Professional Documents
Culture Documents
Original Investigation
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 before
and after immunization.
EXPOSURES At least one immunization between the ages of 53 and 110 days.
MAIN OUTCOMES AND MEASURES Incidence of sepsis evaluations, need for increased
respiratory support, intubation, seizures, and death.
RESULTS Most of the 13 926 infants (91.2%) received 3 or more immunizations. The incidence
of sepsis evaluations increased from 5.4 per 1000 patient-days in the preimmunization
period to 19.3 per 1000 patient-days in the postimmunization period (adjusted rate ratio
[ARR], 3.7; 95% CI, 3.2-4.4). The need for increased respiratory support increased from 6.6
per 1000 patient-days in the preimmunization period to 14.0 per 1000 patient-days in the
postimmunization period (ARR, 2.1; 95% CI, 1.9-2.5), and intubation increased from 2.0 per
1000 patient-days to 3.6 per 1000 patient-days (ARR, 1.7; 95% CI, 1.3-2.2). The
postimmunization incidence of adverse events was similar across immunization types,
including combination vaccines when compared with single-dose vaccines. Infants who were
born at 23 to 24 weeks’ gestation had a higher risk of sepsis evaluation and intubation after
immunization. A prior history of sepsis was associated with higher risk of sepsis evaluation
after immunization.
CONCLUSIONS AND RELEVANCE All ELBW infants in the NICU had an increased incidence of
Author Affiliations: Department of
sepsis evaluations and increased respiratory support and intubation after routine
Pediatrics, Duke University School of
immunization. Our findings provide no evidence to suggest that physicians should not use Medicine, Durham, North Carolina
combination vaccines in ELBW infants. Further studies are needed to determine whether (DeMeo, Hornik, Smith); Duke Clinical
timing or spacing of immunization administrations confers risk for the developing adverse Research Institute, Duke University
School of Medicine, Durham, North
events and whether a prior history of sepsis confers risk for an altered immune response in
Carolina (Raman, Hornik, Smith);
ELBW infants. Greenville Hospital System,
Greenville, South Carolina (Wilson);
Pediatrix-Obstetrix Center for
Research and Education, Sunrise,
Florida (Clark).
Corresponding Author: P. Brian
Smith, MD, MPH, MHS, Duke Clinical
Research Institute, Duke University
School of Medicine, PO Box 17969,
JAMA Pediatr. 2015;169(8):740-745. doi:10.1001/jamapediatrics.2015.0418 Durham, NC 27715 (brian.smith
Published online June 1, 2015. @duke.edu).
T
imely immunization of premature infants in the neona-
tal intensive care unit (NICU) is associated with im- At a Glance
proved immunization coverage throughout childhood.1
• This study investigated the incidence of adverse events after
However, the immunization of extremely low-birth-weight routine immunization in extremely low-birth-weight (ELBW)
(ELBW; birth weight ≤1000 g) infants has been associated with infants.
adverse events, including fever and adverse cardiorespiratory • We analyzed a large multicenter cohort of 13 926 ELBW infants
events, such as apnea and bradycardia, in the immediate postim- born at 28 weeks’ gestation or less.
munization period.2-4 These adverse events can mimic serious • Infants had a higher incidence of sepsis evaluations (adjusted
rate ratio [ARR], 3.7; 95% CI, 3.2-4.4), need for increased
diseases in ELBW infants, including true sepsis, presenting a di-
respiratory support (ARR, 2.1; 95% CI, 1.9-2.5), and intubation
agnostic dilemma for physicians. Fever in ELBW infants after im- (ARR, 1.7; 95% CI, 1.3-2.2) in the 3 days after immunization
munization can often lead to additional workup to rule out true relative to the 3 days before immunization.
sepsis, including collection of blood and urine cultures, and ex- • The incidence of adverse events was similar across immunization
posure to empirical antibiotic therapy. The risks of additional an- types, including combination vaccines when compared with
tibiotic use, exposing the infant to painful procedures, and the single-dose vaccines.
• Lower gestational age (23-24 weeks) and a prior history of sepsis
withholding of enteral feedings must be weighed against the risk
were associated with a higher rate of sepsis evaluation and need
of missing true sepsis in an ELBW infant.
for intubation.
Immunization delay has been reported in hospitalized pre-
mature infants.5 This delay may be related to physicians wait-
ing to immunize relatively well infants, concerns about ad- We identified all infants discharged from January 1, 2007,
verse events, and misconceptions about the ability of an infant’s through December 31, 2012, with the following characteristics: (1)
immune system to tolerate multiple immunizations.6 Better birth weight of 1000 g or less, (2) gestational age at birth of 28
knowledge of the risk factors for and timing of adverse events weeks or less, and (3) receipt of at least one immunization (diph-
after immunization in ELBW infants could lead to better moni- theria, tetanus toxoids, and acellular pertussis [DTaP]; inactivated
toring, prevent unnecessary sepsis evaluations, and reduce im- polio virus [IPV]; hepatitis B [HepB]; Haemophilus influenzae type
munization delay. To date, most studies describing the inci- B [HiB]; 7-valent and 13-valent pneumococcal conjugate; combi-
dence of adverse events after immunization in ELBW have been nation DTaP, IPV, and HepB; combination DTaP, IPV, and HiB; or
small, single-center studies. In this study, we use a large, mul- combination HepB and HiB) between the ages of 53 and 110 days.
ticenter NICU database to investigate the incidence of sepsis This period allowed us to capture most immunizations admin-
evaluations and adverse cardiorespiratory events after immu- istered at approximately 2 months (60 days) of age, the recom-
nization in ELBW infants, describe these events by immuni- mended age of scheduled immunizations, excluding the HepB
zation type, and assess potential risk factors for adverse events. vaccine. Combination products were treated as one immuniza-
tion. Infants discharged during the 3-day observation window
were excluded unless the discharge was due to death. The Duke
University School of Medicine Institutional Review Board ap-
Methods proved this study without the need for written informed consent
Data were obtained from an electronic medical record that pro- because the data lacked patient identifiers.
spectively captures information from daily progress notes gen- The primary outcome measured was sepsis evaluation (blood
erated by physicians from 348 NICUs managed by the Pediatrix culture obtained). Secondary outcomes were (1) the need for in-
Medical Group. These NICUs represent academic and private creased respiratory support (a recorded daily change in respira-
practice centers, encompassing all levels of NICU care. Informa- tory support increased from room air to noninvasive oxygen
tion on multiple aspects of care is entered to generate admis- therapy [nasal cannula, continuous positive airway pressure, and
sion notes, daily progress notes, procedure notes, and dis- nasal intermittent positive pressure ventilation] or the need for
charge summaries. Collected data include maternal history and endotracheal intubation [room air or noninvasive therapy to a
demographic characteristics, medications, laboratory results, form of invasive mechanical ventilation—conventional ventila-
culture results, daily medications, respiratory support, and di- tion or high-frequency ventilation]), (2) the need for endotracheal
agnoses. We defined coagulase-negative Staphylococcus (CoNS) intubation (room air or noninvasive therapy to a form of invasive
sepsis as 2 positive blood culture results on the same day; prob- mechanical ventilation—conventional ventilation or high-
able CoNS sepsis as 2 positive cultures for CoNS within a 4-day frequency ventilation), (3) seizures, and (4) death. The incidence
period, 3 positive cultures for CoNS within a 7-day period, or 4 of adverse events, expressed in events per 1000 patient-days, was
positive cultures for CoNS within a 10-day period; and possible calculated in the preimmunization and postimmunization peri-
sepsis as a culture positive for CoNS that did not meet criteria for ods for each infant. Comparisons of the incidence of adverse
definite or probable CoNS sepsis. We only included definite and events were made between two 3-day periods: the 3 days before
probable CoNS sepsis in the analysis. We excluded sepsis epi- immunization (preimmunization) and the 3 days after immuni-
sodes for organisms considered contaminants, including non- zation (postimmunization; ie, day of immunization plus the fol-
speciated streptococci, Bacillus species, Corynebacterium spe- lowing 2 days). For this main analysis, days that fell within both
cies, Diphtheroids species, gram-positive rods (not including a preimmunization and postimmunization period for different
Listeria species), Lactobacillus species, Micrococcus species, Sto- immunization administrations were classified as a postimmuni-
matococcus species, and Bacteroides species. zation day only. We also examined the daily incidence, expressed
jamapediatrics.com (Reprinted) JAMA Pediatrics August 2015 Volume 169, Number 8 741
742 JAMA Pediatrics August 2015 Volume 169, Number 8 (Reprinted) jamapediatrics.com
Incidence
tus, and postnatal weight at immunization were not significantly 0.3
associated with any of the outcomes.
0.2
Discussion 0.1
jamapediatrics.com (Reprinted) JAMA Pediatrics August 2015 Volume 169, Number 8 743
Table 3. Postimmunization Incidence per 1000 Patient-days of Events and ARRs of Events by Immunization Type
Abbreviations: ARR, adjusted rate ratio; DTaP, diphtheria, tetanus toxoids, and acellular pertussis; HepB, hepatitis B; HiB, Haemophilus influenzae type B;
IPV, inactivated polio virus; PCV, 7-valent and 13-valent pneumococcal conjugate vaccine.
a
The ARR was adjusted for postnatal age and postnatal weight.
the increased morbidity and mortality of vaccine-preventable nization among hospitalized infants in the NICU. These studies
diseases through the first year of life.1,7,8 used much smaller cohorts than the current study. One random-
Fever is a well-known adverse event after immunization. ized clinical trial18 examining adverse events after DTaP vaccina-
A previous retrospective cohort study2 of 490 infants who were tion reported no difference in the incidence of adverse cardiores-
allinpatientsintheNICUformorethan53daysobservedincreased piratory events after only one immunization. When cardiorespira-
rates of fever after immunization but found no increase in the rate tory events occur, they are more likely to occur in populations
of sepsis evaluations. Infants who had acute cardiorespiratory similar to this study group of ELBW infants and those with more
events in the immediate postimmunization period in combina- severe illness at birth.21 Older infants with a diagnosis of chronic
tion with a febrile episode were more likely to undergo an evalu- lung disease who were still hospitalized in the NICU at the time
ation to rule out sepsis—characterized as obtaining a blood cul- of immunization also had a higher incidence of adverse events.22
ture and starting empirical antibiotic therapy—compared with Regarding the use of combination vaccines, a 2007 study22 of the
those infants presenting with fever alone. In addition, there is hexavalent DTaP, IPV, HiB, and HepB vaccine found that apnea
some evidence that infants who receive all 3 routine 2-month im- and/or bradycardia occurred in 11% of study infants, demonstrat-
munizations at once rather than in 2 or 3 administrations have a ing slightly higher rates of adverse events compared with single-
higher risk of postimmunization fever.9 The association between dose vaccines. More recently, a retrospective study3 in 2008 of
immunization and subsequent response to infection in ELBW in- 64 infants who received the combination DTaP, IPV, and HiB vac-
fants is potentially significant. Premature infants have an altered cine and the 7-valent pneumococcal conjugate vaccine found that
immune response to immunization.10 In one of the first studies11 25% of study infants had clinically significant apnea and brady-
in neonates that examined the effects of sepsis on subsequent pro- cardia. However, we do not have current information about the
duction of antibodies after immunization, very low-birth-weight use of single-dose vs combination vaccines in US NICUs.
(<1500 g) infants with a history of bacteremia had an alteration Although our study captured a large cohort of infants, we can-
of immune response to specific serotypes of the pneumococcal not be sure that clinical correlates documented in the electronic
vaccine. Others studies12,13 have found that prior history of sep- medical record, such as collection of a blood culture or an increase
sis in ELBW infants was actually protective against future episodes in respiratory support, truly reflect the occurrence of fever or sep-
of late-onset sepsis, with one preclinical study13 suggesting a more sis evaluations or apnea and bradycardia, respectively. All deaths
robust innate immune response in immature mice. An important occurred after immunization because death before immuniza-
area of future research is to determine whether a causative rela- tion would have excluded an infant from the study. Therefore, a
tionship exists between sepsis in the neonatal period and subse- true comparison before and after immunization cannot be made
quent alterations in the immune response to immunization in an here. A potential bias also exists in the recording of events in the
already medically fragile population. clinical record in that physicians may be more likely to document
Apnea and bradycardia are also commonly observed adverse adverse events that are occurring in close proximity to the admin-
events in the postimmunization period.14 The DTaP-containing istration of immunizations. This potential for bias is reduced in
vaccines have been of particular concern because the whole-cell the most serious adverse events (intubation and seizure) because
pertussis vaccine has been cited as causing apnea and bradycar- we expect these serious events to be more consistently recorded,
dia in 7% of preterm infants,15 and more recently, apnea and bra- as opposed to apneic or bradycardic events in an otherwise stable
dycardia have been observed after immunization with the acel- infant. Although previous researchers have chosen to evaluate
lular pertussis vaccine component.16 Several studies17,18 have the presence of fever in the postimmunization period, we believed
found an increased risk of events leading to new requirements that blood culture was more likely to be specific for the occurrence
for respiratory support, especially in ELBW infants with signifi- of a sepsis evaluation because this was a laboratory test captured
cant lung disease, a history of sepsis during hospitalization,17 and in the electronic record rather than a diagnosis that had to be ob-
preimmunization apnea,18 although other studies19,20 have found served and subsequently entered by a physician. We did not in-
no increased incidence in cardiorespiratory events after immu- vestigate whether specific timing or spacing of immunizations
744 JAMA Pediatrics August 2015 Volume 169, Number 8 (Reprinted) jamapediatrics.com
(such as all given in 1 day vs spaced during 72 hours) during the sepsis evaluations, need for increased respiratory support, and
observation period contributed to an increased incidence of the intubation. The incidence of these adverse events decreased
study outcomes. Finally, a retrospective observational study such sharply just before the first immunization day. Younger ges-
as this can only provide evidence of correlation rather than cau- tational age (23-24 weeks) was associated with a higher risk of
sation. sepsis evaluation and intubation after immunization. A prior
history of sepsis was associated with a higher risk of sepsis
evaluations after immunization. Further studies are needed
to determine whether the order and timing of specific immu-
Conclusions nizations affect the incidence of adverse events in the postim-
This study found an increase in adverse events after the rou- munization period and whether a prior history of sepsis con-
tine immunization of ELBW infants in the NICU, specifically fers risk for an altered immune response in ELBW infants.
ARTICLE INFORMATION schedule improves the long-term vaccinal coverage and Human Development Neonatal Research
Accepted for Publication: February 15, 2015. of ex-preterm children. Vaccine. 2011;29(3):382-386. Network. Early sepsis does not increase the risk of
2. Navar-Boggan AM, Halsey NA, Golden WC, late sepsis in very low birth weight neonates.
Published Online: June 1, 2015. J Pediatr. 2013;162(5):942-948.e1.
doi:10.1001/jamapediatrics.2015.0418. Escobar GJ, Massolo M, Klein NP. Risk of fever and
sepsis evaluations after routine immunizations in 13. Wynn JL, Scumpia PO, Winfield RD, et al.
Author Contributions: Drs DeMeo and Smith had the neonatal intensive care unit. J Perinatol. 2010; Defective innate immunity predisposes murine
full access to all the data in the study and take 30(9):604-609. neonates to poor sepsis outcome but is reversed by
responsibility for the integrity of the data and the TLR agonists. Blood. 2008;112(5):1750-1758.
accuracy of the data analysis. 3. Flatz-Jequier A, Posfay-Barbe KM, Pfister RE,
Study concept and design: DeMeo, Hornik, Clark, Siegrist CA. Recurrence of cardiorespiratory events 14. Sánchez PJ, Laptook AR, Fisher L, Sumner J,
Smith. following repeat DTaP-based combined Risser RC, Perlman JM. Apnea after immunization
Acquisition, analysis, or interpretation of data: immunization in very low birth weight premature of preterm infants. J Pediatr. 1997;130(5):746-751.
DeMeo, Raman, Wilson, Clark, Smith. infants. J Pediatr. 2008;153(3):429-431. 15. Botham SJ, Isaacs D, Henderson-Smart DJ.
Drafting of the manuscript: DeMeo. 4. Anderson J, Noori K, Morris SA. Apnoea after the Incidence of apnoea and bradycardia in preterm
Critical revision of the manuscript for important 2-month immunisation in extremely preterm infants following DTPw and Hib immunization:
intellectual content: Raman, Hornik, Wilson, Clark, infants: what happens with the 4-month a prospective study. J Paediatr Child Health. 1997;33
Smith. immunisation? J Paediatr Child Health. 2013;49(3): (5):418-421.
Statistical analysis: Raman, Hornik, Smith. E217-E220. 16. Schulzke S, Heininger U, Lücking-Famira M,
Obtained funding: Smith. 5. Gad A, Shah S. Special immunization Fahnenstich H. Apnoea and bradycardia in preterm
Administrative, technical, or material support: considerations of the preterm infant. J Pediatr infants following immunisation with pentavalent or
Wilson, Clark. Health Care. 2007;21(6):385-391. hexavalent vaccines. Eur J Pediatr. 2005;164(7):
Study supervision: Clark. 432-435.
6. Offit PA, Quarles J, Gerber MA, et al. Addressing
Conflict of Interest Disclosures: Dr Smith reported parents’ concerns: do multiple vaccines overwhelm 17. Hacking DF, Davis PG, Wong E, Wheeler K,
receiving consulting fees from industry for neonatal or weaken the infant’s immune system? Pediatrics. McVernon J. Frequency of respiratory deterioration
and pediatric drug development (https://www.dcri 2002;109(1):124-129. after immunisation in preterm infants. J Paediatr
.org/about-us/conflict-of-interest/). No other Child Health. 2010;46(12):742-748.
disclosures were reported. 7. Langkamp DLH-WS, Hoshaw-Woodard S, Boye
ME, Lemeshow S. Delays in receipt of 18. Carbone T, McEntire B, Kissin D, et al. Absence
Funding/Support: This study was supported in immunizations in low-birth-weight children: of an increase in cardiorespiratory events after
part by grant 1R18AE000028-01 from the US a nationally representative sample. Arch Pediatr diphtheria-tetanus-acellular pertussis immunization
Department of Health and Human Services Adolesc Med. 2001;155(2):167-172. in preterm infants: a randomized, multicenter
(statistical support), award UL1TR001117 from the study. Pediatrics. 2008;121(5):e1085-e1090.
National Center for Advancing Translational 8. Davis RL, Rubanowice D, Shinefield HR, et al;
Sciences of the National Institutes of Health Centers for Disease Control and Prevention Vaccine 19. Furck AK, Richter JW, Kattner E. Very low birth
(research support), and grants Safety Datalink Group. Immunization levels among weight infants have only few adverse events after
HHSN267200700051C, HHSN275201000003I, premature and low-birth-weight infants and risk timely immunization. J Perinatol. 2010;30(2):118-121.
and UL1TR001117 from the National Institutes of factors for delayed up-to-date immunization status. 20. Klein NP, Massolo ML, Greene J, Dekker CL,
Health and the National Center for Advancing JAMA. 1999;282(6):547-553. Black S, Escobar GJ; Vaccine Safety Datalink. Risk
Translational Sciences of the National Institutes of 9. Ellison VJ, Davis PG, Doyle LW. Adverse factors for developing apnea after immunization in
Health (salary support) (Dr Smith). reactions to immunization with newer vaccines in the neonatal intensive care unit. Pediatrics. 2008;
Role of the Funder/Sponsor: The funding sources the very preterm infant. J Paediatr Child Health. 121(3):463-469.
had no role in the design and conduct of the study; 2005;41(8):441-443. 21. Clifford V, Crawford NW, Royle J, et al.
collection, management, analysis, and 10. D’Angio CT. Active immunization of premature Recurrent apnoea post immunisation: Informing
interpretation of the data; preparation, review, or and low birth-weight infants: a review of re-immunisation policy. Vaccine. 2011;29(34):5681-
approval of the manuscript; and the decision to immunogenicity, efficacy, and tolerability. Paediatr 5687.
submit the manuscript for publication. Drugs. 2007;9(1):17-32. 22. Faldella G, Galletti S, Corvaglia L, Ancora G,
Disclaimer: The content of this article is solely the 11. Wynn JL, Li L, Cotten CM, et al. Blood stream Alessandroni R. Safety of DTaP-IPV-HIb-HBV
responsibility of the authors and does not infection is associated with altered heptavalent hexavalent vaccine in very premature infants. Vaccine.
necessarily represent the official views of the pneumococcal conjugate vaccine immune 2007;25(6):1036-1042.
National Institutes of Health. responses in very low birth weight infants. J Perinatol.
2013;33(8):613-618.
REFERENCES 12. Wynn JL, Hansen NI, Das A, et al; Eunice
1. Denizot S, Fleury J, Caillaux G, Rouger V, Rozé JC, Kennedy Shriver National Institute of Child Health
Gras-Le Guen C. Hospital initiation of a vaccinal
jamapediatrics.com (Reprinted) JAMA Pediatrics August 2015 Volume 169, Number 8 745