Hepatitis B Vaccination of Premature Infants: A Reassessment of Current Recommendations for Delayed Immunization
Authors: Losonsky Genevieve A. , Wasserman Steven S. , Stephens Ina , Mahoney Frank , Armstrong Patricia , Gumpper Karl , Dulkerian Susan , West David J. , Gewolb Ira H. 
Published: August 2004

Objective.
Current American Academy of Pediatrics and United States Public Health Service Immunization Practices Advisory Committee recommendations for hepatitis B immunization in premature infants weighing &lt;2 kg at birth born to hepatitis B surface antigen (HBSAg)-negative mothers are to delay the initiation of vaccination until such infants reach 2 kg or until 2 months of age. This proposal to delay vaccination at birth in these low-risk infants was based on limited studies not conducted in the United States. We sought to reassess current recommendations to delay administration of hepatitis B vaccine in low-risk premature infants by determining the immunogenicity of early hepatitis B vaccination in a US population and identifying variables associated with poor immunogenicity.

Methods.
A total of 148 infants &lt;37 weeks' gestation born to mothers negative for HBSAg were recruited at birth and stratified to three birth weight groups: &lt;1000 g, 1000 to 1500 g, and &gt;1500 g. Recombinant hepatitis B vaccine was administered within the first week of life, at 1 to 2 months of age, and at 6 to 7 months of age. Serum obtained at birth and after the second and third doses of vaccine was tested for antibody to HBSAg. Variables associated with poor response were sought prospectively by collecting demographic and clinical data.

Results.
A total of 118 subjects (83%) completed the study. Postsecond dose sera were available for 117 infants and postthird dose sera were available for 112 infants. The seroprotection rate (attaining ≥10 mIU/mL HBS antibody) after two doses was low (25%) regardless of birth weight; infants weighing &lt;1000 g at birth had the poorest response (11%). The seroprotection response rate after three doses of vaccine increased with birth weight; infants weighing ≤1500 g at birth (groups 1 and 2) had lower rates of response (52% and 68%, respectively) than did infants weighing &gt;1500 g at birth (group 3; 84% response rate). The seroprotection response rate of group 3 infants after three doses of vaccine, although low, could not be differentiated from the response rates reported for full-term infants using 95% confidence intervals. Of all infants who did not achieve protective levels of antibody after three doses of vaccine, 96% (26/27) weighed &lt;1700 g at birth. The geometric mean HBS antibody levels in responders were 88 and 386 mIU/mL after two and three doses, respectively. Of 36 children with a birth weight &gt;1500 g, 33 (91%) achieved levels of HBSantibody &gt;100 mIU/mL after three doses of vaccine, compared with 25/35 (71%) of infants with birth weight &lt;1500 g.
Using logistic regression analysis, nonresponders were more likely than were responders to have been treated with steroids (26% vs 9%) and to have had a low birth weight (1037 g vs 1455 g). In addition, the seroresponse rate of black infants was more likely than that of white infants to be associated with poor weight gain (falling off 2 percentile ranks in weight) in the first 6 months of life: 22% of black and 60% of white children who failed to gain weight adequately responded to vaccination, compared with 92% of black and 70% of white children who were growing adequately. Of interest, the only infant with a birth weight of &gt;1700 g who did not make protective levels of specific antibody after three doses of vaccine was 2300 g at birth, but had inadequate weight gain in the first 6 months of life.

Conclusions.
This study supports current recommendations of the American Academy of Pediatrics and the Centers for Disease Control and Prevention for delaying the initiation of hepatitis B immunization beyond the first week of life for premature infants at low risk for hepatitis B infection, particularly in newborns weighing &lt;1700 g at birth. In addition, we have identified variables other than birth weight that were associated with an inadequate immune response to early hepatitis B vaccination in premature infants, such as poor weight gain in the first 6 months of life and steroid use in the first few months of life.