Child Health Update

Prophylactic antipyretics for prevention

of febrile seizures following vaccination
Nicholas Monfries MD  Ran D. Goldman MD FRCPC

Abstract
Question  Parents of a 12-month-old boy are bringing their son in to my family practice clinic for his well-
baby visit. As the infant is due for his 12-month vaccine series, the parents are concerned after hearing about
the association between certain vaccinations and an increased risk of febrile seizures, and are wondering if
they should administer prophylactic antipyretics to decrease the risk of febrile seizure. What vaccinations are
associated with increased risk of febrile seizure, and is there evidence supporting prophylactic administration
of antipyretics to prevent febrile seizures?

Answer  Vaccinations associated with increased risk of febrile seizure include the following: the measles-
mumps-rubella vaccine; the measles-mumps-rubella-varicella vaccine; the combined diphtheria, tetanus,
acellular pertussis, polio, and Haemophilus influenzae type b vaccine; the whole-cell pertussis vaccine; the
7-valent pneumococcal conjugate vaccine; and concomitant administration of the trivalent inactivated
influenza vaccine with either the 7-valent pneumococcal conjugate vaccine or the diphtheria, tetanus, and
acellular pertussis vaccine. Despite being a higher-risk group, children receiving these vaccinations should not
receive prophylactic antipyretics, as no statistically significant reduction in the rate of febrile seizures has been
documented, and prophylactic antipyretic use potentially decreases the immune response to certain vaccines.

This article is eligible for Mainpro+ certified Self-Learning credits. To earn credits, go to www.cfp.ca and click on the
Mainpro+ link.
La traduction en français de cet article se trouve à www.cfp.ca dans la table des matières du numéro de février 2017 à la page e94.

F ever is one of the most common adverse events fol-

lowing immunization, affecting 1% to 10% of children
in the United States, with the incidence varying depend-
childhood immunizations, an association was reported
between certain vaccinations and febrile seizures. 8
Barlow et al found a statistically significant risk of febrile
ing on the type of vaccination.1 seizure 8 to 14 days after administration of the measles-
Febrile seizure is the most common convulsive event mumps-rubella (MMR) vaccine (relative risk [RR] of 2.83,
presenting in children younger than 5 years of age, 95% CI 1.44 to 5.55).8 The whole-cell pertussis vaccine
occurring in 2% to 5% of children.2 Febrile seizure is a used in isolation was also found to be associated with
misnomer because while the episodes of seizures are an increased risk of febrile seizure on the day of admin-
likely associated with fever, they are not necessarily istration (RR = 5.70, 95% CI 1.98 to 16.42) but not during
caused by the high temperature, and they have a dis- later time periods.8
tinct physiology, different than nonconvulsive febrile Furthermore, some combined vaccinations have
episodes.3 Febrile seizures are simple or complex.4 A a higher risk of febrile seizure than their separately
simple febrile seizure is generalized, lasts less than 15 administered vaccine components do. Using data from
minutes, and occurs only once in a 24-hour period.5 the Vaccine Safety Datalink, Klein et al found a 2-fold
A family history of febrile seizure,4 viral infections such increase in risk of febrile seizure with the combined
as influenza A and human herpesvirus 6,5,6 and certain measles-mumps-rubella-varicella vaccine compared with
vaccinations7-12 are considered risk factors for febrile sei- the separately administered MMR and varicella vaccines;
zures. Febrile seizures recur in an estimated 23% to 43% however, the overall risk was small (equating to an addi-
of all children who experience a first-time episode.13 tional 4.3 febrile seizures per 10 000 doses [95% CI 2.6
to 5.6]).9 Among a similar age demographic in Canada,
Vaccinations and febrile seizures adjusted relative risk of febrile seizure for being vac-
Since the establishment of the Vaccine Safety Datalink cinated approximately doubled with the combination
project, initiated by the Centers for Disease Control measles-mumps-rubella-varicella vaccine (RR = 6.57,
and Prevention in 1990 to study adverse events after 95% CI 4.77 to 9.05), compared with the separately

128  Canadian Family Physician • Le Médecin de famille canadien | Vol 63:  FEBRuary • février 2017
 Child Health Update

administered MMR and varicella vaccines (RR = 3.30, 95% al reported on a group of 230 children (12 to 48 months
CI 2.40 to 4.52).10 In a population-based cohort study old) who had had a febrile seizure and had at least 1
of children born in Denmark in 2003 to 2008, the com- additional risk factor for recurrence (including a family
bined diphtheria, tetanus, acellular pertussis, polio, and history of febrile seizures, a multiple-type febrile seizure,
Haemophilus influenzae type b vaccine increased the risk a temperature of less than 40°C at initial seizure onset,
of febrile seizure for infants on day 1 and day 2 after and recurrent febrile seizures). Each child received ibupro-
administration, with hazard ratios of 6.02 (95% CI 2.86 to fen (5 mg/kg per dose) or a placebo every 6 hours at the
12.65) and 3.94 (95% CI 2.18 to 7.10), respectively.11 first sign of fever (temperature higher than 38.5°C) until the
In a recent study, Duffy et al investigated the associa- child was afebrile for 24 hours. Using an intention-to-treat
tion of febrile seizure risk with the trivalent inactivated analysis, the authors did not find a statistically signifi-
influenza vaccine, a pneumococcal conjugate vaccine cant difference between the 2 groups, with an estimated
(PCV), and a diphtheria, tetanus, and acellular pertussis 2-year probability of recurrence of 32% for the ibuprofen
(DTaP)–containing vaccine, used alone and in combina- group and 39% for the placebo group (P = .7).17
tion, among children 6 to 23 months of age during the Another group of children (aged 4 to 48 months) pre-
2006 to 2011 influenza seasons. The authors reported an senting to 5 hospitals in Finland with febrile seizure
increased risk of febrile seizure when the 7-valent PCV were randomized to receive 1.5 mg/kg of rectal diclof-
was administered alone (RR = 1.98, 95% CI 1.00 to 3.91), enac (a nonsteroidal anti-inflammatory drug) or a pla-
as well as when the trivalent inactivated influenza vac- cebo, followed by either acetaminophen (15 mg/kg),
cine was concomitantly administered with the 7-valent ibuprofen (10 mg/kg), or a placebo up to 4 times per
PCV (RR = 3.50, 95% CI 1.13 to 10.85) or with a DTaP- day as long as their temperature was higher than 38°C.
containing vaccine (RR = 3.50, 95% CI 1.52 to 8.07).12 The seizure recurrence rate was nearly identical at the
It is clear from the evidence that certain vaccines and 2-year follow-up: 23.4% for the treatment group and
vaccine combinations independently increase a child’s 23.5% for the placebo group (difference of 0.2; 95% CI
risk of developing a febrile seizure. While the increased -12.8 to 17.6; P = .99), suggesting no value in administra-
risk of febrile seizure following vaccination is small, wit- tion of antipyretics.18
nessing a febrile seizure can be a frightening experience
for parents and caregivers. In hopes of preventing sei- Antipyretics and vaccinations
zures, as well as caring for pain14 and fever, health care While there is no published literature, to our knowledge,
providers and parents routinely administer antipyretics that specifically addresses prophylactic antipyretic use to
around the time of vaccination. reduce the risk of febrile seizure in the population of chil-
dren receiving vaccinations, there might be some risk of
Antipyretics and febrile seizures decreased immunogenicity.19 A systematic review investi-
Based on past assumption that there was a causal rela- gating the effect of prophylactic antipyretic use and post-
tionship between fever and febrile seizures, investiga- vaccination adverse events in children younger than age
tors hypothesized that antipyretic use might prevent 6 revealed a statistically significant decrease in postvac-
febrile seizures.15 One trial compared the administra- cination antibody levels in patients who received acet-
tion of prophylactic acetaminophen (15 to 20 mg/kg aminophen alone or in combination with ibuprofen at
every 4 hours) with the sporadic administration of acet- the time of vaccination with a diphtheria-containing vac-
aminophen (15 to 20 mg/kg only for temperatures cine (DTaP or whole-cell pertussis), administered alone
higher than 37.9°C) in children aged 6 to 60 months or co-administered with a pneumococcal-containing
presenting to hospital with a simple febrile seizure, and vaccine and Haemophilus influenzae type b vac-
found no statistically significant difference in the rate cine. However, these findings are based on only
of febrile seizures (7.5% and 9.8% recurrence, respec- 2 published heterogeneous studies and are of unclear clin-
tively). Similarly, a 2-phased randomized controlled ical significance, given the lack of established guidelines
trial concluded that acetaminophen (10 mg/kg up to on the necessary antibody levels that will be protective
4 times per day for temperatures higher than 40°C) did for the vaccines studied.20 More research is needed to fur-
not prevent febrile seizure recurrence in children. The ther elucidate the effect of prophylactic antipyretics on the
recurrence rate for each group (placebo and placebo, immune response to vaccines, specifically exploring how
placebo and acetaminophen, diazepam and acetamin- the diminished immune response affects the effectiveness
ophen, and diazepam and diazepam) was 8.2%, 5.2%, of the vaccine at a population level.
9.9%, and 11.5%, respectively.16 Therefore, the evidence Although current literature does not support anti-
suggests that acetaminophen is not effective at pre- pyretic use for reducing the risk of febrile seizure fol-
venting febrile seizure recurrence. lowing vaccination, the age at which a child receives a
The efficacy of ibuprofen in reducing febrile seizure vaccine might be associated with the risk of postvaccina-
recurrence has also been evaluated. Van Stuijvenberg et tion febrile seizure. Rowhani-Rahbar et al reported that,

Vol 63:  february • février 2017 | Canadian Family Physician • Le Médecin de famille canadien  129
Child Health Update

in a group of children aged 12 to 23 months, there was a 12. Duffy J, Weintraub E, Hambidge SJ, Jackson LA, Kharbanda EO, Klein NP, et
al. Febrile seizure risk after vaccination in children 6 to 23 months. Pediatrics
statistically significant decrease in the incidence of febrile 2016;138(1)e1-10. Epub 2016 Jun 6.
seizure in children who received their first dose of MMR 13. Pavlidou E, Tzitiridou M, Kontopoulos E, Panteliadis CP. Which fac-
tors determine febrile seizure recurrence? A prospective study. Brain Dev
vaccine between 12 and 15 months of age, compared 2008;30(1):7-13. Epub 2007 Jun 21.
with those children who received the vaccine at an older 14. Taddio A, Appleton M, Bortolussi R, Chambers C, Dubey V, Halperin S, et al.
Reducing the pain of childhood vaccination: an evidence-based clinical prac-
age.21 Therefore, it appears that prudent timing of MMR tice guideline. CMAJ 2010;182(18):E843-55. Epub 2010 Nov 22.
vaccination is the only known factor that decreases the 15. Schnaiderman D, Lahat E, Sheefer T, Aladjem M. Antipyretic effectiveness
of acetaminophen in febrile seizures: ongoing prophylaxis versus sporadic
rate of febrile seizure recurrence following vaccination. usage. Eur J Pediatr 1993;152(9):747-9.
16. Uhari M, Rantala H, Vainionpää L, Kurttila R. Effect of acetaminophen and

Conclusion of low intermittent doses of diazepam on prevention of recurrences of febrile

seizures. J Pediatr 1995;126(6):991-5.
Febrile seizures are common in children. It is typically a 17. Van Stuijvenberg M, Derksen-Lubsen G, Steyerberg EW, Habbema JD,
Moll HA. Randomized, controlled trial of ibuprofen syrup administered
benign condition with favourable long-term outcomes. during febrile illnesses to prevent febrile seizure recurrences. Pediatrics
While an association between certain vaccines and febrile 1998;102(5):e51.
18. Strengell T, Uhari M, Tarkka R, Uusimaa J, Alen R, Lautala P, et al.
seizures exists, the risk is small and outweighs the risk of Antipyretic agents for preventing recurrences of febrile seizures: randomized
not being vaccinated. Current evidence does not suggest controlled trial. Arch Pediatr Adolesc Med 2009;163(9):799-804.
19. Prymula R, Siegrist CA, Chlibek R, Zemlickova H, Vackova M, Smetana J, et
benefit to providing prophylactic antipyretics, especially al. Effect of prophylactic paracetamol administration at time of vaccination
in face of potential lack of immunogenicity.  on febrile reactions and antibody responses in children: two open-label, ran-
domised controlled trials. Lancet 2009;374(9698):1339-50.
Competing interests 20. Das RR, Panigrahi I, Naik SS. The effect of prophylactic antipyretic adminis-
None declared tration on post-vaccination adverse reactions and antibody response in chil-
Correspondence dren: a systematic review. PLoS One 2014;9(9):e106629.
Dr Ran D. Goldman; e-mail [email protected] 21. Rowhani-Rahbar A, Fireman B, Lewis E, Nordin J, Naleway A, Jacobsen
SJ, et al. Effect of age on the risk of fever and seizures following immu-
References nization with measles-containing vaccines in children. JAMA Pediatr
1. Kohl KS, Marcy SM, Blum M, Connell Jones M, Dagan R, Hansen J, et al. 2013;167(12):1111-7.
Fever after immunization: current concepts and improved future scientific
understanding. Clin Infect Dis 2004;39(3):389-4. Epub 2004 Jul 9.
2. Subcommittee on Febrile Seizures; American Academy of Pediatrics.
Neurodiagnostic evaluation of the child with a simple febrile seizure.
Pediatrics 2011;127(2):389-94.
3. Rantala H, Tarkka R, Uhari M. Systematic review of the role of prostaglan-
dins and their synthetase inhibitors with respect to febrile seizures. Epilepsy
Res 2001;46(3):251-7.
4. Waruiru C, Appleton R. Febrile seizures: an update. Arch Dis Child
2004;89(8):751-6.
5. Schiller JH, Shellhaas RA. Neurology. In: Marcdante KJ, Kliegman R.
Nelson essentials of pediatrics. 7th ed. Philadelphia, PA: Elsevier Saunders; Child Health Update is produced
2015. p. 618-20. by the Pediatric Research in
6. Chiu SS, Tse CY, Lau YL, Peiris M. Influenza A infection is an important
cause of febrile seizures. Pediatrics 2001;108(4):E63. Emergency Therapeutics (PRETx)
Pediatric Research in Emergency Therapeutics

7. Millichap JG, Millichap JJ. Role of viral infections in the etiology of febrile sei- program (www.pretx.org) at the BC
zures. Pediatr Neurol 2006;35(3):165-72.
8. Barlow WE, Davis RL, Glasser JW, Rhodes PH, Thompson RS, Mullooly JP,
Children’s Hospital in Vancouver, BC. Dr Monfries is a member
et al. The risk of seizures after receipt of whole-cell pertussis or measles, and Dr Goldman is Director of the PRETx program. The mission of
mumps, and rubella vaccine. N Engl J Med 2001;345(9):656-61. the PRETx program is to promote child health through evidence-
9. Klein NP, Fireman B, Yih WK, Lewis E, Kulldorff M, Ray P, et al. Measles-
mumps-rubella-varicella combination vaccine and the risk of febrile seizures.
based research in therapeutics in pediatric emergency medicine.
Pediatrics 2010;126(1):e1-8. Epub 2010 Jun 29. Do you have questions about the effects of drugs, chemicals,
10. MacDonald SE, Dover DC, Simmonds KA, Svenson LW. Risk of febrile sei-
zures after first dose of measles-mumps-rubella-varicella vaccine: a
radiation, or infections in children? We invite you to submit
population-based cohort study. CMAJ 2014;186(11):824-9. Epub 2014 Jun 9. them to the PRETx program by fax at 604 875-2414; they will
11. Sun Y, Christensen J, Hviid A, Li J, Vedsted P, Olsen J, et al. Risk of febrile be addressed in future Child Health Updates. Published Child
seizures and epilepsy after vaccination with diphtheria, tetanus, acellular
pertussis, inactivated poliovirus, and Haemophilus influenzae type b. JAMA
Health Updates are available on the Canadian Family Physician
2012;307(8):823-31. website (www.cfp.ca).

130  Canadian Family Physician • Le Médecin de famille canadien | Vol 63:  FEBRuary • février 2017