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Rethinking acetaminophen for immunizations
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Occasionally, studies are conducted and published in which the results and clinical implications contradict common medical practice. Such is the case with a study published recently in The Lancet. This study, described in more detail below, evaluated giving acetaminophen to infants receiving several pediatric immunizations. The results of this study may now cause us to question the relatively common administration of acetaminophen to infants receiving pediatric immunizations.
The administration of acetaminophen prophylaxis to infants receiving pediatric immunizations may be relatively common. As fever may occur after vaccine administration and, as many parents continue to harbor concerns over fever, it may seem reasonable to administer acetaminophen before immunization. Fever more commonly occurred after whole-cell pertussis vaccine administration, compared with the acellular pertussis vaccines given today.
The Advisory Committee on Immunization Practices of the CDC stated in 2006 that acetaminophen could be given to an infant with a history of previous seizures at the time of DTaP vaccination to reduce post-vaccination fever. Acetaminophen may also commonly be given before and after vaccination to minimize pain and discomfort. Acetaminophen prophylaxis was evaluated in a controlled trial of infants receiving DTP vaccination and was found to significantly reduce fever and pain associated with vaccine administration.
New study
Acetaminophen given as prophylaxis for pediatric immunization was evaluated in two consecutive controlled, randomized, open-label trials and included infants from 10 centers in the Czech Republic receiving primary and booster pediatric vaccines.
Vaccines administered included a 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine, a hexavalent diphteria-tetanus-3-component acellular pertussis-hepatitis B-inactivated poliovirus (types 1, 2, 3)-H. influenzae type b vaccine and oral human rotavirus vaccine. Acetaminophen was given rectally as three doses over 24 hours for the primary vaccine study, with the first dose given immediately after vaccine administration, and the second and third doses given at home by caregivers.
Acetaminophen doses of 80 mg or 120 mg were standardized to weight (11.4 mg/kg – 17.9 mg/kg every six to eight hours). Placebo was not given to the control infant group, and thus, acetaminophen administration was not blinded. Additional, therapeutic use of acetaminophen was allowed in both groups. For booster vaccine administration, four doses of acetaminophen given every six hours were allowed (no more than 55.6 mg/kg/24 hours). Four-hundred and fifty-six infants (9-16 weeks of age) completed the primary study and 377 infants (12-15 months) completed the booster study.
The primary outcome was febrile reactions on days 0 to 3, and the secondary outcome was assessment of immunogenicity by measurement of antibody geometric mean concentrations (GMC). The percentage of children with temperature of 38·C was significantly lower in the treatment group for both primary and booster vaccine administration compared with the control group (42%/36% vs. 66%/58%, respectively).
For each vaccine dose, there were 40% to 50% fewer infants with temperature of 38·C in the treatment group compared with the control group, and the difference was greatest with the first acetaminophen dose.
Higher temperatures (>39.5°C) were uncommon: less than 1% in the treatment group and 1% in the control group (not significantly different). There was also no difference between the treatment and control groups for medical advice for fever sought by caregivers, or for swelling and redness greater than 30 mm. Pain and irritability were reported less often in the infants given acetaminophen prophylaxis.
The effect of acetaminophen to reduce discomfort and fever post-vaccination in infants in this study is perhaps not unexpected. The effects of acetaminophen on post-vaccination immune response, however, was unexpected by the study authors.
Overall, most infants developed protective antibody concentrations after immunization: 95.7% of infants for most pneumococcal stains (not 6B or 23F) and 96% of infants for H. influenzae type b, tetanus, diphtheria, hepatitis B, and pertussis. All infants developed protective antibody concentrations for polio.
However, antibody GMCs were significantly lower in the treatment group for many of the vaccine antigens — all 10 pneumococcal vaccine serotypes, anti-H. influenzae, antidiphtheria, antitetanus, and antipertactin (pertussis). Antirotavirus IgA seroconversion rates and GMC were similar in both treatment and control groups. After vaccine booster administration, lower antibody GMC persisted in the treatment group for all pneumococcal serotypes (except 19F), antitetanus and protein D (H. influenzae).
The mechanism of acetaminophen’s effects to blunt immune response to immunization is unknown. The mechanism is not likely due to fever suppression, as acetaminophen similarly affected immune responses in infants with and without febrile reactions to immunization. Acetaminophen’s effect was mainly seen with primary responses to conjugate and toxoid vaccines. This favored the authors’ proposed hypothesis that prophylactic acetaminophen interfered with the early interactions of dendritic (antigen-presenting), B and T cells. An inhibition or diminution of inflammatory signals at the injection site by acetaminophen may have occurred.
Other studies
The study described above is the first to provide data demonstrating an inhibitory effect on immune response from immunization by acetaminophen. Two previous studies evaluating adverse effects and immunogenicity from whole cell pertussis vaccines found no inhibitory effects on immune response from acetaminophen.
Implications
What are the clinical implications of this new study? Should acetaminophen not be given to infants to prevent fever or other adverse effects from pediatric immunizations? As the study authors state, the clinical relevance of the immunologic findings from this study is unknown, and additional studies are needed. It seems reasonable to reconsider, however, the routine use of acetaminophen for pediatric immunizations. More information about this potential effect of acetaminophen is needed — are other pediatric age groups similarly affected, other pediatric immunizations, does ibuprofen have similar effects, are certain infants at more risk to have blunted immune responses?
It is also interesting to wonder whether the rectal use of acetaminophen (vs. oral) may have had a confounding effect. It is known that plasma levels of acetaminophen can vary considerably with rectal administration, as bioavailability from rectal acetaminophen suppositories can differ. As oral acetaminophen is more likely to be given in the United States, it is interesting to contemplate if acetaminophen given orally would have similar effects.
Although the findings of the Prymula study demonstrated a significant lowering of immune response from acetaminophen, most infants developed protective antibody concentrations. Additionally, as acetaminophen’s immune blunting effects were more pronounced when given early, acetaminophen given therapeutically after inflammatory signals and fever have occurred may have less of an immune blunting effect. It may also be reasonable to remind parents that fever is not usually harmful, that fever may actually be beneficial and that drug therapy for fever is often not necessary.
For more information:
- Committee on Drugs, AAP. Acetaminophen toxicity in children. Pediatrics. 2001;108:1020-1024.
- Long SS. Longitudinal study of adverse reactions following diphtheria-tetanus-pertussis vaccine in infancy. Pediatrics. 1990;85:294-302.
- Lewis K. The effect of prophylactic acetaminophen administration on reactions to DTP vaccination. Amer J Dis Children. 1988;142:62-65.
- Prymula R. 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;374:1339-50.
- Uhari M. Effect of prophylactic acetaminophen administration on reaction to DTP vaccination. Acta Paediatrica Scandinavica. 1988;77:747-751.
Edward A. Bell, PharmD, is a Professor of Clinical Sciences at Drake University College of Pharmacy, Blank Children’s Hospital and Clinics in Des Moines, Iowa.