Acetaminophen for Prevention of Post-Vaccination Fever in Infants

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Jackson LA, et al. "A randomized placebo-controlled trial of acetaminophen for prevention of post-vaccination fever in infants". PLoS One. 2011. 6(6):.
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Clinical Question

In pediatric patients receiving routine immunizations, is prophylactic administration of acetaminophen safe and effective at preventing a fever?

Bottom Line

Prophylactic administration of acetaminophen in pediatric patients receiving routine immunizations did not significantly decrease the incidence of post-immunization fever.

Major Points

Fever is an adverse event that is common in infants post-vaccination that can lead to discomfort, disruption of sleep, and hospitalizations. “Two randomized controlled trials conducted in the 1980s reported reductions in risk of post-vaccination fever in infants two through six months of age.”(1)

The 2011 Plos One trial randomized 352 children, age 16-42 weeks, to calculate their rectal temperature post-vaccination. The study resulted in a 30% reduction of rectal temperature (≥38℃) within 32 hours of DTaP vaccine along with other vaccinations recommended for infants. However, this study was not completed in its entirety due to findings from a previous study that stated that the acetaminophen prophylaxis caused many adverse events. Only ⅓ of the goal population of 1000 were assessed.(1)

Due to the fact that there was an increased risk for seizures and not fevers with the DTaP vaccination, this study shows that acetaminophen prophylaxis is not recommended for post-vaccination fever. Prophylactic administration of acetaminophen in pediatric patients receiving immunizations did not significantly decrease the incidence of post-immunization fevers. Therefore, acetaminophen should not be recommended for prevention of post-vaccination fever.(1)

Guidelines

Hepatitis B

Infants are to receive the Hepatitis B vaccination within 24 hours of birth. They then receive a second dose between 1 and 2 months of age, and a third dose between 6 and 18 months of age.(2)


Rotavirus

The Center for Disease Control recommends that infants receive three doses of the rotavirus vaccination at 2, 4, and 6 months.(2)


Diphtheria, Tetanus, and Pertussis (DTaP)

Infants are recommended by the Center for Disease Control to receive three doses of the DTaP vaccination at ages 2, 4, and 6 months.(2)


Pneumococcal (PCV13)

The Pneumococcal Vaccination is recommended in three sequential doses by the Center for Disease Control at ages 2, 4, and 6 months to help eliminate the spread of pneumonia.(2)


Flu Vaccination Guidelines (2017-2018 American Academy of Pediatrics)

Children should receive influenza vaccinations by the end of October, if possible. Children who require two doses (those 6 months through 8 years, who have not previously been fully vaccinated) should receive the first vaccine early in the season for optimal protection. Special effort should be made to vaccinate all children 6 months and older who have conditions that increase their risk of complications of flu including infants born preterm and those with chronic medical conditions, including asthma and other chronic lung diseases, heart disease, diabetes and other metabolic problems, and weakened immune systems, among others.(2)


Prophylactic Administration of Antipyretics

The CDC has found that there is no evidence to support prophylactic administration of antipyretic medications at the time of vaccinations. Fever-reducing agents should be used only to treat post-vaccination pain or fever if present.(3)


Acetaminophen Use in Children

In children gestational age 28 to 32 weeks, the recommended dose of acetaminophen is 10 to 12 mg/kg/dose every 6 to 8 hours with a maximum daily dose of 40 mg/kg/day. In children gestational age 33 to 37 weeks or term neonates <10 days, the recommended dose of acetaminophen is 10 to 15 mg/kg/dose every 6 hours with a maximum daily dose of 60 mg/kg/day. In term neonates ≥10 days the recommended acetaminophen dose is 10 to 15 mg/kg/dose every 4 to 6 hours, not to exceed 5 doses in 24 hours with a maximum daily dose of 75 mg/kg/day.(4)

Design

  • Prospective, randomized double-blind clinical trial
  • N = 374 children aged 6 weeks-9 months old randomized
    • 542 enrolled of which 168 were excluded, 352 were analyzed
    • 176 randomized to acetaminophen and 176 randomized to placebo group
  • Planned to enroll 1,000 children, but enrollment ceased at 352 children due to complications found in other studies
  • Enrollment Period during 2009
    • Potentially eligible children were chosen from the Group Health databases and parents were notified by mail explaining the study and asking for interest
    • A phone interview and medical record review were used for eligibility
    • Randomization was conducted by a biostatician and provided to the pharmacy (neither involved in the enrollment process)
  • Setting: Vaccinations given at Group Health Cooperative Managed Care in Washington State
  • Treatment: Medication (Acetaminophen or Placebo) masked in both color and taste was sent to patient’s home with syringes and a thermometer
  • Analysis: Intent-to-treat for 352 children aged 6-48 weeks old
    • Attempted a per protocol design as well for 2 subgroups, <24 weeks and ≥ 24 weeks who were given a dose between 4 hours prior up until 1 hour post vaccination.
    • Had to also received at least 2 additional doses that were given 4 hours apart within 24 hours of vaccination
    • Results of per protocol were so similar to Intent-to-treat model that they were not included in study findings
  • Primary Outcome:
    • Rectal temperature ≥ 38 degrees Celsius within 32 hours following vaccinations

Population

Inclusion Criteria

  • Children less than 10 months of age
  • Expected to receive 2 or more injected vaccines at an upcoming well child visit occurring between 6 weeks and 10 months of age

Exclusion Criteria

  • Children less than 4 months of age with a birth weight less than 2500 grams or a gestational age of less than 36 weeks

Baseline Characteristics

From the acetaminophen group.

  • Age: 24.8 weeks
  • Female: 44%
  • Weight: 16.7 pounds

Interventions

Participants were indicated in a 1:1 randomization into either the group receiving acetaminophen or placebo. The acetaminophen group received a suspension containing 160mg/5 mL of acetaminophen. The patients were given a dose of 10-15 mg/kg of acetaminophen for treatment. The placebo group received a suspension containing a liquid placebo flavored to match the acetaminophen suspension. Parents were asked to give the first dose within an hour of the vaccination, and then as close to every 4 hours as possible for up to 5 doses.

Outcomes

Comparisons are acetaminophen prophylaxis vs. placebo at 32 hours post-vaccination

Primary Outcomes

  • Rectal temperature ≥38℃ 32 hours post-vaccination
    • 14% vs. 22% (RR 0.66; 95% CI 0.41-1.01; P=0.053)

Secondary Outcomes

  • Rectal temperature ≥39℃ 32 hours post-vaccination
    • 0% vs. 2% (RR --; 95% Cl --; P=0.08)
  • Medical Utilization:
    • 3% vs. 6% (RR 0.45; 95% Cl 0.16-1.28; P=0.14)
  • Infant Fussiness (more than usual vs. much more than usual with normal/less than normal as reference)
    • Normal/Less: 42% vs. 38%
    • More: 58% vs. 62% (RR 0.94; 95% Cl 0.79-1.11; P=0.45)
    • Much More: 10% vs. 24% (RR 0.40; 95% Cl 0.25-0.70; P=0.0001)
  • Parent Sleep (Less than vs. much less than with normal/more than normal as reference)
    • Normal/More: 73% vs. 77%
    • Less: 27% vs. 23% (RR 1.20; 95% Cl 0.85-1.80; P=0.33)
    • Much Less: 3% vs. 5% (RR 0.62; 95% Cl 0.21-1.88; P=0.40)
  • Infant Sleep (less than or much less than with normal/more than normal for reference)
    • Normal/More: 78% vs. 81%
    • Less: 22% vs. 19% (RR 1.15; 95% Cl 0.76-1.75; P=0.51)
    • Much Less: 2% vs. 2% (RR 1.00; 95% Cl 0.25-3.94; P=1.00)
  • Missed work by parents:
    • 4% vs. 1% (RR 2.94; 95% Cl 0.60-14.34; P=0.18)
  • Unblinding of drug assignment:
    • 3% vs. 9% (RR 0.31; 95% Cl 0.11-0.83)

Subgroup Analysis

  • 2 subgroups created, <24 weeks old and ≥ 24 weeks old
  • Per protocol analysis resulted in similar findings to the intent to treat analysis with the subgroup, so per protocol findings were not presented
  • Children ≥ 24 weeks had a significant reduction in fever risk compared to placebo
    • 13% Acetaminophen vs. 25% Placebo (NNT=9, P=0.03)
  • Children <24 weeks did not have a significant reduction in fever risk
    • 16% Acetaminophen vs. 18% Placebo (P=0.8)

Adverse Events

Adverse effects encountered in the study were not discussed.

Criticisms

  • Study outcomes were recorded via study diaries completed by the children’s caregivers.
  • Children’s ages had a bimodal distribution having two mean age peaks
    • One mean less than 24 weeks old and one greater than 24 weeks old
  • Study enrollment was stopped at 352 children due to adverse findings from the Czech Republic.
  • The study included a relatively small number of participants.
  • The study’s small sample size did not create enough power to identify the pre-selected 30% reduction in risk.
  • The study was approved by the Institutional Review Boards at Group Health, which was the same managed care facility that conducted the study and used its patients as participants.

Funding

Financial support was provided by the Centers for Disease Control and Prevention through America’s Health Insurance Plans. The CDC was involved in developing the protocol but neither the CDC nor the AHIP was involved in data collection, data analysis, or the decision to submit the manuscript for publication.

Further Reading

References

  • (1)Jackson LA, Peterson D, Dunn J, Hambidge SJ, Dunstan M, et al. (2011) A Randomized Placebo-Controlled Trial of Acetaminophen for Prevention of Post-Vaccination Fever in Infants. PLoS ONE 6(6): e20102. doi:10.1371/journal.pone.0020102
  • (2)“Immunization Schedules.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 8 Mar. 2018, www.cdc.gov/vaccines/schedules/easy-to-read/child.html.
  • (3)Centers for Disease Control and Prevention. “Vaccine Recommendations and Guidelines of the ACIP.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 27 Feb. 2018, www.cdc.gov/vaccines/hcp/acip-recs/general-recs/administration.html#ref-43.
  • (4)“Acetaminophen-Dosing: Pediatric.” LexiComp, Wolters Kluwer, 27 Apr. 2018, online.lexi.com.ezproxy.wilkes.edu/lco/action/doc/retrieve/docid/patch_f/6264.