Adverse Events After Routine Immunization of Extremely Low Birth Weight Infants

Abstract

Importance

Immunization of extremely low birth weight (ELBW) infants in the neonatal intensive care unit (NICU) is associated with adverse events including fever and apnea/bradycardia in the immediate post-immunization period. This presents a diagnostic dilemma for clinicians, leading to the potential for immunization delay and sepsis evaluations.

Objective

To compare the incidence of sepsis evaluations, need for increased respiratory support, intubation, seizures, and death among immunized ELBW infants in the 3 days pre- and post-immunization.

Design

Multicenter retrospective cohort study.

Setting

348 NICUs managed by the Pediatrix Medical Group.

Participants

13,926 ELBW infants ≤28 weeks gestation who were discharged between 2007 and 2012.

Exposure

At least one immunization between day of life 53 and 110.

Main Outcomes and Measures

Incidence of sepsis evaluations, need for increased respiratory support, intubation, seizures, and death.

Results

Most (91%) of the infants received 3 or more immunizations. The incidence of sepsis evaluations increased from 5.4/1000 patient days in the pre-immunization period to 19.3/1000 patient days post-immunization (adjusted rate ratio [ARR], 3.7; 95% CI, 3.2–4.4). The need for increased respiratory support increased from 6.6/1000 patient days in the pre-immunization period to 14.0/1000 patient days post-immunization (ARR, 2.1; 95% CI, 1.9–2.5), and intubation increased from 2.0/1000 patient days to 3.6/1000 patient days (ARR, 1.7; 95% CI, 1.3–2.2). The post-immunization incidence of adverse events was similar across immunization types, including combination vaccines when compared to single-dose vaccines. Infants who were 23–24 weeks gestation had a higher risk of sepsis evaluation and intubation post-immunization. A prior history of sepsis was associated with higher risk of sepsis evaluation post-immunization.

Conclusion

ELBW infants in the NICU had an increased incidence of sepsis evaluations as well as increased respiratory support and intubation after routine immunization. Our findings provide no evidence to suggest that clinicians should not use combination vaccines in ELBW infants. Further studies are needed to determine whether timing or spacing of immunization administrations confers risk for the developing adverse events and whether a prior history of sepsis confers risk for an altered immune response in ELBW infants.

Timely immunization of premature infants in the neonatal intensive care unit (NICU) is associated with improved immunization coverage throughout childhood.¹ However, the immunization of extremely low birth weight (ELBW; <1000 g birth weight) infants has been associated with adverse events including fever and adverse cardiorespiratory events such as apnea and bradycardia in the immediate post-immunization period.^2–4 These adverse events can mimic serious diseases in ELBW infants, including true sepsis, presenting a diagnostic dilemma for clinicians. Fever in ELBW infants after immunization can often lead to additional workup to rule out true sepsis, including collection of blood and urine cultures, and exposure to empiric antibiotic therapy. The risks of additional antibiotic use, exposing the infant to painful procedures and the withholding of enteral feedings, must be weighed against the risk of missing true sepsis in an ELBW infant.

Immunization delay has been reported in hospitalized premature infants.⁵ This may be related to clinicians waiting to immunize relatively well infants, concerns about adverse events, and misconceptions about the ability of an infant’s immune system to tolerate multiple immunizations.⁶ Better knowledge of the risk factors for and timing of adverse events after immunization in ELBW infants could lead to better monitoring, prevent unnecessary sepsis evaluations, and reduce immunization delay. To date, the majority of studies describing the incidence of adverse events following immunization in ELBW have been small, single-center studies. In this study, we use a large, multicenter NICU database to investigate the incidence of sepsis evaluations and adverse cardiorespiratory events after immunization in ELBW infants, describe these events by immunization type, and assess potential risk factors for adverse events.

METHODS

Data were obtained from an electronic medical record that prospectively captures information from daily progress notes generated by clinicians from 348 NICUs managed by the Pediatrix Medical Group. These NICUs represent both academic and private practice centers encompassing all levels of NICU care. Information on multiple aspects of care are entered to generate admission notes, daily progress notes, procedure notes, and discharge summaries. Collected data includes maternal history and demographics, medications, laboratory results, culture results, daily medications, respiratory support, and diagnoses. We defined coagulase-negative Staphylococcus (CoNS) sepsis as 2 positive blood cultures on the same day; probable CoNS sepsis as 2 positive cultures for CoNS within a 4-day period, 3 positive cultures for CoNS within a 7-day period, or 4 positive cultures for CoNS within a 10-day period; and possible sepsis as a culture positive for CoNS that did not meet criteria for definite or probable CoNS sepsis. We only included definite and probable CoNS sepsis in the analysis. We excluded sepsis episodes for organisms considered contaminants including non-speciated streptococci, Bacillus sp., Corynebacterium sp., diphtheroids sp., gram-positive rods (not including Listeria sp.), Lactobacillus sp., Micrococcus sp., Stomatococcus sp., and Bacteroides sp.

We identified all infants discharged between 2007 and 2012 with the following characteristics: (1) birth weight ≤1000 g, (2) gestational age at birth ≤28 weeks, and (3) received at least one immunization (diphtheria/tetanus/acellular pertussis [DTaP], inactivated polio virus [IPV], hepatitis B [HepB], haemophilus influenza B [HiB], pneumococcal conjugate 7-valent/13-valent [PCV], combination DTaP/IPV/HepB, combination DTaP/IPV/HiB, or combination HepB/HiB) between day of life 53 and 110. This period allowed us to capture the majority of immunizations administered at around 2 months (60 days) of life, the recommended age of scheduled immunizations excluding HepB. Combination products were treated as one immunization. Infants discharged during the 3-day observation window were excluded, unless the discharge was due to death.

The primary outcome measured was sepsis evaluation (blood culture obtained). Secondary outcomes were (1) need for increased respiratory support (a recorded daily change in respiratory support increased from either room air to non-invasive oxygen therapy [nasal cannula, continuous positive airway pressure, nasal intermittent positive pressure ventilation] or need for endotracheal intubation [room air or non-invasive therapy to a form of invasive mechanical ventilation—either conventional ventilation or high-frequency ventilation]), (2) need for endotracheal intubation (room air or non-invasive therapy to a form of invasive mechanical ventilation—either conventional ventilation or high-frequency ventilation), (3) seizures, and (4) death. The incidence of adverse events, expressed in events per 1000 patient days, was calculated in the pre- and post-immunization periods for each infant. Comparisons of the incidence of adverse events were made between two 3-day periods: the 3 days before immunization (pre-immunization) and the 3 days after immunization (post-immunization; i.e., day of immunization plus the following 2 days). For this main analysis, days that fell within both a pre-immunization and post-immunization period for different immunization administrations were classified as a post-immunization day only. We also examined the daily incidence, expressed in events per 1000 patient days, of each outcome measure from 30 days before to 30 days after the first immunization day. We used Poisson regression to compare the overall incidence of adverse events between the pre- and post-immunization periods for all immunizations. We further analyzed risk factors for post-immunization outcomes only, including infant gestational age at birth, small for gestational age status, history of sepsis, and postnatal age and postnatal weight at immunization in a multivariable Poisson regression. Prior history of sepsis was later subgrouped by history of gram-positive versus gram-negative sepsis for comparison. All variables in the above models were categorical except postnatal age and weight.

In the analysis of adverse events by immunization type, days in the pre-immunization period that were also post-immunization days for another type of immunization were excluded. The non-independence of the observations within the same infant was accounted for using generalized estimating equations. We performed a sensitivity analysis comparing how varying lengths of observation periods pre- and post-immunization affected the measured incidence of the effect measures. Standard descriptive statistics were used to describe the study cohort. All data analyses were conducted using SAS 9.3 (SAS Institute, Cary NC). The Duke University School of Medicine Institutional Review Board approved this study without the need for written informed consent as the data lacked patient identifiers.

RESULTS

We identified a total of 13,926 infants who received a total of 48,853 immunizations (Table 1); 91% of the infants received 3 or more immunizations. The median postnatal age at immunization was 64 days (interquartile range, 60–72). A history of sepsis prior to day 53 was observed in 2904 (21%) of the infants. During the pre/post-immunization periods, 5952/13,926 (42%) of the infants in this study received caffeine therapy.

Table 1.

Demographics

Characteristic	n = 13,926
Gestational age (weeks), No. (%)
23–24	3113 (22)
25–26	6818 (49)
27–28	3995 (29)
Birth weight (g), No. (%)
400–600	2019 (15)
601–800	5978 (43)
801–1000	5929 (42)
Small for gestational age, No. (%)	2486 (18)
Race/ethnicity, No. (%)
White	5699 (42)
Black	4328 (32)
Hispanic	2622 (20)
Other	782 (6)
Male, No. (%)	6831 (49)
Postnatal age at first immunization (days), median (IQR)	64 (60–72)
Weight at first immunization (g), median (IQR)	1988 (1735–2235)
Number of immunizations received, No. (%)
1	559 (4)
2	664 (5)
3	9260 (66)
4	1096 (8)
5+	2347 (17)
History of sepsis prior to day 53, No. (%)	2904 (21)

Abbreviation: IQR, interquartile range.

The incidence of sepsis evaluation increased from 5.4/1000 patient days in the pre-immunization period to 19.3/1000 patient days in the post-immunization period (adjusted rate ratio [ARR], 3.7; 95% confidence interval [CI], 3.2–4.4) (Table 2). Of the 235 sepsis evaluations obtained in the pre-immunization period, 5 (2.1%) yielded a positive blood culture, compared to 39/1035 (3.8%) obtained after immunization. Analysis of the secondary outcomes showed an increased incidence of respiratory support and intubations in the post-immunization period as compared to the pre-immunization period (Table 2). The incidence of seizure was 0.2/1000 infant days in the pre-immunization period and 0.1/1000 in the post-immunization period, but this represented only 9 and 3 total events in each period, respectively. There were 5 deaths in the post-immunization period.

Table 2.

Incidence of Events Pre- and Post-immunization (/1000 Patient Days)

Event	Pre-immunization	Post-immunization	Rate ratio (95% CI)	Adjusted rate ratioa (95% CI)
Sepsis evaluation	5.4	19.3	3.5 (3.1–4.1)	3.7 (3.2–4.4)
Increased respiratory support	6.6	14.0	2.1 (1.9–2.4)	2.1 (1.9–2.5)
Intubation	2.0	3.6	1.8 (1.4–2.3)	1.7 (1.3–2.2)
Seizure	0.2	0.1	0.3 (0.1–1.0)	0.3 (0.1–1.1)

Abbreviation: CI, confidence interval.

^aIncidence rate ratio adjusted for gestational age at birth, small-for-gestational-age status, history of sepsis, postnatal age, and postnatal weight.

Three of the 5 infants who died in the 3 days post-immunization had a diagnosis associated with death available in the dataset; one infant had a bowel perforation, one infant had necrotizing enterocolitis and presumed sepsis, and one infant had pneumonia and respiratory failure. The incidence of sepsis evaluations, increased respiratory support, and intubations measured by day, from 30 days before immunization to 30 days after immunization, demonstrated a steady decrease until 5–7 days before immunization, followed by a sharp decrease leading up to the day of immunization (Figure 1). After immunization, there was an increase in the daily incidence between day 0 and day 2 post-immunization, most notably for sepsis evaluations (Figure 1). When analyzing adverse events grouped by type of immunization administered, we found pneumococcal conjugate to be the most commonly administered immunization (Table 3). The incidence of adverse events was similar across all immunization types, with the primary outcome (sepsis evaluation) again demonstrating a higher post-immunization incidence across all types of immunizations (Table 3).

Figure 1.

Daily Incidence of Events Measured for (A) Sepsis Evaluation, (B) Increased Respiratory Support, and (C) Intubation in the 30-Day Period Before and After First Immunization (Day 0).

Table 3.

Post-immunization Incidence (/1000 Patient Days) of Events and Adjusted Rate Ratios of Events by Immunization Type

	n	Sepsis evaluation		Increased respiratory support		Intubated
		Incidence	ARR (95% CI)	Incidence	ARR (95% CI)	Incidence	ARR (95% CI)
HepB/HiB	560	22.7	6.0 (2.5–14.2)	15.6	1.4 (0.8–2.6)	4.8	1.8 (0.6–5.3)
DTaP/IPV/HiB	1236	17.6	4.0 (2.3–6.9)	12.7	2.3 (1.3–4.0)	3.5	2.6 (0.8–7.9)
IPV	3278	15.5	3.0 (2.1–4.2)	13.9	2.1 (1.5–2.9)	4.3	2.5 (1.3–4.9)
DTaP	3391	13.9	3.2 (2.2–4.5)	12.3	1.9 (1.4–2.6)	3.6	2.5 (1.3–4.8)
HepB	4660	12.8	3.1 (2.3–4.1)	11.9	2.1 (1.6–2.8)	2.9	1.5 (0.9–2.6)
DTaP/IPV/HepB	8558	24.6	4.3 (3.6–5.3)	16.4	2.6 (2.1–3.1)	3.6	1.8 (1.3–2.6)
HiB	11,166	21.6	4.0 (3.3–4.8)	14.2	2.1 (1.8–2.5)	3.3	1.6 (1.2–2.7)
PCV	13,004	22.0	4.4 (3.7–5.3)	14.7	2.2 (1.9–2.7)	3.6	2.0 (1.5–2.3)

Abbreviations: ARR, adjusted rate ratio; CI, confidence interval; DTaP, diphtheria/tetanus/acellular pertussis; HepB, hepatitis B; HiB, haemophilus influenza B; IPV, inactivated polio; PCV, pneumococcal conjugate vaccine 7-valent/13-valent.

Incidence rate ratio adjusted for postnatal age and postnatal weight.

In the post-immunization period, infants 23–24 weeks gestation demonstrated an increased incidence of sepsis evaluation (ARR, 1.2; 95% CI, 1.0–1.3) compared to older infants (27–28 weeks gestation). In addition, infants in the 23–24 week group had a higher incidence of intubation (ARR, 1.5; 95% CI, 1.2–2.0) compared to older infants (27–28 weeks gestation) in the post-immunization period. A prior history of sepsis was associated with an increased rate for sepsis evaluation (ARR, 1.4; 95% CI, 1.2–1.5) but not for intubation (ARR, 1.3; 95% CI, 1.0–1.9) or increased respiratory support (ARR, 1.0; 95% CI, 0.8–1.2). For infants with a prior history of sepsis, a history of gram-positive sepsis prior to day 53 was associated with increased risk of sepsis evaluation post-immunization (ARR, 1.3; 95% CI, 1.1–1.5). A history of gram-negative sepsis was not significantly associated with an increased risk of sepsis evaluation post-immunization (ARR, 1.2; 95% CI, 0.9–1.5). Postnatal age at immunization, small-for-gestational-age status, and postnatal weight at immunization were not significantly associated with any of the outcomes.

DISCUSSION

In this large, multicenter cohort of ELBW infants, there was a significant increase in adverse events in the post-immunization period including sepsis evaluations, need for increased respiratory support, and intubation. Despite the large number of sepsis evaluations after immunization, few infants showed evidence of true sepsis (bacteremia). The pneumococcal conjugate vaccine represented the largest number of immunization administrations, likely because for the other routine 2-month immunizations, the total number of administrations is split between those infants who received single-dose DTaP, HepB, HiB or IPV vaccines and those who were administered combination products. In our cohort, all immunization types had similar ARRs comparing the pre- and post-immunization periods. There was no difference in the incidence of adverse events in combination vaccines versus single-dose vaccines. These data provide no evidence to suggest that clinicians should not use combination vaccines in ELBW infants. Lower gestational age was associated with increased risk of sepsis evaluations and need for intubation in the post-immunization period. Postnatal age and postnatal weight at time of immunization were not related to risk of adverse events.

We observed a decrease in the incidence of several of the adverse events leading up to immunization day, especially in the several days before immunization. This is possibly explained by the so-called “healthy vaccinated” effect, by which clinicians wait until infants are more stable to immunize, thus reducing the observed incidence of pre-immunization adverse events and biasing the incidence rate ratios upward. Incidence rates of adverse events on the day of immunization in particular are likely to be artificially low because clinicians are unlikely to immunize infants on a day that they have had clinical instability. To address this potential bias, we performed several sensitivity analyses in which we varied the length of the pre- and post-immunization periods. Results from these analyses were similar to the primary results. Waiting for subjective markers of clinical stability might be a leading factor in immunization delay in ELBW infants. Although we did not assess for immunization delay in this study, previous studies have shown that up to one-fifth of infants who were eligible for immunization were not vaccinated during that time frame, again pointing to the possibility of the healthy-vaccinated effect.² Immunization delay burdens an already fragile patient population with the increased morbidity and mortality of vaccine preventable diseases through the first year of life.^1,7,8

Fever is a well-known adverse event after immunization. A recent retrospective cohort study of 490 infants who were all inpatients in the NICU for >53 days observed increased rates of fever after immunization, but found no increase in the rate of sepsis evaluations.² Infants who had acute cardiorespiratory events in the immediate post-immunization period in combination with a febrile episode were more likely to undergo an evaluation to rule out sepsis—characterized as obtaining a blood culture and starting empiric antibiotic therapy—compared with those infants presenting with fever alone. In addition, there is some evidence that infants who receive all 3 routine 2-month immunizations at once, rather than in 2 or 3 administrations, have a higher risk of post-immunization fever.⁹ The relationship between immunization and subsequent response to infection in ELBW infants is potentially significant. Premature infants have an altered immune response to immunization.¹⁰ In one of the first studies in neonates that examined the effects of sepsis on subsequent production of antibodies following immunization, very low birth weight (<1500 g) infants with a history of bacteremia showed an alteration of immune response to specific serotypes of the pneumococcal vaccine.¹¹ Others have shown that prior history of sepsis in ELBW infants was actually protective against future episodes of late onset sepsis,¹² with one preclinical study suggesting a more robust innate immune response in immature mice.¹³ An important area of future research is to determine whether a causative relationship exists between sepsis in the neonatal period and subsequent alterations in the immune response to immunization in an already medically fragile population.

Apnea and bradycardia are also commonly observed adverse events in the post-immunization period.¹⁴ DTaP-containing vaccines have been of particular concern, as the whole-cell pertussis vaccine has been cited as causing apnea and bradycardia in 7% of preterm infants,¹⁵ and more recently, apnea and bradycardia have been observed after immunization with the acellular pertussis vaccine component.¹⁶ Several studies have found an increased risk of events leading to new requirements for respiratory support, especially in ELBW infants with significant lung disease, a history of sepsis during hospitalization,¹⁷ and pre-immunization apnea,¹⁸ though others showed no increased incidence in cardiorespiratory events after immunization among hospitalized infants in the NICU.^19,20 These studies used much smaller cohorts than the current study. One randomized controlled trial examining adverse events after DTaP reported no difference in the incidence of adverse cardiorespiratory events, only one immunization.¹⁸ When cardiorespiratory events do occur, they are more likely to occur in populations similar to this study group of ELBW infants and those with more severe illness at birth.²¹ Older infants with a diagnosis of chronic lung disease who were still hospitalized in the NICU at time of immunization also had a higher incidence of adverse events.²² Regarding the use of combination vaccines, a 2007 study of the hexavalent DTaP/IPV/HiB/HepB vaccine showed apnea/bradycardia occurring in 11% of study infants,²² demonstrating slightly higher rates of adverse events compared to single-dose vaccines. More recently, a retrospective study in 2008 of 64 infants who received the combination DTaP/IPV/HiB vaccine and pneumococcal-7 vaccine showed that 25% of study infants showed clinically significant apnea and bradycardia.³ However, we do not have current information about the use of single-dose versus combination vaccines in U.S. NICUs.

Although our study captured a large cohort of infants, we cannot be sure that clinical correlates documented in the electronic medical record such as collection of a blood culture or an increase in respiratory support truly reflect the occurrence of fever/sepsis evaluations or apnea and bradycardia, respectively. All deaths occurred after immunization, as death before immunization would have excluded an infant from the study. Therefore, a true comparison pre- and post-immunization cannot be made here. There also exists a potential bias in the recording of events in the clinical record, in that physicians may be more likely to document adverse events that are occurring in close proximity to the administration of immunizations. This potential for bias is reduced in the most serious adverse events (intubation, seizure), as we expect these serious events to be more consistently recorded, as opposed to apneic or bradycardic events in an otherwise stable infant. Although previous researchers have chosen to evaluate the presence of fever in the post-immunization period, we felt that the collection of a blood culture was more likely to be specific for the occurrence of a sepsis evaluation, as this was a laboratory test captured in the electronic record rather than a diagnosis that had to be observed and subsequently entered by a clinician. We did not investigate whether specific timing or spacing of immunizations (such as all given in 1 day versus spaced over 72 hours) during the observation period contributed to an increased incidence of the study outcomes. Finally, a retrospective observational study such as this can only provide evidence of correlation rather than causation.

CONCLUSIONS

This study demonstrates an increase in adverse events after the routine immunization of ELBW infants in the NICU, specifically sepsis evaluations, need for increased respiratory support, and intubation. The incidence of these adverse events decreases sharply just prior to the first immunization day. Lower gestational age (23–24 weeks) was associated with a higher risk of sepsis evaluation and intubation post-immunization. A prior history of sepsis was associated with a higher risk of sepsis evaluations post-immunization. Further studies are needed to determine whether the order and timing of specific immunizations affects the incidence of adverse events in the post-immunization period and whether a prior history of sepsis confers risk for an altered immune response in ELBW infants.