OBJECTIVES. Among hospitalized NICU infants, preimmunization apnea is a well-recognized predictor of postimmunization apnea. However, predictors for postimmunization apnea among NICU infants without preimmunization apnea have not been investigated.
METHODS. Using a large NICU database in the Northern California Kaiser Permanente Medical Care Program, we abstracted NICU charts of infants who were hospitalized for ≥53 days and who were also immunized, capturing preimmunization (24 hours before immunization) and postimmunization (48 hours after immunization) events. We assessed factors associated with postimmunization apnea by using multivariate logistic regression.
RESULTS. Of 16 146 infants admitted to the NICU, 557 received ≥1 vaccine and 497 met the criteria for study entry. All infants with preimmunization apnea (n = 27) and all except 3 infants with postimmunization apnea (n = 65) had gestational ages of <31 weeks. Multivariate analyses revealed preimmunization apnea as the most important predictor of postimmunization apnea, although higher 12-hour Score for Neonatal Acute Physiology II and age of <67 days (mean cohort age) were also associated. Multivariate analysis exclusively among infants without preimmunization apnea similarly found elevated Score for Neonatal Acute Physiology II, age of <67 days, and weight of <2000 g to be associated with postimmunization apnea. Forty-nine infants without preimmunization apnea and with ≥1 apnea predictor were discharged within 48 hours after immunization; 2 were subsequently readmitted because of apnea.
CONCLUSIONS. For infants in the NICU without apnea during the 24 hours immediately before immunization, younger age, smaller size, and more severe illness at birth are important predictors of postimmunization apnea.
Immunization of preterm infants is recommended for all infants after the chronological age of 2 months. Immunization of preterm infants has been generally considered safe, effective, and particularly necessary, because premature infants are at high risk from vaccine-preventable diseases.1 Of concern, however, have been observations that premature infants immunized while in the NICU seem to experience either an increase in or a resurgence of apnea after vaccination.2–8
A number of studies have investigated the incidence of apnea after immunization in the NICU. An early retrospective study observed that 20% of premature infants developed apnea after immunization with the diphtheria/tetanus/whole-cell pertussis (DTP) vaccine.2 Subsequent studies reported an incidence of 12% after administration of the DTP vaccine,3 incidences of 17% to 20% after administration of the DTP vaccine in combination with the Haemophilus influenzae type b (Hib) conjugate vaccine,5,6 and abnormalities in cardiorespiratory signs for 30% of patients after administration of the DTP vaccine, Hib vaccine, inactivated polio vaccine (IPV), and hepatitis B virus (HBV) vaccine.9 Most apneic events have been reported as mild, although one study reported 4 cases of severe apnea after immunization with the DTP and Hib vaccines.8 Studies with the diphtheria/tetanus/acellular pertussis (DTaP) vaccine reported similar incidences of postimmunization apnea.4,7,10 In general, studies have found a number of factors to be associated with postimmunization apnea, including age2,4,6 and weight5,6 at immunization, gestational age,4 and history of mechanical ventilation2 or chronic lung disease.2,5 More-recent studies have suggested that the greatest risk of postimmunization apnea is among patients with preexisting cardiorespiratory events.4,10 No studies to date, however, have identified specific predictors of postimmunization apnea by using multivariate analyses or delineated the relative contributions of each predictor to the development of postimmunization apnea. Furthermore, no studies have determined which, and to what extent, individual preimmunization cardiorespiratory symptoms are able to predict postimmunization apnea.
We used a large database that tracks every infant admitted to a NICU in the Northern California Kaiser Permanente Medical Care Program (KPMCP) to identify a cohort of infants who were immunized while in the NICU. In this study, we report on the characteristics of immunized NICU infants, with special emphasis on factors associated with postimmunization apnea among those vaccinated NICU patients.
This study was conducted with the approval of the Northern California KPMCP institutional review board. The initial subject cohort consisted of all infants identified in the Neonatal Minimum Data Set for the Northern California KPMCP11 who were born between January 1, 1997, and December 31, 2003. All infants in the Neonatal Minimum Data Set with a minimum length of stay of 53 days who received ≥1 vaccine were eligible for study inclusion and subsequent chart abstraction. We chose a hospital stay of 53 days because we wished to study infants who both received vaccines at day 56 or later (corresponding to the time of their 2-month vaccines) and had chart data available for the 72 hours preceding immunization, to meet the criteria for a separate immunization safety study. Because multiple vaccines were sometimes divided and administered over the course of 2 days, a set of vaccines consisted of 1 to 5 vaccines administered over the course of ≤48 hours. We conducted detailed chart abstraction for our subjects for 3 periods, beginning 24 hours before immunization with the first vaccine in a given set (preimmunization) and continuing through two 24-hour periods (0–24 hours and 24–48 hours) after administration of the last vaccine in the set. We obtained baseline information on age, birth weight, gestational age, vaccination status, and Score for Neonatal Acute Physiology II (SNAP-II)12 from the Neonatal Minimum Data Set. The SNAP-II, assessed after 12 hours in the NICU, is designed as a measurement of neonatal severity of illness and is considered the standard for measuring risk when a real risk of death is present. Performance of the SNAP-II was revalidated recently.13 We abstracted additional data on vaccines administered, date/time of immunization, vital signs, feeding route, respiratory status (including a need for supplemental oxygen), presence and severity of cardiorespiratory events (apnea, bradycardia, and desaturation; see below), and medications received for each study subject. Apnea, bradycardia, and desaturation episodes were abstracted from the section of the NICU chart that is used specifically for these events, which includes the record of what actions the infant's nurse took in response to these events. Charts of unimmunized infants with a length of stay of 53 days were not reviewed.
To evaluate apnea after discharge from the NICU, we examined hospital and emergency department visits for apnea diagnoses captured within the KPMCP electronic medical record during the 2 weeks after hospital discharge. We excluded diagnoses of apnea listed in the electronic medical record in conjunction with an identifiable cause (eg, Streptococcus pneumonia infection).
During the 7-year study period (1997–2003), the vaccines administered in the NICU included polio vaccines (IPV and oral poliovirus vaccine), diphtheria/tetanus/pertussis vaccine (either DTP or DTaP vaccine), Hib vaccine, HBV vaccine, Streptococcus pneumoniae vaccine (pneumococcal conjugate vaccine), and trivalent influenza vaccine. Because new vaccines such as the pneumococcal conjugate vaccine were introduced during this period, infants born in the later years might have received additional vaccines not available earlier. Infants born earlier in the study period might have received the combination DTP/Hib or DTaP/Hib vaccines, whereas those born later might have received DTaP/IPV/HBV vaccine (Pediarix, GlaxoSmithKline Biologicals, Rixensart, Belgium).
To be consistent with previous studies and to enable future comparisons, we defined apnea as a cessation of respiration for ≥20 seconds, bradycardia as a decrease in heart rate to ≤100 beats per minute for a period of ≥20 seconds, and desaturation as a decrease in the oxygen saturation to ≤88%, as measured with pulse oximetry.4 We further categorized cardiorespiratory events as benign, moderate, or severe, on the basis of the need for intervention and the type of respiratory support. We considered cardiorespiratory episodes as benign when the resolution was spontaneous or the infant self-recovered, moderate when the infants responded to tactile stimulation and/or low-flow oxygen administration (blow by), and severe when bag-mask ventilation, chest compressions, ventilation/intubation, epinephrine administration, or chemical or electrical resuscitation was required. In addition, we regarded bradycardia as moderate in severity if the heart rate decreased to <40 beats per minute (regardless of duration), even if spontaneous recovery occurred. Similarly, we deemed a desaturation event as moderate if the pulse oximeter reading decreased to <60%, even with spontaneous recovery.
We considered apnea, bradycardia, or desaturation as present during any time period if there was >1 benign episode or ≥1 moderate or severe apneic episode. We categorized preimmunization cardiorespiratory events into 2 groups, the first being apnea either with or without bradycardia and/or desaturation occurring during this time period and the second being bradycardia and/or desaturation without preimmunization apnea. We defined postimmunization apnea as apnea occurring 0 to 48 hours after vaccination. We counted infants with >1 episode of apnea within this 48-hour period only once. We assumed infants who were discharged within 48 hours after vaccination to be apnea-free for this postimmunization time period. We excluded from analyses hospitalized infants with missing postimmunization apnea data.
We performed bivariate analyses by using the χ2 test for categorical variables and the t test for continuous variables. We performed multivariate logistic regression analyses evaluating postimmunization apnea 0 to 48 hours after any vaccine. For the multivariate analyses, to account for the relationship between birth weight and gestational age, we used a small-for-gestational age variable instead of birth weight. We evaluated the relative contribution of each factor to prediction of postimmunization apnea by using a likelihood χ2 test, as described by Render et al.14 We used Stata 8.2 (Stata Corp, College Station, TX) for all analyses.
Of the 16146 infants admitted to a KPMCP NICU between January 1, 1997, and December 31, 2003, 749 (4.6%) had a length of stay of >53 days. Of those 749 infants, 557 (74.4%) received ≥1 vaccine and were eligible for chart abstraction. Sixty of those 557 eligible infants (10.7%) were not reviewed, for the following reasons: missing charts (n = 15), charts missing significant data (n = 7), infants not at KPMCP on day 53 (n = 37), and significant congenital anomalies (n = 1). We abstracted data from the remaining study cohort of 497 infants for the period beginning 24 hours before immunization and continuing to 48 hours after immunization.
Infants with completed chart abstractions consisted of 259 boys (52.1%) and 237 girls (47.7%) (1 infant's gender was not specified) and included 456 infants (91.8%) with gestational age of <31 weeks (Table 1). The mean corrected gestational age at receipt of the first immunization was 36.8 weeks, with a mean weight of 2134 g. At receipt of the first vaccine series, 106 infants (21%) were receiving caffeine as a cardiorespiratory stimulant and 242 infants (49%) were receiving some form of supplemental oxygen (Table 1).
All 497 immunized infants received ≥1 set of vaccines, with 63 (12.7%) of 497 infants receiving 2 sets, 15 (3%) of 497 receiving 3 sets, and 5 (1%) of 497 receiving 4 sets. Seventy-three infants (14.7%) received only the HBV vaccine during their first set of vaccines. The remaining 424 infants (85.3%) received ≥1 of the following vaccines, either with or without the HBV vaccine, as part of their first set of vaccines: DTP vaccine, DTaP vaccine, IPV, oral poliovirus vaccine, Hib vaccine, or pneumococcal conjugate vaccine. A total of 342 infants (68.8%) received the first set of vaccines on the same day, 120 infants (24.1%) over 2 days, 34 infants (6.8%) over 3 days, and 1 infant over 4 days.
During the 24 hours before receipt of the first set of vaccines, 27 infants had ≥1 episode of apnea; during the 48 hours after the first set of vaccines, 65 infants had ≥1 episode of apnea (Table 2). All episodes of preimmunization apnea occurred in infants who were born at <31 weeks of gestation. There were 2 infants who required intubation during the postimmunization period, 1 of whom was intubated during the first 24 hours after receipt of HBV vaccine, DTaP vaccine, IPV, Hib vaccine, and pneumococcal conjugate vaccine and was extubated during the 48- to 72-hour postimmunization period. The other infant was intubated during the 24- to 48-hour period after administration of IPV (third set of vaccines) and was extubated within the next time period. Neither of those infants experienced cardiorespiratory events during the 24 hours before immunization or experienced any other cardiorespiratory events after extubation.
We sought to compare the preimmunization characteristics of infants with postimmunization apnea with those of infants without postimmunization apnea. We limited this analysis to infants with gestational age of <31 weeks because 95% of the episodes of postimmunization apnea (62 of 65 episodes) occurred among infants born at <31 weeks of gestation. Bivariate analysis revealed that postimmunization apnea was markedly associated with the presence of preimmunization apnea (P < .0001), although desaturation and/or bradycardia without apnea was not significantly related (P = .32) (Table 3). Additional analyses of data for all infants did not detect more apneic episodes after the first set of pertussis-containing vaccines, with postimmunization apnea being noted for 49 (13.5%) of 364 infants after DTaP, 5 (11.9%) of 42 infants after DTP vaccine, and 11 (13.3%) of 83 infants after nonpertussis vaccines (P = .96).
To assess predictive risk factors for developing postimmunization apnea, we next tested a multivariate logistic regression model with data for all infants. This model revealed that preimmunization apnea within 24 hours was very strongly associated with postimmunization apnea (adjusted odds ratio [AOR]: 25.3; 95% confidence interval [CI]: 9–71.5), although SNAP-II of >10 (AOR: 3.4; 95% CI: 1.2–9.2) and age less than the mean cohort age of 67 days (AOR: 2.2; 95% CI: 1.1–4.4) also were associated. Bradycardia and/or desaturation without apnea was not predictive of postimmunization apnea (AOR: 1.4; 95% CI: 0.7–2.7) (Table 4). Neither gavage feeding (P = .46) nor race (P = .49) was a significant predictor and, because these factors did not affect the overall model and C statistic, they were not included in the model.
We investigated whether the number of apneic episodes during the 24 hours before immunization predicted postimmunization apnea by evaluating the 24 infants who had moderate preimmunization apnea (representing 92% of infants with preimmunization apnea). Eight of the 16 infants with 1 moderate episode of preimmunization apnea had postimmunization apnea, whereas all 8 infants with >1 episode of preimmunization apnea had postimmunization apnea (P = .02), which suggests that infants with >1 episode of apnea are more likely than those with a single episode to have postimmunization apnea.
Although preimmunization apnea was the most important predictor of postimmunization apnea, it was of interest to identify predictors of postimmunization apnea among infants who were free of apnea in the 24 hours before immunization. Multivariate analysis conducted exclusively among infants without apnea before immunization similarly found that, in addition to SNAP-II of >10 (AOR: 4.2; 95% CI: 1.2–14.3) and age of <67 days (AOR: 2.3; 95% CI: 1.1–4.8), weight of <2 kg (AOR: 2.1; 95% CI: 1–4.5) was associated with postimmunization apnea (Table 4). Additional analyses determined that, among infants without preimmunization apnea, the relative contributions of these predictors to prediction of postimmunization apnea were 37.1% for SNAP-II of >10, 25.6% for age of <67 days, and 20% for weight of <2 kg.
We next reviewed the postdischarge electronic medical record of infants without preimmunization apnea who were discharged within 48 hours after immunization and had ≥1 of these 3 predictors. Of the 49 infants who met these criteria, 1 infant immunized 1 day before discharge was apneic at home 3 days after discharge, requiring emergency bag-mask ventilation and subsequent readmission to the hospital. Another infant immunized 1 day before discharge was readmitted 8 days after discharge with an admission diagnosis of apnea. No other infants in this group had emergency department visits for apnea. By comparison, 448 infants were discharged >48 hours after vaccination, of whom 4 (immunized 6–27 days before discharge) were readmitted to the hospital with a diagnosis of apnea within 2 weeks after discharge; an additional 4 infants (immunized 5–34 days before discharge) were seen in the emergency department with apnea but were not admitted.
In agreement with other studies,2,3,5,6,8 we observed more episodes of apnea during the 48-hour postimmunization time period than during the 24 hours before immunization, with the number of infants with apnea increasing from 27 to 65. Although this study captured preimmunization cardiorespiratory events only for the 24-hour period before immunization, this time frame is consistent with other studies.3,4 Multivariate analyses identified preimmunization apnea as the overwhelming risk factor, with its presence representing a 25-fold risk for apnea within the 48 hours after immunization. To a lesser extent, increased initial illness severity scores at birth (AOR: 3.4) and age of <67 days (AOR: 2.2) also predicted postimmunization apnea. In a separate analysis, we found that infants who had >1 episode of apnea during the 24 hours before immunization were more likely to develop postimmunization apnea than were those who had a single episode of apnea. Because caffeine is used as a treatment for apnea of prematurity, one might expect that caffeine administration could be used to distinguish infants at risk for developing postimmunization apnea. However, caffeine treatment at the time of immunization did not predict postimmunization apnea in the multivariate model. Similarly, neither bivariate nor multivariate analyses identified preimmunization bradycardia and/or desaturation as a risk factor for postimmunization apnea. The finding is somewhat unexpected, because apnea, bradycardia, and desaturation frequently occur in conjunction with each other in premature infants, and infants with cardiorespiratory symptoms before immunization have been noted to have a five- to eightfold greater risk of developing postimmunization events.4 Unlike the current study, however, previous studies grouped infants according to their general clinical status (eg, clinically stable versus unstable) and did not determine the relative contributions of the individual cardiorespiratory events of apnea, bradycardia, and desaturation to the development of postimmunization apnea. In contrast, our study strongly suggests that apnea, with or without bradycardia and/or desaturation, as defined in both this study and previous studies,4 is the critical factor in predicting postimmunization apnea among infants with preimmunization cardiorespiratory symptoms. This is the first study to evaluate postimmunization apnea using multivariate analyses, and the results presented here indicate that infants with apnea within 1 day of vaccination continue to be at risk for postimmunization apnea and require ongoing monitoring for ≥48 hours.
In clinical practice, however, infants who are symptomatic with apnea just before immunization are likely to be already undergoing cardiorespiratory monitoring and to remain in the hospital after immunization because of their clinical condition. In contrast, infants without apnea immediately before immunization may be more likely to be assessed as being in clinically stable condition and to be discharged soon after immunization. For this reason, this study also investigated risk factors for postimmunization apnea exclusively among infants who were free of apnea just before immunization. Higher severity of illness scores at birth and younger age at immunization were associated similarly with postimmunization apnea, and this model also revealed that weight of <2000 g was a significant risk factor for postimmunization apnea. Because none of these 3 predictors by themselves would necessarily delay hospital discharge, it is possible that infants with risk factors who are discharged shortly after immunization experience apneic events at home. Preliminary evaluation of the electronic medical record indicated that 2 discharged infants in this cohort (who each had ≥1 risk factor) were readmitted to the hospital with a diagnosis of apnea. Although additional studies will be needed to determine whether infants with these predictors are at greater risk for hospital readmission because of apnea, this observation, together with the findings from the current study, suggests that cardiorespiratory monitoring after immunization of infants with risk factors, regardless of the presence of preimmunization apnea, should be considered.
An important consideration in this study is that the apnea observed in the postimmunization period may not reflect an adverse response to immunization but may be attributable to normal variations in apnea occurrence in this NICU population. Clinicians may not have vaccinated infants perceived to be at risk for a vaccine-related adverse event until the infants were without apnea for a period of time. This bias, similar to the healthy vaccinee phenomenon,15,16 would result in a healthier preimmunization population, compared with a similar, unvaccinated, NICU population. Although we think that the postimmunization apnea we observed did not result exclusively from this bias, because there were 27 infants with symptoms of apnea (including 4 infants with severe apnea) before the first immunization, this study was unable to assess this confounder, which may be important because preimmunization data were collected for only 24 hours before vaccination. An additional study limitation is that apneic events that occurred between administration of the first and last vaccines in a given set were not captured. Although we assumed that many clinicians would wait for a period of time before completing a set of immunizations for an infant with temporally related severe apnea, it is possible that this study underestimated the true incidence of postimmunization benign and moderate apneic events for infants who received vaccines spread over a period of time. Furthermore, this study limited postimmunization analysis to the 48 hours after vaccination, because of the increasing proportion of infants being discharged from the hospital in the days after immunization. Finally, this study was based on data recorded by nurses, whose thresholds for labeling an event as “apnea” or “bradycardia” might vary, even with specific internal nursery protocols. Although it is true that some variation in accuracy is to be expected from such documentation, it is also true that neonatologists rely on these data when they perform their daily rounds, and basing analyses on such data is reasonable. Future advances in the understanding of apnea of prematurity may permit a more-accurate and more-nuanced reexamination of findings from this and other studies.
Previous studies suggested that postimmunization apnea is associated with administration of both whole-cell2,3,5,6,8 and acellular4,7 pertussis vaccines. Because of its retrospective design, the current study evaluated postimmunization apnea after both pertussis-containing and non–pertussis-containing vaccines; no difference in the occurrence of apnea was observed. This finding suggests that postimmunization apnea in susceptible premature infants may be related to a general inflammatory response, rather than the response to particular vaccine antigens. In support of this idea, Pourcyrous et al9 previously demonstrated a temporal relationship between vaccination of premature infants and increases in interleukin-6 and C-reactive protein levels. Future studies are needed to explore whether inflammatory changes play a role in the development of postimmunization apnea among premature infants.
The findings from this study reveal that the most important risk factor for developing postimmunization apnea is the presence of apnea within the previous 24 hours. It is not known whether apnea occurring >24 hours before immunization is a risk factor but, for infants without apnea during the 24 hours before vaccination, more severe illness at birth, younger age, and lower weight are important predictors of postimmunization apnea. The results from this study support a recommendation for monitoring susceptible infants for 48 hours after immunization in the NICU.
This study was supported by a Vaccine Safety Datalink contract with America's Health Insurance Plans, funded by the Centers for Disease Control and Prevention. Dr Klein received support from the Centers for Disease Control and Prevention through an America's Health Insurance Plans Vaccine Safety Fellowship. Drs Massolo and Escobar received support from the Permanente Medical Group and Kaiser Foundation Hospitals.
We are grateful to Bruce Fireman for valuable discussions and critical review of the manuscript and to John Hansen for assistance with the medical record review.
- Accepted August 9, 2007.
- Address correspondence to Nicola P. Klein, MD, PhD, Kaiser Permanente Vaccine Studies Center, 1 Kaiser Plaza, 16th Floor, Oakland, CA 94612. E-mail:
Financial Disclosure: Dr Klein reports receiving research support from GlaxoSmithKline, Sanofi Pasteur, and Merck & Co. Dr Black reports receiving research support from GlaxoSmithKline and Sanofi Pasteur.
The findings and conclusions in this presentation are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
What's Known on this Subject
There have been concerns that premature infants immunized while in the NICU have an increase in apnea after immunization. Studies note a variety of factors associated with postimmunization apnea, including among infants with preexisting cardiorespiratory events.
What This Study Adds
No studies have identified specific predictors of postimmunization apnea using multivariate analyses or have delineated the relative contributions of each predictor to development of postimmunization apnea, nor have they determined which individual preimmunization cardiorespiratory symptoms can predict postimmunization apnea.
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- ↵Slack MH, Schapira D. Severe apnoeas following immunisation in premature infants. Arch Dis Child Fetal Neonatal Ed.1999;81 (1):F67– F68
- ↵Pourcyrous M, Korones SB, Crouse D, Bada HS. Interleukin-6, C-reactive protein, and abnormal cardiorespiratory responses to immunization in premature infants. Pediatrics.1998;101 (3). Available at: www.pediatrics.org/cgi/content/full/101/3/e3
- ↵Zupancic JA, Richardson DK, Horbar JD, Carpenter JH, Lee SK, Escobar GJ. Revalidation of the Score for Neonatal Acute Physiology in the Vermont Oxford Network. Pediatrics.2007;119 (1). Available at: www.pediatrics.org/cgi/content/full/119/1/e156
- ↵Fine PE, Chen RT. Confounding in studies of adverse reactions to vaccines. Am J Epidemiol.1992;136 (2):121– 135
- ↵Virtanen M, Peltola H, Paunio M, Heinonen OP. Day-to-day reactogenicity and the healthy vaccinee effect of measles-mumps-rubella vaccination. Pediatrics.2000;106 (5):e62
- Copyright © 2008 by the American Academy of Pediatrics