The current recommendation is to administer the first routine immunization to preterm infants at the usual chronological age of 8 weeks as the immunologic response to vaccines at that age is almost equivalent to that of term infants [1]. However, in multiple previous studies, a 7 to 47% incidence of adverse cardiorespiratory events including apnea, bradycardia, and/or desaturation (ABD) has been reported following the first diphtheria-tetanus-pertussis-inactivated polio-Haemophilus influenzae type B (DTP-IPV-Hib) immunization of preterm infants [2–10], with the most common theory being that these events are precipitated by the whole cell pertussis component of the vaccine [3]. Previous studies used infants as their own controls, comparing events prior to and following immunization. Birth weight, current weight, gestational age, and postnatal age have been studied as potential risk factors for ABD with inconclusive results [4–7, 9, 10].

A retrospective stratified cohort study was completed to determine the frequency of adverse cardiorespiratory events among premature infants following their first immunization with DTP-IPV-Hib vaccine and to compare the frequency of events following whole cell versus acellular pertussis vaccines. A further objective was to study possible risk factors for these adverse events.

Approval from the Health Research Ethics Board of the University of Alberta was obtained for conducting this study.

Previous studies have identified a possible increase in the frequency of adverse cardiorespiratory events following the first DTP-IPV-Hib immunization in preterm infants [2–10]. Our study was the first to use a control group and confirmed that in infants ≤ 32 weeks gestation, almost half of infants had an increase of adverse cardiorespiratory events in the 72 hours post-immunization which was statistically significantly higher than in the control group. Furthermore, the number of immunized infants with a reduction in adverse cardiorespiratory events in the 72 hours post-immunization was statistically significantly lower than in the control group at an equivalent chronologic age, and an immunized infant was only 17% as likely as a control infant to have a reduction in adverse cardiorespiratory events. Comparing our adverse event rate to those reported in the literature, one small prospective study found no change in the frequency of apnea or increased oxygen requirements in 16 infants < 29 weeks gestation receiving whole cell pertussis vaccine [11], while other studies reported an incidence of adverse cardiorespiratory events of only ~8% in infants receiving whole cell pertussis vaccine [2, 3]. Also using whole cell pertussis vaccine, a retrospective study of 97 infants [4] and a follow up prospective study [5] by the same group found rates of adverse cardiorespiratory events with incidences of 20% and 17% respectively. Unexpectedly, higher incidences of 38 to 47% that are more comparable to the rate in the current study have been documented in more recent studies with acellular pertussis vaccines [8–10]. However, these varying rates may be partially accounted for by differences in the definition of cardiorespiratory events and in monitoring practices.

Despite the fact that the current study demonstrated an increase in adverse cardiorespiratory events post-immunization, most of these events were clinically insignificant and the number requiring treatment was not statistically different between the immunized and control groups. As described in the previous literature, most events resolved spontaneously or required only brief stimulation or transient low flow oxygen [3–10]. Sixteen percent of the immunized infants in the current study required increased oxygen or CPAP, which fits with the wide range of 0–33% reported in previous studies [3–10], while 16% required increased theophylline doses and a single infant required reintubation on the third day post-immunization. The relationship of this event to the immunization is not clear.

The main reason for changing from whole cell to acellular pertussis vaccine is the decreased reactogenicity of the latter vaccine. However, in the current study there was no statistically significant difference in the frequency of adverse cardiorespiratory events post-immunization with whole cell as compared to acellular pertussis vaccines in preterm infants. This differs from a previous study in preterm infants where increased adverse cardiorespiratory events and increased systemic inflammatory markers (IL-6, CRP) occurred in 30% of infants receiving whole cell pertussis vaccine but in no infants receiving acellular pertussis vaccine [7].

Previous studies found that the risk of adverse cardiorespiratory events post- immunization was higher in infants with lower birth weight [6], lower current weight [6], lower gestational age [4], or postnatal age < 70 days [10], while other studies did not confirm these findings [5, 7] or found a correlation with the presence of adverse cardiorespiratory events during the 24 hours preceding the immunization [9]. In the current study, only the current weight appeared to be a risk factor where the infant's likelihood of having an adverse cardiorespiratory event decreased by 17% for every 100 gram increase in weight. Other potential risk factors such as chronic lung disease, duration of ventilation or oxygen dependency were not addressed in our study.

One limitation of our study is that patients not on electronic cardiorespiratory monitors 72 hours prior to and post-immunization were excluded. These infants would presumably be more stable and may be less likely to have an adverse event precipitated by the immunization. Therefore, the frequency of apnea or bradycardia in preterm infants receiving their first DTP-IPV- Hib immunization may have been over-estimated in the current study. The study dates of the controls that corresponded to the immunization date of the immunized infants were adjusted up to 7 days in 55 patients to avoid confounding factors, which could have affected results. It would have been ideal but impractical to use a shorter window. Charting of adverse cardiorespiratory events by nursing staff can vary and it is possible that nurses were more diligent about observing infants who had recently received an immunization. However, we suspect there was limited awareness amongst nurses or physicians of the potential for immunizations to precipitate adverse cardiorespiratory events, as many infants could not be included in the study as they were not on a monitor post-immunization. It has been suggested that when looking for adverse events related to immunization, it may be inappropriate to use unimmunized children as controls as they may differ in important ways from immunized children [12]. However, almost all control infants in the current study were already immunized or were eventually immunized. Because immunization is often arranged just prior to discharge, if there was a systemic bias, it would be towards the immunized infants being "more stable" than the control infants and less likely to have adverse cardiorespiratory events at this chronologic age.

More hospitalized preterm infants ≤ 32 weeks developed an increase in adverse cardiorespiratory events after their first immunization with DTP-IPV-Hib than did a control group at an equivalent chronologic age. A lower weight at the time of immunization was a risk factor for an increase in adverse cardiorespiratory events. The risk of these events does not appear to have been decreased by the use of acellular pertussis vaccine. The majority of these events were clinically insignificant and should not prompt delays in immunization. However, whenever practical, immunization should be given at least 72 hours prior to planned discharge in this fragile population to allow for cardiorespiratory monitoring post-immunization.