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Frequently Asked Questions

Does acetaminophen reduce the immunologic response to vaccines in children?

Fever and pain reducing medications such as acetaminophen are commonly used in the pediatric population; the use of these agents prior to vaccinations has become a common practice.1 Vaccines, especially diphtheria, tetanus toxoids, and pertussis vaccine (DTP), can cause local (erythema, induration, and tenderness) or systemic (fever, drowsiness, and seizures) reactions.2 These adverse events are more likely to occur with the whole-cell pertussis vaccine than the acellular pertussis formulation.3 To prevent local and systemic reactions in infants and children with a history of seizures, the Advisory Committee on Immunization Practices (ACIP) recommends the administration of age-appropriate doses of acetaminophen at the time of DTP vaccination and every 4 hours for 24 hours.4 It is thought that acetaminophen prevents the occurrence of seizures in patients who are at high risk of having febrile seizures such as those with an individual or family history of seizures.2 However, some clinicians administer prophylactic acetaminophen to all pediatric patients who receive the whole-cell pertussis vaccine.1,5 In the United States, the acellular pertussis vaccine has replaced the whole-cell pertussis vaccine; therefore, this routine practice may no longer be necessary.1 In addition, evidence is scarce regarding the efficacy of acetaminophen in reducing adverse events following acellular pertussis vaccinations.6

The effect of prophylactic administration of acetaminophen on reactions to DTP has been previously studied.7 It was concluded that acetaminophen had a modest effect on the development of fever and pain after vaccination. Recently, Pyrmula and colleagues not only examined the effectiveness of acetaminophen at the time of vaccination on febrile reactions, but also the effect of acetaminophen on antibody responses.5 The vaccines used included a 10-valent pneumococcal non-typeable Haemophilus influenzae (H influenzae) protein D-conjugate vaccine (PHiD-CV) given with hexavalent diphtheria-tetanus-3-component acellular pertussis hepatitis B-inactivated poliovirus types 1, 2, and 3-H influenzae type b vaccine (DTPa-HBV-IPV/Hib), and oral human rotavirus vaccine (HRV).

Methods

A total of 459 healthy infants (aged 9 to 16 weeks at the time of enrollment) were invited to participate in 2 randomized, multicenter, open-label, phase 3 trials for both primary and booster doses of vaccines aforementioned.5 Children who were previously vaccinated with vaccines studied in these trials, required prophylactic antipyretics for reasons other than those being studied, or had a contraindication to acetaminophen treatment were excluded. Primary vaccine doses of PHiD-CV administered with DTPa-HBV-IPV/Hib were administered at 3, 4, and 5 months of age, and HRV was administered at 3 and 4 months of age. Booster doses of PHiD-CV and DTPa-HBV-IPV/Hib were given between 12 and 15 months of age. For the primary vaccination, children were randomly assigned to receive either 3 prophylactic doses of acetaminophen administered rectally at the time of vaccination and every 6 to 8 hours within the first 24 hours after each vaccine dose or no prophylactic acetaminophen treatment. The children remained in the same treatment groups (with or without prophylaxis acetaminophen) during the booster doses. Due to the immunogenicity results of the primary vaccination, the protocol was amended to discontinue the administration of prophylactic acetaminophen at the time of booster vaccination. Therefore, results of the booster study were presented as 3 groups: (1) received primary and booster prophylactic acetaminophen (children boosted before the amendment); (2) received prophylactic acetaminophen only during primary vaccination (children boosted after the amendment); (3) received no prophylactic acetaminophen during either primary or booster vaccination and were boosted before the amendment.

The children received the following doses of acetaminophen: 80 mg per dose for infants weighing between 4.5 kg and less than 7 kg, and 125 mg per dose for infants weighing 7 kg or more.5 At booster vaccination children with a bodyweight of 9 kg or greater received 4 doses of 125 mg each within 24 hours, whereas those between 7 kg and less than 9 kg received the same dose as the primary series. For both trials, the primary endpoint was the reduction in fever (temperature ≥38oC) measured rectally on day 0 to 3.5 The secondary endpoint was the assessment of immunogenicity, and blood samples were taken before the first dose and 1 month after primary vaccination, and before and 1 month after the booster dose.

Results

After primary and booster vaccinations, fever greater than 39.5oC was infrequent (range, <1% to 2% overall).5 After at least 1 dose, there was a significantly lower percentage of children with temperature of 38oC or greater in the prophylactic acetaminophen group (94/226 [42%] after primary vaccination and 64/178 [36%] after booster vaccination) compared to the no prophylactic acetaminophen group (154/233 [66%] after primary vaccination and 100/172 [58%] after booster vaccination). The primary vaccination group difference was 24.50% (95% confidence interval [CI] 15.49 to 33.11, and the booster vaccination group difference was 22.18% (95 % CI 11.78 to 32.11).

One month after primary vaccination, at least 95.7% of children had antipneumococcal antibody concentrations ≥0.20 μg/mL against each serotype excluding serotype 6B and 23F. Despite the robust immune response, there were significantly fewer children with antibody concentrations of ≥0.20 μg/mL in the acetaminophen group compared to the no prophylaxis group. The geometric mean antibody concentration (GMC) was significantly lower in the prophylactic group compared to the no prophylaxis group for all 10 serotypes. Additionally, children in the prophylactic group had lower seroprotective antibody concentrations for H influenzae type b, and lower GMCs for antibodies against H influenzae type b, diphtheria, tetanus, and pertactin.

After the booster, the GMCs for antipneumococcal antibody were significantly lower in the prophylaxis group for all serotypes except serotype 19F compared to no prophylaxis. A significant difference was only reported for antibody concentrations against tetanus. As a result, the authors concluded that prophylactic antipyretic therapy should not be routinely given at the time of vaccination without considering risks versus benefits.

Conclusion

Prophylactic acetaminophen to control pain, fever, and discomfort in infants and children prior to vaccinations is routinely used by some clinicians. Due to the findings of decreased immune response in patients who received prophylactic acetaminophen at the time of vaccination, the benefits of acetaminophen have been questioned. While the results are compelling, the assessment of immunogenicity was not the primary objective of the trials, and the extent of reduction in seroprotection by acetaminophen needs to be determined along with the applicability of the results to all antipyretics and patient populations. In conclusion, the routine use of acetaminophen prior to vaccinations in all patients should be reconsidered, especially due to the lower risk of local and systemic reactions with the acellular pertussis vaccine compared to the whole cell formulation. Clinicians should continue to follow the ACIP recommendations for patients with a history of seizures and neurologic disorders receiving DTP vaccinations and use clinical discretion for patients who develop a fever.

References

  1. Chen RT, Clark TA, Halperin SA. The yin and yang of paracetamol and paediatric immunisations. Lancet. 2009;374(9698):1305-1306.
  2. Centers for Disease Control and Prevention. Update: vaccine side effects, and adverse reactions, contraindications, and precautions. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 1996;45(RR-12):1-35.
  3. Grabenstein, JD. ImmunoFacts: Vaccines and Immunologic Drugs. St. Louis, MO: Wolters Kluwer Health; 2007.
  4. Kroger AT, Atkinson WL, Marcuse EK, Pickering LK; Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-15):1-48.
  5. Prymula R, Siegrist C, Chilbek R, et al. Effect of prophylactic paracetamol administration at time of vaccination on febrile reactions and antibody responses in children: two open-label, randomized controlled trials. Lancet. 2009;374(9698):1339-1350.
  6. Manley J, Taddio A. Acetaminophen and ibuprofen for preventions of adverse events associated with childhood immunizations. Ann Pharmacother. 2007;41(7):1227-1232.
  7. Lewis K, Cherry JD, Sachs MH, et al. The effect of prophylactic acetaminophen administration on reactions to DTP vaccination. Am J Dis Child. 1988;142(1):62-65.