Document text
A Review of the Safety of Hepatitis B Birth Dose
Vaccination
John Su
Acting Director
Immunization Safety Office
Centers for Disease Control and Prevention
September 18, 2025National Center for Emerging and Zoonotic Infectious Diseases
Request to CDC from ACIP Chair
Safety data for HepB administration within 24 hours of birth from CDC’s
Vaccine Safety Datalink and from FDA’s Biologics Effectiveness and Safety
System. Include (i) mild and serious adverse events; (ii) all cause morbidity and mortality; (iii) short term and long -term safety; (iv) both
specific outcomes of pre- determined concern as well as results from data
mining where large numbers of potential adverse events are evaluated; and (v) both combined results and results stratified by sex. If some of these types of safety studies are unavailable, please mention that.
2
Rapid systematic review of hepatitis B post- licensure
safety data
•Key question:
-What is the safety of the hepatitis B
vaccine administered within the first 30 days of life?
•Conducted a new rapid systematic review of published literature
-Search conducted July 31, 2025 with no
date restrictions for publications
•Electronic databases searched:
-MEDLINE
-EMBASE
-CINAHL
-Cochrane
* Population, Intervention, Comparator, and Outcome, Setting, Time frameworkPI/ECO(ST)
ELEMENT*Description for this Review
Population Neonates, Newborns, Infants
Intervention or ExposureHepatitis B vaccine administration within the
first 30 days of birth:
HepB, HepB -BD, HBV, Engerix -B, Recombivax
HB
Comparator (if
applicable)Any or none
Outcome(s) Adverse events
Adverse outcomesSafety outcomesSide effects
Reaction
Adverse reactionAdverse effectSerious adverse event
Setting Any
Time Frame Any publication years
Any duration of follow up Search Strategy
3
Rapid systematic review:
Inclusion/exclusion criteria
Inclusion Criteria Exclusion Criteria
•Newborn infants receiving a hepatitis B vaccine
at birth (i.e., ≤30 days old at dose 1)•Non -English language articles
•Animal studies
•Randomized control trial (RCT)
•Observational studies
•Case series ≥ 10
•Data from surveillance systems•Any population that did not receive hepatitis B vaccine at ≤30 days old at dose 1
•N < 10
Outcomes include any of the following:•Safety
•Adverse events
•Serious adverse events
•Side effects•Clinical trial protocols
•(e.g., clinicaltrials.gov, trialsearch.gov identified in the citation)
•Conference abstracts/ posters
•Conference proceedings in title or journal title
•Title starts with a number
•Poster
4
Results
Results of rapid systematic review of hepatitis B safety
administered in the first 30 days of life
Identification Screening IncludedStudies from databases/registers (n = 1916)
MEDLINE (n = 1916)Studies removed (n = 9)
Duplicates identified manually (n = 9)
Duplicates identified by Covidence (n = 0)
Marked as ineligible by automation tools (n = 0)
Other reasons (n = 0)
Studies screened at title & abstract (n = 1907) Studies excluded at title & abstract (n = 1678)
Did not meet inclusion criteria (n = 1678)
Studies assessed for eligibility at full text
review (n = 229) Studies excluded at full text review (n = 158)
No intervention of interest (n = 48)
No outcome of interest (n = 30)
Not relevant to key question (n = 7)No population of interest (n = 51)Not available in English (n = 5)
Insufficient methodologic reporting (i.e., poster, abstract, letter to editor) (n = 8)
No primary data collection or secondary data not systematically collected (n = 8)No full text available (n = 0)
Studies assessed for outcomes stratified by hepatitis
B birth dose (n = 71) Studies excluded (n = 51)
Outcome or population not stratified by h epatitis B birth dose (n = 47)
Systematic reviews/meta -analyses (n = 4)
Studies extracted for h epatitis B birth dose (n = 20)
6
Summary of publications meeting search criteria
•Total of 20 studies of hepatitis B
vaccine administration within 30 days of life included in review
-Five studies defined birth dose as hepatitis
B vaccine administered within 24 hours of
birth
•VSD: 1 study
-Four studies used other terms to define
hepatitis B vaccine birth dose
•Terms used: Given at birth, Birth dose,
within 120 hours of birth
•One study stated that 85% received hepatitis B on date of birth, none received the vaccine beyond 8 days of life
•VSD: 1 studyCharacteristic # of Studies
Study design RCT 5
Cohort 7
Surveillance report 2
Case control 4
Case series 1
Cross -sectional 1
Vaccine
administeredEngerix -B 5
Recombivax 1
Hepatitis B product not -
specified14
Timing of administration as noted in the paper≤ 24 hours 5
Within 8 days of birth 4
Within first month of life 11Study characteristics (N = 20)
7
Studies evaluating local reactions: Pain
Hepatitis B vaccination within 24 hours of birth (n = 1 study)
In one RCT, pain was reported for 7.7% of infants in the 5 days after Engerix -B vaccination.
Study Study Type Outcome Outcome Window Comparison groupsLocal reactions
Intervention Results %
(N)Comparison Results %
(N)
Yerushalmi 1997 RCT Pain with movement Within 5 days of vaccination Engerix -B vs BioHepB* 7.7 (4) 2.6 (4)
Yerushalmi 1997 RCT Pain with pressure Within 5 days of vaccination Engerix -B vs BioHepB* 7.7 (4) 1.3 (2)
Study Study Type Outcome Outcome Window Comparison groupsLocal reactions
Intervention Results %
(N) Comparison Results %
(N)
Greenberg 2002 RCT Pain or soreness Within 3 days of vaccinationEngerix -B vs DTaP -HepB, OPV,
and Hib at 2 months of age8.1 (NR);
0 (0) severe**35.7 (NR);
1.6 (NR) severe**,†
Lopez 2002 Cohort Pain or soreness Within 4 days of vaccinationEngerix -B only
(no comparison group)6.0 (7);
4.3 (5) severe§NA
Wood 2018 RCT Pain or soreness Within 2 days of vaccinationEngerix -B alone vs Engerix -B+
investigational acellular Pertussis
vaccine9.3 (14);
0 (0) severe¶19.7 (41);
0.5 (1) severe¶Hepatitis B vaccination within 0-5 days of birth (n = 3 studies)^
Pain or soreness within the 4 days after Engerix -B was reported for <10% of newborns; few were severe.
NA = not applicable; NR = not reported
*The hepatitis B vaccine BioHepB is not approved for use in the United States
^Studies indicated hepatitis B administration at birth, within 120 hours of birth**Severe: soreness that caused crying when limb moved;
†Severe reported for any injection site; §Severe: not defined; ¶Severe: crying when limb moved/spontaneously painful or prevents daily activities8
Studies evaluating local reactions: Redness or erythema
Hepatitis B vaccination within 0-5 days of birth (n = 3 studies)^
Redness or erythema within 4 days after Engerix -B was reported for 8 -20% of newborns; none were severe.
StudyStudy
TypeOutcome Outcome Window Comparison groupsLocal reactions
Intervention Results % (N) Comparison Results % (N)
Greenberg 2002 RCTRedness or
erythemaWithin 3 days of vaccinationEngerix -B within 4 days of
birth vs DTaP -HepB, OPV, and
Hib at 2 months of age8.8 (NR);
0 (0) severe**11.6 (NR);
0 (0) severe**,†
Lopez 2002 CohortRedness or
erythema Within 4 days of vaccinationEngerix -B only
(no comparison group)11.1 (13);
0 (0) severe**NA
Wood 2018 RCTRedness or
erythema Within 2 days of vaccinationEngerix -B alone vs Engerix -
Bwith an investigational
acellular Pertussis vaccine20.0 (30);
0 (0) severe§27.4 (57);
0 (0) severe§
NA = not applicable; NR = not reported
*The hepatitis B vaccine BioHepB is not approved for use in the United States
^Studies indicated hepatitis B administration at birth, within 120 hours of birth
**Severe: diameter >20 mm; †Severe reported for any injection site; §Severe: diameter ≥30 mmStudyStudy
TypeOutcome Outcome Window Comparison groupsLocal reactions
Intervention Results % (N) Comparison Results % (N)
Yerushalmi 1997 RCTRedness or
erythemaWithin 5 days of
vaccinationEngerix -B vs BioHepB* 0 (0) 0 (0)Hepatitis B vaccination within 24 hours of birth (n = 1 study)
In one RCT, redness or erythema was not reported in either comparison arm.
9
Studies evaluating local reactions: Swelling
Hepatitis B vaccination within 0-5 days of birth (n = 3 studies)^
Swelling within 4 days was reported in 0-4% for newborns who received Engerix -B; there were no severe
reports.
StudyStudy
TypeOutcome Outcome Window Comparison groupsLocal reactions
Intervention Results % (N) Comparison Results % (N)
Greenberg
2002RCT Swelling Within 3 days of
vaccinationEngerix -B vs DTaP -HepB, OPV, and
Hib at 2 months of age0 (0);
0 (0) severe**16.3 (NR);
3.1 (NR) severe**,†
Lopez
2002Cohort SwellingWithin 4 days of
vaccinationEngerix -B only
(no comparison group)4.3 (5);
0 (0) severe**NA
Wood 2018 RCT Swelling Within 2 days of
vaccinationEngerix -B alone vs Engerix -B+
investigational acellular Pertussis
vaccine 4.0 (6);
0 (0) severe§12.5 (26);
0 (0) severe§
NA = not applicable; NR = not reported
*The hepatitis B vaccine BioHepB is not approved for use in the United States
^Studies indicated hepatitis B administration at birth, within 120 hours of birth
**Severe: diameter >20 mm; †Severe reported for any injection site; §Severe: diameter ≥30 mmStudyStudy
TypeOutcome Outcome Window Comparison groupsLocal reactions
Intervention Results % (N) Comparison Results % (N)
Yerushalmi
1997RCT SwellingWithin 5 days of
vaccinationEngerix -B vs BioHepB* 7.7 (4) 2.0 (3)Hepatitis B vaccination within 24 hours of birth (n = 1 study)
In one RCT, swelling was reported for 7.7% of newborns in the days after they received Engerix -B.
10
Studies evaluating any local reactions
StudyStudy
TypeOutcome Outcome Window Comparison groupsLocal reactions
Intervention Results %
(N)Comparison Results % (N)
Bassily 1995 RCT Local side effects Within 1 week of vaccinationRecombivax at birth vs
Recombivax at 18 months 2.8 (5) 1.6 (3)
11Hepatitis B vaccination within 0-5 days of birth (n = 1 study)
In one RCT, any local reaction* during the week of Recombivax was reported for 2.8% of newborns
*Local reaction: local soreness, temporary redness/induration at the injection site
Studies evaluating systemic reactions: Fever
StudyStudy
TypeOutcome Outcome Window Comparison groupsSystemic reactionsMeasure of
Association Intervention Results % (N)Comparison Results
% (N)
Bassily 1995 RCT FeverWithin 1 week of
vaccinationRecombivax at birth vs
Recombivax at 18 months5.6 (10) 2.1 (4) NR
Linder 1999 Cohort Fever, >37.5 °CWithin birth
hospitalizationHepatitis B vaccine vs No
Hepatitis B vaccine 1.2 (68) 0.5 (27) p = 0.001
0.9 (50) >38° C 0.5 (27) >38° C p = 0.05
Lewis 2001 Cohort FeverWithin first 21 days
of lifeHepatitis B vaccine vs. No
Hepatitis B Vaccine0.8 (21) 1.1 (25)aRR§: 0.85 (95%CI:
0.6-1.1); p=0.28
Yerushalmi
1997RCT Fever, ≥38 °CWithin 5 days of
vaccinationEngerix -B vs BioHepB* 0 (0) 1.3 (2) NRHepatitis B vaccination within 24 hours of birth (n = 4 studies)
Fever in the days to weeks after hepatitis B vaccination was reported for 0 -5.6% of newborns
StudyStudy
TypeOutcome Outcome Window Comparison groupsSystemic reactionsMeasure of
Association
Intervention Results %
(N)Comparison Results %
(N)
Greenberg
2002RCT Fever, ≥38.0oCWithin 3 days of
vaccinationEngerix -B vs DTaP -HepB,
OPV, and Hib at 2 months
ofage5.9 (NR);
0 (NR) >39.5oC14.7 (NR);
0.8 (NR) >39.5oCNR
Wood 2018 RCT Fever, ≥38.0oCWithin 2 days of
vaccinationEngerix -B alone vs Engerix -B+
investigational
acellular Pertussis vaccine0.7 (1);
0 (0) ≥39.0oC0 (0);
0 (0) ≥39.0oCNR
Lopez 2002 Cohort Fever, ≥38.0oCWithin 4 days of
vaccinationEngerix -B only
(no comparison group)0.9 (1);
0.9 (1) >39.0oC axillary
or >39.5° C rectalNA NAHepatitis B vaccination within 0-5 days of birth (n = 3 studies)^
Fever within 4 days after Engerix -B vaccination was reported for 0 -5.9% of newborns; few were severe.
NA = not applicable; NR = not reported. * The hepatitis B vaccine BioHepB is not approved for use in the United States.; ^Studies indicated hepatitis B administration at birth, within 120 hours of birth
§ Adjusted relative risk; Adjusted for maternal age, low Apgar at 1 minute, low Apgar at 5 minutes, maternal smoking, gestation period and congenital heart disease status 12
Studies evaluating systemic reactions: anorexia or decreased appetite
StudyStudy
TypeOutcome Outcome Window Comparison groupsSystemic reactions
Intervention Results % (N) Comparison Results % (N)
Greenberg 2002 RCTAnorexia/Decreased
appetite Within 3 days of
vaccinationEngerix -B vs DTaP -HepB, OPV, and
Hib at 2 months of age14.0 (NR);
1.5 (NR) severe**25.6 (NR);
0.8 (NR) severe**
Lopez 2002 CohortAnorexia/Decreased
appetite Within 4 days of
vaccinationEngerix -B only
(no comparison group)2.6 (3);
1.7 (2) severe†NA
Wood 2018 RCTFeeding
issues/Decreased
appetite Within 2 days of
vaccinationEngerix -B alone vs Engerix -B+
investigational acellular Pertussis
vaccine16.5 (17);
1.0 (1) severe§12.7 (28);
0 (0) severe§
**Severe: prevents normal daily activities; †Severe: not defined; §Severe: prevents normal daily activities or requires significant medical interventionHepatitis B vaccination within 0-5 days of birth ( n= 3 studies)^
Anorexia or decreased appetite was reported for 2.6 -16.5% of newborns after Engerix -B vaccination; there
were few severe reports.StudyStudy
TypeOutcome Outcome Window Comparison groupsSystemic reactions
Intervention Results %
(N)Comparison Results %
(N)
Yerushalmi 1997 RCT Anorexia/ decreased appetite Within 5 days of vaccination Engerix -B vs BioHepB* 0 (0) 2.0 (3)
NA = not applicable; NR = not reported
*The hepatitis B vaccine BioHepB is not approved for use in the United States
^Studies indicated hepatitis B administration at birth, within 120 hours of birthHepatitis B vaccination within 24 hours of birth (n = 1 study)
In one RCT, anorexia or decreased appetite was not reported for newborns who received Engerix -B.
13
Studies evaluating systemics reactions: Gastrointestinal (GI) symptoms
StudyStudy
TypeOutcome Outcome Window Comparison groupsSystemic reactions
Intervention Results % (N)Comparison
Results % (N)
Greenberg 2002 RCT DiarrheaWithin 3 days
ofvaccinationEngerix -B vs DTaP -HepB, OPV, and Hib
at 2 months ofage8.1 (NR);
0.7 (NR) severe**10.1 (NR);
0 (0) severe**
Wood 2018 RCT DiarrheaWithin 2 days
ofvaccinationEngerix -Balone vs Engerix -B+
investigational acellular Pertussis
vaccine11.7 (12);
0 (0) severe†17.2 (38);
0 (0) severe†
Greenberg 2002 RCT VomitingWithin 3 days of
vaccinationEngerix -B vs DTaP -HepB, OPV, and Hib
at 2 months ofage4.4 (NR);
0 (0) severe**7.8 (NR);
0 (0) severe**
Wood 2018 RCT VomitingWithin 2 days of
vaccinationEngerix -Balone vs Engerix -B+
investigational acellular Pertussis
vaccine22.3 (23);
0 (0) severe†20.4 (45);
0 (0) severe†
NR = not reported
*The hepatitis B vaccine BioHepB is not approved for use in the United States
^Studies indicated hepatitis B administration at birth, within 120 hours of birth**Severe: prevents normal daily activities;
†Severe: prevents normal daily activities or requires significant medical interventionHepatitis B vaccination within 0-5 days of birth (n = 2 studies)^
GI symptoms were reported for 0 -22% of newborns who received Engerix -B; there were no reports.StudyStudy
TypeOutcome Outcome Window Comparison groupsSystemic reactions
Intervention Results %
(N)Comparison Results %
(N)
Yerushalmi 1997 RCT Diarrhea or vomitingWithin 5 days of
vaccinationEngerix -B vs BioHepB* 0 (0) 0.6 (1)Hepatitis B vaccination within 24 hours of birth (n = 1 study)
In one RCT, diarrhea or vomiting was not reported for newborns who received Engerix -B
14
Hepatitis B vaccination within 24 hours of birth (n = 1 study)
In one RCT, irritability or fussiness was reported for 11.5% of infants in the days after Engerix -B vaccination.
StudyStudy
TypeOutcome Outcome Window Comparison groupsSystemic reactions
Intervention Results %
(N)Comparison Results %
(N)
Greenberg 2002 RCT Irritability or fussinessWithin 3 days of
vaccinationEngerix -B vs DTaP -HepB, OPV, and Hib
at 2 months of age22.1 (NR)
0.7 (NR) severe**54.3 (NR);
3.9 (NR) severe**
Wood 2018 RCT Irritability or fussinessWithin 2 days of
vaccinationEngerix -B alone vs Engerix -B+
investigational acellular Pertussis
vaccine20.4 (21);
1.0 (1) severe†24.4 (54);
0.9 (2) severe†
Lopez 2002 Cohort Irritability or fussinessWithin 4 days of
vaccinationEngerix -B only
(no comparison group)2.6 (3);
1.7 (2) severe§NA
Greenberg 2002 RCT Unusual cryingWithin 3 days of
vaccinationEngerix -B vs DTaP -HepB, OPV, and Hib
at 2 months ofage1.5 (NR);
0 (0) severe**3.1 (NR);
0.8 (NR) severe**
NA = not applicable; NR = not reported
*The hepatitis B vaccine BioHepB is not approved for use in the United States
^Studies indicated hepatitis B administration at birth, within 120 hours of birth
**Severe: prevents normal daily activities; †Severe: prevents normal daily activities or requires significant medical intervention ; §Severe: not definedHepatitis B vaccination within 0-5 days of birth (n = 3 studies)^
Irritability, fussiness, or crying was reported for 1.5 -22.1% of newborns who received Engerix -B; there were
few severe reports.StudyStudy
TypeOutcome Outcome Window Comparison groupsSystemic reactions
Intervention Results %
(N)Comparison Results %
(N)
Yerushalmi 1997 RCT Irritability or fussinessWithin 5 days of
vaccinationEngerix -B vs BioHepB* 11.5 (6) 3.3 (5)
15Studies evaluating systemic reactions: Irritability or fussiness or crying
Studies evaluating systemic reactions: Sleep disturbance
StudyStudy
TypeOutcomeOutcome
WindowComparison groupsSystemic reactions
Intervention Results % (N) Comparison Results % (N)
Greenberg
2002RCTDrowsiness or
sleeping moreWithin 3 days
of vaccinationEngerix -Bvs DTaP -HepB, OPV, and Hib at 2
months of age 32.4 (NR);
2.9 (NR) severe*40.3 (NR);
0.8 (NR) severe*
Wood
2018RCTDrowsiness or
sleeping moreWithin 2 days
of vaccinationEngerix -B alone vs Engerix -B+
investigational acellular Pertussis vaccine 27.2 (28);
1.0 (1) severe§17.6 (39);
0.5 (1) severe§
Lopez
2002CohortDrowsiness or
sleeping moreWithin 4 days
of vaccinationEngerix -B only
(no comparison group)5.1 (6);
0.9 (1) severe†NA
Greenberg RCTRestlessness or
sleeping lessWithin 3 days
of vaccinationEngerix -B vs DTaP -HepB, OPV, and Hib at 2
months ofage16.9 (NR);
1.5 (NR) severe*26.4 (NR);
0.8 (NR) severe*
Wood
2018RCTRestlessness or
sleeping lessWithin 2 days
of vaccinationEngerix -B alone vs Engerix -
B+investigational acellular Pertussis vaccine31.1 (32);
2.9 (3) severe§22.2 (49);
0.9 (2) severe§
NA = not applicable; NR = not reported
^Studies indicated hepatitis B administration at birth, within 120 hours of birth
*Severe: prevents normal daily activities; †Severe: not defined; §Severe: prevents normal daily activities or requires significant medical interventionThere were no studies evaluating sleep disturbance for children who received hepatitis B vaccine within
24 hours of birth
Hepatitis B vaccination within 0-5 days of birth (n = 3 studies)^
Sleep disturbances were reported for 5.1 -32.4% of newborns who received Engerix -B; there were few severe
reports .
16
Studies evaluating allergic reaction or atopy
StudyStudy
TypeOutcome Outcome Window Comparison groupsAllergic Reaction
Measure of
Association Intervention
Results % (N)Comparison
Results % (N)
Lewis 2001 Cohort Allergic reaction Within 3 weeks of life Hepatitis B vaccine vs No hepatitis B vaccine <0.1 (1) <0.1 (1)RR†: 0.87
(95% CI: 0.05- 13.8);
p=0.99Hepatitis B vaccination within 24 hours of birth (n = 1)
There were no differences between vaccinated and unvaccinated newborns in the proportion of those
who received care for an allergic reaction in the first 21 days of life.
†Relative risk 17There were no studies evaluating allergic reaction or atopy for newborns who received hepatitis B vaccine within
0-5 days of birth
Studies evaluating infections
StudyStudy
TypeOutcome Outcome Window Comparison groupsNumber of cultures
Measure of
Association Intervention
Results % (N)Comparison Results %
(N)
Lewis 2001 CohortBlood or CSF culture
performedWithin 3 weeks of lifeHepatitis B vaccine vs no
hepatitis B vaccine4.6 (126) 8.6 (203)RR: 0.71 (95% CI: 0.63-
0.80); p<0.001
Lewis 2001 CohortBlood or CSF culture
positiveWithin 3 weeks of lifeHepatitis B vaccine vs no
hepatitis B vaccine 0.3 (7) 0.7 (16)RR: 0.57 (95% CI: 0.35-
0.94); p=0.027Hepatitis B vaccination within 24 hours of birth (n = 1 )
Newborns vaccinated against hepatitis B were less likely to be evaluated for possible sepsis and less
likely to have a positive blood or cerebrospinal fluid (CSF) culture.
†Relative risk 18There were no studies evaluating infection for newborns who received hepatitis B vaccine within 0-5
days of birth
Studies evaluating other adverse events
StudyStudy
TypeOutcome Outcome Window Comparison groupsAdverse Event
Measure of
Association Intervention
Results % (N)Comparison Results %
(N)
Lewis 2001 Cohort Seizures Within 3 weeks of lifeHepatitis B vaccine vs no
hepatitis B vaccine0.04 (1) 0.17 (4)RR†: 0.22 (95% CI:
0.02- 1.9), p=0.19
Lewis 2001 CohortNeurological
disorders other than
seizuresWithin 3 weeks of lifeHepatitis B vaccine vs no
hepatitis B vaccine0.15 (4) 0.08 (2)RR†: 1.7 (95% CI: 0.3-
9.4), p=0.69
Morgan
2025*CohortBPD in preterm
infants born at <29
gestational weeks36 weeks postmenstrual
age**Hepatitis B vaccine vs no
Hepatitis B vaccine50.7 (155) 61.9 (317)aRR§: 0.83 (95% CI:
0.68- 1.0)Hepatitis B vaccination within 24 hours of birth (n = 3)
Hepatitis B vaccination does not appear to affect risk of seizures or neurological disorders. It may have a
slight protective effect on bronchopulmonary dysplasia (BPD) among preterm infants.
StudyStudy
TypeOutcome Outcome Window Comparison groupsAdverse Event
Measure of
Association Intervention
Results % (N)Comparison Results %
(N)
Lopez 2002 Cohort Serious adverse eventWithin 30 days of
vaccinationEngerix -B only
(no comparison)0.9 (1) NA NAHepatitis B vaccination within 0-5 days of birth (n =1)
There was one report of cough requiring hospitalization 37 days after Engerix -B birth dose vaccination.
19NA = not applicable; *Extremely preterm infants <29 weeks gestation; †Relative risk
§ Adjusted relative risk; Adjusted for maternal age, low Apgar at 1 minute, low Apgar at 5 minutes, maternal smoking, gestation period and congenital heart disease status (unadjusted RR: 0.81; 95% CI:
0.67- 0.98); ** A diagnosis of BPD was evaluated for all infants once they reached 36 weeks postmenstrual age
Studies evaluating all cause mortality
Study Study Type OutcomeOutcome
WindowComparison groupsDeathsMeasure of
AssociationIntervention
Results % (N)Comparison Results
% (N)
Morgan
2025*CohortAll-cause mortality in
preterm infants born at
<29 gestational weeksWithin 3
months of lifeHepatitis B Vaccine vs No Hepatitis
BVaccine2.3 (7) † 2.7 (14)aRR§: 1.13
(95%CI: 0.42-
2.81)Hepatitis B vaccination within 24 hours of birth (n = 1 )
There were no differences in all cause-mortality within 3 months of life among preterm infants who
received hepatitis B vaccine within 24 hours of birth and those who did not.
StudyStudy
TypeOutcomeOutcome
WindowComparison groupsNeonatal deathsMeasure of
AssociationIntervention Results
% (N)Comparison Results
% (N)
Eriksen 2004 CohortExpected neonatal
deathWithin 29 days of
vaccinationHepatitis B Vaccine vs No Hepatitis
BVaccine69 (50) 65 (128) p=0.6
Eriksen 2004 CohortUnexpected neonatal
deathWithin 29 days of
vaccinationHepatitis B Vaccine vs No Hepatitis
BVaccine31 (22) 35 (68) p=0.6
Eriksen 2004 CohortUnexpected neonatal
death from SIDSWithin 29 days of
vaccinationHepatitis B Vaccine vs No Hepatitis
BVaccine3.3 per 100,000
births3.3 per 100,000
birthsp=0.99
Greenberg 2
002RCT All-cause mortalityWithin 7 months
ofvaccinationEngerix -B vs DTaP -HepB , OPV, and Hib 0 (0) 0 (0) NAHepatitis B vaccination within 0-8 days of birth (n = 2 studies)^
One cohort suggested no difference in expected or unexpected deaths, deaths due to SIDS, among newborns who received hepatitis B vaccine and those who did not. There were no deaths reported in one RCT.
NA = not applicable.
^ Greenberg indicated hepatitis B administration occurred within 4 days (median 1 day) of birth. Eriksen stated that 85% receive d HBV on date of birth, none received the vaccine beyond 8 days of life
*Extremely preterm infants <29 weeks gestation. † Infants may have received other vaccines within the 3 -month period. The cause of death for most of these infants appeared to be unrelated to the disease
and multifactorial in nature, with most deaths probably a result of prematurity or congenital abnormalities (i.e. preceding t he HBV vaccination). § Adjusted relative risk; Adjusted for maternal age, low Apgar
at 1 minute, low Apgar at 5 minutes, maternal smoking, gestation period and congenital heart disease status (unadjusted RR: 0 .83; 95% CI: 0.32– 2.00)20
Lack of association between hepatitis B birth immunization and
neonatal death: A population- based study from the Vaccine Safety
Datalink Project
•Methods:
•Birth cohort was defined from Southern and Northern California Kaiser Permanente Health Plans of more than
350,000 live births from 1993 – 1998
•All deaths were ascertained occurring under 29 days of age
•Expected deaths:
•Deaths among extremely low birth weight (ELBW) neonates (defined as birth weight 600 g or extremely preterm 24
weeks of gestation)
•Death because of lethal congenital anomalies or other genetic conditions
•Deaths from multiple cardiac or multiple (individually) nonlethal conditions
•Potentially fatal conditions present at or within several hours of birth, such as neonatal sepsis or severe respiratory distress syndrome
.
•Unexpected deaths: No apparent preexisting medical conditions
•The proportion of deaths among birth hepatitis b vaccinated and unvaccinated were compared
•Medical record review conducted
•Results:
•1,363 neonatal deaths identified during the study period
•66% of the entire birth cohort received hepatitis B vaccine at birth
•Among all deaths, only 5% (72) neonates who died received hepatitis vaccine at birth
•No significant difference in the proportion of hepatitis B vaccinated to unvaccinated dying of unexpected causes
•Conclusion: A relationship between hepatitis B and neonatal death was not identified
Eriksen EM, Perlman JA, Miller A, et al. Lack of association between hepatitis B birth immunization and neonatal death: A pop ulation -based study from the Vaccine Safety Datalink Project. Pediatr Infect Dis J .
July 2004;23(7):656- 661. doi:10.1097/01.inf.0000130953.08946.d0
Limitation of rapid systematic review
22•Not all papers specified the exact timing of hepatitis B administration
•There were variable approaches to data collection, data analysis, and
reporting in the studies
•Primary end points included short -term outcomes (e.g., <30 days) such as
reactogenicity and mortality
•Studies that met the inclusion criteria of hepatitis B administration within 24 hours or at birth did not include long -term outcomes
•Studies that did not meet the inclusion criteria of hepatitis b administration within 24
hours or at birth do include long -term safety outcomes (e.g., > 30 days)
Summary of evidence
•The safety data available for hepatitis B vaccine administered at birth did not
identify an increased risk:
-Allergic reaction
-All-cause mortality
-Expected, or unexpected deaths or deaths due to sudden infant death syndrome (SIDS)
-Seizures or neurologic disease other than seizures
•Compared to those who did not receive a hepatitis B vaccine administered at birth, there was a reduction in risk among those who received hepatitis B vaccine for:
-An invasive diagnostic procedure (blood and CSF cultures) and a reduction in positive
cultures
-Bronchopulmonary dysplasia
•Reactogenicity within 1 week of vaccination varied by study.
23
References (1 of 2)
24Studies that defined birth dose as hepatitis B vaccine administered within 24 hours of birth
• Bassily S, Kotkat A, Gray G, et al. Comparative study of the immunogenicity and safety of two dosing schedules of hepatitis B vaccine in neonat es. Am J Trop Med Hyg . Oct
1995;53(4):419- 22. doi:10.4269/ajtmh.1995.53.419
• Lewis E, Shinefield HR, Woodruff BA, et al. Safety of neonatal hepatitis B vaccine administration. Pediatr Infect Dis J . Nov 2001;20(11):1049- 54. doi:10.1097/00006454-
200111000- 00009
• Linder N, Raz M, Reichman B, et al. Unexplained fever in neonates may be associated with hepatitis B vaccine. Archives of Disease in Childhood: Fetal and Neonatal Edition .
1999;81(3):F206- F207. doi:10.1136/fn.81.3.F206
• Morgan HJ, Nold MF, Kattan GS, et al. Hepatitis B vaccination of preterm infants and risk of bronchopulmonary dysplasia: a co hort study, Australia. Vaccination contre l'hepatite
B de prematures et risque de dysplasie bronchopulmonaire : etude de cohorte en Australie , Vacunacion contra la hepatitis B en neonatos prematuros y riesgo de displasia
broncopulmonar : estudio de cohortes en Australia. Bull World Health Organ . 2025;103(3):187- 193. doi:10.2471/BLT.24.291683
• Yerushalmi B, Raz R, Blondheim O, Shumov E, Koren R, Dagan R. Safety and immunogenicity of a novel mammalian cell -derived recombinant hepatitis B vaccine containing Pre-
S1 and Pre -S2 antigens in neonates. Pediatr Infect Dis J . Jun 1997;16(6):587- 92. doi:10.1097/00006454- 199706000- 00009
Studies that indicated hepatitis B vaccine administered within 0 -8 days of birth
• Eriksen EM, Perlman JA, Miller A, et al. Lack of association between hepatitis B birth immunization and neonatal death: A popula tion -based study from the Vaccine Safety
Datalink Project. Pediatr Infect Dis J . July 2004;23(7):656- 661. doi:10.1097/01.inf.0000130953.08946.d0
• Greenberg DP, Wong VK, Partridge S, Howe BJ, Ward JI. Safety and immunogenicity of a combination diphtheria -tetanus toxoids -acel lular pertussis -hepatitis B vaccine
administered at two, four and six months of age compared with monovalent hepatitis B vaccine administered at birth, one month and six months of age. Pediatr Infect Dis J . Aug
2002;21(8):769- 77. doi:10.1097/00006454- 200208000- 00014
• Lopez P, Rubiano L, del Pilar Rubio M, David MP, Safary A. Immunogenicity and reactogenicity of DTPw -HB/Hib vaccine administered to colombian infants after a birth dose of
hepatitis B vaccine. Clinical Trial. Expert Rev Vaccines. Oct 2002;1(3):277- 83. doi:10.1586/14760584.1.3.277
• Wood N, Nolan T, Marshall H, et al. Immunogenicity and Safety of Monovalent Acellular Pertussis Vaccine at Birth: A Randomize d Clinical Trial. Jama, Pediatr . 11 01
2018;172(11):1045- 1052. doi:10.1001/jamapediatrics.2018.2349
References (2 of 2)
25Studies that indicated hepatitis B vaccine administered within >8 days of birth and within first month of life
•Gallagher CM, Goodman MS. Hepatitis B vaccination of male neonates and autism diagnosis, NHIS 1997 -2002. Journal of Toxicology and Environmental Health - Part A: Current Issues .
January 2010;73(24):1665- 1677. doi:10.1080/15287394.2010.519317
•Geier DA, Hooker BS, Kern JK, King PG, Sykes LK, Geier MR. A two -phase study evaluating the relationship between Thimerosal -cont aining vaccine administration and the risk for an autism
spectrum disorder diagnosis in the United States. Transl Neurodegener . Dec 19 2013;2(1):25. doi:10.1186/2047 -9158- 2-25
•Geier DA, Kern JK, Hooker BS, et al. Thimerosal exposure and increased risk for diagnosed tic disorder in the United States: A case-control study. Interdisciplinary Toxicology . 01 Jun
2015;8(2):68- 76. doi:10.1515/intox -2015- 0011
•Geier DA, Kern JK, Hooker BS, King PG, Sykes LK, Geier MR. A longitudinal cohort study of the relationship between Thimerosal -containing hepatitis B vaccination and specific delays
indevelopment in the United States: Assessment of attributable risk and lifetime care costs. Journal of Epidemiology and Global Health. 01 Jun 2016;6(2):105-
118. doi:10.1016/j.jegh.2015.06.002
•Geier DA, Kern JK, Homme KG, Geier MR. Thimerosal exposure and disturbance of emotions specific to childhood and adolescence: A case -control study in the Vaccine Safety Datalink
(VSD) database. Brain Injury. 28 Jan 2017;31(2):272- 278. doi:10.1080/02699052.2016.1250950
•Geier DA, Kern JK, Geier MR. Premature puberty and thimerosal -containing Hepatitis B vaccination: A case -control study in the va ccine safety datalink. Toxics. 15 Nov 2018;6(4) (no
pagination)67. doi:10.3390/toxics6040067
•Haber P, Moro PL, Ng C, et al. Safety of currently licensed hepatitis B surface antigen vaccines in the United States, Vaccin e Adverse Event Reporting System (VAERS), 2005 -2015. Historical
Article. Vaccine. 01 25 2018;36(4):559- 564. doi:10.1016/j.vaccine.2017.11.079
•Niu MT, Davis DM, Ellenberg S. Recombinant hepatitis B vaccination of neonates and infants: emerging safety data from the Vac cine Adverse Event Reporting System. Pediatr Infect Dis J.
Sep 1996;15(9):771- 6. doi:10.1097/00006454- 199609000- 00007
•Niu MT, Salive ME, Ellenberg SS. Neonatal deaths after hepatitis B vaccine: the vaccine adverse event reporting system, 1991 -1998. Arch Pediatr Adolesc Med . Dec 1999;153(12):1279- 82.
doi:10.1001/archpedi.153.12.1279
•Sapru A, Kulkarni PS, Bhave S, Bavdekar A, Naik SS, Pandit AN. Immunogenicity and reactogenicity of two recombinant hepatitis B vaccines in small infants: a randomiz ed, double -blind
comparative study. J Trop Pediatr. Oct 2007;53(5):303- 7. doi:10.1093/ tropej /fmm016
•Verstraeten T, Davis RL, DeStefano F, et al. Safety of Thimerosal- Containing Vaccines: A Two -Phased Study of Computerized Health Maintenanc e Organization Databases. Pediatrics.
November 2003;112(5):1039- 1048. doi:10.1542/peds.112.5.1039
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The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.
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