Prophylactic paracetamol for the prevention of fever in children receiving vaccination as part of a standard childhood immunization schedule
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To evaluate the efficacy and safety of prophylactic paracetamol to prevent fever in children receiving vaccination as part of a childhood immunization schedule.
Background
Description of the condition
Children are given vaccines to prevent specific infectious diseases during their childhood. Despite benefits of long term protection, children are at risk of developing fever and other adverse events following any vaccination (Kelso 2012). Vaccination schedules vary across countries and regions. The World Health Organization (WHO) recommends at least 10 vaccines for routine immunization for children (WHO 2016). Of these, some antigens are administered as simultaneous multiple vaccines and as combination vaccines (Wallace 2014). Certain types of vaccines, such as the whole‐cell pertussis vaccine have a higher risk of causing fever (Zhang 2014), up to 24.3% as compared to 7.3% with acellular vaccines (WHO 2015). Although most post‐immunization fevers are self‐limiting, serious adverse events including febrile seizures can occur with any vaccine including the acellular pertussis vaccine (Jackson 2002), leading to emergency department visits. The occurrence of post‐vaccination fever and discomfort could adversely influence parents' perception of the safety of routine childhood immunizations (Jackson 2011).
See Appendix 1 for a glossary of terms.
Description of the intervention
Paracetamol, also known as acetaminophen, is the most common antipyretic medication used in children for prophylaxis and treatment of post‐immunization fever and pain (Cranswick 2000; De Martino 2015; Dhingra 2011). While treating pain and discomfort in children is recommended (Russell 2003), evidence regarding the benefits of treating fever with paracetamol is not conclusive. Suggestions of the benefits for fever and behavioral changes in infants who receive whole‐cell diphtheria, pertussis, and tetanus (DPT) vaccine (Ipp 1987; Lewis 1988), diphtheria, tetanus, and acellular pertussis (DTaP) vaccine, and other currently used vaccines (Jackson 2011) need to be considered against the concern that paracetamol use following immunization could lead to reduced immune responses (Prymula 2009). Nevertheless, the use of paracetamol to reduce anxiety related to fever is common (Allotey 2004). Children who have had febrile seizures are given antipyretics following immunization to prevent further seizures, although paracetamol is not effective in preventing febrile seizures (Rosenbloom 2013; Schnaiderman 1993).
Oral paracetamol absorbed via the gastrointestinal tract has a high bio‐availability of around 80%. Peak blood levels and temperature reduction is similar in children and adults, occurring after about two hours following the oral dose (Brown 1992; Kelley 1992; Moriarty 2016). A commonly used dose in children is 10 mg/kg to 15 mg/kg every four to six hours orally, with a maximum daily (24 hours) dose of 75 mg/kg (Lane 2015; Van den Anker 2013). Parenteral administration is rarely needed.
Paracetamol in therapeutic doses is generally well‐tolerated and has few side effects. Adverse effects are rare and hepatotoxicity is related to overdose (Cranswick 2000; Kelley 1992). Overdosing is particularly concerning when used along with other analgesics and opioids (Graham 2013).
How the intervention might work
Fever is considered to be a response of the body to internal and external stimuli to facilitate effective immunologic defence mechanisms. Neurological and immune responses play a role with endogenous cytokines such as interleukin (IL)‐1 beta, IL‐6, and tumor necrosis factor‐alfa from white blood cells mediating an increase in prostalandin‐E2 (PGE2) levels and the anterior hypothalamic thermoregulatory set‐point being raised. The fever that results seems to facilitate activation of protective immune mechanisms (Kluger 1995; Kwiatkowski 1995).
The exact pathophysiological processes influenced by paracetamol in controlling fever have not been ascertained. It is postulated that warm‐sensitive neurons that initiate heat loss through physiological responses are inhibited by prostaglandins produced during fever (Fields 2013). Paracetamol seems to reduce fever through unblocking these heat‐loss neurons by impairing the formation of prostaglandins and fever‐causing cytokines in the central nervous system (Feldberg 1973; Mackowiak 1998; Morrison 2011).
Although a weaker analgesic than non‐steroidal analgesic medications (Graham 2013), paracetamol is generally preferred for children because it is better tolerated. Analgesic effects of paracetamol are mediated by inhibition of cyclooxygenase‐1 and 2 enzymes. This is believed to be achieved through descending serotonergic pathways and by impairing prostaglandin synthesis (Graham 2013; Marzuillo 2014).
Why it is important to do this review
Fever and local reactions, although usually self‐limiting over a few days, may cause considerable concern among parents and healthcare professionals (Crocetti 2001; De Bont 2015). Due to the concern of fever and local reaction, paracetamol continues to be prescribed widely despite contrary views on its benefits. Conclusive evidence is also lacking on the beneficial effects of paracetamol in preventing serious complications such as febrile seizures (Rosenbloom 2013). Following a report on the possibility of a reduced immune response to vaccines in children who are given paracetamol for fever prophylaxis (Prymula 2009), routine prophylaxis is no longer recommended in some countries such as Canada and New Zealand (Government of Canada 2016; NZ Ministry of Health 2015). A non‐Cochrane systematic review affirmed that there is a reduction in antibody responses to some vaccine antigens with prophylactic use of antipyretics, although this review suggested that such a reduction in immune responses might not be clinically significant (Das 2014). In 2015, with the introduction of a meningococcal vaccine in the UK and Ireland immunization schedules, guidance was issued recommending prophylactic administration of paracetamol to infants around the time of immunization and post‐immunization (NHS 2015; Public Health Agency 2015; Public Health Agency (HSE) 2016). Given such continuing uncertainties, this systematic review could help inform clinical and policy decisions on paracetamol given as a prophylactic to prevent fever following vaccination in children.
Objectives
To evaluate the efficacy and safety of prophylactic paracetamol to prevent fever in children receiving vaccination as part of a childhood immunization schedule.
Methods
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials (RCTs). We will include studies reported either as full text or as abstract only. We will also include unpublished data.
Types of participants
Healthy children (aged up to 18 years) who received any vaccine as part of an immunization schedule and who did not need paracetamol for any other reason will be included.
Types of interventions
We will include trials that evaluate paracetamol given as a prophylaxis at the time of immunization or after vaccination but prior to onset of fever (NHS 2015).
Dose: single or multiple doses, 10 mg/kg to 15 mg/kg.
Route of administration: oral preparation or rectal suppository.
Comparision: We will consider any of the following for comparison with the intervention:
-
No antipyretic prophylaxis or placebo;
-
Single dose over 15 mg/kg;
-
Multiple doses over 15 mg/kg;
-
Any other antipyretic medication;
-
Non‐pharmacological interventions for fever prophylaxis such as tepid sponging.
Types of outcome measures
Primary outcomes
-
Fever within 24 hours of vaccination (as defined by trialists).
-
Immunogenicity measured by quantitative immunoglobulin assays one month post‐vaccination and beyond. Adequacy of immune response will be determined based on standards accepted by the World Health Organization (WHO) (Plotkin 2010; WHO 2013).
Secondary outcomes
-
Fever after 24 hours and up to 72 hours.
-
Serious adverse events (e.g. death, hospitalization, disability etc, as defined by FDA 2016).
-
Visit to accident and emergency department or other outpatient visit to a physician for any adverse event related to immunization.
-
Any adverse event (e.g. nausea, vomiting, behavioral abnormalities).
-
Febrile seizures.
-
Local reaction (site tenderness, redness and swelling, intensity of tenderness).
-
Abnormal cry (prolonged/persistent cry as described by the trialists).
-
Time lost from work (parent/guardian) or school/activities (child).
Reporting of the outcomes listed here will not be an inclusion criterion for the review.
Search methods for identification of studies
Electronic searches
We will conduct a literature search to identify all published and unpublished RCTs. We will not place any restriction on the language or time of publication when searching the electronic databases. We will translate the non‐English language papers and fully assess them for potential inclusion in the review as necessary.
We will search the following electronic databases for identifying potential studies:
-
Cochrane Central Register of Controlled Trials (CENTRAL);
-
MEDLINE (1946 to present) (Appendix 2);
-
Embase (1974 to present); and
-
CINAHL (1937 to present).
Searching other resources
We will check reference lists of all primary studies and review articles for additional references. We will contact authors of identified trials and ask them to identify other published and unpublished studies. We will also contact manufacturers and experts in the field.
Grey literature databases
We will search the following grey literature databases for theses, dissertations and conference proceedings:
-
ProQuest Dissertations & Theses Global;
-
Conference Proceedings Citation Index ‐ Science; and
-
OCLC PapersFirst.
Clinical trials registers/trial result registers
We will conduct searches of clinical trial registers/trial result registers:
Data collection and analysis
Selection of studies
Two review authors (RK and AV) will independently screen titles and abstracts for inclusion of all the potential studies we identify as a result of the search and code them as 'retrieve' (eligible or potentially eligible/unclear) or 'do not retrieve'. We will retrieve the full text study reports/publication and two review authors (RK and AV) will independently screen the full text and identify studies for inclusion, as well as identify and record reasons for exclusion of the ineligible studies. We will resolve any disagreement through discussion or, if required, we will consult a third author (RZK). We will identify and exclude duplicates and collate multiple reports of the same study so that each study rather than each report is the unit of interest in the review. We will record the selection process in sufficient detail to complete a PRISMA flow diagram and characteristics of excluded studies table.
Data extraction and management
We will use a standard data collection form for study characteristics and outcome data which has been piloted on at least one study in the review. Two review authors independently (RK and AV) will extract study characteristics from included studies. We will extract the following study characteristics:
-
Methods: study design, total duration study and run in, number of study centres and location, study setting, withdrawals, date of study.
-
Participants: N, mean age, age range, sex, severity of condition, diagnostic criteria, inclusion criteria, exclusion criteria, combined versus single vaccine, age at administration of dose(s), vaccine dose number.
-
Interventions: intervention, comparison, concomitant medications, excluded medications.
-
Outcomes: primary and secondary outcomes specified and collected, time points reported.
-
Notes: funding for trial, notable conflicts of interest of trial authors.
Two review authors (RK and AV) will independently extract outcome data from included studies. We will note in the characteristics of included studies table if outcome data were reported in an unusable way. We will resolve disagreements by consensus or by involving a third author (RZK). One review author (RK) will copy data from the collection form into the Review Manager file (Review Manager 2014). We will double check that the data are entered correctly by comparing the study reports with how the data are presented in the systematic review. A second review author will spot‐check study characteristics for accuracy against the trial report.
Assessment of risk of bias in included studies
Review authors (RK and AV) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreement will be resolved by discussion or by involving a third author (RZK). We will assess the risk of bias according to the following domains:
-
Random sequence generation;
-
Allocation concealment;
-
Blinding of participants and personnel;
-
Blinding of outcome assessment;
-
Incomplete outcome data;
-
Selective outcome reporting; and
-
Other bias.
We will grade each potential source of bias as high, low, or unclear and provide a quote form the study report together with a justification for our judgement in the risk of bias table. We will summarise the risk of bias judgements across different studies for each of the domains listed. We will consider blinding separately for different key outcomes where necessary. Where information on risk of bias relates to unpublished data or correspondence with a study author, we will note this in the risk of bias table.
When considering treatment effects, we will take into account the risk of bias for the studies that contribute to that outcome.
Assesment of bias in conducting the systematic review
We will conduct the review according to this published protocol and report any deviations from it in the 'Differences between protocol and review' section of the systematic review.
Measures of treatment effect
We will analyse and report dichotomous data as risk ratio and continuous data as mean difference or standardised mean difference (SMD) along with 95% confidence interval (CI). SMD will be used when the same outcomes are measured using different scales. We will ensure that higher scores for continuous outcomes have the same meaning for the particular outcome, explain the direction of effect to the reader, and report where the directions were reversed if this is necessary.
We will undertake meta‐analyses only where this is meaningful i.e. if the treatments, participants, and the underlying clinical question are similar enough for pooling to make sense.
A common way authors indicate skewed data is by reporting medians and interquartile ranges. When we encounter this, we will note that the data were skewed and discuss such data descriptively.
Unit of analysis issues
The unit of analysis will be the individual, with a single measurement of each outcome for each participant being collected and analysed. Where multiple study arms are reported in a single study, we will include only the relevant arms. If two comparisons (e.g. drug A versus placebo and drug B versus placebo) must be entered into the same meta‐analysis, we will halve the control group to avoid double counting.
Dealing with missing data
We will contact investigators or study sponsors in order to verify key study characteristics and obtain missing numerical outcome data where possible (e.g. when a study is identified as an abstract only).
Assessment of heterogeneity
We will use the I² statistic (Higgins 2003) to measure heterogeneity among the studies in each analysis. If we identify substantial heterogeneity (I² > 60%) we will explore causes in pre‐specified subgroup analyses.
Assessment of reporting biases
We will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, the impact of including such studies in the overall assessment of results will be explored by a sensitivity analysis.
If we are able to pool more than 10 studies, we will create and examine a funnel plot to explore possible publication biases.
Data synthesis
If appropriate we will perform a meta‐analysis using the Mantel‐Haenszel random‐effects method for dichotomous data using Review Manager software (RevMan 2014). We will use the inverse‐variance random‐effects method for continuous data.
'Summary of findings' table
We will create a summary of findings table for the main comparisons:
-
Paracetamol versus no antipyretic prophylaxis or placebo;
-
Paracetamol standard dose versus higher dose of paracetamol (single or multiple);
-
Paracetamol versus any other antipyretic medication;
using the following primary and secondary outcomes
-
Fever within 24 hours of vaccination (as defined by trialist);
-
Immunogenicity measured by quantitative immunoglobulin assays one month post‐vaccination and beyond. Adequacy of immune response will be determined based on standards accepted by the World Health Organization (Plotkin 2010; WHO 2013);
-
Fever after 24 hours and up to 72 hours;
-
Serious adverse events (e.g. death, hospitalization, disability etc, as defined by FDA 2016);
-
Visit to accident and emergency department or other outpatient visit to a physician for any adverse event related to immunization;
-
Any adverse event (e.g. nausea, vomiting, behavioral abnormalities); and
-
Febrile seizures.
We will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness and publication bias) to assess the quality of a body of evidence as it relates to the studies which contribute data to the meta‐analyses for the pre‐specified outcomes (GRADEpro GDT). We will use methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook (Higgins 2011) and using GRADEpro software. We will justify all decisions to down‐ or up‐grade the quality of studies using footnotes and make comments to aid a reader's understanding of the review where necessary. If meta‐analysis is not possible, we will present the results in a narrative format. We will consider whether there is any additional outcome information that was not able to be incorporated into meta‐analyses and note this in the comments and state if it supports or contradicts the information from the meta‐analyses.
Subgroup analysis and investigation of heterogeneity
We plan to carry out subgroup analyses based on the following characteristics:
-
Vaccine dose number. Pertussis containing vaccine combinations, whole and acellular, produce increasing fever with increasing dose number.
-
Whole‐cell or acellular pertussis containing vaccines. Acellular and whole cell pertussis vaccines are available either singly or are combined with diphtheria, tetanus, hepatitis B, Haemophilus influenza B, and Inactivated polio vaccines in various combinations. Of these, single acellular pertussis vaccine and acellular pertussis containing vaccines are known to be less pyrogenic than their whole cell counterparts. Hence, we intend to distinguish whole cell pertussis containing vaccines from acellular pertussis containing vaccines in the analysis.
-
Combination vaccines or simultaneous multiple vaccination. Mumps‐measles‐rubella‐varicella (MMRV) combination vaccine has a greater risk of febrile seizures than when mumps‐measles‐rubella (MMR) and varicella are given simultaneously and separately.
-
Children aged up to six months, or six months to five years or more. Febrile seizures are common between six months and five years of age. Furthermore, immune responses have been reported to be more robust with advancing age.
-
Paracetamol given every four to six hours or less frequent dosing.
The following outcomes will be used in subgroup analysis:
-
Fever within 24 hours of vaccination.
-
Immunogenicity measured by quantitative Immunoglobulin assays within 30 days.
We will use the interaction test to assess the subgroup difference.
Sensitivity analysis
We will perform sensitivity analysis defined a priori to assess the robustness of our conclusions. This will involve excluding the studies at high risk of bias. We will classify studies as having a high risk of bias based on random sequence generation and allocation concealment.
Reaching conclusions
We will base our conclusions only on findings from the quantitative or narrative synthesis of included studies for this review. We will avoid making recommendations for practice and our implications for research will give the reader a clear sense of where the focus of any future research in the area should be and what the remaining uncertainties are.
