hep b at birth vax safety summary 508

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not
be construed to represent any agency determination or policy .  Page 1 of 84
 ACIP BRIEFING MATERIALS FOR PUBLIC POSTING
The Safety of Hepatitis B Vaccines  administered within 24 hrs of birth and within 30 days of
birth: A Rapid Systematic Review
Table of Contents
Table of Tables  ................................ ................................ ................................ ................................ ................................ .... 2
Table of Figures  ................................ ................................ ................................ ................................ ................................ ... 3
A. Methods  ................................ ................................ ................................ ................................ ................................ ..............  4
A.1. Key Question Development  ................................ ................................ ................................ ................................ .........  4
A.2. Literature Search  ................................ ................................ ................................ ................................ .........................  4
A.3. Study Selection  ................................ ................................ ................................ ................................ ............................  4
A.4. Data Extraction, Study Assessment, and Synthesis  ................................ ................................ ................................ ..... 7
A.5. GRADE -ing and Recommendation Development  ................................ ................................ ................................ ........  7
B. Summary of Evidence  ................................ ................................ ................................ ................................ .........................  8
B.1. GRADE -ed Summary of Findings for Hepatitis B vaccine administered in the first 24 hours of life  ............................  8
B.2. GRADE -ed Summary of Findings for Hepatitis B vaccine administered in the first 30 days of life  ............................  15
C. Extracted Evidence from Included Studies  ................................ ................................ ................................ .......................  42
C.1. Study Characteristics for All Included Studies  ................................ ................................ ................................ ...........  42
C.2. Outcomes for All Included Studies  ................................ ................................ ................................ .............................  44
C.3. Risk of Bias Assessments for All Included Studies  ................................ ................................ ................................ ..... 75
D. Search Strategies  ................................ ................................ ................................ ................................ ..............................  80
E. References  ................................ ................................ ................................ ................................ ................................ .........  83

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not
be construed to represent any agency determination or policy .  Page 2 of 84
 Table of Tables
Table 1. PI/ECO(ST) Criteria for Key Question  ................................ ................................ ................................ .......................  4
Table 2. GRADE Table: Allergic Reaction or Atopy Outcomes and the Administration of the Hepatitis B Vaccine in the
first 24 hours of life  ................................ ................................ ................................ ................................ ................................  8
Table 3. GRADE Table: All -cause Mortality Outcomes and the Administration of the Hepatitis B Vaccine in the first 24
hours of life  ................................ ................................ ................................ ................................ ................................ .............  8
Table 4. GRADE Table: Infection or Infection -related Outcomes and the Administration of the Hepatitis B Vaccine in
the first 24 hours of life  ................................ ................................ ................................ ................................ ..........................  9
Table 5. GRADE Table: Local Injection Site Reaction Outcomes and the Administration of the Hepatitis B Vaccine in the
first 24 hours of life  ................................ ................................ ................................ ................................ ................................  9
Table 6. GRADE Table: Systemic Reaction Outcomes and the Administration of the Hepatitis B Vaccine in the first 24
hours of life  ................................ ................................ ................................ ................................ ................................ ...........  11
Table 7. GRADE Table: Cardiopulmonary Outcomes and the Administration of the Hepatitis B Vaccine in the first 24
hours of life  ................................ ................................ ................................ ................................ ................................ ...........  13
Table 8. GRADE Table: Neurological Outcomes and the Administration of the Hepatitis B Vaccine in the first 24 hours
of life  ................................ ................................ ................................ ................................ ................................ .....................  14
Table 9. GRADE Table: Adverse event following immunization (AEFI) outcomes and administration of the Hepatitis B
Vaccine in the first 30 days of life  ................................ ................................ ................................ ................................ ........  15
Table 10. GRADE Table: Allergic reaction and atopy outcomes and administration of the Hepatitis B Vaccine in the first
30 days of life ................................ ................................ ................................ ................................ ................................ ........  16
Table 11. GRADE Table: Mortality outcomes and administration of the Hepatitis B Vaccine in the first 30 days of life  17
Table 12. GRADE Table: Infection outcomes and administration of the Hepatitis B Vaccine in the first 30 days of life  . 18
Table 13. GRADE Table: Local injection site outcomes and administration of the Hepatitis B Vaccine in the first 30 days
of life  ................................ ................................ ................................ ................................ ................................ .....................  20
Table 14. GRADE Table: Neurodevelopmental outcomes and administration of the Hepatitis B Vaccine in the first 30
days of life  ................................ ................................ ................................ ................................ ................................ ............  23
Table 15. GRADE Table: Neurologic outcomes and administration of the Hepatitis B Vaccine in the first 30 days of life
 ................................ ................................ ................................ ................................ ................................ ..............................  28
Table 16. GRADE Table: Cardiopulmonary outcomes and administration of the Hepatitis B Vaccine in the first 30 days
of life  ................................ ................................ ................................ ................................ ................................ .....................  30
Table 17. GRADE Table: Systemic reactions and administration of the Hepatitis B Vaccine in the first 30 days of life  .. 31
Table 18. GRADE Table: Other outcomes and administration of the Hepatitis B Vaccine in the first 30 days of life  ...... 40
Table 19. Characteristics of Studies Meeting Inclusion Criteria  ................................ ................................ .........................  42
Table 20 . Adverse Events Following Immunization (AEFI)  Results of Studies Meeting Inclusion Criteria  ........................  44
Table 21. Allergic Reaction and Atopy Results of Studies Meeting Inclusion Criteria  ................................ .......................  44
Table 22. All Death Outcomes Results of Studies Meeting Inclusion Criteria  ................................ ................................ .... 45
Table 23. Infection Results of Studies Meeting Inclusion Criteria  ................................ ................................ ......................  47
Table 24. Local Injection -site Outcomes Results of Studies Meeting Inclusion Criteria  ................................ ....................  48
Table 25. Neurodevelopmental Results of Studies Meeting Inclusion Criteria  ................................ ................................ . 52
Table 26. Neurologic Results of Studies Meeting Inclusion Criteria  ................................ ................................ ...................  60
Table 27. Cardiopulmonary Results of Studies Meeting Inclusion Criteria  ................................ ................................ ........  61
Table 28. Systemic Reactions Results of Studies Meeting Inclusion Criteria  ................................ ................................ ..... 63
Table 29. Other Reactions Results of Studies Meeting Inclusion Criteria  ................................ ................................ ..........  74
Table 30. Search Strategies and Results  ................................ ................................ ................................ ..............................  80

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not
be construed to represent any agency determination or policy .  Page 3 of 84
 Table of Figures
Figure 1. Results of the Study Selection Process  ................................ ................................ ................................ ..................  6
Figure 2. Risk of Bias Assessments for Randomized Controlled Trials  ................................ ................................ ...............  75
Figure 3. Risk of Bias Assessments for Cohort Studies  ................................ ................................ ................................ ........  77
Figure 4. Risk of Bias Assessments for Case Control Studies  ................................ ................................ ..............................  78
Figure 5. Risk of Bias Assessments for Case Series Studies  ................................ ................................ ................................  79

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not
be construed to represent any agency determination or policy .  Page 4 of 84
 A. Methods
A.1. Key Question Development
The Key Question s were  developed  by infectious disease and systematic review methodology subject matter experts
using the PICO  framework1 (Population, Intervention, Comparator, and Outcome ). The Key Question  and PI /ECO(ST)
Criteria  used to guide the literature review are below and in Table 1.
1. What is the safety of the hepatitis B vaccine administered within the first 24 hours  of life ?
2. What is the safety of the hepatitis B vaccine administered within the first 30 days of life?
Table 1. PI/ECO(ST) Criteria for Key Question
PI/ECO(ST) ELEMENT  Description for this Review
Population  Neonates, Newborns, Infants
Intervention or
Exposure  Hepatitis B vaccine administration  within the first 30 days  of birth
• HepB, HepB -BD, HBV, Engerix -B, Recombivax HB
• Administration in the f irst 24 hours of life:
o Studies clearly identify vaccination within
▪ the first 24 hours of life or birth,
▪ the first day of life, or
▪ the day of or the day after birth
• Administration  in the first 30 days of life :
o Studies clearly identify vaccination
▪ in first 30 days of life ,
▪ at <0.1 years of age,  or
▪ of Neonate (aged 28 days or less)
Comparator (if
applicable)  Any or none
Outcome(s)  Adverse events
Adverse outcomes
Safety outcomes
Side effects
Reaction
Adverse reaction
Adverse effect
Serious adverse event
Setting  Any
Time Frame  Any publication years
Any duration of follow up

A.2. Literature Search
A CDC informationist (J.T.)  developed search strategies from the Key Question  and PICO criteria,  and performed the
search in MEDLINE, EMBASE , CINAHL , and Cochrane Library  from  the start of each database to July 31, 2025 . Search
strategies and results are provided in  Section D of this document ( Search Strategies ).
A.3. Study Selection
Results of the literature searches were uploaded into EndNote 21 (Clarivate Analytics©, Thomson Reuters, New
York, NY, USA), duplicate records were removed, and unique t itles and abstracts  were uploaded to Covidence
(Veritas Health Innovation Ltd., Melbourne, VIC, Australia) where a second round of deduplication was conducted.

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not
be construed to represent any agency determination or policy .  Page 5 of 84
 Two reviewers (AH, LZ, MM1, MM2, RG, TM ) independently screened all titles and abstracts and removed irrelevant
references. Relevant  full texts  were screened independent ly by two  reviewers  (AH, LZ, MM1, MM2, RG, TM ) and
disagreements were resolved by consensus . All studies were screened according to the pre -identified exclusion
criteria below, and results of the study selection process are provided in Figure 1 .

Criteria for excluding studies from the literature review include:
1. No full text  available;
2. Not available in English;
3. Not relevant to key question ;
4. No p opulation of interest  (e.g., no neonates) ;
5. No intervention  of interest  (e.g., no hepatitis b vaccine) ;
6. No outcome of interest  (e.g., no adverse event outcomes) ;
7. No primary data  or secondary data not systematically collected  (no reproducible methods) ;
8. Data collected prior to licensure ; or
9. Insufficient methodologic reporting ( i.e., poster, abstract, letter to editor )

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not
be construed to represent any agency determination or policy .  Page 6 of 84

   Figure 1. Results of the Study Selection Process

Identification
Studies screened (n = 1907)
Studies sought for retrieval (n = 229)
Studies assessed for eligibility (n = 229)     References 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 excluded (n = 1678)
Studies not retrieved (n = 0)
Studies excluded (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)
Included  Studies assessed for administration of HepB birth
dose alone and HepB vaccine specific outcomes
(n = 71)
Screening  Studies from databases/registers (n = 1916 )
MEDLINE  (n = 1916 )
Studies excluded  (n = 51)
Outcome or population not stratified  by HepB birth dose or
HepB vaccine outcome  (n = 47)
Systematic reviews/meta -analyses (n = 4)
Studies extracted  for HepB birth dose (n = 20)
Reported HepB birth dose within 24 hours of birth  (n = 5)

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policy .  Page 7 of 84
 A.4. Data Extraction , Study Assessment , and Synthesis
Data from studies meeting inclusion criteria were independently extracted by two reviewers using a standardized Microsoft Excel (2021) form, and
differences were reconciled by discussion. Extracted data included study characteristics, population characteristics (e.g., case and control definitions),
outcome definitions, an d results (presented in Section C ). Outcome data were extracted as presented in the studies or calculated using data provided. For
the purposes of this review, statistical significance was defined as p ≤ 0.05 . The r isk of bias for each study was assessed according to study type  using
standardized  risk of bias tools  appropriate to the identified study type. Tools were modified to specify  birthweight, age at administration, prematurity, and
maternal hepatitis b status as  confounding factors  and to include an assessment of conflict -of-interest  disclosures . The Newcastle -Ottawa Scale was used for
cohort and case control studies , R.O.B2. for randomized controlled trials (RCTs) , and JBI tools were used to assess the risk of  bias for Case Series and
Systematic Reviews2-4. The signaling questions used to assess study conduct and risk of bias and results are presented in Section C.3 . The evidence was
narratively synthesized for  each  outcome domain, and for specific outcomes where definitions aligned.
A.5. GRADE -ing and Recommendation Development
The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach  was used to assess the  risk of bias , imprecision,
inconsistency, and indirectness , and final confidence for the body of evidence  foreach outcome  using .5 The Summary of findings and confidence in the
evidence are found in Section B .

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policy .  Page 8 of 84
 B. Summary of Evidence
B.1. GRADE -ed Summary of Findings  for Hepatitis B vaccine administered in the first 24 hours of life
Key Question: Among children, what is the safety of the hepatitis B vaccine administered in the first 24 hours  of life?
 Table 2. GRADE Table: Allergic Reaction or Atopy Outcomes and the Administration of the Hepatitis B Vaccine in the first 24 hours of l ife
Outcome  Summary  Studies  Risk of
Bias  Imprecision  Inconsistency  Indirectness  Confidence
Summary Events  The evidence from one cohort study suggests there is no
difference in the risk of an allergic reaction and the receipt
hepatitis B vaccination in the first 24 hours of life.  1 Cohort6
(N = 5,655)  No
concerns No concerns No concerns  No concerns  Low
confidence
Allergic reaction  One cohort6 of normal birthweight, full term, U.S. infants in
the VSD (NCK) reported no difference in the risk of an allergic
reaction among infants with a record of Hepatitis B
vaccination on the first day of life or the day after compared
with infants with no record of Hepatitis B vaccination  within
the first 21 days of life . [RR: 0.87; (95%CI: 0.05 -13.8); p=0.99;
1/2,718 vs 1/2,353].  1 Cohort6
(N = 5,655)  No
concerns  No concerns  No concerns  No concerns  Low
confidence

Table 3. GRADE Table: All -cause Mortality  Outcomes and the Administration of the Hepatitis B Vaccine in the first 24 hours of life
Outcome  Summary  Studies  Risk of
Bias  Imprecision  Inconsistency  Indirectness  Confidence
Summary Events  The evidence from one Cohort7 suggest s no difference in the
risk of all-cause mortality among those who did and did not
and receive a hepatitis B vaccination in the first 24 hours of
life. 1 Cohort7
(N = 818)  No
concerns No concerns No concerns  No concerns  Low
confidence
All-cause mortality  One cohort7 of extremely preterm infants (<29 wks gestation)
in Australia’s Surveillance of Adverse Events Following
Immunization in the Community suggested there is no
difference in risk of death during the first 3 months of life
when comparing infants with a record of receiving Hepatitis B
vaccine within 24 hours of birth to infants with no record in
the first 24  hours  [aRR: 1.13; (95%CI: 0.42 -2.81); 7/306 vs
14/512].  1 Cohort7
(N = 818)  No
concerns  No concerns  No concerns  No concerns  Low
confidence

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policy .  Page 9 of 84
 Table 4. GRADE Table: Infectio n or Infection -related  Outcomes and the Administration of the Hepatitis B Vaccine in the first 24 hours of life
Outcome  Summary  Studies  Risk of
Bias  Imprecision  Inconsistency  Indirectness  Confidence
Infections  The evidence from one cohort study suggests there is a reduction
in the risk of an invasive diagnostic procedure including blood and
CSF cultures , and a reduction in positive cultures , among infants
who recei ved a hepatitis B vaccination in the first 24 hours of life ,
compared to those who did not . 1 Cohort6
(N = 5,655)
 No
concerns No concerns No concerns  No concerns  Low
confidence
Blood or CSF culture
performed  One cohort6 of normal birthweight, full term U.S. infants in the  VSD
(NCK) reported  a reduction in the age -stratified risk of having a
blood or CSF culture performed in the first three weeks of life when
comparing infants with a record of receiving thimerosal -containing
Hepatitis B vaccine on the day of birth or the day after compared to
infants with no record of Hepatitis B vaccination [RR: 0.71; (95%CI:
0.63 -0.80); p <0.001; 126/2,718 vs 203/2,353].  1 Cohort6
(N = 5,655)  No
concerns  No concerns  No concerns  No concerns  Low
Confidence
Blood or CSF culture
positive  One cohor t6 of normal birthweight, full term U.S. infants in the VSD
(NCK) reported  a reduction in the age -stratified risk of having a
positive blood or CSF culture in the first three weeks of life when
comparing infants with a record of receiving thimerosal -containing
Hepatitis B vaccine on the day of birth or the day after compared to
infants with no record of Hepatitis B vaccination [RR: 0.57; (95%CI:
0.35 -0.94); p <0.027; 7/2,718 vs 16/2,353].  1 Cohort6
(N = 5,655)  No
concerns  No concerns  No concerns  No concerns  Low
Confidence

Table 5. GRADE Table: Local Injection Site Reaction  Outcomes and the Administration of the Hepatitis B Vaccine in the first 24 hours of life
Outcome  Summary  Studies  Risk of
Bias  Imprecision  Inconsistency  Indirectness  Confidence
Local Injection Site
Reactions  Two RCTs suggest no difference in local side effects, pain or
soreness, redness, or swelling at the injection site within 1
week of vaccination or less when comparing infants who
received a dose of a Hepatitis B Vaccine within the first 24
hours, compared to those who were vaccinated never or
later.  2 RCT8,9
(N = 741)
 Serious
concernsa No concerns No concerns  No concerns  Low
confidence
Local side effects  One RCT of Egyptian infants8, compared the outcome of local
side effects (e.g., local soreness, or temporary
redness/induration at the injection site) 1 week after
vaccination among infants randomized to administration of
the first of dose of Recombivax immediately after delivery, at 1 RCT8
(N = 536)
 Serious
concernsa No concerns  No concerns  No concerns  Low
confidence

a Inadequate randomization, unclear allocation concealment and blinding

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policy .  Page 10 of 84
 Outcome  Summary  Studies  Risk of
Bias  Imprecision  Inconsistency  Indirectness  Confidence
two months of age, or at 18 months of age, and reported a
higher proportion of local side effects among those who
received the vaccine at birth  (2.8% (5/178) at birth, vs  7.2%
(12/167), vs. 1.6% (3/191) at 18 months]. No relationship was
found between side effects and weight or prematurity.
Pain  In a RCT of Israeli infants9, 4/52 (7.7%) infants who received
Engerix -B within 24 hours of birth and 4/153 (2.6%) who
received BioHepB within 24 hours of birth experienced pain
with movement within 5 days of vaccination. Additionally,
4/52 (7.7%) infants who received Engerix -B withi n 24 hours of
birth and 2/153 (1.3%) who received BioHepB within 24 hours
of birth experienced pain with pressure within 5 days of
vaccination.  The HepB vaccine BioHepB is not approved for
use in the United States.  1 RCT9
(N = 205)  Serious
concernsb Some
concernsc No concerns  No concerns  Very low
confidence

Redness or erythema  One RCT of Israeli infants9 reported no redness or erythema
within 5 days of vaccination among infants randomized to
receipt of Engerix -B or BioHepB within 24 hours of birth (0/52
vs. 0/153). The HepB vaccine BioHepB is not approved for use
in the United States.  1 RCT9
(N = 205)

 Serious
concernsd

 Some
concernsd

 No concerns

 No concerns

 Very low
confidence

Swelling  One randomized control trial of Israeli infants9 reported a
higher proportion of swelling at the injection site within five
days of vaccination among infants who received thimerosal -
containing Engerix -B within 24 hours of birth compared with
those who received BioHepB within 24 hours of birth [4/52
(7.7%) vs. 3/153 (2.0%)]  The HepB vaccine BioHepB is not
approved for use in the United States.  1 RCT9
(N = 205)
 Serious
concernse
 Some
concernsd
 No concerns

 No concerns

 Very low
confidence

b Unclear allocation concealment; absence of statistical analyses and reporting on protocol deviations
c Small sample size
d Unclear allocation concealment; absence of statistical analyses and reporting on protocol deviations
e Unclear allocation concealment; absence of statistical analyses and reporting on protocol deviations

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 11 of 84
 Table 6. GRADE Table: Systemic Reaction  Outcomes and the Administration of the Hepatitis B Vaccine in the first 24 hours of life
Outcome  Summary  Studies  Risk of
Bias  Imprecision  Inconsistency  Indirectness  Confidence
Systemic Reactions  2 RCTs and 2 cohorts suggested no difference in fever
when comparing infants who were vaccinated in the first
24h with a Hep B Vaccine to those who were vaccinated
later , not at all , or with a different vaccine.

One RCT9 of Israeli infants suggested no difference in
anorexia/ decreased appetite, diarrhea or vomiting,
however, it did suggest an increase in  irritability or
fussiness  when comparing  infants who received hepatitis
B vaccine in the first 24 hours after birth with infants who
received the BioHepB (not approved in U.S.) vaccine in
the first 24 hours.  2 RCTs8,9
(N = 741)

2 cohort6,10
(N = 16,484)  Serious
concernsf

Some
concernsg

 Some
concernsh

No concerns

 No concerns

No concerns

 No concerns

No concerns

 Very low
confidence

Very low
confidence
Anorexia/Decreased
appetite  In a RCT of Israeli infants9, 0/52 infants who received
Engerix -B within 24 hours of birth and 3/153 (2.0%) who
received BioHepB within 24 hours of birth experienced
anorexia within 5 days of vaccination.  The HepB vaccine
BioHepB is not approved for use in the United States.  1 RCT9
(N = 205)  Serious
concernsi Some concernsj No concer ns No concer ns Very low
confidence
 Diarrhea  or vomiting  In a RCT of Israeli infants9, 0/52 infants who received
Engerix -B within 24 hours of birth and 1/153 (0.64%) who
received BioHepB within 24 hours of birth experienced
diarrhea or vomiting within 5 days of vaccination. The
HepB vaccine BioHepB is not approved for use in the
United State s. 1 RCT 9
(N = 205)  Serious
concernsk Some concernsl
 No concerns  No concerns  Very low
confidence
Fever  Two RCTs  reported no difference in fever among infants
who received Hepatitis B vaccination within 24 hours of
birth whether compared to the same vaccine at 2 months
and at 18 months of age, or a combination vaccine
delivered at birth.

Very low
confidence

f Inadequate randomization, unclear allocation concealment and blinding; absence of statistical analyses and reporting on proto col deviations
g One study compared groups with different birth years , and did not adjust or age stratify the results.
h One study had a small sample size in one group.
i Unclear allocation concealment; absence of statistical analyses and reporting on protocol deviations
j Small sample size
k Unclear allocation concealment; absence of statistical analyses and reporting on protocol deviations
l One study had a small sample size in one group.

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 Outcome  Summary  Studies  Risk of
Bias  Imprecision  Inconsistency  Indirectness  Confidence
• One RCT of Egyptian infants8, compared the
outcome of local side effects 1 week after
vaccination among infants randomized to
administration of the first of dose of Recombivax
immediately after delivery (n=178), or at 18 months
of age (n=191). There was no difference in the
proportion who experienced fever among those
who received the vaccine immediately after delivery
(5.6%) compared to  at 2 months (7.2%) or  at 18
months (2.1%).
• In a RCT of Israeli infants9, 0/52 infants who received
Engerix -B within 24 hours of birth and 2/153 (1.3%)
who received BioHepB within 24 hours of birth
experienced a temperature ≥38 ⁰C within 5 days of
vaccination. The HepB vaccine BioHepB is not
approved for use in the United States.

Two cohorts reported inconsistent results on the
proportion fever among  infants who did and did not
receive a dose of Hepatitis B vaccine in the first day of life ,
with the stronger study reporting no difference  when
adjusting for age at birth and year of vaccination ; however,
the study that compared different birth years and did not
adjust or age -stratify the results  report ed a higher
proportion of fever among those who received the Hep B
vaccine in the first day of life .
• One cohort6 of normal birthweight, full term, U.S.
infants in the Vaccine Safety Datalink (NCK) reported
no difference in the risk of a fever in the first three
weeks of life when comparing infants with a record
of receiving thimerosal -containing Hepatitis B
vaccine on the day of birth or day after birth with
infants with no record of Hepatitis B vaccination
within the first 21 days of life [RR: 0.85; (95%CI: 0. 6-
1.1); p=0. 28; 21/2,718 vs 25/2,353].
• In a cohort study of full -term Israeli infants10,
68/5,819 (1.2%) full -term infants receiving hepatitis
2 RCTs8,9
(N = 741)

2 cohort6,10
(N = 16,484 )

Serious
concernsm

Some
concernsn

 Some  concernso

No concerns

No concerns

No concerns

No concerns

No concerns

Very low
confidence

m Inadequate randomization, unclear allocation concealment and blinding; absence of statistical analyses and reporting on proto col deviations
n One study compared groups with different birth years and did not adjust , or age stratify the results.
o One study had a small sample size  in one group.

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policy .  Page 13 of 84
 Outcome  Summary  Studies  Risk of
Bias  Imprecision  Inconsistency  Indirectness  Confidence
B vaccination and 27/5,010 (0.54%) full -term infants
not receiving hepatitis B vaccine had a birth
hospitalization discharge diagnosis of “neonatal
fever” above 37. 5⁰C (p<0.001). Fevers above 38⁰C
were noted in 50 (0.9%) of vaccinated infants and 27
(0.54%) of unvaccinated infants (p<0.05).
Identifiable causes of fever (e.g ., sepsis,
dehydration, maternal fever, respiratory distress)
were noted among 15 vaccinated inf ants (0.3%) and
13 unvaccinated infants (0.3%). Unexplained fevers
were noted among 35 (0.6%) vaccinated infants and
14 (0.3%) unvaccinated infants (p=0.013).
 Irritability or fussiness  In a RCT of Israeli infants9, 6/52 (11.5%) infants who
received Engerix -B within 24 hours of birth and 5/153
(3.3%) who received BioHepB within 24 hours of birth
experienced irritability within 5 days of vaccination. The
HepB vaccine BioHepB is not approved for use in the
United States  1 RCT9
(N = 205)  Serious
concernsp Some concernsq No concerns  No concerns  Very low
confidence

Table 7. GRADE Table: Cardiopulmonary  Outcomes and the Administration of the Hepatitis B Vaccine in the first 24 hours of life
Outcome  Summary  Studies  Risk of
Bias  Imprecision  Inconsistency  Indirectness  Confidence
Cardiopulmonary  The evidence from one cohort study of extremely preterm
infants suggests a reduction in the adjusted risk of
bronchopulmonary dysplasia among infants with a record of
receiving Hepatitis B  vaccine in the first 24 hours of life
compared to infants with no record in the first 24h  1 Cohort7
(N = 818)  No
concerns No concerns No concerns  No concerns  Low
confidence
Bronchopulmonary
dysplasia  One cohort7 of extremely preterm infants (<29 wks gestation)
in Australia’s Surveillance of Adverse Events Following
Immunization in the Community suggested there is a
reduction in risk of bronchopulmonary dysplasia when
comparing infants with a record of receiving Hepatitis B
vaccine within 24 hours of birth to infants with no record
when adjusting for maternal age, maternal smoking, Apgar 1 Cohort7
(N = 818)  No
concerns  No concerns  No concerns  No concerns  Low
confidence

p Unclear allocation concealment; absence of statistical analyses and reporting on protocol deviations
q Small sample size

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 14 of 84
 score and congenital heart disease status [aRR: 0.83; (95%CI:
0.68 -1.0); 155/306 vs 317/512].

Table 8. GRADE Table: Neurological  Outcomes and the Administration of the Hepatitis B Vaccine in the first 24 hours of lif e
Outcome  Summary  Studies  Risk of
Bias  Imprecision  Inconsistency  Indirectness  Confidence
Neurological  The evidence from one cohort of normal birthweight, full
term infants in the U.S.VSD suggested there is no difference
in the risk of seizures or Neurologic disease other than
seizures  when comparing infants who received Hepatitis B
vaccine on the day of birth or the day after birth to infants
with no record of vaccination in the first 24 hours of life . 1 Cohort6
(N = 5,655)
  No
concerns No concerns No concerns  No concerns  Low
confidence
Seizure  One cohort6 of normal birthweight, full term U.S. infants in
the VSD (NCK) suggested there is no difference in the risk of
seizures in the first three weeks of life when comparing
infants with a record of receiving thimerosal -containing
Hepatitis B vaccine on the day  of birth or day after birth with
infants with no record of Hepatitis B vaccination within the
first 21 days of life [RR: 0.22; (95%CI: 0.02 -1.9); p=0.19;
1/2,718 vs 4/2,353].  1 Cohort6
(N = 5,655)
  No
concerns  No concerns  No concerns  No concerns  Low
confidence
Neurologic disease, other
than seizure  One cohort6 of normal birthweight, full term U.S. infants in
the VSD (NCK) suggested there is no difference in the risk of
neurologic disease in the first three weeks of life when
comparing infants with a record of receiving thimerosal -
containing Hepatitis B vaccine on the day of birth or day after
birth with infants with no record of Hepatitis B vaccination
within the first 21 days of life [RR: 1.7; (95%CI: 0.3 -9.4);
p=0.69; 4/2,718 vs 2/2,353].  1 Cohort6
(N = 5,655)
 No
concerns  No concerns  No concerns  No concerns  Low
confidence

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 15 of 84
 B.2. GRADE -ed Summary of Findings for Hepatitis B vaccine administered in the first 30 days of life
Key Question: Among children, what is the safety of the hepatitis B vaccine administered in the first 30 days  of life?

Table 9. GRADE Table: Adverse event following immunization (AEFI)  outcomes and administration  of the Hepatitis B Vaccine in the first 30 days of life
Outcome  Summary  Studies  Risk of
Bias Imprecision  Inconsistency  Indirectness  Confidence
All Adverse events
following immunization
(AEFI)  The evidence from two single group studies suggest ing that
serious adverse events can occur  following the administration
of a thimerosal -containing Hepatitis  B vaccine in the first 30
days of life  in neonates in Columbia and the U.S. The three
serious adverse events in the U.S. occurred in the context of
the administration of 12 million doses among infants less than
1 year of age . 2 DES11,12
(N = 177)
 Some
concernsr
 Some
concernss No concerns  No concerns  Very low
confidence
Cerebral venous
thrombosis/intraventricular
hemorrhage
 One case series examined  VAERS reports of U.S. neonates <0.1
years of age  who received a thimerosal -containing Hepatitis B
vaccine between 1991 – 199412 and identified  one serious
report of c erebral venous thrombosis/intraventricular
hemorrhage  [1.7% (1/60)] . 1 DES12
(N = 60) Some
concernst No concerns  No concerns  No concerns  Very Low
confidence
Disseminated intravascular
coagulation  One case series12 examined  VAERS reports  of U.S. neonates
<0.1 years of age who received a thimerosal -containing
Hepatitis B vaccine between 1991 – 1994 and identified one
(1.7%) serious report of d isseminated intravascular coagulation
[1.7% (1/60)] .  1 DES12
(N = 60)  Some
concernsa No concerns  No concerns  No concerns  Very Low
confidence
Necrotizing enterocolitis  One case series12 examined  VAERS reports of U.S. neonates
<0.1 years of age who received a thimerosal -containing
Hepatitis B vaccine between 1991 – 1994 and identified one
serious report of necrotizing enterocolitis  [1.7% (1/60 )]. 1 DES12 (N
= 60)  Some
concernsa No concerns  No concerns  No concerns  Very Low
confidence
Serious adverse events  A single group cohort11 of 117 healthy neonates  in Colombia
who received a n Engerix -B Hepatitis B vaccine dose  at birth ,
reported one adverse event (cough requiring hospitalization)
37 days after vaccination deemed serious, but unrelated to
vaccine by study investigators  [0.9% (1/117)].  1 DES11
(N = 117)  Some
concernsu Some
concernsv No concerns  No concerns  Very low
confidence

r Measurement bias: -1 for retrospective reporting and unclear temporality
s Small sample size
t Measurement bias: -1 for retrospective reporting  and unclear temporality
u Measurement & misclassification: -1 for unclear day of dosing; -1 for no comparator group
v Small sample size

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 16 of 84

Table 10. GRADE Table: Allergic reaction and atopy outcomes and administration of the Hepatitis B Vaccine in the first 30 days of life
Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
All Allergic reactions
and Atopy  One RCT13 and one Cohort6 suggest a low rate of occurrence
of allergic reactions and atopy among infants vaccinated with
Hepatitis -B vaccines in the first 30 days of life, and no
difference in the occurrence or risk of allergic reactions and
atopy when comparing those who did rece ive the vaccine in
the first 30 days compared to those who did not receive the
vaccine, or compared to those receiving a Hepatitis -B vaccine
that is not approved in the United States  (U.S.) . 1 RCT13
(N = 360)

1 Cohort6
(N = 5,655)  Some
concernsw No concerns  No concerns  No concerns  Moderate
confidence
Allergic reaction  One cohort6 of normal birthweight, full term , U.S.  infants in
the VSD (NCK) reported  no difference in the  risk of an allergic
reaction in the first three weeks of life when comparing infants
with a record of receiving thimerosal -containing Hepatitis B
vaccine in the first 21 days of life to infants with no record of
Hepatitis B vaccination during the same time  [RR: 0. 71 (95%CI:
0.04-11.4 ); p=0.99 ; 1/3,302 vs 1/2,353]. This remained
consistent in a sub -analysis restricting the infants with a record
of Hepatitis B vac cination on the day of birth or day after birth
with infants with no record of Hepatitis B vaccination  in the
first 21 days of life  [RR: 0. 87; (95%CI: 0. 05-13.8 ); p=0.99 ;
1/2,718 vs 1/2,353].  1 Cohort6
(N = 5,655)  Some
concerns1 No concerns  No concerns  No concerns  Low
confidence
Eczema  One RCT of healthy infants in India13 reported no cases of
eczema in  infants vaccinated with Engerix -B in the first 2
weeks of life  or in infants vaccinated with HepB Gene Vac -B
within first 2 weeks of life  (0/130 vs. 0/ 1320, p=NR ). The HepB
Gene Vac -B is not approved for use in the United States.  1 RCT13 (N =
360)  No concerns  No concerns  No concerns  No concerns  High
confidence

w Measurement & misclassification: -1 for unclear duration of follow up.

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 17 of 84
 Table 11. GRADE Table: Mortality outcomes and administration of the Hepatitis B Vaccine in the first 30 days of life
Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
All Death
Outcomes  The evidence  from 1 RCT14 and 2 cohort studies7,15 suggests
no difference in the proportion of deaths among infants
vaccinated with  any Hepatitis B Vaccine  at birth compared to
those who were not vaccinated at birth.

The evidence from one cohort study15 suggests no difference
in expected, or un expected deaths or deaths due to sudden
infant death syndrome (SIDS).   1 RCT14
(N = 280)

2 Cohorts7,15
(N =1,086)  Some  concernsx No concerns  No concerns  No concerns  Low
Confidence
All-cause
mortality  One RCT14 of unvaccinated, healthy infants in the U.S. reported
no deaths (N=208) at 7 months follow up among infants who
received  different timing of the first lifetime dose and the
subsequent series of any HBV Vaccine, specifically  DTaP-HepB
vaccine s at 2, 4 and 6 months of age, and infants who received
HepB  vaccine at birth, 1 month and 6 months of age and DTaP
at 2, 4 and 6  months of age.

One cohort7 of extremely preterm infants (<29 wks gestation)
in Australia’s Surveillance of Adverse Events Following
Immunization in the Community suggested there is no
difference in risk of death during the first 3 months of life
when comparing infants with a record  of receiving hepatitis b
vaccine within 24 hours of birth to infants with no record in
the first 24 hours  [aRR: 1.13; (95%CI: 0.42 -2.81); 7/306 vs
14/512].

Three case series  summarizing VAERS data16  for infants <1
month of age, reported 18 neonatal death reports were
submitted between 2005 -201516 and 27 reports of death
between 1991 -199812,17
• One case series16 of reports following single antigen
thimerosal containing Hepatitis B vaccine in U.S.
infants aged <1 month in the VAERS between  2005 -
2015 reported on Hepatitis B vaccine, 27/240
(11.3%) reports of death, including one due to sepsis.
• There were two case series  of VAERS reports in
neonates following vaccination with a thimerosal -1 RCT14
(N = 265)

1 Cohort7
(N = 818)

3 DES12,16,17
(N = 2,011)

 Some  concernse

No concerns

Some  concernsq

 No concerns

No concerns

No concerns

 No concerns

No concerns

No concerns

 No concerns

No concerns

No concerns

 Low
confidence

Low
confidence

Low
confidence

x Unanalyzed loss to follow up.

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 18 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
containing H epatitis B  vaccine during overlapping
study periods 1991 - 199512 and 1991 – 199817. The
study examining a longer window of time  for
neonates aged <28d, reported 18 deaths among
1,771 VAERS reports .17 Causes of death included
accidental suffocation (1), congenital heart disease
(1), infection (3), intracerebral hemorrhage (1), and
SIDS (12).

Expected
neonatal death  One cohort study15 of neonates in the VSD (NCK, SCK)
suggested no difference in the proportion of deaths during the
first 29 days of life from expected causes when comparing
neonates who received Hepatitis B vaccine during the first 29
days of life to neonates who did not [50/72 (69%) vs. 128/196
(65%0; p=0.6 ]. 1 Cohort15
(N = 268)
 No concerns  No concerns  No concerns  No concerns  Low
Confidence
Unexpected
neonatal death  One cohort study15 of neonates in the VSD (NCK, SCK)
suggested no difference in the proportion of deaths during the
first 29 days of life from unexpected causes when comparing
neonates who received Hepatitis B vaccine during the first 29
days of life to neonates who did not [22/72 (31%) vs. 68/196
(35%); p=0.6 ].  1 Cohort15
(N = 268)
 No concerns  No concerns  No concerns  No concerns  Low
Confidence
Unexpected
neonatal death
from SIDS   One cohort study15 of neonates in the VSD (NCK, SCK)
suggested no difference in the death rate from SIDS when
comparing neonates who received Hepatitis B vaccine during
the first 29 days of life to neonates who did not [8/240,717
(3.3 deaths per 105 births) vs. 4/120,979 (3.3 deaths per 105
births); p=0.99].  1 Cohort15
(N = 361,696 )
 Serious concernsy No concerns  No concerns  No concerns  Very low
Confidence

Table 12. GRADE Table: Infection outcomes and administration of the Hepatitis B Vaccine in the first 30 days of life
Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
All Infection
outcomes  Evidence from 1 cohort6 suggests a reduction in risk of having
a blood or CSF culture performed to evaluate a fever, and a
suggested reduction in positive blood or CSF cultures , among
infants who received a thimerosal -containing Hepatitis  B
vaccine in the first 21 days of life  when stratifying by age in
days . This study also reported no difference in the incidence
of fever due to infectious reasons.  These results were 2 studies
1 Cohort6
(N = 5,655)

1 DES16
No concerns

No concerns

No concerns

No concerns

 Low
confidence

y No adjustment for confounding by age at administration, maternal or perinatal risk factors, or years of study.

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 19 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
consistent in a sub analysis of infants who received the
Hepatitis B  vaccine on the day of birth or day after birth .

1 case series16 summarizing reports in neonates following
thimerosal -containing Hepatitis B  vaccine immunization in
VAERS reported 11 report s coded using  the Medical
Dictionary for Regulatory Activities as “infection and
infestation ” in 10 years (2005 – 2015).  (N = 240)  Some
concernsz
No concerns
No concerns
No concerns
Very low
confidence
Blood or CSF culture
performed  One cohort6 of normal birthweight, full term U.S. infants in the
VSD (NCK) suggested there is a reduction in the age -stratified
risk of having a blood or CSF culture performed in the first
three weeks of life when comparing infants with a record of
receiving thimerosal -containing Hepatitis B vaccine in the first
21 days  of life to infants with no record of Hepatitis B
vaccination [RR: 0.73 (95%CI: 0.65 -0.82); p <0.001; 133/3,302
vs 203/2,353]. This reduction in risk remained consistent in a
sub-analysis restricting the infants with a record of Hepatitis B
vaccination on the day of birth or day after birth with infants
with no record of Hepatitis B vaccination. [RR: 0.71; (95%CI:
0.63 -0.80); p <0.001; 126/2,718 vs 203/2,353].  1 Cohort6
(N = 5,655)  No concerns  No concerns  No concerns  No concerns  Low
Confidence
Blood or CSF culture
positive  One cohort6 of normal birthweight, full term U.S. infants in the
VSD (NCK) suggested there is a reduction in the age -stratified
risk of having a positive blood or CSF culture in the first three
weeks of life when comparing infants with a record of
receiving thimerosa l-containing Hepatitis B vaccine in the first
21 days of life to infants with no record of Hepatitis B
vaccination [RR: 0.60 (95%CI: 0.38 -0.95); p=0.030; 8/3,302 vs
16/2,353]. This reduction in risk remained consistent in a sub -
analysis restricting the i nfants with a record of Hepatitis B
vaccination on the day of birth or day after birth  with no
record of Hepatitis B vaccination. [RR: 0.57; (95%CI: 0.35 -0.94);
p <0.027; 7/2,718 vs 16/2,353].  1 Cohort6
(N = 5,655)  No concerns  No concerns  No concerns  No concerns  Low
Confidence
Fever due to
infectious reasons  One cohort6 of normal birthweight, full term, U.S. infants in
the Vaccine Safety Datalink (NCK) reported no difference in the
risk of a fever due to infectious reasons  in the first three weeks
of life when comparing infants with a record of receiving
thimerosal -containing Hepatitis B vaccine in the first 21 days of
life to infants with no record of Hepatitis B vaccination during
the same time when adjusting  by age in days  [aRR: 0.92
(95%CI: 0.7 -1.2); p=0.51; 26/3,302 vs 25/2,353]. This remained 1 Cohort6
(N = 5,655)  No concerns  No concerns  No concerns  No concerns  Low
Confidence

z Descriptive study, no comparison

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 20 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
consistent in a sub -analysis restricting the infants with a record
of Hepatitis B vaccination on the day of birth or day after birth
with infants with no record of Hepatitis B vaccination. [RR:
0.85; (95%CI: 0. 6-1.1); p=0. 28; 21/2,718 vs 25/2,353].

Infections and
infestations  One case series16 (Haber 2018) of reports following single
antigen thimerosal -containing Hepatitis B vaccine in U.S.
infants aged <1 month in VAERS between 2005 - 2015 reported
4.6% (11/240) non -death serious reports coded using the
Medical Dictionary for Regulatory Activities as Error!
Bookmark not defined.  “infections and infestations ”. 1 DES16
(Haber
2018)
(N = 240)  Some
concernsaa No concerns  No concerns  No concerns  Very low
confidence

Table 13. GRADE Table: Local injection site outcomes and administration of the Hepatitis B Vaccine in the first 30 days of life
Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
All Local
injection site
reactions  Evidence from five RCTs suggest s no difference in parent reported
local injection site reactions including pain or soreness, swelling, or
redness or erythema in the first 5 days post -vaccination among
infants vaccinated with Engerix -B in the first five days of birth
compared with combina tion vaccines or other Hepatitis B  vaccines
that were administered at birth or later. One RCT8 suggested an
increase in local side effects when comparing doses of Recombivax
administered at 2 months of age compared with birth or 18
months.  5
RCT8,9,13,14,18
(N = 1, 626)

 Some
concernsn
 No concerns  No concerns  No concerns  Moderate
confidence
Local side effects  One RCT8 of Egyptian infants , compared the outcome of local side
effects (e.g., local soreness, or temporary redness/induration at the
injection site)  1 week after vaccination among infants randomized to
administration of the first of dose of Recombivax immediately after
delivery, at two months of age, or at 18 months of age, and reported
a higher proportion of local side effects among those who received
the vaccine at two months of age (2.8% (5/178) at birth, vs  7.2%
(12/167) at two months, vs. 1.6% (3/191 ) at 18 months].  No
relationship was found between side effects and weight or
prematurity.  1 RCT8
(N = 536) Serious
concernsbb No concerns  No concerns  No concerns  Low
confidence

aa No comparison group
bb Inadequate randomization, u nclear allocation conce alment and blinding

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 21 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
Pain with
movement  or
pressure  One RCT9 of healthy Israeli infants , reported no difference in parent
reports of pain with movement and pain with pressure within 5 days
of vaccination among infants who received thimerosal -containing
Engerix -B within 24 hours of birth compared with those who
received thimerosal -containing BioHepB within 24 hours of birth
[4/52 (7.7%) vs. 4/153 (2.6%)] and [4/52 (7.7%) vs. 2/153 (1.3%)] .
The HepB  vaccine  BioHepB is not approved for use in the United
States.  1 RCT9
(N = 205)  Serious
concernscc Some
concernsdd No concerns  No concerns  Very l ow
confidence
Pain  or soreness  Two RC T reported a lower proportion of infants with soreness or
pain with the administration of Hepatitis B vaccine  alone at birth
compared to the combination  vaccines at any age.
• One RCT18 of healthy, full term Australian infants aged five days
or less reported a higher proportion of parent identified pain at
the injection site among those who received co-administration
of thimerosal -containing Energix -B vaccine and an
investigational acellular pertussis vaccine compared with
thimerosal -containing Energix -B vaccine alone within 120 hours
of birth  [41/208 (20%) vs. 14/150 (9%)]. One grade 3 reaction,
defined as crying when the limb was moved or pain that
prevents daily activities, was repo rted in the co -administration
group.
• One RCT of healthy U.S. infants14 reported a higher proportion
parent reports of soreness at the injection site within three days
of vaccination  with the first lifetime dose of a HBV Vaccine
among infants who received Engerix -B alone within 4 days of
birth compared with those who received DT aP-HepB  or DT ,  at 2
months of age compared with those ( 8.1% vs. 35.7%).

One single group cohort11 of 117 healthy neonates in Colombia who
received the  thimerosal -containing  Engerix -B Hepatitis B vaccine at
birth reported 7 (6%) infants experienced pain and 5 (4.3%)
experienced severe pain that resolved during the 4 days following
vaccination.  2 RCT14,18
(N = 623)

1 Cohort11
(N = 117)  Some
concernsee

Some
concernsff No concerns

Some concernsh No concerns

No concerns  No concerns

No concerns  Low
confidence

Very low
confidence
Redness or
erythema  Three RCTs suggest no difference in redness or erythema at the
injection site when comparing thimerosal -containing Energix -B
vaccine at birth with  thimerosal -containing  Energix -B at one month .  3 RCT9,14,18
(N = 8 41)
 Some
concernsgg
 No concerns

 No concerns

 No concerns

Low
confidence

cc Unclear allocation concealment ; absence of statistical  analyses  and reporting on protocol deviations
dd Small sample size
ee Unclear allocation concealment and no blinding , unanalyzed loss to follow up
ff Measurement & misclassification: -1 for unclear day of dosing; -1 for no comparator group
gg Unclear allocation concealment and no blinding

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 22 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
• One RCT14 reported no difference in the proportion of  parent
reports of  redness at the vaccination site within 3 days of
vaccination  with the first lifetime dose of HBV vaccine  among
infants who received Engerix -B within 4 days of birth or
among those who received DTaP -HepB vaccines at 2 months
of age (8.8% vs 11.6 %); no grade 3 reactions were reported.
• One RCT of Israeli infants9 reported no redness or erythema
within 5 days of vaccination among infants randomized to
receipt of  Engerix -B or BioHepB within 24 hours of birth
(0/52 vs. 0/153 ). The HepB vaccine BioHepB is not approved
for use in the United States.
• One RCT18 of Australian infants , 57/208 (27%) infants who
were co -administered an acellular pertussis vaccine and
Engerix -B within 120 hours of birth and 30/150 (20%) infants
who received Engerix -B alone within 120 hours of birth
experienced injection site erythema within 2 days of
vacci nation. No grade 3 reactions were reported.

In one single group cohort11 of 117 Columbian neonates who
received a  thimerosal -containing  Engerix -B Hepatitis B birth dose , 13
(11.1%) experienced redness during the 4 days following vaccination;
there were no reports of severe redness.

1 DES11
(N = 117)

Serious
concernshh

Some concerns

No concerns

No concerns

Very  low
confidence
Swelling  Four RCTs  reported no difference in the proportion of parent
reported swelling for infants who received Engerix -B within 5 days of
birth compared with a combination vaccine or a novel vaccine
administered in the same timeframe.
• In a randomized non -blinded clinical trial18 of Australian
infants , 26/208 (12.5%) infants who received an
investigational acellular pertussis vaccine and Engerix -B
within 120 hours of birth and 6/150 (4%) infants who
received Engerix -B within 120 hours of birth experienced
injection site swelling within 2 days of vaccina tion. No
grade 3 reactions were reported.
• One RCT14 of healthy U.S. infants  reported a lower
proportion of parent reports of swelling at the injection
site within three days of the first lifetime dose of a HBV 4
RCT9,13,14,18
(N = 1,090 )

 Some
concernsn

 No concerns

 No concerns

 No concerns

 Moderate
confidence

hh No blinding, unclear sequence allocation, unanalyzed loss to follow up.

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 23 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
Vaccine among those who received Engerix -B alone within
4 days of birth  and among infants who received DTaP-
HepB  vaccines  at 2 months of age (0 vs. 16.3%) .
• One RCT13 of healthy infants in India , reported no cases of
injection site swelling among infants vaccinated with
Engerix -B or infants vaccinated with the HepB Gene Vac -B
within first 2 wks of life (0/ 130 vs. 0/ 132, p=NR). The HepB
Gene Vac -B is not approved for use in the United States.
• A RCT9 of Israeli infants  reported a higher proportion of
swelling at the site within five days of vaccination among
infants who received thimerosal -containing Engerix -B
within 24 hours of birth compared with those who
received BioHepB within 24 hours of birth [4/52 (7.7%) vs.
3/153 (2.0%)]  The HepB vaccine BioHepB is not approved
for use in the United States.

In a single group cohort11 of 117 neonates in Colombia who received
an Engerix -B Hepatitis B birth , there were 5 reports of any swelling
(4.3%), and no reports of severe swelling.

1 DES11
(N = 117)

Serious
concernsii

No concerns

No concerns

No concerns

Very low
confidence

Table 14. GRADE Table: Neurodevelopmental outcomes and administration of the Hepatitis B Vaccine in the first 30 days of life
Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
All
Neurodevelopmental
outcomes  The evidence from four  studies report inconsistent results on
the association between autism or autism spectrum disorder19-
21, Emotional disorders / Emotional disturbances19,22 and Tics/
Tic disorders19,22, and the receipt of an HBV vaccine in the first
month of life . The  strongest study19 report ed no difference  in
the adjusted  risk of any of these diagnoses among infants in the 1 Cohort19
(N = 110,833)

4 Case -
control20,22 -24
(N = unclear
due to No concerns

 No concerns

 Some concernsll
 No concerns

 Low
confidence

ii Unclear timing of dosing (“at birth”) and no comparison group
ll Inconsistent results across studies using different inclusion criteria, different analytic approaches, and differences in adj ustment for confounding.

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 24 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
U.S. VSD with  receipt of Hepatitis B vaccine in the first month of
life, while the unadjusted case control studies22-24 examined the
same infants in the U.S. VSD  and the cross -sectional study of
parent interviews  reported an increase in the unadjusted odds
or adjusted  risk of these diagnoses with  exposure to Hepatitis B
vaccine in the first month of life .

Results from one cohort19, suggest no difference in the adjusted
risk of attention deficit disorder (ADD), coordination disorder,
speech or language delay, eating disorders, emotional
disturbances, other childhood psychosis, sleep disorders, or
stammering  among infants in the U.S. VSD

Results from one case -control study24 of children in the U.S.
VSD suggests an increase in the risk of diagnoses for s pecific
delays in development  among infants who were exposed to a
dose of thimerosal -containing Hep B vaccine in the first 30 days
of life compared to those who were not  overlapping
populations )

1 Cross -
sectional21
(N = 7,381)  Serious
concernsjj

Serious
concernskk
 No concerns

No concerns
 No concerns

No concerns

Very low
confidence

Very low
confidence

Attention deficit
disorder ( ADD ) One cohort study19 of U.S. infants  at three VSD sites (HMO A -C)
reported no difference in the  risk of an ADD diagnosis after  the
first year of life with the receipt of a thimerosal -containing
Hepatitis  B vaccine  within 1 month of age , when stratified by
HMO, year of birth, and sex, and adjusted for birth weight  (HMO
A: aHR: 0.92 (95%CI 0.52 -1.59 )); adjusted for clinic (HMO B: aHR:
0.90  (95%CI 0.74 -1.10 )) (HMO C : aHR: 0.88  (95CI% 0.53 -1.48 )). 1 Cohort19
(N = 140,887 ) No concerns  No concerns  No concerns  No concerns  Low
confidence
Autism/Autism
Spectrum Disorder  Results  from three studies are inconsistent on the  relationship
between the receipt of  HBV vaccine in the first month of life and
autism. The largest and strongest study19 (N = 110,833)
suggested no relationship between the adjusted risk of a medical
record of an autism diagnosis and HBV vaccine in the first month
of life , while one case -control study20 and one cross sectional
study that did not adjust for age of administration,  year of
administration, or health seeking behaviors, suggested an
increase in the odds of HBV vaccination among children with an
autism diagnosis20 (N=25,939 ) or parent report of an autism
diagnosis in  boys21 (N=7,381 ).
 1 Cohort19
(N = 110,833)

1 Case -
control20
(N = 25,939)  No concerns

 No concerns

No concerns
 Some
concernsoo
 No concerns

No concerns
 Low
confidence

Very low
confidence

jj No adjustment age at administration, birthweight, year of administration, cases and controls taken from different study years .
kk No adjustment for birthweight, age at administration, year of administration taken from different study years, outcome is not  medically validated.
oo Inconsistent results across studies using different inclusion criteria , different analytic approaches, and differences in adjustment for confounding .

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 25 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
• One cohort study19  of U.S. infants in VSD site HMO B
reported no difference in the risk of an autism diagnosis
after the first year of life with the receipt of a thimerosal -
containing Hep B vaccine within 1 month of age, when
stratified by year of birth, and sex, and adjus ted for birth
weight and clinic (HMO B: aHR: 1.16 (95%CI 0.78 -1.71 )).
Measures of association not assessed for HMOs with <50
cases.
• One case -control study20 of children in the U.S. VSD (KPNW,
KPC), suggested the unadjusted odds of an exposure to  a
dose of  thimerosal -containing HepB vaccine within the first
month of life  was greater among children with an autism
spectrum disorder diagnosis  compared to children without
an autism spectrum diagnosis  [OR: 2.18; (95%CI: 1.74 -2.73);
p<0.00001; 155/ 302 vs 8161 /25632 ]. A cross -sectional
study21 of U.S. boys aged 3 -17 years suggested the odds of a
parent report of an autism diagnosis was greater among
boys aged 3 -17 years of age who received the Hepatitis B
vaccine within 1 month of age born before 1999, when
compared to late - or never - vaccinated boys when adjusting
for race and ethnicity, family structure, and maternal
education [ aOR: 3.002; (95%CI: 1.109 -8.126); p=0.031].
1 Cross -
sectional21
(N = 7,381)  Serious
concernsmm

Serious
concernsnn

No concerns

No concerns

Very low
confidence

Coordination
Disorder  One cohort study19 of U.S. infants in VSD site HMO A  suggested a
potential increase  in the  risk of a coordination disorder after the
first year of life with the receipt of a thimerosal -containing Hep  B
vaccine within 1 month of age , when stratified by year of birth,
and sex, and adjusted for birth weight  (HMO A: aHR: 1.67 ( 95%CI
0.78-3.57 )). Measures of association not assessed for HMOs with
<50 cases.  1 Cohort19
(N = 13,337)  No concerns  No concerns  No concerns  No concerns  Low
confidence
Speech or language
delay  One cohort study19 of U.S. infants in three  VSD sites (HMO A -C)
reported no difference in the  risk of an speech or language delay
diagnosis after the first  year of life with the receipt of a
thimerosal -containing Hep  B vaccine within 1 month of age ,
when stratified by HMO, year of birth, and sex, and adjusted for
birth weight  (HMO A: aHR: 1.14 (95%CI 0. 88-1.46 )); adjusted for
clinic  (HMO B: aHR: 1.03 ( 95%CI 0. 91-1.17)); (HMO C: HR: 0.91
(95%CI 0. 79-1.04)).  1 Cohort19
(N = 140,887)  No concerns  No concerns  No concerns  No concerns  Low
confidence
Eating disorders  One cohort study19 of U.S. infants in VSD site HMO B reported no
difference in the  risk of an eating disorder  diagnosis after the 1 Cohort19
(N = 110,833)  No concerns  No concerns  No concerns  No concerns  Low
confidence

mm No adjustment age at administration, birthweight, year of administration , cases and controls taken from different study years.
nn No adjustment for birthweight, age at administration, year of administration  taken from different study years , outcome is not medically validated .

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 26 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
first year of life with the receipt of a thimerosal -containing Hep  B
vaccine within 1 month of age , when stratified by year of birth,
and sex, and adjusted for birth weight  and clinic  HMO B: aHR:
0.90 ( 95%CI 0. 50-1.61). Measures of association not assessed for
HMOs with <50 cases.
Emotional disorders /
Emotional
disturbances  One cohort study19 of U.S. infants in two VSD sites (HMO A,B)
reported no difference in the risk of an emotional disturbances
diagnosis  (313.8)  after the first year of life with the receipt of a
thimerosal -containing Hep B vaccine within 1 month of age,
when stratified by HMO, year of birth, and sex, and adjusted for
birth weight (HMO A: aHR: 1.00 (95%CI 0.42 -2.36 )); adjusted for
clinic (HMO B: aHR: 0.76 (95%CI 0.54 -1.07 )). Measures of
association not assessed for HMOs with <50 cases.

One case -control study22 of children in the VSD (KPNW, KPC,
KPNCK) between 1991 – 2000, suggested that the unadjusted
odds of an expos ure to a thimerosal -containing HepB vaccine
within the first month of life was greater among children with
ICD-9 diagnosis code for emotional disorder (313.xx) than
children without that code in their records  [OR: 1.34; 95 %CI:
1.12 -1.60; p<0.005, 204/517 vs 9003/27,491]. This association
remained consistent in a sub -analysis restricted to males [OR:
1.36; 95% CI: 1.11, 1.66); p<0.005; 158/399 vs  4568/14 ,013) but
not females [OR: 1.30; (95% CI: 0.90, 1.89); p=0.15, 46/118 vs
4435/13 ,478].  1 Cohort19
(N = 124,170)

1 case -control
study22
 (n=28,008)
No concerns

Serious
concernspp
No concerns

No concerns
Some
concernsqq

No concerns

No concerns  Low
confidence

Very low
confidence
Other childhood
psychosis  One cohort study19 of U.S. infants in VSD site HMO B reported no
difference in the  risk of a otherhood childhood psychosis
diagnosis after the first  year of life with the receipt of a
thimerosal -containing Hep  B vaccine within 1 month of age ,
when stratified by year of birth, and sex, and adjusted for birth
weight  and clinic  HMO B: aHR: 1.03 ( 95%CI 0. 60-1.74). Measures
of association not assessed for HMOs with <50 cases.  1 Cohort19
(N = 110,833)  No concerns  No concerns  No concerns  No concerns  Low
confidence
Sleep disorders  One cohort study19 of U.S. infants in three  VSD sites (HMO A -C)
reported no difference in the  risk of a sleep disorder  diagnosis
after the first  year of life with the receipt of a thimerosal -
containing Hep  B vaccine within 1 month of age , when stratified
by HMO, year of birth, and sex, and adjusted for birth weight
(HMO A: aHR: 0.79 ( 95%CI 0. 38-1.61 )); adjusted for clinic  (HMO
B: aHR: 1.24 ( 95%CI 0. 80-1.93)); (HMO C: HR: 0.97 ( 95%CI 0. 79-
1.19)).  1 Cohort19
(N = 140,887)  No concerns  No concerns  No concerns  No concerns  Low
confidence

pp No adjustment age at administration, birthweight, year of administration, cases and controls taken from different study years .
qq Inconsistent results across studies using different inclusion criteria, different analytic approaches, and differences in adj ustment for confounding.

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 27 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
Specific delays in
development
One retrospective cohort study24 of children in the VSD born
between 1991 – 1994,  suggested that the risk  of specific delays
in development (ICD -9 code 315.xx) was greater among children
who were exposed to a thimerosal -containing HepB vaccine
within the first month of life compared to children who were not
exposed to a thimerosal -containing HepB vaccine in the first
month of life [RR: 1.22, ( 95% CI: 1.12, 1.33), p<0.001, 82 8/18,637
vs 1127/31,198]. This association remained consistent in a sub -
analysis restricted to males [ RR: 1.23, ( 95%CI: 1.11, 1.37),
p<0.001, 567/9514 vs 771/16,110] and females [ RR: 1.21; (95%
CI: 1.03, 1.41); p<0. 05, 261/9 ,122 vs 356/15,088].
 1 Cohort
study24
(n=49,835 ) Serious
concernsrr No concerns  No concerns  No concerns  Very low
confidence
Stammering  One cohort study19 of U.S. infants in two VSD sites (HMO A -C)
reported no difference in the risk of a stammering diagnosis after
the first year of life with the receipt of a thimerosal -containing
Hep B vaccine within 1 month of age, when stratified by HMO,
year of birth, and sex, and adjusted for birth weight (HMO  A:
aHR: 0.89 (95%CI 0.40 -1.97)); and adjusted for clinic  in HMO B
(HMO B:  aHR: 0.61 (95%CI 0.33 -1.14 )); (HMO C: HR: 0.77 (95%CI
0.47 -1.26)).  1 Cohort19
(N = 140,887 ) No concerns  No concerns  No concerns  No concerns  Low
confidence
Tic Disorder, Tics  One cohort19 and one case control23 examined infants in the U.S.
VSD during the same time period and reported inconsistent
results. When stratifying results by location, year of birth, s ex,
HMO and clinic, there was no difference in the risk of Tic disorder
among infants who received a dose of thimerosal -containing Hep
B vaccine in the first month of life, compared to those who did
not19. However , a case control23 using different enrollment
criteria and not adjusting for confounding factors .
• One cohort study19 of U.S. infants in three VSD sites between
1991 – 1998 (HMO A -C) reported no difference in the risk of
a tics diagnosis after the first year of life with the receipt of a
thimerosal -containing Hep B vaccine within 1 month of age,
when stratified by HMO, year of birth, and sex, and adjusted
for birth weight (HM O A: aHR: 1.25 (95%CI 0.47 -3.29));
adjusted for clinic  (HMO B: aHR: 0.85 (95%CI 0.55 -1.30));
(HMO C: HR: 0.93 (95%CI 0.45 -1.92)).  1 Cohort19
(N = 140,887)

1 Case -
control23
(N = 28,360 ) No concerns

Serious
Concernsss

No concerns

No concerns

Some
concernstt

No concerns

No concerns
Low
confidence

Very low
confidence

rr No adjustment age at administration, birthweight, year of administration, cases and controls taken from different study years .
ss Unadjusted for confounding of age at administration, birthweight, healthcare seeking behavior, duration of follow up, and diff erent inclusion criteria & study years for each
group.
tt Inconsistent results across studies using different inclusion criteria, different analytic approaches, and differences in adj ustment for confounding.

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 28 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
• One case -control study23 of children in the VSD (KPNW, KPC,
NCK)  between 1991 - 2000 , suggested the odds of an
exposure to thimerosal -containing HepB vaccine within the
first month of life  was great er among children with a medical
diagnosis code for a tic disorder diagnosis than among those
with no tic disorder diagnosis [OR: 1.59; (95%CI: 1.29 -1.98);
p<0.00001; 151/344 vs 9222/28016 ]. This association
remained consistent in a sub -analysis restricted to males
[OR: 1.65; (95%CI: 1.29 -2.12); p<0.0001; 113/ 253 vs
4697/14327 ], but n ot females [OR: 1.45; (95%CI: 0.95 -2.21);
p=0.09; 38/ 91 vs 4525/13 ,689].

Table 15. GRADE Table: Neurologic outcomes and administration of the Hepatitis B Vaccine in the first 30 days of life
Outcome  Summary  Studies  Risk of
Bias  Imprecision  Inconsistency  Indirectness  Confidence
All Neurologic outcomes  The evidence from cohort6 suggest ed there is no
difference in the risk of seizures and neurologic disease
other than seizures  among infants receiving with Hep B
vaccine in the first 21 days of life, compared to those
who did not , and this did not change when restricted
to those vaccinated in the first day of life .

One case control study23 did not one case series
suggest ed a lower odds of exposure to a thimerosal -
containing hep B vaccine in the first 30 days of life
among infants diagnosed with  cerebral degeneration
compared to those who were not diagnosed.

Two case series12,16 identified reports of abnormal CSF,
convulsions, and nervous system disorders among the
reports in the U.S. VAERS between 1991 -1995 and
2005 – 2015.  1 Cohort6
(N = 5,655)

1 Case -
control23
(N =
136,536)

2 Case
Series12,16
(N = 300 ) No
concerns

Serious
concernsuu

Some
concernsvv No concerns

No concerns

No concerns  No concerns

No concerns

No concerns  No concerns

No concerns

No concerns  Low
confidence

Very low
confidence

Very low
confidence

uu Unadjusted for confounding of age at administration, birthweight, healthcare seeking behavior, duration of follow up, and diff erent inclusion criteria & study years for each
group.
vv Descriptive study, no comparison

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 29 of 84
 Outcome  Summary  Studies  Risk of
Bias  Imprecision  Inconsistency  Indirectness  Confidence
Abnormal CSF  In one case series of reports12 following single antigen
thimerosal -containing Hepatitis B vaccine in U.S. infants
aged <1 month in VAERS between 1991 -1995 , there
were 4 (6.7%) serious reports of abnormal CSF . 1 Case
Series12
(N = 60)  Some
concernsww No concerns  No concerns  No concerns  Very low
confidence
Cerebral degeneration  One case -control study23 of children in the VSD (KPNW,
KPC, NCK), suggested the unadjusted odds of exposure
to thimerosal -contain ing Hepatitis B vaccine within the
first month of life was lower  among childr en diagnosed
with cerebral degeneration than among those without a
diagnosis of cerebral degeneration [OR: 0.43; (95%CI:
0.36 -0.52); p <0.00001; 175/ 647 vs 62637/135 ,889]. 1 Case -
control23
(N =
136,536)  Serious
concernsxx No concerns  No concerns  No concerns  Very low
confidence
Convulsions  One case series12 of 60 VAERS reports for neonates <0.1
years of age who received a thimerosal -containing
Hepatitis B vaccine between 1991 – 1995 reported 6
(10%) reports of convulsions, 4 of which were
considered serious.  1 DES12
(N = 60)  Some
concernsq  No concerns  No concerns  No concerns  Very low
confidence
Seizure  One cohort6 of normal birthweight, full term U.S. infants
in the VSD (NCK) suggested there is no difference in the
risk of seizures  in the first three weeks of life when
comparing infants with a record of receiving thimerosal -
containing Hepatitis B vaccine in the first 21 days of life
to infants with no record of Hepatitis B vaccination [RR:
0.18 (95%CI: 0.02 -1.6); p=0.17; 1/3,302 vs 4/2,353]. This
remained consistent in a sub -analysis restricting the
infants with a record of Hepatitis B vaccination on the
day of bi rth or day after birth compared  with infants
with no record of Hepatitis B vaccination [RR: 0.22;
(95%CI: 0.02 -1.9); p=0.19; 1/2,718 vs 4/2,353].  1 Cohort6
(N = 5,655)  No concerns  No concerns  No concerns  No concerns  Low
confidence
Nervous system disorders  In one case series16 of reports following single antigen
thimerosal containing Hepatitis B vaccine in U.S. infants
aged <1 month in the VAERS between 2005 - 2015, 6.3%
(15/240) were non -death serious reports coded  using
the Medical Dictionary for Regulatory Activities as
“Nerv ous Systems Diso rders ”. 1 DES16
(N = 240)  Some
concernsyy No concerns  No concerns  No concerns  Very low
confidence
Neurologic disease, other than
seizure  One cohort6 of normal birthweight, full term U.S. infants
in the VSD (NCK) suggested there is no difference in the 1 Cohort6
(N = 5,655)  No concerns  No concerns  No concerns  No concerns  Low
confidence

ww Descriptive study, no comparison
xx Unadjusted for confounding of age at administration, birthweight, healthcare seeking behavior,  duration of follow up, and different inclusion criteria & study years for each
group.
yy Descriptive study, no comparison

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 30 of 84
 Outcome  Summary  Studies  Risk of
Bias  Imprecision  Inconsistency  Indirectness  Confidence
risk of neurologic disease in the first three weeks of life
when comparing infants with a record of receiving
thimerosal -containing Hepatitis B vaccine in the first 21
days of life to infants with no record of Hepatitis B
vaccination [RR: 1.4 (95%CI: 0.3 -7.8); p=0.99; 4/3,302 vs
2/2,353]. This remained consistent in a sub -analysis
restricting the infants with a record of Hepatitis B
vaccination on the day of birth or day after birth
compared with infants with no record of Hepatitis B
vaccination [RR: 1.7; ( 95%CI: 0.3 -9.4); p=0.69; 4/2,718 vs
2/2,353].

Table 16. GRADE Table: Cardiopulmonary outcomes and administration of the Hepatitis B Vaccine in the first 30 days of life
Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
All Cardiopulmonary
outcomes  The evidence from one cohort7 suggests that receipt of
Hepatitis B vaccine in the first 24 hours of life is not
associated with an increase in the risk of bronchopulmonary
dysplasia.
The evidence from one case series12 suggests that between
1991 -1995, 13 of 60 events in VAERS were cardiopulmonary
(including apnea, bradycardia, and cyanosis) .  2 studies
1 Cohort7
(N = 818)

1 DES12
(N = 60)  No concerns

Some
concernszz No concerns

No concerns  No concerns

No concerns  No concerns

No concerns  Low
confidence

Very low
confidence
Bronchopulmonary
dysplasia  One cohort7 of extremely preterm infants (<29 wks gestation)
in Australia’s Surveillance of Adverse Events Following
Immunization in the Community suggested there is a reduction
in the adjusted risk of bronchopulmonary dysplasia when
comparing infants with a record o f receiving hepatitis b
vaccine within 24 hours of birth to infants with no record [aRR:
0.83; (95%CI: 0.68 -1.0); 155/306 vs 317/512].   1 Cohort7
(N = 818)  No concerns  No concerns  No concerns  No concerns  Low
confidence
Apnea  In a case series12 of 60 VAERS reports for neonates <0.1 years
of age who received a thimerosal -containing Hepatitis B
vaccine between 1991 – 1995  there were 5 (8.3%) reports of
apnea, 3 of which were considered serious.  1 DES12
(N = 60)  Some
concernst No concerns  No concerns  No concerns  Very low
confidence
Bradycardia  In a case series12 of 60 VAERS reports for neonates <0.1 years
of age who received a thimerosal -containing Hepatitis B
vaccine between 1991 - 1995 , there was 1 (1.7%) serious
report of bradycardia.  1 DES12
(N = 60)  Some
concernst No concerns  No concerns  No concerns  Very low
confidence

zz No comparison group

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 31 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
Cyanosis  In a case series12 of 60 VAERS reports for neonates <0.1 years
of age who received a thimerosal -containing Hepatitis B
vaccine between 1991 - 1995 , there were 7 (11.7%) reports of
cyanosis, 5 of which were considered serious.  1 DES12
(N = 60)  Some
concernst  No concerns  No concerns  No concerns  Very low
confidence

Table 17. GRADE Table: Systemic reactions  and administration of the Hepatitis B Vaccine in t he first 30 days of life
Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
All Systemic Reactions  The evidence8-14,18 suggested that systemic reactions do
occur after vaccination,  and there may be no difference in
the occurrence of some outcome when comparing infants
vaccinated with a Hepatitis B dose in the first 30 days of
life compared with those who receive a different vaccine,
or a Hepatitis B vaccine later or never.  Outcomes for
which the evidence suggests there is no difference include
fever8-14,18, rash13, constipation13, diarrhea8-10,12 -14,18,
unusual crying14,18, and vomiting13,14,18 .

Systemic reactions for which the evidence reported
inconsistent results include anorexia/ decreased
appetite/ feeding issues9 14,18 and restlessness/ sleeping
less14,18. The differences in these outcomes may be due to
parent perceptions (all were based on parent reports),
differences in vaccines, or differences in outcome
definitions used across these studies.

Evidence was sufficient to determine that agitation12
occurs  in 13 of 60 neonatal U.S. VAERS reports between
1991 -1995, but not sufficient to determine if this is
different from the rate of occurrence in the general
neonatal population.  5
RCT8,9,13,14,18
(N = 1,627)

1 cohort10
(N = 10,829)

2 DES11,12
 (N = 177)  Some concerns
aaa

Serious
concernsbbb

Some
concernsccc
 No concerns

No concerns

No concerns
 No concerns

No concerns

No concerns
 No concerns

No concerns

No concerns
 Moderate
confidence

Very low
confidence

Very low
confidence

Agitation  In a case series12 of 60 VAERS reports for neonates <0.1
years of age who received a thimerosal -containing
Hepatitis B vaccine between 1991 – 1995 , there were 13
(21.7%) reports of agitation, 7 of which were considered
serious.
 1 DES12
(N = 60)  Some
concernsccc  No concerns  No concerns  No concerns  Very low
confidence

aaa Unclear allocation concealment and no blinding
bbb No adjustment for confounding, unclear presence of outcomes at start of study
ccc Descriptive study, no comparator

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 32 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
Anorexia/Decreased
appetite/ Feeding
Issues  Three RCTs of healthy infants reported inconsistent results
for the outcome of decreased appetite . That may be
attributable to differences in the comparator vaccine or
the timing of comparator vaccine or the differences in
outcome definitions used in each study.
• One RCT14 of full -term U.S. infants reported a higher
proportion of decreased appetite within 3 days of
vaccination among infants who received DTPa -HepB,
OPV, and Hib vaccines at 2 months of age compared
with those who received Engerix -B within 4 days of
birth [25. 6% of 129 vs 14% of 136; ] .
• In a RCT of Israeli infants9, 0/52  infants who received
Engerix -B within 24 hours of birth and 3/153 (2.0%)
who received BioHepB within 24 hours of birth
experienced anorexia within 5 days of vaccination.
The HepB vaccine BioHepB is not approved for use in
the United States.
• In a randomized non -blinded clinical trial of
Australian infants18, 28/221 (13%) infants who
received an investigational acellular pertussis
vaccine and Engerix -B within 120 hours of birth and
17/103 (17%) infants who received Engerix -B within
120 hours of birth experienced feeding issues within
2 days of vaccination. On e grade 3 feeding reaction
(defined as preventing normal activities or requiring
significant medical intervention) was reported
among the 103 infants (0.9%) who received only
Engerix within 120 hours of birth.

One single group cohort of 117 Columbian neonates11 who
received an Engerix -B Hepatitis B birth dose, 3 (2.6%)
experienced a loss of appetite during the 4 days following
vaccination, 1.7% (2/117) were considered severe . In one
single group cohort of 117 Columbian neonates who
received an Engerix -B Hepatitis B birth dose (Lopez 2002),
3 (2.6%) experienced a loss of appetite during the 4 days
following vaccination, 1.7% (2/117) were considered
severe . 3 RCTs9 14,18
(N = 794)

1 DES11
 (N = 117)  Some
concernsddd

Some
concernseee No concerns

No concerns

Some
concernsfff
 No concerns

No concerns
Moderate
confidence

Very low
confidence

ddd Unanalyzed loss to follow up
eee Descriptive study, no comparator, unclear timing of dosing (“at birth”)
fff Inconsistent results across studies using different inclusion criteria, different analytic approaches, and differences in adj ustment for confounding.

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 33 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
Constipation  One RCT of healthy infants in India13 reported no cases of
constipation in infants vaccinated with Engerix -B in the first
2 weeks of life or in infants vaccinated with HepB Gene
Vac-B within first 2 weeks of life (0/130 vs. 0/132). The
HepB Gene Vac -B is not approved for use in the United
States.  1 RCT13
(N = 262)  No concerns  No concerns  No concerns  No concerns  High
confidence
Diarrhea  Four RCTs suggested no difference in the proportion of
diarrhea cases among infants who received the HBV
vaccine in the first 2 weeks of life or less, and those who
receive the dose later, or a different vaccine.
• One RCT of Israeli infants9, reported no
difference in diarrhea or vomiting within 5 days
of vaccination among infants who received
Engerix -B within 24 hours of birth and who
received BioHepB within 24 hours of birth0/52
vs. 1/153 (0.64%). The HepB vaccine BioHepB is
not approved for use in the United States.
• One RCT14 of full -term U.S. infants reported no
difference in the proportion of parents reporting
diarrhea within 4 days of birth when comparing
infants who received Engerix B within 3 days of
birth and infants who received DTaP -HepB, OPV,
and Hib vaccines at 2 mon ths of age, (8.1% vs.
10.1%). There was no difference in the
proportion experiencing a grade 3 reaction
(defined as preventing normal activities) (0.7%
vs. 0).
• One RCT of healthy infants in India13 reported no
cases of loose motions in infants vaccinated with
Engerix -B in the first 2 weeks of life or in infants
vaccinated with HepB Gene Vac -B within first 2
weeks of life (0/130 vs. 0/132, p=NR). The HepB
Gene Vac -B is not approved for use in the United
States.
• In a RCT of Australian infants18, 38/221 (17.0%)
infants who received an investigational acellular
pertussis vaccine and Engerix -B within 120 hours
of birth and 12/103 (12%) infants who received
Engerix -B within 120 hours of birth experienced 4 RCT9,13,14,18
(N = 927)

1 DES12
(N = 60)
 Some
concernsggg

Some
concernshhh

No concerns

No concerns

No concerns

No concerns

No concerns

No concerns

 Low
confidence

Very low
confidence

ggg Unclear allocation concealment, no blinding, unclear assessment of loss to follow up
hhh Descriptive study, no comparator

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 34 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
diarrhea within 2 days of vaccination. No grade 3
reactions (defined as preventing normal activities
or requiring significant medical intervention)
were reported.

In one case series12 of 60 VAERS  reports for neonates <0.1
years of age who received a thimerosal -containing
Hepatitis B vaccine between 1991 – 1995 , there was 1
report of diarrhea, which was not categorized as serious.
Drowsiness or sleeping
more  Two RCTs report inconsistent results for increased
drowsiness when comparing Engerix B as a birth dose with
DTPA -HepB14 or both acellular pertussis and Engerix -B
vaccines18 at 2 months of age. Inconsistencies may be
explained by the different comparison vaccine or by the
different outcome definitions of “increased sleep” and
“drowsiness”
• One RCT14 of full -term U.S. infants reported a
lower proportion of parents reporting increased
infant sleep within 3 days of birth when
comparing infants who received Engerix B within
4 days of birth and infants who received DTPa -
HepB, OPV, and Hib vaccines at 2 mo nths of age,
(32.4% vs. 40.3%). There was higher proportion
of infants receiving Engerix B within 4 days of
birth whose parents reported them experiencing
a grade 3 reaction (defined as preventing normal
activities) (2.9% vs. 0.8%).
• One RCT of Australian infants18 reported a higher
proportion of parents reported drowsiness within
2 days of vaccination among parents of infants
who received Engerix -B within 120 hours of birth
compared with infants who received an
investigational acellular pertussis vaccine and
Engeri x-B within 120 hours of birth and [29/103
(28%) vs. 39/221 (18%)]. There was no difference
in drowsiness of grade 3 severity (defined as
preventing normal activities or requiring
significant medical intervention) between those
2 RCTs14,18
(N = 591)

1 DES11
(N = 117)

Some
concernsiii

Some
concernsjjj

 No concerns

No concerns  Some
concernskkk

No concerns

No concerns

 Very low
confidence

Very low
confidence

iii Unclear allocation concealment and no blinding
jjj Descriptive study, no comparator
kkk Inconsistent results across studies using different inclusion criteria, different analytic approaches, and differences in adj ustment for confounding.

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 35 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
receiving the both acellular pertussis and
Engerix -B vaccines and by 1 (0.9%) of the infants
receiving only Engerix -B vaccines at birth (1/221
(0.5%) vs. 1/103 (0.9%).
Among a single group cohort of 117 Columbian neonates11
who received an Engerix -B Hepatitis B birth dose (Lopez
2002), 6 (5.1%) experienced drowsiness during the 4 days
following vaccination; 1 (0.9%) was reported to be severe.

Fever
Five RCT suggested no difference in parent reports of fever
between infants vaccinated with HBV vaccines in the first
two weeks of life and infants vaccinated with the same
vaccine HBV vaccine at later ages, different HBV vaccines at
the same age, or diffe rent HBV and HBV combination
vaccines at lat er ages.
• One RCT of Egyptian infants8, reported no difference
in parent reports of fever (reported as 1 -2 days of low -
grade fever ≤102⁰F) among those vaccinated with
Recombinant HB vaccine immediately after birth
(5.6% n=178), at 2 months (7.2%, n=167), or 18
months of age (2.1%, n=191). No relationship was
found between side effects and weight or
prematurity.
• In a randomized non -blinded clinical trial of Australian
infants18, reported no difference in parent reports of
fever ≥38⁰C within 2 days of vaccination among
infants who received an investigational acellular
pertussis vaccine and Engerix -B within 120 hours of
birth and infants who received Engerix -B within 120
hours of birth (0/221 vs 1/138 (0.7%)). No fevers
≥39⁰C were reported among participants in either
arm.
• One RCT of Israeli infants9 reported no difference in a
temperature ≥38 ⁰C within 5 days of vaccination
infants who re ceived Engerix -B within 24 hours of
birth compared with those who received BioHepB
within 24 hours of birth [0/52 vs. 2/153 (1.3%)]. The
HepB vaccine BioHepB is not approved for use in the
United States.

5
RCT8,9,13,14,18
(N = 1,627)

Some concerns
lll

No concerns

No concerns

No concerns

Low
confidence

lll Unclear allocation concealment and no blinding

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 36 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
• One RCT of full -term U.S. infants14 reported no
difference in fever (defined as rectal temperature
≥38⁰C within 4 days of vaccination among infants who
received Engerix B within 3 days of birth and infants
who received DTPa -HepB, OPV, and Hib vaccines at 2
months of age, (5.9%, n = 136 vs. 14.7%, n=129).
There was also no difference in parent reports grade 3
reaction (defined as temperature >39.5 ⁰C ) (0% vs.
0.8%).
• An RCT of healthy infants in India13 reported no
difference in parent -reported fever (defined as axillary
temperature ≥38⁰C) in infants vaccinated wit h
Engerix -B in the first 2 weeks of life and infants
vaccinated with HepB Gene Vac -B within first 2 weeks
of life [6/130 (4.6%) vs. 4/132 (3.0%)].

In a cohort study of full -term Israeli infants10, 68/5,819
(1.2%) full -term infants receiving hepatitis B vaccination
and 27/5,010 (0.54%) full -term infants not receiving
hepatitis B vaccine had a birth hospitalization discharge
diagnosis of “neonatal fever” above 37.5 C (p<0.001).
Fevers above 38C were  noted in 50 (0.9%) of vaccinated
infants and 27 (0.54%) of unvaccinated infants (p<0.05).
Identifiable causes of fever (e.g. sepsis, dehydration,
maternal fever, respiratory distress) were noted among 15
vaccinated infants (0.3%) and 13 unvaccinated i nfants
(0.3%). Unexplained fevers were noted among 35 (0.6%)
vaccinated infants and 14 (0.3%) unvaccinated infants
(p=0.013).

Two single group studies, one cohort and one case series of
adverse reports in neonates who received HBV vaccine as a
birth does or within 1 month reported identified 18 U.S.
VAERS reports of fever between 1991 – 1995, and 13
serious U.S. VAERS reports of fever, and reported 1 severe
fever among 117 Columbian neonates,
• Among a cohort of 117 Columbian neonates11 who
received an Engerix -B Hepatitis B birth dose, 1 (0.9%)
experienced a severe fever during the 4 days following

1 cohort10
(N = 10,829)

2 DES 11,12
(N = 177)

Serious
concernsmmm

No concerns

No concerns

No concerns

Very low
confidence

mmm No adjustment for confounding, unclear presence of outcomes at start of study

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 37 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
vaccination (severe: >39⁰C axillary or >39.5⁰C rectal). In
a case series12 of 60 VAERS reports for n eonates <0.1
years of age who received a thimerosal -containing
Hepatitis B vaccine between 1991 – 1995 , there were
18 (30%) reports of fever, 13 of which were
considered serious. Median number of days from
vaccination to onset of fever was 1 day and mean
maximum temperature was 38.9 ⁰C (range: 38.0 -
40.6 ⁰C). Of 10 infants with follow -up from fever, all 10
had recovered.

Some
concernsnnn

No concerns

No concerns

No concerns

Very low
confidence

Irritability or fussiness  Three RCTs report inconsistent results for irritability or
fussiness among infants vaccinated with Engerix B within
24h9, 3 days14, and 120 hours of birth18. These differences
could be due to timing of birth dose, differences in
outcome definitions, or comparison vaccine.
• One RCT14 of full -term U.S. infants reported a
lower proportion of parents reporting irritability
or fussiness within 3 days of vaccination when
comparing infants who received Engerix B within
4 days of birth and infants who received DTPa -
HepB, OPV, and Hib vaccine s at 2 months of age,
(22.1% vs. 54.3%).
• One randomized non -blinded clinical trial of
Australian infants18 reported no difference in
irritability within 2 days of vaccination among
infants who received an investigational acellular
pertussis vaccine and Engerix -B within 120 hours
of birth compared with infants who received
Engerix -B within 120 hours of birth [5 4/221
(24.0%) vs.21/103 (20%)]. There was also no
difference in Grade 3 irritability reactions
reported by parents (defined as preventing
normal activities or requiring significant medical
intervention) [2/221 (0.9%) vs. 1/103 (0.9%)].
• One RCT of Israeli infants9 reported a higher
proportion of irritability among infants who 3 RCT9,14,18
(N = 794)

1 DES11
(N = 117)
 Serious
concernsooo

Some
concernsppp No concerns

No concerns  Some
concernsqqq
 No concerns

No concerns  Very low
confidence

Very low
confidence

nnn Descriptive study, no comparator
ooo Unclear allocation concealment and no blinding, no assessment of loss to follow up or missing data
ppp
 Descriptive study, no comparator
qqq Inconsistent results across studies using different inclusion criteria, different analytic approaches, and differences in adj ustment for confounding.

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 38 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
received Engerix -B within 24 hours of birth and
[6/52 (11.5%) vs. 5/153 (3.3%)] who received
BioHepB within 24 hours of birth experienced
irritability within 5 days of vaccination. The HepB
vaccine BioHepB is not approved for use in the
United States.

One cohort of 117 Columbian neonates11 who received an
Engerix -B Hepatitis B birth dose, reported 3 (2.6%) infants
experienced irritability during the 4 days following
vaccination; 2 cases (1.7%) were reported to be severe.

Rash  One RCT of healthy infants in India13 reported no cases of
rashes in infants vaccinated with Engerix -B in the first 2
weeks of life or in infants vaccinated with HepB Gene Vac -B
within first 2 weeks of life (0/130 vs. 0/132, p=NR). The
HepB vaccine BioHepB is not approved for use in the
United States.

In a case series12 of 60 VAERS reports for neonates <0.1
years of age who received a thimerosal -containing
Hepatitis B vaccine between 1991 – 1995 were 2 serious
reports (3.3%) reports of rash that included fever.  1 RCT13
 (N = 262)

1 DES12
(N = 60)

 No Concerns

Some
concernsrrr

 No concerns

No concerns

 No concerns

No concerns

 No concerns

No concerns

 High
confidence

Very low
confidence

Restlessness or
sleeping less  Two randomized trials of full -term infants reported
inconsistent results for restlessness and sleeping less which
could be due to the differences in outcome definition,
timing of HepB birth dose, or comparator vaccine.
• One randomized trial14 of full -term U.S. infants
reported a lower proportion of parents reporting
restlessness or sleeping less within 3 days of
vaccination when comparing infants who received
Engerix B within 4 days of birth and infants who
received DTPa -HepB, OPV, and Hib vac cines at 2
months of age, (16.9% vs. 26.4%; ).
• One randomized non -blinded clinical trial of Australian
infants18 reported was a higher proportion of parent 2 RCT14,18
(N = 585)

 Serious
concernssss No concerns  Some
concernsttt No concerns  Very Low
confidence

rrr Descriptive study, no comparator
sss Unclear allocation concealment and no blinding, no assessment of loss to follow up.
ttt Inconsistent proportions for Engerix -B associated symptoms, and inconsistent directionality of comparisons

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 39 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
reports of restlessness within 2 days of vaccination
among of infants who received Engerix -B within 120
hours of birth compared to infants who received an
investigational acellular pertussis vaccine and Engerix -
B within 120 hours of birth  [32/103 (31%) vs .  49/221
(22.0%)].  There was no difference in parent reports of
grade 3 restless reactions (defined as preventing
normal activities or requiring significant medical
intervention) [3/103 (3%) vs. 2/221 (1%)].

Unusual crying
One RCT14 of full -term U.S. infants reported a no difference
in parent reports of unusual crying within 4 days of
vaccination when comparing infants who received Engerix -
B within 3 days of birth and those who received DTPa -
HepB, OPV, and Hib vaccines at 2 months of  age (1.5% of
136 infants vs. 3.1% of 129 infants). Results were similar
for parent reports of grade 3 unusual crying (defined as
preventing normal daily activity) (0 vs. 0.8%).  1 RCT14
(N = 136)  Some
concernsuuu No concerns  No concerns  No concerns  Moderate
confidence
Vomiting  Three RCTs suggested no difference in the incidence
vomiting when comparing infants who received HBV at
birth with those who received HBV 1 month after birth,
infants who received a different HBV at birth, or infants
who received HBV co -administered with a n acellular
pertussis vaccine.
• One RCT14 of full -term U.S. infants reported no
difference in the incidence of vomiting within 4 days
of vaccination as reported by parents between infants
who received Engerix -B within 3 days of birth and
those who received DTPa -HepB, OPV, and Hib
vaccines at 2 mo nths of age (4.4% of 136 infants vs.
7.8% of 129 infants). None reported a grade 3 reaction
of vomiting.
• One RCT of healthy infants in India13 reported no
cases of vomiting among infants who received
Engerix -B or GeneVac -B within 30 days of birth. (0/130
v. 0/132) GeneVac -B is not approved for use in the
U.S. 3 RCT13,14,18
(N = 853)

 Some
concernsvvv No concerns  No concerns  No concerns  Moderate
confidence

uuu -1 absence of randomization & blinding, and no assessment of loss to follow up.
vvv -1 absence of randomization & blinding, and no assessment of loss to follow up.

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 40 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
• In a randomized non -blinded clinical trial of Australian
infants18, 45/221 (20.0%) infants who received an
investigational acellular pertussis vaccine and Engerix -
B within 120 hours of birth and 23/103 (24%)  infants
who received Engerix -B within 120 hours of birth
experienced vomiting within 2 days of vaccination. No
grade 3 vomiting reactions (defined as preventing
normal activities or requiring significant medical
intervention) were reported.

Table 18. GRADE Table: Other outcomes and administration of the Hepatitis B Vaccine in the first 30 days of life
Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
All Other  outcomes  One case control25 reported an increase in the odds of
thimerosal -containing Hep atitis B vaccine exposure  in the
first month of life  among children with an ICD9 code for
premature puberty in their HMO medical records, compared
to children without the code , and when stratified by sex, this
increase was seen among females but not males.

One  case series16 of VAERS reports following single antigen
thimerosal containing H epatitis B vaccine  between 2000 –
2015 reported ten reports coded  using the Medical Dictionary
of Regulatory Activities of “general disorders and
administration site conditions ” in 15 years ( 10/240) ; and an
earlier  case series12 of VAERS reports of U.S. neonates  with
HepB exposure  between 1991 – 1995 reported one report  for
Hyperbilirubenemia /HbSAg+ (1/60) .

1 case
control25
(N=58,675)

2 DES12,16
(n=300)
 Serious
concerns

Some
concernswww No concerns

No concerns  No concerns

No concerns  No concerns

No concerns  Very low
confidence

Very low
confidence
Premature puberty  One case -control study25 of children enrolled in the VSD
(KPNW, KPC, KPNC) suggested the odds of exposure to to
thimerosal -containing HepB vaccine with in the first month of
life was greater among children w ith a medical record of am
ICD9 code for  premature puberty  compared to children who
did not   [OR: 1.80, (95% CI: 1.51, 2.16), p<0.00001; 255/ 486 vs
20582/54199 ]. When stratified by sex, the association was
observed among females [OR: 1.87, (95% CI: 1.55, 2.25, 1 case
control25 (N
= 58,685)  Serious
concernsxxx No concerns  No concerns  No concerns  Very low
confidence

www Descriptive study, no comparison
xxx -2 Very serious concerns for confounding factors such as prematurity or birthweight, age at administration, or year of adminis tration.

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policy .  Page 41 of 84
 Outcome  Summary  Studies  Risk of Bias  Imprecision  Inconsistency  Indirectness  Confidence
p<0.00001), 245/ 458 vs 9997/26209 ] but not among males
[OR: 0.91, (95% CI: 0. 42, 1.98), p>0.99; 10/ 28 vs 10584/27989 ].
General disorders
and administration
site conditions  One case series16 of reports following single antigen thimerosal
containing Hepatitis B vaccine in U.S. infants aged <1 month in
VAERS between 2005 – 2015, reported 4.2% ( 10/240) - were
coded using the Medical Dictionary for Regulatory Activities
(MedDRA) as general  disorders and administration site
conditions ”. 1 DES16
(N = 240)
 Some
concernsyyy No concerns  No concerns  No concerns  Very low
confidence
Hyperbilirubenemia
/HbSAg+  In a case series12 of 60 VAERS  reports for neonates <0.1 years
of age who received a thimerosal -containing Hepatitis B
vaccine  between 1991 -1995 , there was 1 (1.7%) serious report
of hyperbilirubenemia/HbSAg+.  1 DES12
(N = 60)  Some
concernsh Some concernszzz No concerns  No concerns  Very low
confidence

yyy Descriptive study, no comparison
zzz Small sample size

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 42 of 84
 C. Extracted Evidence from Included Studies
C.1. Study Characteristics for All Included Studies
Table 19. Characteristics of Studies Meeting Inclusion Criteria
Author Year  Study design  Data Collection P eriod  Sample size, N  Surveillance System (if Applicable)  Country
Bassily 19958 Randomized
Controlled Trial  Not reported  536 infants  Not reported  Egypt
Eriksen 200415 Retrospective
cohort  January 1, 1993 - December
31, 1998  361,696 newborns in Kaiser SCK &
NCK HMO birth cohort

268 neonatal deaths analyzed for
expected and unexpected death  Vaccine Safety Datalink
(Kaiser Permanente, Southern California  and Kaiser
Permanente Northern California ) United States
Gallagher
201021 Cross -sectional  1997 -2002  7,381 boys aged 3 -17 Not reported  United States
Geier
201320 Case -control  1991 -1999  Not reported
25,939 infants in analysis  Vaccine Safety Datalink  United States
Geier 201523 Case control  1991 -2000  28,360 (344 cases with tics: 253
male, 91 female; 28,016 controls,
14,327 males, 13,689 females)

136,536 ( 647 cases  with cerebral
degeneration: 359 male, 288
female; 135,888 controls, 69,426
males, 66,462 females)  Vaccine Safety Datalink
United States
Geier 201624 Retrospective
cohort  1991 -2000  49,835 children  Vaccine Safety Datalink  United States
Geier 201722 Nested case
control  1991 -2000  28,008 children  Vaccine Safety Datalink
(Kaiser Permanente North -West  and Kaiser Permanente
Northern California ) United States
Geier 201825 Case  control  1991 -2000  54,685 children  Vaccine Safety Datalink  United States
Greenberg
200214 Randomized
Trial  Not reported  280 infants  Kaiser Permanente, Southern California  United States
Haber 201816 Case series  January  1, 2005 –
December  31, 2015  20,231 VAERS reports  Vaccine Adverse Event Reporting System  United States

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 43 of 84
 Author Year  Study design  Data Collection P eriod  Sample size, N  Surveillance System (if Applicable)  Country
Lewis 20016 Cohort  November  1, 1991 –
April 30, 1994  5,655 normal birthweight,  full term
infants  Vaccine Safety Datalink  (Northern California Kaiser
Permanente)  United States
Linder 199910 Cohort  Birth/record
January  1, 1991 –
December  31, 1992  10,829 neonates  Not reported  Israel
Lopez 20 0211 Cohort  NR 117 neonates  Centro Materno Infantil Los Farallones  Colombia
Morgan 20257 Cohort  January  1, 2017 –
December  31, 2020  818 extremely preterm infants  Surveillance of Adverse Events Following Immunization
in the Community  Australia
Niu 199612 Case series  January  1, 1991 –
May 31, 1995  12,520 VAERS reports  Vaccine Adverse Event Reporting System  United States
Niu 199917 Case series  January  1, 1991 –
October  5,1998  1,771  Vaccine Adverse Event Reporting System  United States
Sapru 200713 Randomized
Controlled Trial
(control arm)  Not reported  262 Not reported  India
Verstraeten
200319 Retrospective
cohort study  1995 -end of 2000  140,887  at 3 HMOs ( 13,337 at A,
110,833 at B, 16,717 at C)  Vaccine Safety Datalink  United States
Wood 201818 Randomized
Controlled Trial  June 11, 2010 - March 14,
2013  440 Not reported  Australia
Yerushalmi
19979 Randomized
Controlled Trial  Not reported  205 (46% were male)  Not reported  Israel

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 44 of 84
 C.2. Outcomes for All Included Studies
Table 20. Adverse Events Following Immunization (AEFI)  Results of Studies Meeting Inclusion Criteria
Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-value  Measure of
Association  Adjusted  Risk of Bias
Niu
199612 Case
series  Cerebral venous
thrombosis/intraventricular
hemorrhage   NR HepB vaccine
(unspecified )
in neonates
aged <0.1
years  (Y) 1.7% (1/60)  NR NR NR NR NR Some
concernsaaaa
Niu
199612 Case
series  Disseminated intravascular
coagulation   NR HepB vaccine
(unspecified)
in neonates
aged <0.1
years (Y)  1.7% (1/60)  NR NR NR NR NR Some
concernsa
Niu
199612 Case
series  Necrotizing enterocolitis   NR HepB vaccine
(unspecified)
in neonates
aged <0.1
years (Y)  1.7% (1/60)  NR NR NR NR NR Some
concernsbbbb
Lope z
200211 Cohort  Serious adverse events   Unsolicited
symptoms
collected
during 30 -day
follow -up
window  HepB Engerix -
B at birth ( Y) 0.9% (1/117)  NR NR NR NR NR Some
concerns2

Table 21. Allergic Reaction and Atopy Results of Studies Meeting Inclusion Criteria
Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control %
(n/N)  p-
value  Measure of
Association  Adjusted  Risk of
Bias
Lewis
20016 Cohort  Allergic
reaction  ICD 10 Codes  Hep B Vax
(unspecified)
within first 21 d
(Y) <0.1%
(1/3302)  Unvaccinated
within first 21 d  <0.1%
(1/2353)  NR RR: 0.71 (0.04 -
11.4); p = 0.99  None  Some
concerns

aaaa Descriptive study, no comparison
bbbb Descriptive study, no comparison

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 45 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control %
(n/N)  p-
value  Measure of
Association  Adjusted  Risk of
Bias
Lewis
20016 Cohort  Allergic
reaction  ICD 10 Codes  Hep B Vax
(unspecified)
within day of birth
or day after birth
(Y) <0.1%
(1/2718)  Unvaccinated
within first 21 d <0.1%
(1/2937)  NR RR: 0.87 (0.05 -
13.8); p = 0.99  None  Some
concerns
Sapru
200713 RCT Eczema  Parent assessment
or medical exam  HepB
Engerix -B within
first 2 wks  0 (0/130)  HepB
Gene Vac -B within
first 2 wks  0 (0/132)  NA NR NR No
concerns

Table 22. All Death Outcomes Results of Studies Meeting Inclusion Criteria
Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control %
(n/N)  p-value  Measure of
Association  Adjusted  Risk of Bias
Greenberg
200214 RCT All -cause
mortality   NR; at 7
months follow -
up Engerix -B
vaccine at
birth, 1
month, and 6
months of
age and
DTaP , OPV,
and Hib
vaccines  at 2,
4, and 6
months of
age ( NR) 0% (0/1 40) DTaP -HepB ,
OPV , and Hib
vaccine s at 2,
4, and 6
months of
age 0% (0/ 140)  NR NR NR Some
concernse
Morgan
20257 Cohort  All -cause
mortality   Victorian
Deaths index;
all cause
mortality
occurring in
the 3 months
after birth  Hep B vaccine
(unspecified)
within  24h of
birth  for
extremely
premature
infants (<29
weeks
gestation)
(NR)  2.30% (7/306)  No recorded
Hep B
vaccine
within 24h of
birth  for
extremely
premature
infants (<29
weeks
gestation)  2.70%
(14/512)  NR aRR: 1.13;
(95%CI: 0.42 -
2.81)  Maternal
age, low
Apgar at 1
minute, low
Apgar at 5
minutes,
maternal
smoking,
gestation
period and
congenital
heart No concerns

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 46 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control %
(n/N)  p-value  Measure of
Association  Adjusted  Risk of Bias
disease
status
Haber
201816 Case series  All -cause
mortality   VAERS reports
of death
verified by
death
certificate or
autopsy report  Hep B vaccine
(unspecified)
infants aged
<1 month  (Y) 11.3%
(27/240 ) NR NR NR NR NR Some
concernscccc
Niu
199612 Case series  All -cause
mortality   VAERS reports
of death  Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of
age (Y) 10% (6/60)  NR NR NR NR NR Some
concernsdddd
Niu
199917 Case series  All -cause
mortality   VAERS reports
of death  Hep B vaccine
(unspecified)
infants aged
<28 days (Y)  1% ( 18/1771 ) NR NR NR NR NR Some
concernseeee
Eriksen
200415 Cohort  Expected
neonatal
death   ICD-9 codes
and
determined by
medical
autopsy ; four
categories
considered
expected  Hep B vaccine
(unspecified)
before 29
days of age
(Y); 85%
vaccinated of
day of birth,
none  beyond
8 days of life  69% (50/72)  No HepB
vaccine with
death at <29
days of age  65%
(128 /196)  0.6 NR NR No concerns
Eriksen
200415 Cohort  Unexpected
neonatal
death   ICD-9 codes
and
determined by
medical
autopsy  Hep B vaccine
(unspecified)
before 29
days of age
(Y); 85%
vaccinated of
day of birth,
none beyond
8 days of life  31% (22/72)  No HepB
vaccine with
death at <29
days of age  35%
(68/196)  0.6 NR NR No concerns

cccc Descriptive study, no comparison
dddd Descriptive study, no comparison
eeee Descriptive study, no comparison

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 47 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control %
(n/N)  p-value  Measure of
Association  Adjusted  Risk of Bias
Eriksen
200415 Cohort  Unexpected
neonatal
death from
SIDS   ICD-9 codes
and
determined by
medical
autopsy  Hep B vaccine
(unspecified)
before 29
days of age
(Y); 85%
vaccinated of
day of birth,
none beyond
8 days of life  8/240,717
(3.3 deaths
per 100,000
births)  No HepB
vaccine at
<29 days of
age 4/120,979
(3.3 deaths
per 100,000
births)  0.99  NR NR Serious
concerns27

Table 23. Infection Results of Studies Meeting Inclusion Criteria
Study  Study Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control %
(n/N)  p-value  Measure of
Association  Adjusted  Risk of Bias
Lewis
20016 Cohort  Blood or CSF
culture
performed   Clinical
laboratory
data  Hep B vaccine
(unspecified)
withi n first 21
days of life (Y)  4%
(133/3,302 ) No Hep B
vaccine
within first
21 days of
life 8.6%
(203/2,353 ) <0.001  RR: 0.73
(95%CI: 0.65 -
0.82)  NR No concerns
Lewis
20016 Cohort  Blood or CSF
culture
performed   Clinical
laboratory
data  Hep B vaccine
(unspecified)
on day  of
birth or day
after birth  (Y) 4.6%
(126/2,718 ) No Hep B
vaccine
within first
21 days of
life 8.6%
(203/2,353 ) <0.001  RR: 0.71;
(95%CI: 0.63 -
0.80)  NR No concerns
Lewis
20016 Cohort  Blood or CSF
culture
positive   Clinical
laboratory
data  Hep B vaccine
(unspecified)
within first 21
days of life (Y)  0.2%
(8/3,302 ) No Hep B
vaccine
within first
21 days of
life 0.7%
(16/2,353 ) 0.030  RR: 0.60
(95%CI: 0.38 -
0.95)  NR No concerns
Lewis
20016 Cohort  Blood or CSF
culture
positive   Clinical
laboratory
data  Hep B vaccine
(unspecified)
on day of
birth or day
after birth (Y) 0.3%
(7/2,718 ) No Hep B
vaccine
within first
21 days of
life 0.7%
(16/2,353 ) 0.027  RR: 0.57;
(95%CI: 0.35 -
0.94)  NR No concerns
Lewis
20016 Cohort  Fever  (in first
3 weeks of
life) ICD-9 codes,
computerized
database
search  Hep B vaccine
(unspecified)
within first 21
days of life (Y)  (26/3,302 ) No Hep B
vaccine
within first (25/2,353 ) 0.51  aRR: 0.92
(95%CI: 0.7 -
1.2) Adjusted by
age in days  No concerns

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 48 of 84
 Study  Study Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control %
(n/N)  p-value  Measure of
Association  Adjusted  Risk of Bias
21 days of
life
Lewis
20016 Cohort  Fever  (in first
3 weeks of
life) ICD-9 codes,
computerized
database
search  Hep B vaccine
(unspecified)
on day of
birth or day
after birth (Y) (21/2,718 ) No Hep B
vaccine
within first
21 days of
life (25/2,353 ) 0.28 aRR: 0.85;
(95%CI: 0. 6-
1.1) Adjusted by
age in days  No concerns
Haber
201816 Case series  Infections
and
infestations   VAERS, non -
death, serious
reports  Hep B vaccine
(unspecified)
infants aged
<1 month (Y)  4.6%  (11/240)  NR NR NR NR NR Some
concerns7

Table 24. Local Injection -site Outcomes Results of Studies Meeting Inclusion Criteria
Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-
value  Measure of
Association  Adjusted  Risk of
Bias
Bassily
19958 RCT Local side effects  Parental report of
local soreness or
temporary
redness/induration at
the injection site  Recombivax
immediately
after  birth (Y)  2.8% ( 5/178)  Recombivax
at 18 months
of age (Y)  1.6%
(3/191)  NR NR NR Serious
concerns8
Bassily
19958 RCT Local side effects  Parental report of
local soreness or
temporary
redness/induration at
the injection site  Recombivax
at 2 months of
age (Y)  7.2% ( 12/167)  Recombivax
at 18 months
of age (Y)  1.6%
(3/191)  NR NR NR Serious
concerns8
Yerushalmi
19979 RCT Pain with movement   Parental report on
diary card for 5 days
post -vaccination  Engerix -B
vaccine within
24 hrs of birth
(Y) 7.7% (4/52)  BioHepB
vaccine within
24 hrs of birth
(Y) 2.6%
(4/153)  NR NR NR Serious
concerns9
Yerushalmi
19979 RCT Pain with pressure   Parental report on
diary card for 5 days
post -vaccination  Engerix -B
vaccine within
24 hrs of birth
(Y) 7.7% (4/52)  BioHepB
vaccine within
24 hrs of birth
(Y) 1.3%
(2/153)  NR NR NR Serious
concerns9
Wood
201818 RCT Pain or soreness  (any)  Parental report of
pain at injection site
within 2 days after
dose  Engerix -B
vaccine given
alone within
120 hrs of 9% (14/150)  Engerix -B co-
administered
with
investigational 20%
(41/208)  NR NR NR Some
concerns11

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 49 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-
value  Measure of
Association  Adjusted  Risk of
Bias
birth (Y );
87.6 %
vaccinated
days 0 -2 acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2
Wood
201818 RCT Pain or soreness
(severe)  Parental report of
pain at injection site
within 2 days after
dose , severe classified
as crying when limb is
moved/spontaneously
painful or prevents
daily activities  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y );
87.6 %
vaccinated
days 0 -2 0% (0/150)  Engerix -B co-
administered
with
investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2 0.5%
(1/208)  NR NR NR Some
concerns11
Greenberg
200214 RCT Pain or soreness  (Any)  Solicited parental
report for day of
vaccination and 3
days following
vaccination  Engerix -B
vaccine within
4 days of birth
(NR)  8.1%
(NR/136)  DTaP -HepB ,
OPV, and Hib
vaccines  at 2
months of age
(NR)  35.7%
(NR/129)  NR NR NR Some
concerns11
Greenberg
200214 RCT
Pain or soreness (Grade
3/Severe)  Solicited parental
report for day of
vaccination and 3
days following
vaccination ; Grade 3 -
soreness that caused
crying when limb was
move d; reported  at
any vaccination site  Engerix -B
vaccine within
4 days of birth
(NR)
0% (0/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  1.6%
(NR/129)  NR NR NR Some
concerns11
Lopez
200211 Cohort  Pain or soreness  (Any)  Solicited self -report
by diary card during
4-day follow -up
window  HepB Engerix -
B at birth ( Y) 6% (7/117)  NR NR NR NR NR Some
concerns12
Lopez
200211 Cohort  Pain or soreness
(Severe)  Solicited self -report
by diary card during
4-day follow -up
window  HepB Engerix -
B at birth (Y)  4.3% (5/117)  NR NR NR NR NR Some
concerns12

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 50 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-
value  Measure of
Association  Adjusted  Risk of
Bias
Wood
201818 RCT Redness or
erythema  (Any)  Parental report ,
within 2 days of dose;
grade 1: <10mm,
grade 2 -10-<30mm;
grade 3: >=30mm  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y) ;
87.6 %
vaccinated
days 0 -2 20% (30/150)  Engerix -B co-
administered
with
investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2 27%
(57/208)  NR NR NR Some
concerns13
Wood
201818 RCT Redness or
erythema  (Severe/Grade
3) Parental report,
within 2 days of dose;
grade 3: >=30mm  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y );
87.6 %
vaccinated
days 0 -2 0 Engerix -B co-
administered
with
investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2 0 NR NR NR Some
concerns13
Yerushalmi
19979 RCT Redness or erythema   Parental report on
diary card for 5 days
post -vaccination  Engerix -B
vaccine within
24 hrs of birth
(Y) 0/52  BioHepB
vaccine within
24 hrs of birth
(Y) 0/153  NR NR NR Some
concerns14
Greenberg
200214 RCT Redness or
erythema  (Any)  Solicited parental
report for day of
vaccination and 3
days following
vaccination  Engerix -B
vaccine within
4 days of birth
(NR)  8.8%
(NR/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  11.6%
(NR/129)  NR NR NR Some
concerns14
Greenberg
200214 RCT Redness or
erythema  (Severe/Grade
3) Solicited parental
report for day of
vaccination and 3
days following
vaccination ; Grade 3 -
diameter >20mm;
reported at any
vaccination site  Engerix -B
vaccine within
4 days of birth
(NR)  0% (0/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  0%
(0/129)  NR NR NR Some
concerns14
Lopez
200211 Cohort  Redness or
erythema  (Any)  Solicited self -report
by diary card during HepB Engerix -
B at birth ( Y) 11.1%
(13/117)  NR NR NR NR NR Serious
concerns15

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 51 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-
value  Measure of
Association  Adjusted  Risk of
Bias
4-day follow -up
window
Lopez
200211 Cohort  Redness or
erythema  (Severe)  Solicited self -report
by diary card during
4-day follow -up
window; severe
>20mm  HepB Engerix -
B at birth (Y)  0% (0/117)  NR NR NR NR NR Serious
concerns15
Sapru
200713 RCT Swelling  Parental report until
total follow -up period
of 18 weeks  Engerix -B
vaccine within
first 2 weeks
of life (NR)  0% (0/130)  GeneVacB
(HepB)
vaccine within
first 2 weeks
of life (NR)  0%
(0/132)  NR NR NR Some
concernsn
Greenberg
200214 RCT Swelling  (Any)  Solicited parental
report for  day of
vaccination and  3
days following
vaccination  Engerix -B
vaccine within
4 days of birth
(NR)  0% (0/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  16.3%
(NR/129)  NR NR NR Some
concernsn
Greenberg
200214 RCT Swelling  (Severe/Grade
3) Solicited parental
report for day of
vaccination and 3
days following
vaccination ; Grade 3 -
diameter >20mm;
reported at any
vaccination site  Engerix -B
vaccine within
4 days of birth
(NR)  0% (0/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  3.1%
(NR/129)  NR NR NR Some
concernsn
Yerushalmi
19979 RCT Swelling  Parental report on
diary card for 5 days
post -vaccination  Engerix -B
vaccine within
24 hrs of birth
(Y) 7.7% (4/52)  BioHepB
vaccine within
24 hrs of birth
(Y) 2.0%
(3/153)  NR NR NR Some
concernsn
Wood
201818 RCT Swelling  (Any)  Parental report,
within 2 days of dose;
grade 1: <10mm,
grade 2 -10-<30mm;
grade 3: >=30mm  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y) ;
87.6 %
vaccinated
days 0 -2 4% (6/150)  Engerix -B co-
administered
with
investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2 12.5%
(26/208)  NR NR NR Some
concerns16

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 52 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-
value  Measure of
Association  Adjusted  Risk of
Bias
Wood
201818 RCT Swelling (Severe/Grade
3) Parental report,
within 2 days of dose;
grade 3: >=30mm  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y );
87.6 %
vaccinated
days 0 -2 0 Engerix -B co-
administered
with
investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2 0 NR NR NR Some
concerns16
Lopez
200211 Cohort  Swelling  (Any)  Solicited self -report
by diary card during
4-day follow -up
window  HepB Engerix -
B at birth (Y)  4.3% (5/117)  NR NR NR NR NR Serious
concerns17
Lopez
200211 Cohort  Swelling  (Severe)  Solicited self -report
by diary card during
4-day follow -up
window; severe
>20mm  HepB Engerix -
B at birth (Y)  0% (0/117)  NR NR NR NR NR Serious
concerns17

Table 25. Neurodevelopmental Results of Studies Meeting Inclusion Criteria
Study  Study
Type  Outcome  or
Case  Outcome
Identification  Intervention
or Exposure
(Thimerosal
Y/N/NR)  Intervention
or Exposure %
(n/N)  Control
(Thimerosal
Y/N/NR)  Control % (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
Verstraeten
200319 Cohort  Attention
deficit
disorder
(ADD )  ICD-9 codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO A (Y)  (Not stratified
by dose timing)  NR NR NR aHR: 0.92
(95%CI 0.52 -
1.59)  Stratified
by HMO,
year of
birth, and
sex, and
adjusted
for birth
weight  No
concerns
Verstraeten
200319 Cohort  Attention
deficit
disorder
(ADD )  ICD-9 codes  HepB vaccine
(unspecified)
within 1 (Not stratified
by dose timing)  NR NR NR aHR: 0.90
(95%CI 0.74 -
1.10)  Stratified
by HMO,
year of
birth, and No
concerns

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 53 of 84
 Study  Study
Type  Outcome  or
Case  Outcome
Identification  Intervention
or Exposure
(Thimerosal
Y/N/NR)  Intervention
or Exposure %
(n/N)  Control
(Thimerosal
Y/N/NR)  Control % (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
month of age
at HMO B  (Y) sex, and
adjusted
for birth
weight
and clinic
Verstraeten
200319 Cohort  Attention
deficit
disorder
(ADD )  Costar codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO C  (Y) (Not stratified
by dose timing)  NR NR NR HR: 0.88
(95CI% 0.53 -
1.48)  none  No
concerns
Verstraeten
200319 Cohort  Autism/Autism
Spectrum
Disorder   ICD-9 codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO B (Y)  (Not stratified
by dose timing)  NR NR NR aHR: 1.16
(95%CI 0.78 -
1.71)  Stratified
by HMO,
year of
birth, and
sex, and
adjusted
for birth
weight
and clinic  No
concerns
Geier
201320 Case -
control  Autism/Autism
Spectrum
Disorder   ICD-9 codes  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life
for cases
(diagnosed
with autism
spectrum
disorder)  Exposure/Cases:
(155/302)  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life
for controls
(no diagnosis
of autism
spectrum
disorder)  Exposure/Controls:
(8161/ 25632)  <0.00001  OR: 2.18;
(95%CI:
1.74 -2.73)
(assessed as
OR of
exposure to
thimerisol -
containing
vaccine in
cases v.
controls)  NR Serious
concerns38
Gallagher
201021 Cross -
sectional  Autism/Autism
Spectrum
Disorder   Parent
reported
autism
diagnosis to
National
Health HepB vaccine
(unspecified)
within 1
month of age
in males born
before 1999
(NR)  NR No HepB
vaccine
(unspecified)
in first
month of life
(vaccinated
late or never NR 0.031  aOR: 3.002;
(95%CI:
1.109 -8.126)  when
adjust ing
for race
and
ethnicity ,
family
structure, Serious
concerns39

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 54 of 84
 Study  Study
Type  Outcome  or
Case  Outcome
Identification  Intervention
or Exposure
(Thimerosal
Y/N/NR)  Intervention
or Exposure %
(n/N)  Control
(Thimerosal
Y/N/NR)  Control % (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
Interview
Survey  vaccinated)
in males
born before
1999 (NR)  and
maternal
education
Verstraeten
200319 Cohort  Coordination
Disorder   ICD-9 codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO A (Y)  (Not stratified
by dose timing)  NR NR NR aHR: 1.67
(95%CI 0.78 -
3.57)  Stratified
by HMO,
year of
birth, and
sex, and
adjusted
for birth
weight  No
concerns
Verstraeten
200319 Cohort  Speech or
language
delay   ICD-9 codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO A (Y)  (Not stratified
by dose timing)  NR NR NR aHR: 1.14
(95%CI 0.88 -
1.46)  Stratified
by HMO,
year of
birth, and
sex, and
adjusted
for birth
weight  No
concerns
Verstraeten
200319 Cohort  Speech or
language
delay   ICD-9 codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO B (Y)  (Not stratified
by dose timing)  NR NR NR aHR: 1.03
(95%CI 0.91 -
1.17)
 Stratified
by HMO,
year of
birth, and
sex, and
adjusted
for birth
weight
and clinic  No
concerns
Verstraeten
200319 Cohort  Speech or
language
delay   Costar codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO C (Y)  (Not stratified
by dose timing)  NR NR NR HR: 0.91
(95%CI 0.79 -
1.04)  none  No
concerns
Verstraeten
200319 Cohort  Eating
disorders   ICD-9 codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO B (Y)  (Not stratified
by dose timing)  NR NR NR aHR: 0.90
(95%CI 0.50 -
1.61)  Stratified
by HMO,
year of
birth, and
sex, and
adjusted No
concerns

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 55 of 84
 Study  Study
Type  Outcome  or
Case  Outcome
Identification  Intervention
or Exposure
(Thimerosal
Y/N/NR)  Intervention
or Exposure %
(n/N)  Control
(Thimerosal
Y/N/NR)  Control % (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
for birth
weight
and clinic
Geier
201722 Case -
control  Emotional
disorders   ICD-9 codes  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life
for cases
(diagnosed
with
emotional
disorders)  Exposure/Cases:
(204/513)  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life
for controls
(no diagnosis
of emotional
disorders)  Exposure/Controls:
(9003/ 27491)  <0.005  OR: 1.34 (95
%CI: 1.12 -
1.60 )
(assessed as
OR of
exposure to
thimerisol -
containing
vaccine in
cases v.
controls)  none  Serious
concerns41
Geier
201722 Case -
control  Emotional
disorders   ICD-9 codes  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life
for male
cases
(diagnosed
with
emotional
disorders)  Exposure/Cases:
(158/ 399)  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life
for male
controls (no
diagnosis of
emotional
disorders)  Exposure/Controls:
(4568/ 14013)  <0.005  OR: 1.36;
(95% CI:
1.11 -1.66 )
(assessed as
OR of
exposure to
thimerisol -
containing
vaccine in
cases v.
controls)  Stratified
by sex  Serious
concerns41
Geier
201722 Case -
control  Emotional
disorders   ICD-9 codes  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first Exposure/Cases:
(46/118)  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first Exposure/Controls:
(4435/13478)  0.15  OR: 1.30;
(95% CI:
0.90 -1.89)
(assessed as
OR of
exposure to
thimerisol -
containing Stratified
by sex  Serious
concerns41

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 56 of 84
 Study  Study
Type  Outcome  or
Case  Outcome
Identification  Intervention
or Exposure
(Thimerosal
Y/N/NR)  Intervention
or Exposure %
(n/N)  Control
(Thimerosal
Y/N/NR)  Control % (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
month of life
for female
cases
(diagnosed
with
emotional
disorders)  month of life
for female
controls (no
diagnosis of
emotional
disorders)  vaccine in
cases v.
controls)
Verstraeten
200319 Cohort  Emotional
disturbances   ICD-9 codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO A (Y)  (Not stratified
by dose timing)  NR NR NR aHR: 1.00
(95%CI 0.42 -
2.36)  Stratified
by HMO,
year of
birth, and
sex, and
adjusted
for birth
weight  No
concerns
Verstraeten
200319 Cohort  Emotional
disturbances   ICD-9 codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO B (Y)  (Not stratified
by dose timing)  NR NR NR aHR: 0.76
(95%CI 0.54 -
1.07)  Stratified
by HMO,
year of
birth, and
sex, and
adjusted
for birth
weight
and clinic  No
concerns
Verstraeten
200319 Cohort  Other
childhood
psychosis   ICD-9 codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO B (Y)  (Not stratified
by dose timing)  NR NR NR aHR: 1.03
(95%CI 0.60 -
1.74)  Stratified
by HMO,
year of
birth, and
sex, and
adjusted
for birth
weight
and clinic  No
concerns
Verstraeten
200319 Cohort  Sleep
disorders   ICD-9 codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO A (Y)  (Not stratified
by dose timing)  NR NR NR aHR: 0.79
(95%CI 0.38 -
1.61)  Stratified
by HMO,
year of
birth, and
sex, and
adjusted No
concerns

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 57 of 84
 Study  Study
Type  Outcome  or
Case  Outcome
Identification  Intervention
or Exposure
(Thimerosal
Y/N/NR)  Intervention
or Exposure %
(n/N)  Control
(Thimerosal
Y/N/NR)  Control % (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
for birth
weight
Verstraeten
200319 Cohort  Sleep
disorders   ICD-9 codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO B (Y)  (Not stratified
by dose timing)  NR NR NR aHR: 1.24
(95%CI 0.80 -
1.93)  Stratified
by HMO,
year of
birth, and
sex, and
adjusted
for birth
weight
and clinic  No
concerns
Verstraeten
200319 Cohort  Sleep
disorders   Costar codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO C (Y)  (Not stratified
by dose timing)  NR NR NR HR: 0.97
(95%CI 0.79 -
1.19)  none  No
concerns
Geier
201624 Cohort  Specific delays
in
development   ICD-9 codes  HepB vaccine
(unspecified)
within first
month of life
(Y) (828/18,637 ) No HepB
vaccine
within first
month of life  (1127/31,198 ) <0.001  RR: 1.22,
(95% CI:
1.12 -1.33)  none  Serious
concerns42
Geier
201624 Cohort  Specific delays
in
development   ICD-9 codes  HepB vaccine
(unspecified)
within first
month of life
for males (Y)  (567/9514 ) No HepB
vaccine
within first
month of life
for males  (771/16,110 ) <0.001  OR: 1.23,
(95%CI:
1.11 -1.37)  none  Serious
concerns42
Geier
201624 Cohort  Specific delays
in
development   ICD-9 codes  HepB vaccine
(unspecified)
within first
month of life
for females
(Y) (261/9122 ) No HepB
vaccine
within first
month of life
for females  (356/15,088 ) <0.0 5 OR: 1.21;
(95% CI:
1.03 -1.41)  none  Serious
concerns42
Verstraeten
200319 Cohort  Stammering   ICD-9 codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO A (Y)  (Not stratified
by dose timing)  NR NR NR aHR: 0.89
(95%CI 0.40 -
1.97)  Stratified
by HMO,
year of
birth, and
sex, and
adjusted
for birth
weight  No
concerns

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 58 of 84
 Study  Study
Type  Outcome  or
Case  Outcome
Identification  Intervention
or Exposure
(Thimerosal
Y/N/NR)  Intervention
or Exposure %
(n/N)  Control
(Thimerosal
Y/N/NR)  Control % (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
Verstraeten
200319 Cohort  Stammering   ICD-9 codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO B (Y)  (Not stratified
by dose timing)  NR NR NR aHR: 0.61
(95%CI 0.33 -
1.14)  Stratified
by HMO,
year of
birth, and
sex, and
adjusted
for birth
weight
and clinic  No
concerns
Verstraeten
200319 Cohort  Stammering   Costar codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO C (Y)  (Not stratified
by dose timing)  NR NR NR HR: 0.77
(95%CI 0.47 -
1.26)  none  No
concerns
Verstraeten
200319 Cohort  Tic Disorder,
Tics  ICD-9 codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO A (Y)  (Not stratified
by dose timing)  NR NR NR aHR: 1.25
(95%CI 0.47 -
3.29)  Stratified
by HMO,
year of
birth, and
sex, and
adjusted
for birth
weight  No
concerns
Verstraeten
200319 Cohort  Tic Disorder,
Tics  ICD-9 codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO B (Y)  (Not stratified
by dose timing)  NR NR NR aHR: 0.85
(95%CI 0.55 -
1.30)  Stratified
by HMO,
year of
birth, and
sex, and
adjusted
for birth
weight
and clinic  No
concerns
Verstraeten
200319 Cohort  Tic Disorder,
Tics  Costar codes  HepB vaccine
(unspecified)
within 1
month of age
at HMO C (Y)  (Not stratified
by dose timing)  NR NR NR HR: 0.93
(95%CI 0.45 -
1.92)  none  No
concerns
Geier
201523 Case -
control  Tic Disorder,
Tics  ICD-9 codes  HepB vaccine
(unspecified)
(Y) or
combined Exposure/Cases:
(151/ 344) HepB vaccine
(unspecified)
(Y) or
combined Exposure/Controls:
(9222/28016 ) <0.00001  OR: 1.59;
(95%CI:
1.29 -1.98)
(assessed as none  Serious
Concerns43

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 59 of 84
 Study  Study
Type  Outcome  or
Case  Outcome
Identification  Intervention
or Exposure
(Thimerosal
Y/N/NR)  Intervention
or Exposure %
(n/N)  Control
(Thimerosal
Y/N/NR)  Control % (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
Hib-HepB
vaccine or no
vaccine
within first
month of life
for cases
(diagnosed
with tic
disorder)  Hib-HepB
vaccine or no
vaccine
within first
month of life
for controls
(no diagnosis
of tic
disorder)  OR of
exposure to
thimerisol -
containing
vaccine in
cases v.
controls)
Geier
201523 Case -
control  Tic Disorder,
Tics  ICD-9 codes  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life
for male
cases
(diagnosed
with tic
disorder)  Exposure/Cases:
(113/253)  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life
for male
controls (no
diagnosis of
tic disorder)  Exposure/Controls:
(4697/ 14327)  <0.0001  OR: 1.65;
(95%CI:
1.29 -2.12)
(assessed as
OR of
exposure to
thimerisol -
containing
vaccine in
cases v.
controls)  Stratified
by sex  Serious
Concerns43
Geier
201523 Case -
control  Tic Disorder,
Tics  ICD-9 codes  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life
for female
cases
(diagnosed
with tic
disorder)  Exposure/Cases:
(38/ 91) HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life
for female
controls (no
diagnosis of
tic disorder)  Exposure/Controls:
(4525/ 13689)  0.09  OR: 1.45;
(95%CI:
0.95 -2.21)
(assessed as
OR of
exposure to
thimerisol -
containing
vaccine in
cases v.
controls)  Stratified
by sex  Serious
Concerns43

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 60 of 84
 Table 26. Neurologic Results of Studies Meeting Inclusion Criteria
Study  Study
Type  Outcome  or
Case  Outcome
Identification  Intervention
or Exposure
(Thimerosal
Y/N/NR)  Intervention
or Exposure
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control % (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
Niu
199612 Case
series  Abnormal
CSF (Any)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of
age (Y) 6.7% (4/60)  NR NR NR NR NR Some
concerns20
Niu
199612 Case
series  Abnormal
CSF (Serious)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of
age (Y) 6.7% (4/60)  NR NR NR NR NR Some
concerns20
Geier
201523 Case -
control  Cerebral
degeneration   ICD-9 codes  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life
for cases
(diagnosed
with cerebral
degeneration)  Exposure/Cases:
(175/ 647)  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life
for controls
(no diagnosis
of tic
disorder)  Exposure/Controls:
(62637/ 135889)  <0.00001  OR: 0.43;
(95%CI:
0.36 -0.52)
(assessed as
OR of
exposure to
thimerisol -
containing
vaccine in
cases v.
controls)  none  Serious
concerns47
Niu
199612 Case
series  Convulsions
(Any)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of
age (Y) 10% (6/60)  NR NR NR NR NR Some
concerns20
Niu
199612 Case
series  Convulsions
(Serious)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of
age (Y) 6.7% (4/60)  NR NR NR NR NR Some
concerns20
Lewis
20016 Cohort  Seizure  ICD-9 codes,
computerized
database
search  Hep B vaccine
(unspecified)
within first 21
days of life (Y)  (1/3302)  No Hep B
vaccine
within first (4/2353)  0.17  RR: 0.18
(95%CI:
0.02 -1.6) NR No
concerns

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 61 of 84
 Study  Study
Type  Outcome  or
Case  Outcome
Identification  Intervention
or Exposure
(Thimerosal
Y/N/NR)  Intervention
or Exposure
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control % (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
21 days of
life
Lewis
20016 Cohort  Seizure  ICD-9 codes,
computerized
database
search  Hep B vaccine
(unspecified)
on day of
birth or day
after birth (Y) (1/2718)  No Hep B
vaccine
within first
21 days of
life (4/2353)  0.19  RR: 0.22;
(95%CI:
0.02 -1.9) NR No
concerns
Haber
201816 Case
series  Nervous
system
disorders   VAERS, non -
death, serious
reports  Hep B vaccine
(unspecified)
infants aged
<1 month (Y)  6.3%  (15/240 ) NR NR NR NR NR Some
concerns39
Lewis
20016 Cohort  Neurologic
disease,
other than
seizure   computerized
database
search  Hep B vaccine
(unspecified)
within first 21
days of life (Y)  (4/3,302 ) No Hep B
vaccine
within first
21 days of
life (2/2,353 ) 0.99  RR: 1.4
(95%CI: 0.3 -
7.8) NR No
concerns
Lewis
20016 Cohort  Neurologic
disease,
other than
seizure   computerized
database
search  Hep B vaccine
(unspecified)
on day of
birth or day
after birth (Y) (4/2,718 ) No Hep B
vaccine
within first
21 days of
life (2/2,353 ) 0.69  RR: 1.7;
(95%CI: 0.3 -
9.4) NR No
concerns

Table 27. Cardiopulmonary Results of Studies Meeting Inclusion Criteria
Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control %
(n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
Morgan
20257 Cohort  Bronchopulmonary
dysplasia  ICD-10
Australian
modification
codes  Hep B vaccine
(unspecified)
within 24h of
birth  for
extremely
premature
infants (<29
weeks
gestation)
(NR)  (155/306)  No recorded
Hep B
vaccine
within 24h of
birth  for
extremely
premature
infants (<29
weeks
gestation)  (317/512)  NR aRR: 0.83;
(95%CI: 0.68 -
1.0) Maternal
age, low
Apgar at 1
minute, low
Apgar at 5
minutes,
maternal
smoking,
gestation
period and
congenital No
concerns

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 62 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control %
(n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
heart
disease
status
Niu
199612 Case series  Apnea  (Any)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of
age (Y) 8.3% ( 5/60)  NR NR NR NR NR Some
concernst
Niu
199612 Case series  Apnea  (Serious)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of
age (Y) (3/60)  NR NR NR NR NR Some
concernst
Niu
199612 Case series  Bradycardia  (Any)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of
age (Y) 1.7% (1/60)  NR NR NR NR NR Some
concernst
Niu
199612 Case series  Bradycardia  (Serious)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of
age (Y) 1.7% (1/60)  NR NR NR NR NR Some
concernst
Niu
199612 Case series  Cyanosis  (Any)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of
age (Y) 11.7% ( 7/60)  NR NR NR NR NR Some
concernst
Niu
199612 Case series  Cyanosis  (Serious)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of
age (Y) (5/60)  NR NR NR NR NR Some
concernst

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 63 of 84
 Table 28. Systemic Reactions Results of Studies Meeting Inclusion Criteria
Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
Niu
199612 Case
series  Agitation  (Any)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of age
(Y) 21.7% (13/60)  NR NR NR NR NR Some
concernsq
Niu
199612 Case
series  Agitation  (Serious)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of age
(Y) 11.7% (7/60)  NR NR NR NR NR Some
concernsq
Yerushalmi
19979 RCT Anorexia/Decreased
appetite    Parental
report on diary
card for 5 days
post -
vaccination  Engerix -B
vaccine within
24 hrs of birth
(Y) 0% (0/52)  BioHepB
vaccine within
24 hrs of birth
(Y) 2.0%
(3/153)  NR NR NR Some
concerns28
Greenberg
200214 RCT Anorexia/Decreased
appetite  (Any)  Solicited
parental
report for day
of vaccination
and 3 days
following
vaccination  Engerix -B
vaccine within
4 days of birth
(NR)  14.0%
(NR/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  25.6%
(NR/129)  NR NR NR Some
concerns28
Greenberg
200214 RCT Anorexia/Decreased
appetite  (Severe/Grade
3) Solicited
parental
report for day
of vaccination
and 3 days
following
vaccination ;
Grade 3 -
prevented
normal daily
activities  Engerix -B
vaccine within
4 days of birth
(NR)  1.5%
(NR/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  0.8%
(NR/129)  NR NR NR Some
concerns28
Wood
201818 RCT Feeding
issues /Anorexia (Any)  Parental
report, within
2 days of dose  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y) ;
87.6 % 17% (17/103)  Engerix -B co-
administered
with
investigational
acellular
Pertussis 13%
(28/221)  NR NR NR Some
concerns32

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 64 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
vaccinated
days 0 -2 vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2
Wood
201818 RCT Feeding
issues /Anorexia (Grade
3/Severe)  Parental
report, within
2 days of dose;
Grade 3 -
prevents
normal
everyday
activities or
requires
significant
medical
intervention  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y) ;
87.6 %
vaccinated
days 0 -2 0.9% (1/103)  Engerix -B co-
administered
with
investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2 0 NR NR NR Some
concerns32
Lopez
200211 Cohort  Anorexia/Decreased
appetite  (Any)  Solicited self -
report by diary
card during 4 -
day follow -up
window  HepB Engerix -
B at birth (Y)  2.6% (3/117)  NR NR NR NR NR Some
concerns54
Lopez
200211 Cohort  Anorexia/Decreased
appetite  (Severe)  Solicited self -
report by diary
card during 4 -
day follow -up
window  HepB Engerix -
B at birth (Y)  1.7% (2/117)  NR NR NR NR NR Some
concerns54
Sapru
200713 RCT Constipation   Parental
report until
total follow -up
period of 18
weeks  Engerix -B
vaccine within
first 2 weeks
of life (NR)  0% (0/130)  GeneVacB
(HepB)
vaccine within
first 2 weeks
of life (NR)  0%
(0/132)  NR NR NR No
concerns

Wood
201818 RCT Diarrhea  (Any)  Parental
report, within
2 days of dose  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y) ;
87.6 %
vaccinated
days 0 -2 12% (12/103)  Engerix -B co-
administered
with
investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91% 17.0%
(38/221)  NR NR NR Some
concerns25

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 65 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
vaccinated
days 0-2
Wood
201818 RCT Diarrhea  (Severe/Grade
3) Parental
report, within
2 days of dose ;
Grade 3 -
prevents
normal
everyday
activities or
requires
significant
medical
intervention  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y) ;
87.6 %
vaccinated
days 0 -2 0 Engerix -B co-
administered
with
investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2 0 NR NR NR Some
concerns25
Sapru
200713 RCT Diarrhea  (loose
motions)  Parental
report until
total follow -up
period of 18
weeks  Engerix -B
vaccine within
first 2 weeks
of life (NR)  0% (0/130)  GeneVacB
(HepB)
vaccine within
first 2 weeks
of life (NR)  0%
(0/132)  NR NR NR Some
concerns30
Greenberg
200214 RCT Diarrhea  (Any)  Solicited
parental
report for day
of vaccination
and 3 days
following
vaccination  Engerix -B
vaccine within
4 days of birth
(NR)  8.1%
(NR/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  10.1%
(NR/129)  NR NR NR Some
concerns30
Greenberg
200214 RCT Diarrhea  (Severe/Grade
3)  Solicited
parental
report for day
of vaccination
and 3 days
following
vaccination ;
Grade 3 -
prevented
normal daily
activities  Engerix -B
vaccine within
4 days of birth
(NR)  0.7%
(NR/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  0%
(0/129)  NR NR NR Some
concerns30
Yerushalmi
19979 RCT Diarrhea   Parental
report on diary
card for 5 days Engerix -B
vaccine within
24 hrs of birth
(Y) 0% (0/52)  BioHepB
vaccine within
24 hrs of birth
(Y) 0.64%
(1/152)  NR NR NR Some
concerns30

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 66 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
post -
vaccination
Niu
199612 Case
series  Diarrhea  (Any)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of age
(Y) 1.7% (1/60)  NR NR NR NR NR Some
concerns24
Niu
199612 Case
series  Diarrhea  (Serious)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of age
(Y) 1.7% (1/60)  NR NR NR NR NR Some
concerns24
Greenberg
200214 RCT Drowsiness or sleeping
more  (Any)  Solicited
parental
report for day
of vaccination
and 3 days
following
vaccination  Engerix -B
vaccine within
4 days of birth
(NR)  32.4%
(NR/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  40.3%
(NR/129)  NR NR NR Some
concerns31
Greenberg
200214 RCT Drowsiness or sleeping
more  (Severe/Grade 3)  Solicited
parental
report for day
of vaccination
and 3 days
following
vaccination ;
Grade 3 -
prevented
normal daily
activities  Engerix -B
vaccine within
4 days of birth
(NR)  2.9%
(NR/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  0.8%
(NR/129)  NR NR NR Some
concerns31
Wood
201818 RCT Drowsiness or sleeping
more  (Any)  Parental
report, within
2 days of dose  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y) ;
87.6 %
vaccinated
days 0 -2 28% (28/103)  Engerix -B co-
administered
with
investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2 18%
(39/221)  NR NR NR Some
concerns29

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 67 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
Wood
201818 RCT Drowsiness or sleeping
more  (Severe/Grade 3)  Parental
report, within
2 days of dose;
Grade 3 -
prevents
normal
everyday
activities or
requires
significant
medical
intervention  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y) ;
87.6 %
vaccinated
days 0 -2 0.9% (1/ 103) Engerix -B co-
administered
with
investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2 0.5%
(1/221) NR NR NR Some
concerns29
Lopez11
2002  Cohort  Drowsiness or sleeping
more  (Any)  Solicited self -
report by diary
card during 4 -
day follow -up
window  HepB Engerix -
B at birth (Y)  5.1% (6/117)  NR NR NR NR NR Some
concerns26
Lopez
200211 Cohort  Drowsiness or sleeping
more  (Severe)  Solicited self -
report by diary
card during 4 -
day follow -up
window  HepB Engerix -
B at birth (Y)  0.9% (1/117)  NR NR NR NR NR Some
concerns26
Linder
199910 Cohort  Fever  (neonatal fever
>37.5 ⁰C) Birth
hospitalization
discharge
diagnosis  HepB vaccine
(unspecified)
on first day of
life (NR)  1.2%
(68/5819)  No HepB
vaccine on
first day of life  0.54%
(27/5010)  0.001  NR NR Serious
concerns34
Linder
199910 Cohort  Fever  (neonatal fever
>38⁰C) Birth
hospitalization
discharge
diagnosis  HepB vaccine
(unspecified)
on first day of
life (NR)  0.9%
(50/5819)  No HepB
vaccine on
first day of life  0.54%
(27/5010)  0.05 NR NR Serious
concerns34
Linder
199910 Cohort  Fever  (explained
neonatal fever)  Birth
hospitalization
discharge
diagnosis  HepB vaccine
(unspecified)
on first day of
life (NR)  0.3%
(15/5819)  No HepB
vaccine on
first day of life  0.3%
(13/5010)  NR NR NR Serious
concerns34
Linder
199910 Cohort  Fever  (unexplained
neonatal fever)  Birth
hospitalization
discharge
diagnosis  HepB vaccine
(unspecified)
on first day of
life (NR)  0.6%
(35/5819)  No HepB
vaccine on
first day of life  0.3%
(14/5010)  0.013  NR NR Serious
concerns34
Lopez
200211 Cohort  Fever  (Any)  Solicited self -
report by diary
card during 4 -HepB Engerix -
B at birth (Y)  0.9% (1/117)  NR NR NR NR NR Some
concerns
28

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 68 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
day follow -up
window
Lopez
200211 Cohort  Fever  (Severe)  Solicited self -
report by diary
card during 4 -
day follow -up
window ;
severe >39
axillary or
>39.5 rectal  HepB Engerix -
B at birth (Y)  0.9% (1/117)  NR NR NR NR NR Some
concerns
28
Niu
199612 Case
series  Fever  (Any)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of age
(Y) 30% (18/60)  NR NR NR NR NR Some
concerns24
Niu
199612 Case
series  Fever (Serious)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of age
(Y) 21.7% (13/60)  NR NR NR NR NR Some
concerns24
Bassily
19958 RCT Fever  Parental
report of 1-2
days of fever
≤102⁰F  Recombivax
immediately
after birth (Y)  5.6%
(NR/178)  Recombivax
at 18 months
of age (Y)  2.1%
(NR/191)  NR NR NR Some
concerns
33
Bassily
19958 RCT Fever  Parental
report of 1 -2
days of fever
≤102⁰F  Recombivax
at 2 months of
age (Y)  7.2%
(NR/167)  Recombivax
at 18 months
of age (Y)  2.1%
(NR/191)  NR NR NR Some
concerns
33
Yerushalmi
19979 RCT Fever  (≥38⁰C ) Parental
report on diary
card for 5 d ays
post -
vaccination  Engerix -B
vaccine within
24 hrs of birth
(Y) 0% (0/52)  BioHepB
vaccine within
24 hrs of birth
(Y) 1.3%
(2/153)  NR NR NR Some
concerns
59
Greenberg
200214 RCT Fever  (Any )  Solicited
parental
report for day
of vaccination
and 3 days
following
vaccination ;
Rectal Engerix -B
vaccine within
4 days of birth
(NR)  5.9%
(NR/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  14.7%
(NR/129)  NR NR NR Some
concerns
59

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 69 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
temperature
≥38⁰C
Greenberg
200214 RCT Fever  (Severe/Grade 3)  Solicited
parental
report for day
of vaccination
and 3 days
following
vaccination ;
Grade 3 -fever
>39.5 ⁰C Engerix -B
vaccine within
4 days of birth
(NR)  0% (0/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  0.8%
(NR/129)  NR NR NR Some
concerns
59
Sapru
200713 RCT Fever (axillary
temperature ≥38⁰C ) Parental
report until
total follow -up
period of 18
weeks  Engerix -B
vaccine within
first 2 weeks
of life (NR)  4.6% (6/130)  GeneVacB
(HepB)
vaccine within
first 2 weeks
of life (NR)  3.0%
(4/132)  NR NR NR Some
concerns
59
Wood
201818 RCT Fever  (≥38⁰C ) Parental
report, within
2 days of dose  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y) ;
87.6 %
vaccinated
days 0 -2 0.7% (1/138)  Engerix -B co-
administered
with
investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2 0 NR NR NR Some
concerns
59
Wood
201818 RCT Fever ( ≥39⁰C) Parental
repo rt, within
2 days of dose  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y) ;
87.6 %
vaccinated
days 0 -2 0 Engerix -B co-
administered
with
investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2 0 NR NR NR Some
concerns
59
Wood
201818 RCT Irritability or
fussiness  (Any)  Parental
report, within
2 days of dose  Engerix -B
vaccine given
alone within 20% (21/103)  Engerix -B co-
administered
with 24.0%
(54/221)  NR NR NR Serious
concerns34

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 70 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
120 hrs of
birth (Y) ;
87.6 %
vaccinated
days 0 -2 investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2
Wood
201818 RCT Irritability or fussiness
(Severe/Grade 3)   Parental
report, within
2 days of dose;
Grade 3 -
prevents
normal
everyday
activities or
requires
significant
medical
intervention  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y) ;
87.6 %
vaccinated
days 0 -2 0.9% ( 1/103 ) Engerix -B co-
administered
with
investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2 0.9%
(2/221 ) NR NR NR Serious
concerns34

Greenberg
200214 RCT Irritability or
fussiness  (Any)  Solicited
parental
report for day
of vaccination
and 3 days
following
vaccination  Engerix -B
vaccine within
4 days of birth
(NR)  22.1%
(NR/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  54.3%
(NR/129)  NR NR NR Serious
concerns34
Greenberg
200214 RCT Irritability or
fussiness  (Severe/Grade
3) Solicited
parental
report for day
of vaccination
and 3 days
following
vaccination ;
Grade 3 -
prevented
normal daily
activities  Engerix -B
vaccine within
4 days of birth
(NR)  0.7%
(NR/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  3.9%
(NR/129)  NR NR NR Serious
concerns34
Yerushalmi
19979 RCT Irritability or fussiness   Parental
report on diary
card for 5 days Engerix -B
vaccine within 11.5% (6/52)  BioHepB
vaccine within 3.3%
(5/153)  NR NR NR Serious
concerns34

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 71 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
post -
vaccination  24 hrs of birth
(Y) 24 hrs of birth
(Y)
Lopez
200211 Cohort  Irritability or
fussiness  (Any)  Solicited self -
report by diary
card during 4 -
day follow -up
window  HepB Engerix -
B at birth (Y)  2.6% (3/117)  NR NR NR NR NR Some
concerns65
Lopez
200211 Cohort  Irritability or
fussiness  (Severe)  Solicited self -
report by diary
card during 4 -
day follow -up
window  HepB Engerix -
B at birth (Y)  1.7% (2/117)  NR NR NR NR NR Some
concerns65
Sapru
200713 RCT Rash  Parental
report until
total follow -up
period of 18
weeks  Engerix -B
vaccine within
first 2 weeks
of life (NR)  0% (0/130)  GeneVacB
(HepB)
vaccine within
first 2 weeks
of life (NR)  0%
(0/132)  NR NR NR No
Concerns
Niu
199612 Case
series  Rash  (Any)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of age
(Y) 3.3% (2/60)  NR NR NR NR NR Some
concerns31

Niu
199612 Case
series  Rash (Serious)  NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of age
(Y) 3.3% (2/60)  NR NR NR NR NR Some
concerns31

Wood
201818 RCT Restlessness or sleeping
less (Any)  Parental
report, within
2 days of dose  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y) ;
87.6 %
vaccinated
days 0 -2 31% (32/103)  Engerix -B co-
administered
with
investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2 22.0%
(49/221)  NR NR NR Serious
concerns38
Wood
201818 RCT Restlessness or sleeping
less (Severe/Grade 3)  Parental
report, within
2 days of dose; Engerix -B
vaccine given
alone within 3% (3/103)  Engerix -B co-
administered
with 1%
(2/221)  NR NR NR Serious
concerns38

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 72 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
Grade 3 -
prevents
normal
everyday
activities or
requires
significant
medical
intervention  120 hrs of
birth (Y) ;
87.6 %
vaccinated
days 0 -2 investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0-2
Greenberg
200214 RCT Restlessness or sleeping
less (Any)  Solicited
parental
report for day
of vaccination
and 3 days
following
vaccination  Engerix -B
vaccine within
4 days of birth
(NR)  16.9%
(NR/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  26.4%
(NR/129)  NR NR NR Serious
concerns38
Greenberg
200214 RCT Restlessness or sleeping
less (Severe/Grade 3)  Solicited
parental
report for day
of vaccination
and 3 days
following
vaccination;
Grade 3 -
prevented
normal daily
activities  Engerix -B
vaccine within
4 days of birth
(NR)  1.5%
(NR/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  0.8%
(NR/129)  NR NR NR Serious
concerns38
Greenberg
200214 RCT Unusual crying  (Any)  Solicited
parental
report for day
of vaccination
and 3 days
following
vaccination  Engerix -B
vaccine within
4 days of birth
(NR)  1.5%
(NR/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  3.1%
(NR/129)  NR NR NR Some
concerns40
Greenberg
200214 RCT Unusual
crying  (Severe/Grade 3)  Solicited
parental
report for day
of vaccination
and 3 days
following
vaccination; Engerix -B
vaccine within
4 days of birth
(NR)  0% (0/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  0.8%
(NR/129)  NR NR NR Some
concerns40

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 73 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
Grade 3 -
prevented
normal daily
activities
Wood
201818 RCT Vomiting  (Any)  Parental
report, within
2 days of dose  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y) ;
87.6 %
vaccinated
days 0 -2 24% (23/103)  Engerix -B co-
administered
with
investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y ); 91%
vaccinated
days 0 -2 20.0%
(45/221)  NR NR NR Some
concerns41
Wood
201818 RCT Vomiting
(Severe/Grade 3)  Parental
report, within
2 days of dose ;
Grade 3 -
prevents
normal
everyday
activities or
requires
significant
medical
intervention  Engerix -B
vaccine given
alone within
120 hrs of
birth (Y) ;
87.6 %
vaccinated
days 0 -2 0 Engerix -B co-
administered
with
investigational
acellular
Pertussis
vaccine within
120 hrs of
birth (Y) ; 91%
vaccinated
days 0 -2 0 NR NR NR Some
concerns41
Sapru
200713 RCT Vomiting  Parental
report until
total follow -up
period of 18
weeks  Engerix -B
vaccine within
first 2 weeks
of life (NR)  0% (0/130)  GeneVacB
(HepB)
vaccine within
first 2 weeks
of life (NR)  0%
(0/132)  NR NR NR Some
concerns41
Greenberg
200214 RCT Vomiting  (Any)  Solicited
parental
report for day
of vaccination
and 3 days
following
vaccination  Engerix -B
vaccine within
4 days of birth
(NR)  4.4%
(NR/136)  DTaP -HepB,
OPV, and Hib
vaccines at 2
months of age
(NR)  7.8%
(NR/129)  NR NR NR Some
concerns41
Greenberg
200214 RCT Vomiting
(Severe/Grade 3)  Solicited
parental Engerix -B
vaccine within 0% (0/136)  DTaP -HepB,
OPV, and Hib 0%
(0/129)  NR NR NR Some
concerns41

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 74 of 84
 Study  Study
Type  Outcome  Outcome
Identification  Intervention
(Thimerosal
Y/N/NR)  Intervention
% (n/N)  Control
(Thimerosal
Y/N/NR)  Control
% (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
report for day
of vaccination
and 3 days
following
vaccination;
Grade 3 -
prevented
normal daily
activities  4 days of birth
(NR)  vaccines at 2
months of age
(NR)

Table 29. Other Reactions Results of Studies Meeting Inclusion Criteria
Study  Study
Type  Outcome  or Case  Outcome
Identification  Intervention
or Exposure
(Thimerosal
Y/N/NR)  Intervention or
Exposure  %
(n/N)  Control
(Thimerosal
Y/N/NR)  Control % (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
Geier
201825 Case -
control  Premature puberty   ICD-9 codes  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life
for cases
(diagnosed
with
premature
puberty ) Exposure/Cases:
(255/486)  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life
for controls
(no
premature
puberty ) Exposure/Controls:
(20582/54199)  <0.00001  OR: 1.80,
(95% CI:
1.51 -2.16)
(assessed as
OR of
exposure to
thimerisol -
containing
vaccine in
cases v.
controls)  none  Serious
concerns67
Geier
201825 Case -
control  Premature puberty   ICD-9 codes  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life Exposure/Controls:
(10/28)  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life Exposure/Controls:
(10584/ 27989)  >0.99  OR: 0.91,
(95% CI:
0.42-1.98)
(assessed as
OR of
exposure to
thimerisol -
containing
vaccine in Stratified
by sex  Serious
concerns67

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 75 of 84
 Study  Study
Type  Outcome  or Case  Outcome
Identification  Intervention
or Exposure
(Thimerosal
Y/N/NR)  Intervention or
Exposure  %
(n/N)  Control
(Thimerosal
Y/N/NR)  Control % (n/N)  p-value  Measure of
Association  Adjusted  Risk of
Bias
for male
cases
(diagnosed
with
premature
puberty)  for male
controls (no
premature
puberty)  cases v.
controls)
Geier
201825 Case -
control  Premature puberty   ICD-9 codes  HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life
for female
cases
(diagnosed
with
premature
puberty)  Exposure/Controls:
(245/ 458)
 HepB vaccine
(unspecified)
(Y) or
combined
Hib-HepB
vaccine or no
vaccine
within first
month of life
for female
controls (no
premature
puberty)  Exposure/Controls:
(9997/26209)  <0.00001  OR: 1.87,
(95% CI:
1.55 -2.25 )
(assessed as
OR of
exposure to
thimerisol -
containing
vaccine in
cases v.
controls)  Stratified
by sex  Serious
concerns67
Haber
201816 Case
series  General disorders
and administration
site conditions   VAERS, non -
death, serious
reports  Hep B vaccine
(unspecified)
infants aged
<1 month (Y)  4.2% (10/240)  NR NR NR NR NR Some
concerns39
Niu
199612 Case
series  Hyperbilirubenemia
/HbSAg+   NR Hep B vaccine
(unspecified)
infants aged
<0.1 yrs of
age (Y) 1.7% (1/60)  NR NR NR NR NR Some
concernsh
C.3. Risk of Bias Assessments for All Included Studies

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 76 of 84
 Figure 2. Risk of Bias Assessments for Randomized Controlled Trials

 Legend: Green = Yes or Possibly Yes , Yellow = Unclear , Red = No or Possibly No, Grey or Black = Not applicable

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 77 of 84
 Figure 3. Risk of Bias Assessments for Cohort Studies

 Legend: Green = Yes or Possibly Yes, Yellow = Unclear, Red = No or Possibly No, Grey or Black = Not applicable

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 78 of 84
 Figure 4. Risk of Bias Assessments for Case Control Studies

 Legend: Green = Yes or Possibly Yes, Yellow = Unclear, Red = No or Possibly No, Grey or Black = Not applicable

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 79 of 84
 Figure 5. Risk of Bias Assessments for Case Series Studies

 Legend: Green = Yes or Possibly Yes, Yellow = Unclear, Red = No or Possibly No, Grey or Black = Not applicable

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 80 of 84
 D. Search Strategies
Table 30. Searc h Strategies  and Results
DATABASE  STRATEGY  RUN DATE  RECORD
COUNT
Medline
(OVID)
1946 - 1. exp Hepatitis B Vaccines/
2. (((Hepatitis B OR HepB OR Hep B OR HBV) ADJ5 vaccin*) OR HepB -BD OR Engerix -B OR Recombivax HB).ti,ab,kf.
3. 1 OR 2
4. Exp Infant/
5. (Infant* OR newborn* OR new born* OR neonat* OR birth OR birth -dose*).ti,ab,kf.
6. 4 OR 5
7. Exp Safety/ OR exp Treatment Outcome/
8. (safety OR (vaccin* ADJ2 safe*) OR treatment outcome* OR adverse* OR harm OR harmful OR harms OR side effect* OR
reaction*).ti,ab,kf. OR ae.fs
9. 7 OR 8
10. Exp Clinical Study/ OR exp Product Surveillance, Postmarketing/
11. (trial* OR observational stud* OR observation stud* OR clinical stud* OR surveillance OR reporting system* OR VAERS OR
postmarket* OR post -market*).ti,ab,kf,hw.
12. 10 OR 11
13. 3 AND 6 AND 9 AND 12  07/31/2025  599
Embase
(OVID)
1947 - 1. exp Hepatitis B Vaccine/
2. (((Hepatitis B OR HepB OR Hep B OR HBV) ADJ5 vaccin*) OR HepB -BD OR Engerix -B OR Recombivax HB).ti,ab,kf.
3. 1 OR 2
4. Exp Infant/
5. (Infant* OR newborn* OR new born* OR neonat* OR birth OR birth -dose*).ti,ab,kf.
6. 4 OR 5
7. Exp Safety/ OR exp Treatment Outcome/ OR adverse drug reaction/
8. (safety OR (vaccin* ADJ2 safe*) OR treatment outcome* OR adverse* OR harm OR harmful OR harms OR side effect* OR
reaction*).ti,ab,kf. OR ae.fs
9. 7 OR 8
10. Exp Clinical Study/ OR exp Postmarketing Surveillance/
11. (trial* OR observational stud* OR observation stud* OR clinical stud* OR surveillance OR reporting system* OR VAERS OR
postmarket* OR post -market*).ti,ab,kf,hw.
12. 10 OR 11
13. 3 AND 6 AND 9 AND 12
14. limit 13 to "pubmed/medline"
15. 13 NOT 14
16. limit 15 to conference abstract status
17. 15 NOT 16  07/31/2025  1527

-
DUPLICATES

=165
UNIQUE
RECORDS
Cochrane
Library
 #1 [mh "Hepatitis B Vaccines"]  07/31/2025  400

-

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 81 of 84
 DATABASE  STRATEGY  RUN DATE  RECORD
COUNT
#2 ((("Hepatitis B":ti,ab,kw OR HepB:ti,ab,kw OR "Hep B":ti,ab,kw OR HBV:ti,ab,kw) NEAR/5 vaccin*:ti,ab,kw) OR HepB -
BD:ti,ab,kw OR Engerix -B:ti,ab,kw OR "Recombivax HB":ti,ab,kw)
#3 #1 OR #2
#4 [mh Infant]
#5 (Infant*:ti,ab,kw OR newborn*:ti,ab,kw OR ("new" NEXT born*):ti,ab,kw OR neonat*:ti,ab,kw OR birth:ti,ab,kw OR birth -
dose*:ti,ab,kw)
#6 #4 OR #5
#7 [mh Safety] OR [mh "Treatment Outcome"]
#8 (safety:ti,ab,kw OR (vaccin*:ti,ab,kw NEAR/2 safe*:ti,ab,kw) OR ("treatment" NEXT outcome*):ti,ab,kw OR
adverse*:ti,ab,kw OR harm:ti,ab,kw OR harmful:ti,ab,kw OR harms:ti,ab,kw OR ("side" NEXT effect*):ti,ab,kw)
#9 #7 OR #8
#10 [mh ^"Clinical Study"] OR [mh ^"Product Surveillance, Postmarketing"]
#11 (trial*:ti,ab,kw OR ("observational" NEXT stud*):ti,ab,kw OR ("observation" NEXT stud*):ti,ab,kw OR ("clinical" NEXT
stud*):ti,ab,kw OR surveillance:ti,ab,kw OR ("reporting" NEXT system*):ti,ab,kw OR VAERS:ti,ab,kw OR
postmarket*:ti,ab,kw OR post -market*:t i,ab,kw)
#12 #10 OR #11
#13 #3 AND #6 AND #9 AND #12  DUPLICATES

=145
UNIQUE
RECORDS
CINAHL
(EBSCOHost)  S1 (MH "Hepatitis B Vaccines+")
S2 ((((TI "Hepatitis B" OR AB "Hepatitis B" OR SU "Hepatitis B") OR (TI HepB OR AB HepB OR SU HepB) OR (TI "Hep B" OR AB
"Hep B" OR SU "Hep B") OR (TI HBV OR AB HBV OR SU HBV)) N5 (TI vaccin* OR AB vaccin* OR SU vaccin*)) OR (TI HepB -BD
OR AB HepB -BD OR SU He pB-BD) OR (TI Engerix -B OR AB Engerix -B OR SU Engerix -B) OR (TI "Recombivax HB" OR AB
"Recombivax HB" OR SU "Recombivax HB"))
S3 S1 OR S2
S4 (MH Infant+)
S5 ((TI Infant* OR AB Infant* OR SU Infant*) OR (TI newborn* OR AB newborn* OR SU newborn*) OR (TI "new born*" OR AB
"new born*" OR SU "new born*") OR (TI neonat* OR AB neonat* OR SU neonat*) OR (TI birth OR AB birth OR SU birth) OR
(TI birth -dose* OR AB birt h-dose* OR SU birth -dose*))
S6 S4 OR S5
S7 (MH Safety+) OR (MH "Treatment Outcomes+") OR (MH "Adverse Drug Event+")
S8 ((TI safety OR AB safety OR SU safety) OR ((TI vaccin* OR AB vaccin* OR SU vaccin*) N2 (TI safe* OR AB safe* OR SU safe*))
OR (TI "treatment outcome*" OR AB "treatment outcome*" OR SU "treatment outcome*") OR (TI adverse* OR AB
adverse* OR SU adverse*) OR (TI harm OR AB harm OR SU harm) OR (TI harmful OR AB harmful OR SU harmful) OR (TI
harms OR AB harms OR SU harms) OR (TI "side effect*" OR AB "side effect*" OR SU "side effect*"))
S9 S7 OR S8
S10 (MH "Clinical Study+") OR (MH "Product Surveillance, Postmarketing+")
S11 ((TI trial* OR AB trial* OR SU trial*) OR (TI "observational stud*" OR AB "observational stud*" OR SU "observational stud*")
OR (TI "observation stud*" OR AB "observation stud*" OR SU "observation stud*") OR (TI "clinical stud*" OR AB "clinical
stud*" OR S U "clinical stud*") OR (TI surveillance OR AB surveillance OR SU surveillance) OR (TI "reporting system*" OR AB
"reporting system*" OR SU "reporting system*") OR (TI VAERS OR AB VAERS OR SU VAERS) OR (TI postmarket* OR AB
postmarket* OR SU postmarket*) OR (TI post -market* OR AB post -market* OR SU post -market*))
S12 S10 OR S11  07/31/2025  22

-
DUPLICATES

=7
UNIQUE
RECORDS

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not be construed to represent any agency determination or
policy .  Page 82 of 84
 DATABASE  STRATEGY  RUN DATE  RECORD
COUNT
S13 S3 AND S6 AND S9 AND S12

Limiters  - Exclude  MEDLINE  records

Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not
be construed to represent any agency determination or policy .  Page 83 of 84
 E. References

1. Hosseini M -S, Jahanshahlou F, Akbarzadeh MA, Zarei M, Vaez -Gharamaleki Y. Formulating research questions for
evidence -based studies. Journal of Medicine, Surgery, and Public Health . 2024/04/01/ 2024;2:100046.
doi:https://doi.org/10.1016/j.glmedi.2023.100046
2. Wells GA, Wells G, Shea B, et al. The Newcastle -Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised
Studies in Meta -Analyses. 2014:
3. Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. Bmj. Aug
28 2019;366:l4898. doi:10.1136/bmj.l4898
4. Moola S, Munn Z, Tufanaru C, et al. Chapter 7: Systematic reviews of etiology and risk. In : Aromataris E, Munn Z,
eds. JBI Reviewer's Manual . 2020. https://synthesismanual.jbi.global .  https://doi.org/10.46658/JBIMES -20-08
5. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength
of recommendations. Bmj. Apr 26 2008;336(7650):924 -6. doi:10.1136/bmj.39489.470347.AD
6. 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
7. Morgan HJ, Nold MF, Kattan GS, et al. Hepatitis B vaccination of preterm infants and risk of bronchopulmonary
dysplasia: a cohort 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
8. Bassily S, Kotkat A, Gray G, et al. Comparative study of the immunogenicity and safety of two dosing schedules
of hepatitis
…[truncated]

Summary: Disclaimer: The findings and conclusions herein are draft and have not been formally disseminated by the Centers for Disease Control and Prevention and should not  be construed to represent any agency determination or policy .  Page 1 of 84   ACIP BRIEFING MATERIALS FOR PUBLIC POSTING   The Safety of Hepatitis B Vaccines  administered within 24 hrs of birth and within 30 days of  birth: A Rapid Systematic Review   Table of Contents   Table of Tables  ................................…