whom serology is considered suboptimal.15
The aim of this prospective birth cohort study was to investigate the acquisition of H. pylori infection in early childhood and to clarify the role of parental infection status in transmission of H. pylori to the child.
Study Design and Study Population
Mothers, their partners, and their offspring were recruited for the study, as described previously.16 Briefly, mothers who gave birth to a healthy child at the Department of Gynecology and Obstetrics at the University of Ulm, Germany, between November 2000 and November 2001 were recruited. Overall, 1066 families were included in this study (67% of the 1593 eligible families who fulfilled the inclusion criteria). Active follow-up of children was performed at age 12 months, 24 months, and 36 months.
Participation was voluntary, and informed consent was obtained in each case. The study was approved by the Ethics Boards of the University of Ulm and of the Physicians’ Boards of the states of Baden-Wuerttemberg and Bavaria.
At baseline examination, all mothers underwent standardized interviews conducted by trained interviewers during the hospitalization after delivery. At all yearly follow-up examinations, the parents again filled out a detailed questionnaire. Medical information was also obtained from the child's primary healthcare pediatricians around the first, second, and third birthdays of the child.
Helicobacter pylori Infection
Among the mothers, active infection with H. pylori at baseline was determined using the 13C-urea breath test (for details, see Weyermann et al16). Infection status of fathers at baseline and of children at the age of 1, 2, and 3 years was determined by means of an monoclonal antigen immunoassay for detection of H. pylori in stool (Ridascreen Femtolab H. pylori; R-biopharm AG, Darmstadt, Germany). Both the 13C-urea breath test and the stool antigen test have been shown to have sensitivities and specificities close to 100%.17 Furthermore, the stool test is the best available means to define H. pylori infection status in children within the context of an epidemiologic study in which endoscopy is not indicated.15,18,19
We describe the prevalence of H. pylori infection among children at the age of 3 years and sociodemographic characteristics of their families for the 834 children with available stool samples at this age. We used unconditional logistic regression to estimate prevalence odds ratios (ORs) and their 95% confidence intervals (CIs) to describe the independent association of maternal and paternal infection status with children's’ infection status. These analyses were restricted to 612 families for whom H. pylori infection status of both parents was available. We also excluded 139 mothers who received antibiotics within the previous 4 weeks before the 13C-urea breath test was conducted because of the possibility of a false-negative result and 99 fathers from whom no stool specimen was available. We used a forward variable selection procedure. H. pylori infection status of both parents were forced in the model, and covariates were added if they contributed to the model at an α = 0.05 or if their inclusion changed the parameter estimates for the infection status of the parents by more than 10%.
Prevalence of H. pylori infection at birth was 17% among mothers and 18% among fathers. Stool samples to estimate H. pylori infection status among children were available for 890, 870, and 834 children at the age of 1, 2, and 3 years, respectively. Incidence of H. pylori infection was 1.1% (10 of 890) in the first year of life, 1.4% (12 of 841 children with a negative test result at age 1 year) in the second year of life, and 0.6% (5 of 801 children with a negative test result at ages 1 and 2 years) in the third year of life.
The overall prevalence of H. pylori infection was 2.4% in children at the age of 3 years (Table 1). Prevalence of infection was much higher in children of H. pylori-positive mothers than in children of 13C-urea breath test-negative mothers (10.9% vs 0.9%) and somewhat higher in children of H. pylori-positive fathers than in children of H. pylori-negative fathers (5.9% vs 1.7%). Among the other variables listed in Table 1, only nationality and residential crowding were strongly associated with H. pylori infection status of the child in bivariate analysis.
Only nationality of parents was added to the final multivariable model, because it contributed substantially to the model that already included parental infection. The adjusted OR for H. pylori infection of the child was 12.9 (95% CI = 3.2–53) if the mother was H. pylori-positive and 1.4 (0.4–4.6) if the father was H. pylori-positive (Table 2).
This prospective birth cohort study delivers very strong evidence that infected mothers were the main source of H. pylori infection of their children in the population studied.
The much stronger relationship of maternal infection status compared with paternal infection status is plausible given that in this population (like in most other societies), the mother usually has much closer contact with the child during the first years of life. In most families studied, the mother was the primary caretaker (79% of mothers were housewives and only 3% were employed full-time at the 1-year follow-up, whereas 93% of the fathers were employed full-time and only 2% were house-husbands).
Two recently published studies from Brazil20,21 have also found that H. pylori-infected mothers are a much stronger risk factor for H. pylori infection of their children than infected fathers, whereas a third study from Brazil reported no association between mothers and their children.22 However, apart from the problem of serologic measurement of H. pylori infection, the number of mothers included in the latter study (n = 39) was too small to assess this association with adequate power.
In this prospective birth cohort study (like in our earlier cross-sectional studies12–14), we found no evidence that transmission among siblings was of relevance. These findings are in contrast to the results of a large population-based study from Colombia, which reported a major role for siblings in the transmission of H. pylori infection.11 Although infection among siblings may be of more relevance in high-prevalence countries, recent studies conducted in high-prevalence populations also indicated that sibling-to-sibling transmission may be of less importance.23,24
Some recently published studies have suggested that infected mothers as well as infected siblings are independent risk factors for childhood H. pylori infection.21,25 Whether child-to-child transmission occurs independently of maternal infection or whether siblings serve as intermediates in transmission from mothers to children remains to be resolved. This will require genotyping of bacterial strains among all family members.
When considering these results, the following limitations should be kept in mind. First, measurement of H. pylori infection of parents was done at baseline only; however, given the very low rate of acquisition and loss of infection during adulthood,2 parental infection status is likely to have been stable over time in most parents. Also, we were not able to recognize transient H. pylori infections among children that might have been acquired and lost between points in time of stool sampling.
In summary, this large-scale birth cohort study provides strong epidemiologic evidence that in developed countries, an infected mother as the primary caretaker is likely to be the main source for H. pylori infection of her children.
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