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Prophylactic Paracetamol After Meningococcal B Vaccination Reduces Postvaccination Fever and Septic Screens in Hospitalized Preterm Infants

Dubus, Magali MBBS, MSc*; Ladhani, Shamez PhD; Vasu, Vimal MD(Res), LLM*

Author Information
The Pediatric Infectious Disease Journal: January 2020 - Volume 39 - Issue 1 - p 78-80
doi: 10.1097/INF.0000000000002507


Neisseria meningitidis remains a major cause of morbidity and mortality in children. Six serogroups (A, B, C, W, X and Y) are responsible for nearly all invasive infections worldwide, although serogroup B is responsible for nearly all childhood cases in the United Kingdom and across Europe.1 Unlike serogroups A, C, W and Y for which highly effective polysaccharide-conjugate vaccines are available, a similar vaccine for Meningococcal B has been challenging because its polysaccharide capsule is structurally similar to human fetal neural cells and, therefore, poorly immunogenic with a potential to induce autoantibodies.2

In September 2015, a novel, multicomponent, recombinant protein-based vaccine against Meningococcal B (4CMenB; Bexsero, GlaxoSmithKline, Rixensart, Belgium) was introduced into the UK infant immunization schedule. The vaccine is highly immunogenic and aims to protect against 73%–88% of all Meningococcal B strains causing invasive disease in England and Wales.3 The vaccine was introduced at a reduced 2-dose infant priming schedule at 8 and 16 weeks alongside the routine vaccinations, followed by a booster at 12 months. The vaccine has been shown to be safe4 and effective in the prevention of Meningococcal B disease.3

However, 4CMenB is associated with increased rates of fever and other vaccine-associated reactions during the first 24–72 hours after vaccination, especially when coadministered with routine infant immunizations.4 Prophylactic paracetamol, with the first dose given just before or at the time of vaccination, followed by 2 additional doses 4–6 hours apart, has been shown to reduce the rates of postvaccination fever and other related vaccine reactions without altering the immune responses to any of the vaccine antigens.5 Consequently, infants in England were recommended to receive prophylactic paracetamol when attending their 8- and 16-week immunization visits.

In the United Kingdom, preterm infants are vaccinated at their chronologic age, meaning they are often still resident on neonatal units when their first vaccines are due. When 4CMenB was introduced, prophylactic paracetamol was also recommended for preterm infants receiving 4CMenB with their routine vaccinations even although little was known about the potential reactogenicity of the vaccine or the effect of prophylactic paracetamol in this vulnerable group. As with any medication, paracetamol administration may be associated with potential risks (eg, drug errors and toxicity).6 Because preterm infants in the neonatal unit have close observation by experienced staff, our local neonatal unit policy initially restricted the use of paracetamol to infants who were febrile or experiencing discomfort postvaccination. The aim of this study was to assess:

  • i. the rates of fever and predefined vaccine-related adverse events in preterm infants before and after 4CMenB were introduced into the national immunization schedule.
  • ii. the impact of a change in neonatal unit policy on administration of routine prophylactic paracetamol with 4CMenB vaccination.


The neonatal unit at the William Harvey Hospital in Ashford, Kent, United Kingdom, is a level 3 neonatal unit, with more than 4000 deliveries annually and between 500 and 600 admissions each year.

Ethical Approval

Ethics approval was not sought as per guidance from the Health Research Authority website7 as this was an evaluation of routine clinical practice before and after the introduction of 4CMenB.

Before September 2015, babies admitted to the neonatal unit were vaccinated according to the UK routine immunization schedule which did not include 4CMenB. Prophylactic paracetamol was not administered (period 1) pre-4CMenB: September 2014–September 2015.

In September 2015, 4CMenB was introduced in the UK routine immunization schedule. Although prophylactic paracetamol was recommended, local neonatal unit policy did not change because of limited evidence relating directly to preterm infants and potential for harm (period 2) 4CMenB without prophylactic paracetamol: September 2015–March 2016.

In June 2016, after an evaluation of postvaccination adverse events in periods 1 and 2, local neonatal unit policy was amended so that prophylactic paracetamol was given to babies receiving 4CMenB (period 3) with paracetamol; June 2016–May 2018. Prophylactic paracetamol was given initially at the time of vaccination with 2 further doses 4–6 hours apart, as per Public Health England guidance.8

A retrospective case-note analysis was conducted for periods 1, 2 and 3 to evaluate the following adverse events in the first 48 hours after vaccination in hospitalized preterm infants: (i) number (%) of babies with temperature >37.5°C; (ii) highest temperature (°C); (iii) number (%) of babies who received evaluation for possible sepsis and (iv) number (%) of babies who received intravenous antibiotics in the 48 hours after vaccination. The infants for inclusion were identified using our national neonatal admissions database, BadgerNet, by checking for all preterm infants who had reached 8 weeks postnatal age, the age at which the first set of vaccinations are administered, and then reviewing the clinical notes and drug charts of all these babies.

We chose a cut off value of >37.5°C to define fever in this study as (i) 37.5°C is the upper end of normal temperature as defined in the national neonatal audit project9 and (ii) the recognized definition of fever in a neonate being a rectal temperature of >38°C and available data indicate that axillary temperature measurement in the newborn period read approximately 0.5°C lower than rectal temperature.10 During this study, the temperature was measured with underarm thermometers, so our cut off for defining a fever was pragmatically set at a temperature of >37.5°C.

Data Analysis

Data were analyzed using GraphPad Prism 7 (GraphPad Software San Diego, CA). Median and interquartile ranges were calculated for continuous data, with P values calculated using the Mann-Whitney U test. Relative risk with 95% confidence intervals for each adverse event was calculated for periods 1 versus 2, 1 versus 3 and 2 versus 3.


We identified 94 preterm infants (<37 weeks gestation at birth) who were eligible to receive routine vaccination with 4CMenB while in-patient on the neonatal unit during the 3 periods (September 2014–May 2018). Eleven babies were excluded from analysis because medical notes could not be located (n = 5), vaccinations were administered in another neonatal unit (n = 4) or data were incomplete (n = 2). All eligible infants who were present in our neonatal unit at the recommended time of vaccination received parental consent for these and were vaccinated. Therefore, 83 patients with 95 vaccination events were included in the final analysis (Fig. 1).

Preterm infants included in the study and reasons for noninclusion.

In comparison to period 1 (pre-4CMenB), there was a higher proportion of infants who developed fever in period 2 (4CMenB without prophylactic paracetamol). This reduced to levels comparable in period 1 (pre-4CMenB) in period 3 (4CMenB with prophylactic paracetamol). Forty percent of infants in period 2 (4CMenB without prophylactic paracetamol) had a partial septic screen and 33% received intravenous antibiotics although none turned out to have positive blood cultures. In period 3 (4CMenB with prophylactic paracetamol), there were fewer infants noted with postvaccination fever, fewer partial septic screens and reduced intravenous (IV) antibiotic usage in comparison to period 2 (4CMenB without prophylactic paracetamol) (Table, Supplemental Digital Content 1, There were no adverse events related to prophylactic paracetamol during this period.

Table 1 shows the relative risk and 95% confidence intervals of developing a temperature >37.5°C, undergoing partial septic screen or receiving antibiotic therapy in preterm infants in the 48 hours after vaccination between periods 1 and 2 (pre-4CMenB vs. 4CMenB without prophylactic paracetamol), periods 1 and 3 (pre-4CMenB vs. 4CMenB with prophylactic paracetamol) and periods 2 and 3 (4CMenB without prophylactic paracetamol vs. 4CMenB with prophylactic paracetamol). Comparison of period 1 and period 2 indicates that the use of 4CMenB without prophylactic paracetamol was associated with a 4-fold increase in postvaccination fever, a 22-fold increase in partial septic screens and a 19-fold increase in IV antibiotic use. Implementation of prophylactic paracetamol in period 3 reduced the risk of fever and adverse events to the levels seen before the introduction of the vaccine (period 1). Comparison of periods 2 and 3 (4CMenB without prophylactic paracetamol vs. 4CMenB with prophylactic paracetamol) demonstrates a 50% reduction in postvaccination fever, a 91% reduction in partial septic screens and an 89% reduction in IV antibiotic use.

Relative Risk and 95% CI of Developing a Temperature >37.5°C, Undergoing Partial Septic Screen or Receiving Antibiotic Therapy in Preterm Infants in the 48 Hours After Vaccination Between Periods 1 and 2, 1 and 3 and 2 and 3


In preterm infants, 4CmenB administered with routine infant vaccinations without paracetamol prophylaxis is associated with fever in almost half the cases, leading to invasive investigations and potentially unnecessary antibiotic use. Implementation of routine prophylactic paracetamol for preterm infants immunized with 4CMenB led to significantly lower rates of fever after vaccination, similar to the background rate pre-4CMenB implementation, resulting in fewer partial septic screens and reduced antibiotic use. Over this time, there were no other changes in practice or policy in relation to screening for or managing sepsis in the neonatal unit.

Our findings are consistent with previous randomized controlled trials and systematic reviews confirming lower rates of fever and other vaccine-related adverse events in healthy, term infants receiving prophylactic paracetamol with their routine immunizations including 4CMenB5 and provide data specific to the hospitalized preterm infant.

The strength of our study lies in its comparison of 3 discrete periods that enabled evaluation of (i) the impact of introduction of 4CMenB without the use of prophylactic paracetamol and (ii) the impact of changing local practice to incorporate the use of prophylactic paracetamol with 4CMenB upon a number of predefined adverse events.

Important limitations are that our patient cohort was from a single center and that the sample size was pragmatic and not amenable to an a priori sample size calculation. For this reason, period 2 (4CMenB without prophylactic paracetamol) had a smaller sample size than the other periods which could confound results. Another limitation of data collection being retrospective is the increased risk of missing data or patients; however, we are confident that despite having to exclude some patients due to incomplete or missing notes that we identified all infants eligible for inclusion as all admissions are recorded on the BadgerNet system. All other patients had complete recordings of temperatures for the 48 hours after vaccination.

In a recent national audit involving 19 neonatal units across England, 7% (8/108) of infants receiving 4CMenB with paracetamol had fever (>38°C) after vaccination compared with 20% (5/25) of those receiving 4CMenB without paracetamol (P = 0.06) and 0% in a historical cohort of infants receiving routine immunizations before use of 4CMenB.8 Eighty-one percent of the infants in the national audit received paracetamol, leaving a proportionally much smaller comparison group of infants receiving 4CMenB without paracetamol. Although the difference in the incidence of fever in the 2 groups was not statistically significant, that could be due to the small size of the group not receiving paracetamol, and therefore may still represent a clinically significant difference. The national audit did not compare rates of antibiotic use between the groups as the initial cohort being used as a control group of vaccination before the introduction of 4CMenB did not collect any data on this.

One area for future research, however, would be to investigate the effect of prophylactic paracetamol on 4CMenB immunogenicity in preterm infants given that the United Kingdom opted for a reduced primary vaccination schedule for 4CMenB and that preterm infants generally manifest attenuated vaccine immune responses when compared with term infants.

It would also be of great interest to evaluate the course of fever after vaccination to help establish a pragmatic method by which clinicians may decide whether or not to investigate and/or administer empiric antibiotics to infants who are febrile in the postvaccination period. This is particularly important because C-reactive protein levels11 are often raised, consistent with a proinflammatory response after 4CMenB vaccination, and therefore do not aid decisions to initiate empiric antibiotics for suspected underlying bacterial infection.


The administration of 4CMenB with routine infant vaccinations is associated with significant adverse events in hospitalized preterm infants and the addition of prophylactic paracetamol administration is associated with a significant reduction in these events. Our findings support the current national recommendations to offer prophylactic paracetamol to premature infants receiving 4CMenB with their routine vaccinations at 8 and 16 weeks of age.


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7. NHS Health Research Authority. Is my study research?. Available at: Accessed October 15, 2017.
8. Neonatal Audit Programme. 2018 audit measures. Available at: Accessed October 4, 2019.
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10. Morley CJ, Hewson PH, Thornton AJ, et al. Axillary and rectal temperature measurements in infants. Arch Dis Child. 1992;67:122–125.
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Bexsero; paracetamol; premature neonates; fever; immunization

Supplemental Digital Content

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