Hepatitis B Vaccine Is Not Associated with Liver Problems in U.S. Children Less Than 6 Years Old

Abstract

To the Editor: Fisher and Eklund question the problem of external validity in previous studies in high-risk populations by evaluating the benefit of hepatitis B vaccination for the general population of American children. 1 The authors claim that their data do not support a protective effect of HB vaccine against liver problems for U.S. children; to the contrary, they report on liver problems among U.S. children that they consider associated with hepatitis B vaccination. The data presented, however, do not support the suggested associations and do not support the authors’ conclusions. First, the ICD-9 codes that Fisher and Ecklund used do not allow any conclusion on the protective effect of HB vaccine in U.S. children (used ICD-9 codes: acute and sub-acute necrosis of liver, chronic passive congestion of liver, unspecified fetal and neonatal jaundice, unspecified jaundice (not of new-born) and biliuria, each excluding any instances of viral hepatitis). The hepatitis B vaccine aims to protect against HB infection (including its chronic sequelae), not to prevent against these non-infectious acute or sub-acute pathologies. Second, some of these ICD-9 pathologies could have been already present before or at the moment of administration of the HB vaccine (eg, neonatal jaundice). Third, the authors did not consider the possibility of an exposure bias: in many industrialized countries it is good clinical practice to vaccinate children with pre-existing liver problems against hepatitis B to prevent further deterioration of the liver. The associations calculated in this paper show serious methodological limitations, and the results give no information on causality between hepatitis B vaccine and liver problems in American children. At several occasions in this paper, the authors consider the hepatitis B infection risk negligible for 99.5% of U.S. children. Indeed, in the U.S., each year 20,000 neonates are born to hepatitis B surface antigen positive mothers. In the United States, however, the lifetime risk to contract hepatitis B has been estimated at approximately 5%. 2 Infant immunization programs have not been set up to protect only infants against perinatal hepatitis B infections, but to offer a cohort of infants life-long protection against an infection they could contract from birth to death. Indeed, in the United States, HBV infection occurs mainly in adolescents and young adults. 3 The age distribution of HBV infections is indicative of a life-style disease linked with at risk behavior, such as sexual activity and injecting drug use. Moreover, part of the aim of the infant immunization programs is to vaccinate a higher proportion of the population than could be reached by targeting a teenage population, and to control the infection in the general population through an increasing herd immunity. In contrast with the authors’ statement, several trials have been conducted in low risk populations with a well-documented immunogenicity and safety profile of these vaccines, 4,5 and currently implemented universal hepatitis B immunization programs in low endemic countries have been shown effective in controlling HBV infection. 6,7 Fisher and Eklund are unclear on the eligibility criteria of the study (21.9% of the children eliminated) and on the completeness of the vaccination course. Does the classification “HB vaccinated” mean having been administered the full course? In addition, the use of parent’s memory to recall vaccination status of their children introduces the likelihood of recall bias. This possibility is reinforced by the lack of clarity over the period of time elapsed between immunization and questionnaire survey. In addition, the help-seeking behavior in the exposed group could be different from that of the un-exposed group, a difference that could introduce a selection bias. Parents who did not have their children participate in a universal HB vaccination program could be less willing to seek any kind of medical advice for their children. A number of liver problems could therefore remain unnoticed or undiagnosed, causing an under-registration of these disorders in the non-vaccinated group. Thus, the internal validity of this study leaves much to be desired. The methodology used does not permit a sound conclusion on the causality between hepatitis B vaccines and liver problems in American children. A prospective cohort study would have been more appropriate to the task. Pierre van Damme Koen van Herck André Meheus