Clinical and laboratory observations Response of preterm infants to hepatitis B vaccine Yu-Lung Lau, MD, Alfred Y. C . Tam, FRCP, K. W. Ng, PhD, N. S. Tsoi, MRCP, Barbara Lam, MRCP, Paul Lam, MRCP, a n d C. Y. Yeung, FRCP From the Departments of Pediatrics and Statistics, University of Hong Kong, Queen Mary Hospital, Hong Kong Ninety-nine preterm infants with birth weights 1000 gm (group I) and 42 when they weighed _>2000 gm (group 2). The final seropositive rotes a n d geometric mean titers of group 1 infants (79%, 61 mlU/ml) and group 2 infants (91%, 262 mlU/ml) were less than that of 43 normal term infants (100%, 679 mlU/ml). (J PEDIATR1992;121:962-5) Hepatitis B vaccination and HB immunoglobulin prevent perinata ! transmission of hepatitis B in normal term infants born of mothers who are chronic carriers of hepatitis B surface antigen. 1 In November 1988 HB vaccination was extended to all newborn infants in Hong Kong, irrespective of their maternal HB status, 2 because of the high local HBsAg carrier rate. 3 However, data on the immunogenicity of HB vaccination in preterm infants are not available4 to allow a recommendation to start immunization at birth. To establish guidelines for routine use of HB vaccine in preterm infants, we compared the immune response of preterm infants immunized with that of normal term infants according to two schedules. METHODS One hundred thirty-two newborn infants with birth weights less than 1750 gm were enrolled in the study between September 1989 and March 1991 with parental consent. There were 4 Indian, 7 Vietnamese, 10 white, and 111 Chinese infants. This study was approved by the University of Hong Kong Ethics Committee. Infants were stratified by birth weight at 250 gm intervals. Within each stratum, blocks of four were used. Group 1 infants received the first dose of HB vaccine (Engerix-B, 10 tzg/0.5 ml, Submitted for publication March, 31, 1992; accepted July 28, 1992. Reprint requests: Yu-Lung Lau, MD, Department of Pediatrics, University of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong. 9/24/41455 962
[Smith Kline Biologicals, Rixensart, Belgium]) at birth if they weighed ~ 1000 gin; if the birth weight was < 1000 gm, the first dose was delayed until the weight reached 1000 gm. Group 2 infants received the first dose of HB vaccine when they reached 2000 gin. The second dose of HB vaccine was given 1 month after the first dose, and the mean _+ SD intervals between the second and third doses were 115 _+ 22 days and 112 _+ 21 days for group 1 and 2 infants, respectively. Normal term infants (group 3) were recruited into the study from the maternal and child health clinic with parental consent. They were recruited in a cross-sectional fashHB HBcAb HB:rG HBsAb HBsAg
Hepatitis Hepatitis Hepatitis Hepatitis Hepatitis
B B core antibody B immunoglobulin B surface antibody B surface antigen
ion as they came to the clinic for vaccinations. The first and second doses of HB vaccine were given at birth and 1 month of age. The mean (+_ SD) interval between the second and thirct doses was 81 _+ 23 days. Twenty-four infants (12 boys) were examined after the second dose, and another group of 43 infants (21 boys) after the third dose. Their mean ( + S D ) birth weight was 3114 _+ 467 gin. If the mothers had HBsAg, the infants were also given 0.5 ml HBIG (Abbott Laboratories, North Chicago, Ill.) at birth. Venous blood was taken 4 to 6 weeks after the second and third doses of HB vaccine, and serum was stored at - 7 0 ~ C until assayed for anti-HB surface antibody titers and
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HBsAg by enzyme immunoassay (Abbott Laboratories). Preimmunization titers were not measured. Seropositivity was defined as an HBsAb titer _ 10 m l U / m l after vaccination, which was in part a function of preimmunization titers. Student t tests, chi-square tests, and analysis of variance were performed where appropriate. The overall chi-square test was used to test for differences of seropositivity rates of all three groups simultaneously before comparison between two groups by chi-square tests. Analysis of variance was used to test for differences of HBsAb titers (in tog scale) of all three groups, with and without separation into groups of infants born to mothers with detectable HBsAg and infants of mothers with no detectable HBsAg, before comparison between two groups by a Student t test (Fisher protected least significant difference). RESULTS Of the 132 preterm infants recruited at birth, 23 died, 10 were not followed because of emigration or withdrawal by parents, and 99 completed the vaccination schedules. At the point of entry into the study, there were no significant differences between group 1 (n -- 71) and group 2 (n -- 61) in gender distribution (47% boys vs 51% boys; p = 0.619), mean (_+SD) gestational age (30.6 ___ 3.1 vs 30.6 ___2.8 weeks; p - - 0 . 9 8 4 ) , and mean ( + S D ) birth weight (1318 ___273 vs 1248 ___295 gm; p = 0.155). There were slightly fewer infants born of mothers with detectable HBsAg in group 1 than in group 2 (4 vs 10 infants; p = 0.045). At the point of data analysis for the 99 infants who completed the study, there were no significant differences between group 1 (n = 57; 5 < 1000 gm, 52 _> 1000 gm) and group 2 (n = 42) in gender distribution (44% boys vs 45% boys; p = 0.891), mean ( + S D ) gestational age (30.8 _+ 3.0 vs 31.1 _+ 2.3 weeks; p = 0.65), and mean ( + S D ) birth weight (1336 _+ 253 vs 1313 + 247 gm, p -- 0.65). There were again fewer infants born of mothers with detectable HBsAg in group 1 than in group 2 (3 vs 9 infants; p =0.015). In addition, 2 of the 24 and 11 of the 43 normal term infants examined after the second and third doses of HB vaccine, respectively, were born of mothers with detectable HBsAg. Of the 57 infants in group 1, five had birth weights less than 1000 gm (690 to 990 gm) and therefore had their first dose of vaccine delayed by a mean of 20 days (range, 2 to 50 days). Their geometric mean titer after the third dose of vaccine (104.8 m lU/ml; 95% confidence limits: 7.54, 1456.4) was not significantly different (p -- 0.7387) from that of the 52 infants with birth weights more than 1000 gm and who therefore had the first dose of vaccine at birth (57.6 m l U / m l ; 95% confidence limits: 19.2, 172.9). All 14 preterm infants born of mothers who were HBsAg carriers were given HBIG at birth. One died and one did not complete the study. Nine completed schedule 2 and three
Clinical and laboratory observations
~63
T a b l e I. Maternal HBsAg status has no effect on final HBsAb titer Log10 HBsAb titer ( m e a n • SD) Group I (n = 57)
Group 2 (n = 42)
Group 3 (n = 43)
Maternal HBsAg-
1.76 • 1.67 2.58 • 1.40 2.85 • 0.52 (n = 54) (n = 33) (n = 32) Maternal HBsAg+ 2.15 • 1.09 1.84 • 1.73 2.77 • 0.78 (n = 3) (n = 9) (n = 11) Significance:for "group,"p = 0.001;for "maternalHBsAg,"p = 0.1746(on its own),p = 0.2191 (after controllingfor "group"). schedule 1. All 12 infants became seropositive eventually, and none had detectable HBsAg. Moreover, 10 of these 12 infants had no HB core antibody, whereas two of the group 2 infants carried HBcAb when tested at 9 and 10 months of age. The mean delay of giving the first dose of HB vaccine to the 9 infants in group 2 was 31.7 days (range, 11 to 59 days). Of these 9 infants, 7 were seropositive after three doses of HB vaccine, but the remaining two showed seroconversion only after a fourth dose. Two infants in group 1 were given the first dose of HB vaccine at birth because their birth weights were >1000 gm. The remaining infant was given the first dose of HB vaccine on day 20 Of life. All three infants became seropositive after three doses of HB vaccine. The maternal HBsAg status had no effect on the final geometric mean titers of the three groups of infants (Table I). Therefore the infants born of mothers with and without HBsAg were grouped together for comparisons among the three groups (Table II). Seropositivity rates were significantly different among the three groups of infants after the second (p = 0.0016) and third (p = 0.0012) HB vaccinations (Table II). Geometric mean titers were also significantly different among the three groups of infants after the second (p = 0.0009) and third (p = 0.0007) HB vaccinations (Table II). No infants subsequently had HBsAg detected. DISCUSSION The Committee on Infectious Diseases of the American Academy of Pediatrics stated in 1991 that "data on the effectiveness of HB vaccine are not available for infants with birth weights less than 2000 grams." 4 Recently a study of 25 premature infants weighing an average of 1678 gm at birth (range, 1300 to 2000 gm) and immunized with 10 #g of Engerix-B vaccine at birth and at 1 and 6 months of age was reported from Thailand. 5 The seropositive rate was only 88% at 9 months of age. Our study has addressed this issue to allow us to formulate guidelines for routine immunization of preterm infants weighing
[Smith Kline Biologicals, Rixensart, Belgium]) at birth if they weighed ~ 1000 gin; if the birth weight was < 1000 gm, the first dose was delayed until the weight reached 1000 gm. Group 2 infants received the first dose of HB vaccine when they reached 2000 gin. The second dose of HB vaccine was given 1 month after the first dose, and the mean _+ SD intervals between the second and third doses were 115 _+ 22 days and 112 _+ 21 days for group 1 and 2 infants, respectively. Normal term infants (group 3) were recruited into the study from the maternal and child health clinic with parental consent. They were recruited in a cross-sectional fashHB HBcAb HB:rG HBsAb HBsAg
Hepatitis Hepatitis Hepatitis Hepatitis Hepatitis
B B core antibody B immunoglobulin B surface antibody B surface antigen
ion as they came to the clinic for vaccinations. The first and second doses of HB vaccine were given at birth and 1 month of age. The mean (+_ SD) interval between the second and thirct doses was 81 _+ 23 days. Twenty-four infants (12 boys) were examined after the second dose, and another group of 43 infants (21 boys) after the third dose. Their mean ( + S D ) birth weight was 3114 _+ 467 gin. If the mothers had HBsAg, the infants were also given 0.5 ml HBIG (Abbott Laboratories, North Chicago, Ill.) at birth. Venous blood was taken 4 to 6 weeks after the second and third doses of HB vaccine, and serum was stored at - 7 0 ~ C until assayed for anti-HB surface antibody titers and
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HBsAg by enzyme immunoassay (Abbott Laboratories). Preimmunization titers were not measured. Seropositivity was defined as an HBsAb titer _ 10 m l U / m l after vaccination, which was in part a function of preimmunization titers. Student t tests, chi-square tests, and analysis of variance were performed where appropriate. The overall chi-square test was used to test for differences of seropositivity rates of all three groups simultaneously before comparison between two groups by chi-square tests. Analysis of variance was used to test for differences of HBsAb titers (in tog scale) of all three groups, with and without separation into groups of infants born to mothers with detectable HBsAg and infants of mothers with no detectable HBsAg, before comparison between two groups by a Student t test (Fisher protected least significant difference). RESULTS Of the 132 preterm infants recruited at birth, 23 died, 10 were not followed because of emigration or withdrawal by parents, and 99 completed the vaccination schedules. At the point of entry into the study, there were no significant differences between group 1 (n -- 71) and group 2 (n -- 61) in gender distribution (47% boys vs 51% boys; p = 0.619), mean (_+SD) gestational age (30.6 ___ 3.1 vs 30.6 ___2.8 weeks; p - - 0 . 9 8 4 ) , and mean ( + S D ) birth weight (1318 ___273 vs 1248 ___295 gm; p = 0.155). There were slightly fewer infants born of mothers with detectable HBsAg in group 1 than in group 2 (4 vs 10 infants; p = 0.045). At the point of data analysis for the 99 infants who completed the study, there were no significant differences between group 1 (n = 57; 5 < 1000 gm, 52 _> 1000 gm) and group 2 (n = 42) in gender distribution (44% boys vs 45% boys; p = 0.891), mean ( + S D ) gestational age (30.8 _+ 3.0 vs 31.1 _+ 2.3 weeks; p = 0.65), and mean ( + S D ) birth weight (1336 _+ 253 vs 1313 + 247 gm, p -- 0.65). There were again fewer infants born of mothers with detectable HBsAg in group 1 than in group 2 (3 vs 9 infants; p =0.015). In addition, 2 of the 24 and 11 of the 43 normal term infants examined after the second and third doses of HB vaccine, respectively, were born of mothers with detectable HBsAg. Of the 57 infants in group 1, five had birth weights less than 1000 gm (690 to 990 gm) and therefore had their first dose of vaccine delayed by a mean of 20 days (range, 2 to 50 days). Their geometric mean titer after the third dose of vaccine (104.8 m lU/ml; 95% confidence limits: 7.54, 1456.4) was not significantly different (p -- 0.7387) from that of the 52 infants with birth weights more than 1000 gm and who therefore had the first dose of vaccine at birth (57.6 m l U / m l ; 95% confidence limits: 19.2, 172.9). All 14 preterm infants born of mothers who were HBsAg carriers were given HBIG at birth. One died and one did not complete the study. Nine completed schedule 2 and three
Clinical and laboratory observations
~63
T a b l e I. Maternal HBsAg status has no effect on final HBsAb titer Log10 HBsAb titer ( m e a n • SD) Group I (n = 57)
Group 2 (n = 42)
Group 3 (n = 43)
Maternal HBsAg-
1.76 • 1.67 2.58 • 1.40 2.85 • 0.52 (n = 54) (n = 33) (n = 32) Maternal HBsAg+ 2.15 • 1.09 1.84 • 1.73 2.77 • 0.78 (n = 3) (n = 9) (n = 11) Significance:for "group,"p = 0.001;for "maternalHBsAg,"p = 0.1746(on its own),p = 0.2191 (after controllingfor "group"). schedule 1. All 12 infants became seropositive eventually, and none had detectable HBsAg. Moreover, 10 of these 12 infants had no HB core antibody, whereas two of the group 2 infants carried HBcAb when tested at 9 and 10 months of age. The mean delay of giving the first dose of HB vaccine to the 9 infants in group 2 was 31.7 days (range, 11 to 59 days). Of these 9 infants, 7 were seropositive after three doses of HB vaccine, but the remaining two showed seroconversion only after a fourth dose. Two infants in group 1 were given the first dose of HB vaccine at birth because their birth weights were >1000 gm. The remaining infant was given the first dose of HB vaccine on day 20 Of life. All three infants became seropositive after three doses of HB vaccine. The maternal HBsAg status had no effect on the final geometric mean titers of the three groups of infants (Table I). Therefore the infants born of mothers with and without HBsAg were grouped together for comparisons among the three groups (Table II). Seropositivity rates were significantly different among the three groups of infants after the second (p = 0.0016) and third (p = 0.0012) HB vaccinations (Table II). Geometric mean titers were also significantly different among the three groups of infants after the second (p = 0.0009) and third (p = 0.0007) HB vaccinations (Table II). No infants subsequently had HBsAg detected. DISCUSSION The Committee on Infectious Diseases of the American Academy of Pediatrics stated in 1991 that "data on the effectiveness of HB vaccine are not available for infants with birth weights less than 2000 grams." 4 Recently a study of 25 premature infants weighing an average of 1678 gm at birth (range, 1300 to 2000 gm) and immunized with 10 #g of Engerix-B vaccine at birth and at 1 and 6 months of age was reported from Thailand. 5 The seropositive rate was only 88% at 9 months of age. Our study has addressed this issue to allow us to formulate guidelines for routine immunization of preterm infants weighing
