TRANSIENT BULGING FONTANELLE AFTER VACCINATION:

CASE REPORT AND REVIEW OF THE VACCINE ADVERSE

EVENT REPORTING SYSTEM
STEPHEN B. FREEDMAN, MDCM, MSCI, JOHN REED, MD, MPH, DALE R. BURWEN, MD, MPH,
ROBERT P. WISE, MD, MPH, AMY WEISS, MD, AND ROBERT BALL, MD, MPH

Objective To describe the features of transient bulging fontanelle (TBF) after vaccination.
Study design We searched the Vaccine Adverse Event Reporting System database for reports describing bulging fontanelle.
We defined a definite TBF case as a patient with a bulging fontanelle, normal neuroimaging and cerebrospinal fluid analysis, and
absence of a depressed level of consciousness, focal neurologic findings, or identified cause. Follow-up had to reveal normal
development. Probable cases lacked either lumbar puncture or neuroimaging or both but met all other criteria.
Results We identified 18 patients with definite or probable TBF. The median age at presentation was 4.5 months, interval
from vaccination to symptom onset was 18 hours, and time to resolution was 3 days. Fifteen children were febrile.
Conclusions We cannot conclude that vaccines cause TBF. Further controlled studies are necessary. Even if further
research verifies TBF as a rare side effect, immunization benefits would still vastly outweigh this hypothetical risk. How-
ever, confirmation of a vaccine association could modify the management of infants who develop TBF after immunizations.
(J Pediatr 2005;147:640-4)

bulging fontanelle reflects elevated intracranial pressure or volume in an infant

A with open cranial sutures. Important differential diagnoses with immediate ther-
apeutic implications include hydrocephalus, trauma, tumor, and meningitis.1
Viral infections can also cause bulging fontanelles. If no cause is found, the diagnosis
becomes idiopathic or benign intracranial hypertension, also known as pseudotumor cerebri.
Bulging fontanelles have been reported after diphtheria-tetanus-pertussis (DTP) and
diphtheria-tetanus (DT) immunizations in sporadic case reports.2-6 The largest previous
series7 preceded acellular pertussis vaccines’ use and other recent changes in routine immu-
nization schedules. Including 3 previously published cases, bulging fontanelles developed
in 9 infants, shortly after receiving vaccinations7; all resolved within 2 days. Follow-up in-
From the Division of Pediatric
formation available for 7 patients identified no neurologic or developmental abnormality, Emergency Medicine, Department of
but bulging fontanelles recurred in 2 children with subsequent doses of DT (positive Pediatrics, The Hospital for Sick Chil-
rechallenges). dren, University of Toronto, Toronto,
Ontario, Canada; Office of Biostatis-
tics and Epidemiology, Center for Bio-
logics Evaluation and Research, Food
CASE REPORT and Drug Administration, Rockville,
Md; and the Division of Neonatology,
A 6-month-old male was brought to the emergency department because of a bulging Northwestern University, The Fein-
fontanelle that had been present, along with fever, for 1 day, beginning the day after he berg School of Medicine, Chicago, Ill.
Submitted for publication Feb 7,
received injections of diphtheria-tetanus-acellular pertussis (DTaP) and pneumococcal 2005; last revision received May 5,
conjugate vaccines (PCV). He had previously received DTaP, PCV, inactivated polio vac- 2005; accepted Jun 3, 2005.
cine, and Haemophilus influenzae type B conjugate vaccine (HIB) at 2 and 4 months of age Reprint requests: Robert P. Wise,
MD, MPH, FDA CBER HFM-225,
1401 Rockville Pike, Rockville, MD
20852-1448. E-mail: R.P.Wise@cber.
COSTART Coding symbols for thesaurus of adverse reaction HIB Haemophilus influenzae type B conjugate fda.gov.
terms vaccine
DT Diphtheria-tetanus vaccine PCV Pneumococcal conjugate vaccine 0022-3476/$ - see front matter
DTP Diphtheria- tetanus-(whole cell) pertussis vaccine TBF Transient bulging fontanelle Copyright ª 2005 Elsevier Inc. All rights
(given separately or with HIB) VAERS Vaccine Adverse Event Reporting System reserved.
DTaP Diphtheria-tetanus-acellular pertussis vaccine
10.1016/j.jpeds.2005.06.009

640
without complications. Physical examination was normal
except for a bulging anterior fontanelle and temperature of
38.4
C. Cerebrospinal fluid cell count, Gram stain, protein,
glucose, and bacterial culture and computed tomography of
the head were normal. The opening pressure was not mea-
sured. Follow-up the next day revealed nearly complete reso-
lution of the bulging fontanelle. Over the subsequent 8
months, head circumference growth continued at the fiftieth
percentile along with normal neurologic development and at-
tainment of milestones.
This case prompted a search of the medical literature,
followed by this review. We hypothesized that occasional
patients might develop a self-limited bulging fontanelle after
vaccinations.
METHODS
We used the Vaccine Adverse Event Reporting System
(VAERS), a passive safety surveillance program for licensed
vaccines, to find potential transient bulging fontanelle (TBF)
cases and to describe the characteristics of definite and proba-
ble cases of TBF reported from January 1997 through June
2002, including follow-up data.
VAERS
VAERS is a national reporting program and database
for adverse events observed after administration of any
U.S.-licensed vaccine. Between January 1, 1997 and June 30,
2002, VAERS received 73,198 distinct case reports. Like
other passive safety surveillance systems, important limitations
include under-ascertainment and potential biases,8 the extent
of which are generally unknown but likely variable and
substantial. Data from VAERS usually do not allow clear in-
ference about whether administered vaccines actually contrib-
uted to the reported symptoms and signs. VAERS indexes
adverse events with Coding Symbols for Thesaurus of Adverse
Reaction Terms (COSTART).9 We used both COSTART
and text searches in report narratives to identify potential cases
of TBF.
Case Definition and Ascertainment
If an infant’s bulging fontanelle resolved promptly and
spontaneously, we use the term ‘‘transient bulging fontanelle.’’
We defined definite TBF for patients reported to VAERS, re-
gardless of vaccine(s) administered or interval after vaccina-
tion, with (1) bulging fontanelle; (2) normal neuroimaging
study; (3) normal cerebrospinal fluid cell count and bacterial
culture; (4) absence of a documented depressed level of con-
sciousness; (5) normal neurologic evaluation, defined as ab-
sence of localized findings on examination in the VAERS
report and follow-up data; (6) no known cause for the bulging
fontanelle; and (7) telephone follow-up by physicians (JR and
RPW) using a structured questionnaire to verify normal sub-
sequent neurologic development and absence of etiologic diag-
nosis for the bulging fontanelle. A probable TBF was defined as
a case in which lumbar puncture or neuroimaging or both were
Transient Bulging Fontanelle After Vaccination: Case Report And
Review Of The Vaccine Adverse Event Reporting System
not performed but all other criteria were met. We assumed
that patients with a persistent bulging fontanelle most likely
would have had an underlying cause identified.
We searched the VAERS database for reports with the
COSTART term for increased intracranial pressure or with
‘‘bulging fontanelle’’ or variations in the event description
and other text fields. Our focus on 44 potential cases from
U.S. locations with vaccination dates of January 1997 through
June 2002 reflected an expectation that these more recent do-
mestic reports would allow greater efficiency and success of
follow-up. After excluding reports with diagnoses or other in-
formation inconsistent with our case definition, we performed
telephone follow-up with a detailed questionnaire, particularly
inquiring about neuroimaging studies, cerebrospinal fluid re-
sults, and the definitive diagnosis, if available. We attempted
to clarify if and when the bulging fontanelle had resolved
and whether there had been any sequelae. We asked whether
subsequent vaccinations had been withheld and if there had
been any recurrence of bulging fontanelle or any other adverse
event. Lot identification codes allowed verification of in-
consistent or missing vaccine information. We tabulated 2
combination vaccine products by component: DTP-HIB
(Tetramune) and HIB-hepatitis B vaccine (Comvax). The
Institutional Review Board of Children’s Memorial Hospital
approved this case review project. Because VAERS is a public
health surveillance program, evaluation of VAERS data does
not require consent from individual patients.
RESULTS
Of the 44 reports identified, 23 did not meet our criteria
for definite or probable TBF, because 8 had bacterial or viral
infections, 6 had abnormal neuroimaging studies, 4 did not
describe a bulging fontanelle, 2 had syndromic hydrocephalus,
2 had possible speech or motor developmental delay, and 1 pa-
tient had subdural and intracerebral hemorrhages after head
trauma. Three additional cases were lost to follow-up, leaving
18 cases.
We identified 7 reports of definite TBF and 11 of prob-
able TBF (Table). None described papilledema. The 9 males
and 9 females ranged in age from 2.7 to 6.5 months (median =
4.5). They had received various vaccines, including HIB (n =
16 patients), DTaP (n = 12), DTP (n = 6), hepatitis B vaccine
(n = 8), PCV (n = 7), inactivated polio vaccine (n = 5), oral
polio vaccine (n = 5), and rotavirus vaccine (n = 1). All children
received either DTaP or DTP and at least 1 other vaccine.
These 18 patients developed TBF at intervals from 5 hours
to 4 days (median = 0.75 days) after vaccination. Nine (50%)
children were hospitalized, and 15 (83%) had fevers. Temper-
atures were reported for 10 of the febrile patients, with a me-
dian of 39.3
C. Neuroimaging was performed on all definite
cases but none of the probable cases. Cerebrospinal fluid anal-
ysis and bacterial cultures (all definite cases and 6 of the 11
probable cases) were normal. Antibiotics were administered
to 4 of the 17 patients (1 unknown) for 2 or 3 days.
The time to resolution of the signs and symptoms
of TBF ranged from 1 to 7 days (1 unknown; median = 3
641
Table. Cases of transient bulging fontanelle following immunization
Time to Vaccines Subsequent
Age Onset CSF Days to Months of Subsequently Adverse
No. (mo) Sex Vaccines (days) Analysis Resolution Follow-up Withheld Event

DEFINITE CASES
1 6.3 M DTaP, HIB-HepB, PCV 0.3 Normal 7 18 Pertussis No
2 6.2 F DTaP, HepB, HIB, PCV 1 Normal 7 18 Pertussis No
3 4.0 M DTaP, HIB, IPV 2 Normal 4 16 None No
4 4.6 M DTaP, HIB-HepB, IPV, RV 0.4 Normal 3 23 Pertussis No
5 4.3 F DTP-HIB, OPV ,1 Normal 2 66 Pertussis No
6 4.4 F DTaP, HIB, IPV, PCV 1 Normal 2 22 None No
7 6.1 M DTaP, PCV 2 Normal 1 8 None No
PROBABLE CASES
8 6.4 F DTaP, PCV 4 Normal 1 2 None N/A
9 4.2 M DTaP, HIB, IPV, PCV 2 Normal 3 9 All N/A
10 6.3 F DTP, HIB , 1 Not done 3 31 ? ?
11 4.1 F DTaP, HIB, IPV , 1 Normal 1 39 None No
12 6.2 M DTaP, HepB, HIB 0.5 Not done 3 48 None No
13 4.1 M DTP-HIB, HepB, OPV 1 Not done 1 14 Pertussis No
14 4.0 F DTP-HIB, OPV 1 Normal 2 66 Pertussis No
15 2.7 F DTP-HIB, HepB, OPV , 1 Normal ? 10 None No
16 6.1 M DTaP, HIB, PCV , 0.5 Normal 3 10 Pertussis No
17 6.5 M DTaP, HIB-HepB 0.2 Not done 2 14 None No
18 4.2 F DTP-HIB, HepB, OPV 0.2 Not done 3 36 Pertussis No
CT, computed tomography; CSF, cerebrospinal fluid; N/A, not applicable; F, female; M, male; Vaccines: DTP, diphtheria-tetanus-pertussis; DTP-HIB,
DTP combined with HIB (Tetramune); DTaP, diphtheria-tetanus-acellular pertussis; HepB, hepatitis B; HIB, Haemophilus influenzae type b; HIB-HepB,
HIB combined with HepB (Comvax); IPV, inactivated polio; OPV, oral polio; PCV, pneumococcal conjugate; RV, Rotavirus; ?, unknown.

days). The follow-up intervals after vaccination ranged from
2 months to 5.5 years (median = 18 months). Subsequent
immunization histories, available for 16 children, indicate
that 1 child had all future vaccinations withheld. All 15 others
have received vaccinations without recurrent TBF, but 8 had
pertussis vaccine withheld.
DISCUSSION
Unique features in this series of infants with TBF
shortly after vaccinations are the neuroimaging, lumbar punc-
ture, and follow-up information that revealed no other disease,
either as the apparent cause or as possible sequelae. This series
also demonstrates that TBF continues to be reported in spite
of changes in the pediatric vaccination schedule, including
the use of an acellular pertussis vaccine.
Although none of the VAERS cases had a positive
rechallenge, several published reports list vaccinations among
causes of bulging fontanelle,10-12 and previously reported
positive rechallenges7 favor that hypothesis. Because the
median interval from vaccination to development of TBF
was only 18 hours, it is possible that these cases could have
been reported to VAERS simply because proximity to recent
vaccination resulted in an ‘‘information’’ or selection bias.
Hence, these data must be interpreted cautiously, as a
reasonable basis for hypothesis formulation, not as conclusive
evidence that vaccines cause TBF.
Several randomized trials in developing countries have
demonstrated that bulging fontanelle can follow vitamin A
supplementation of young infants.10,13-19 In most of these
studies, vitamin A or placebo was administered with routine
immunizations, and the fontanelles were assessed with the
baby calm and in an upright position.20 Because none of the
trials14-21 compared immunization with placebo, they do not
clarify whether vaccines contribute to a bulging fontanelle.
However, one study’s baseline examinations identified a back-
ground TBF point prevalence rate of 7.7 cases per 1000 young
infants.15 Two follow-up studies21,22 of development among
3-year-old children with previous episodes of bulging fonta-
nelle found generally normal growth and development.
If human herpes virus 6 (HHV-6) were a likely expla-
nation for the cases in this report, we would not expect the
median age to be 4.5 months, as HHV-6 generally is acquired
between ages 6 and 15 months.23 Among 152 Japanese chil-
dren with serologically confirmed HHV-6 infection, 39 had
a bulging fontanelle for an average of 3 days.24 The clinical
features of 15 children with bulging fontanelles attributed
to viral infections25 differed from our series. Four children
had lateral rectus palsies, and the median duration of symp-
toms before presentation was 2.5 weeks, with resolution after

642 Freedman et al The Journal of Pediatrics  November 2005

a median of another 1.5 weeks. Because 83% of our patients
had fever, some or all might have had undiagnosed viral in-
fections. However, high fevers ($39.5
C) after DTaP vacci-
nation occur in up to 1% of children receiving their third dose
and 0.5% of those receiving their second dose.26
We did not evaluate 15 patients with abnormal neuroi-
maging studies or an alternative cause identified. We do not
know if such children can be easily distinguished at initial pre-
sentation from those with subsequently benign courses. We
caution clinicians to continue to promptly evaluate and conser-
vatively manage children with bulging fontanelles, even when
they present soon after vaccinations. Should future research
prove TBF to be a distinct entity, development of an algorithm
might allow certain children to be managed with close obser-
vation, avoiding the cost and invasiveness of neuroimaging
and lumbar puncture.
Assessment of the background TBF incidence rate in
the U.S. and estimation of whether or to what extent immu-
nizations may affect risk would require a systematic epidemi-
ologic analysis. It would be particularly important to evaluate
potential dietary and viral iteologies. Although the reporting
rate has been low, with many millions of vaccine doses admin-
istered over the study period, the point prevalence of TBF in
the baseline observations from one vitamin A study suggests
the possibility that the event may not be rare.15 Because our
inclusion criteria required normal neurologic development,
this case series does not contribute information about potential
sequelae, which should be evaluated in future studies.
In summary, we report the largest case series to date of
patients with TBF after vaccinations. Unique features include
neuroimaging, lumbar puncture, follow-up information, and
continued reporting with the recently implemented vaccine
schedule. Nonetheless, we cannot conclude that vaccines cause
TBF. Prospective systematic studies are needed with attention
to dietary histories and potential viral iteologies. Studies with
consistent case ascertainment could test for vaccine associa-
tions, estimate incidence rates, and assess subsequent neuro-
logic development. Even if further research were to verify
TBF as a rare side effect of vaccinations, it should remain a
diagnosis of exclusion after urgent consideration of other
causes with immediate therapeutic requirements, and immu-
nization benefits from prevention of target diseases would still
vastly outweigh this hypothetical risk. Verification of a rela-
tionship between vaccinations and TBF could lead to modifi-
cations in the acute and long-term management of infants
with development of bulging fontanelles shortly after
immunizations.
Susan Ellenberg, Miles Braun, Karen Farizo, Hector Izurieta, and
Ann McMahon provided helpful comments on drafts of this report.
Staff of Constella Group, Inc., supported the VAERS database. We
also appreciate the roles of the other VAERS Working Group members
(at CDC: Ahmed Ahmed, Angela Calugar, Robert T. Chen, Roseanne
English-Bullard, Penina Haber, Sharon Holmes, John Iskander,
Alena Khromova, Elaine Miller, Liisa Oakes, Susanne Pickering,
Vitali Pool, Sean Shadomy, and Weigong Zhou; at FDA: Marthe
Bryant-Genevier, Soju Chang, David Davis, Hesha Duggirala,
Hector Izurieta, Ann McMahon, Phil Perucci, Frederick Varricchio,
and Jane Woo). We particularly appreciate the cooperation of patients’
Transient Bulging Fontanelle After Vaccination: Case Report And
Review Of The Vaccine Adverse Event Reporting System
parents, nurses, pharmacists, and physicians who reported suspected
side effects to the VAERS program. Additional information about
VAERS is available at: http://www.dhhs.vaers.gov.
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