To our knowledge, this is the first study to investigate the effects of immunization and acetaminophen use on infant sleep duration and temperature changes over a 24-hour period after immunization. Our first hypothesis was supported by the finding that infants slept longer in the first 24 hours after immunization, compared with the 24 hours before immunization. This was particularly true for infants who received their immunizations after 1:30 pm. The increased sleep time was primarily in active sleep rather than quiet sleep.
Our second hypothesis also was supported. Infants who had elevated temperatures in response to vaccines also slept longer in the 24 hours after immunization than in the 24 hours before immunization. Temperature increase is considered a marker of immune responses and is thought to be related to release of endogenous pyrogens (eg, interleukin 1 and tumor necrosis factor α) associated with increased T cell activity, enhanced antigen recognition, and immune responses.22
Therefore, longer sleep duration and increased temperature after immunization may be indicators of the degree of antibody responses.9
Studies have suggested that sleep quantity is a potential mediator of antibody responses to vaccines in adults, perhaps through stress-related modulation of cytokine production by activated T cells.23,24
Although antibody development can take several weeks, 2 studies demonstrated that even relatively brief periods of sleep restriction could disrupt adult antibody responses.4,24
It was beyond the scope of this study to determine whether infant sleep quantity on a single night after immunization was associated with antibody responses. Future research should address this important question by assessing infant sleep and antibody responses over longer time frames. If relationships between time of day of vaccine administration, increased sleep, and antibody responses are substantiated, then our findings suggest that afternoon immunizations should be recommended, to facilitate increased infant sleep after immunization.
In this RCT, infants were assigned randomly to 3 groups, namely, control mothers with infants who received usual care, intervention mothers with infants who received usual care, and intervention mothers with intervention infants, who were instructed to provide prophylactic and continuing doses of acetaminophen. Although group assignment had no effect on postimmunization sleep in intent-to-treat analysis, 71% in the usual-care group received acetaminophen and 20% received it prophylactically, which made it more difficult to detect group differences. Nevertheless, the findings support one aspect of our third hypothesis regarding the effects of prophylactic acetaminophen treatment on infant temperature. The large effect sizes (with P
= .053) suggest that the study was underpowered for an intent-to-treat analysis to detect large differences, when effects of group contamination with acetaminophen administration are considered. These differences would require 64 infants per group for statistical significance.17
In comparison with the few infants who did not receive any acetaminophen (n = 14), the 56 infants who received ≥1 dose had smaller increases in postimmunization sleep duration, regardless of acetaminophen administration timing. The rationale for postimmunization administration of acetaminophen cannot be completely explained by group assignment, which suggests that these infants might have experienced more symptoms, for which they received acetaminophen. However, acetaminophen use was not significant in the regression analysis, which suggests that the primary mechanism for increased sleep time may involve higher temperature.
Our findings are consistent with those of Prymula et al9
and, taken together, suggest that antipyretic agents should not be given prophylactically for infant immunization. Therefore, research on alternative pain-management strategies for immunization discomfort is urgently needed. As immunization practices shift from single-antigen to multiple-antigen vaccine delivery, sleep duration should be measured in future studies of combination vaccine products, because of the potential for fever or pain responses to such products and sleep implications.25
These findings were limited to term firstborn infants receiving their first immunization series, and they may not be applicable to premature or older infants and children. The small number of infants who did not receive acetaminophen (n = 14) and the likelihood that acetaminophen often was used for symptom relief also may limit the generalizability of these findings; larger, placebo-controlled trials are warranted. Findings should be interpreted with caution because of the limited study period (ie, 24 hours before and after immunization) and the use of ankle movements to estimate infant sleep. Infants mature at a rapid rate, however, and comparisons of more-proximal times around the immunization protocol are critical for understanding how sleep is influenced. Differences in active and quiet sleep times should be explored further by using polysomnography, and longitudinal studies of sleep and responses to immunization are needed for a better understanding of the interactions between immunization time of day, active and quiet sleep, temperature, and antibody responses.