ON THE RELEVANCY OF PARACETAMOL AND BREASTFEEDING POST INFANTS VACCINATION

Background: Paracetamol may be use as antipyretic agent for the treatment of fever, as well as an analgesic in the treatment of mild to moderate pain on post vaccination in infants. The use of Paracetamol during fever may be or may not be recommended since it may alter natural human body immune response although it may reduce pain. Objectives: This study described the relevancy of Paracetamol use post infants vaccination based on data collection systematic review analyses. This study aims to describe the effectiveness of breastfeeding in reducing pain and Paracetamol in reducing fever and pain post infants vaccination. Data Sources and Study Selection: Electronic literature search by hand searching six (6) databases which include Ovid LWW Total Access Collection and Medline, CINAHL (Cumulative Index to Nursing and Alled Health Literature) Plus with Fulltext, Science Direct, Proquest Dissertations and Theses, Proquest Education Journal and Proquest Health and Medical Complete. Additionally, manual reference checks of all articles on Paracetamol and breastfeeding post infants vaccination published in English Language between 1978 and 2017. Two level of screening were used on 9614 citations which include screening of abstracts and titles followed by full text screening. Data Synthesis: Data synthesis were tabulated into study characteristics, quality and effects. Authors of trials were not contacted for further details or provision of original data if the published report contained insufficient information. The study findings, as reported by the authors, were included in this review. The data in this research cannot be pool due to not enough data regarding odd ratio or relative risk as well as confidence interval in each study. Results: Systematic review of breastfeeding included three (3) studies from 9614 of database searching. The reviews of all these three (3) studies found significant benefit from breastfed in pain score and duration of crying as well as behavioral changes. None study stated the unbeneficial of breastfeeding before, during and after immunization. Meanwhile, systematic review of Paracetamol effectiveness included four (4) studies from 1177 of database searching. The reviews of two (2) studies found significant benefit from prophylaxis Paracetamol in fever and only one (1) study found significant benefit from prophylaxis Paracetamol in fussiness. On the other hand, there was one (1) study found not signifiant benefit from prophylaxis Paracetamol in fever. Other than that, there were two (2) studies evaluate the safety of prophylactic Paracetamol which revealed different outcomes, in which study by Prymula et. al. in 2009 found that antibody responses to several antigens were reduced significantly, and the other study by Uhari et. al. in 1988 found that antibody titres to DTP bacteria of placebo and PCM not differ significantly. Thus, Paracetamol seems to be not relevant post infants vaccination and breastfeeding was found to be beneficial post infants vaccination. Conclusions: The relevancy of giving Paracetamol post all types of vaccination may be questionable since the safety issue of this intervention may be arised. Breastfeeding before, Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 12 January 2018 doi:10.20944/preprints201801.0108.v1

of breastfeeding were placed in two (2) categories: (i) breastfeeding (ii) held in mothers' arms but not fed.This study aims to determine the efficacy of breastfeeding as an analgesic properties and the efficacy as well as safety of Paracetamol as an antipyeretic properties post infants vaccination and provide evidence-based recommendations for clinical practice.

METHOD Search Strategies
A wide range of medical, environmental and scientific databases were search to identify primary studies of the effects of breastfeeding before, during and after immunization as well as the effects of antipyretic agent following infants immunization in order to capture as many relevant citations as possible.The electronic searches were supplemented by hand searching of six ( 6  The titles and abstracts of the articles were scanned by two (2) reviewers (N. S. and S. H. S.).Articles selected by the reviewers were retrieved in full and assessed for eligibility by the two (2) reviewers.The reviewers did not contact the authors to identify additional studies but the reviewers referred to reference lists from the identified trials.The reviewers were not blinded to the authors or settings of the scanned articles.

Study Selection: Inclusion Criteria
Only reports with information on infants (for this study defined as up to 1 year of age) were included.All randomized trials and cohort (nonrandomized) studies that included a placebo or unexposed group were included for the determination of efficacy.Trials of different designs, however, were handled separately.The efficacy of breastfeeding as an analgesia and physical intervention of fever as antipyretic were reviewed for the immunization and/ vaccination procedure only.All prospective studies that reported data on variables of noxious stimuli with behavioral, physiologic, hormonal, and metabolic changes were included since infants respond to these variables.For determination of safety, all prospective studies were included.Paper that have funding sources also included in this study.

Study Selection: Exclusion Criteria
Reviews, meta-analyses, editorials, commentary or conference abstracts were excluded in this study.Meta-analysis was excluded in this study because it was not feasible due to extensive variation in study features and methodological quality (Coomarasamy A., Taylor R. & Khan K. S., 2003) Data Collection and Analysis There were two reviewers in this study.The study from World Health Organization also included two reviewers for systematic review (Khan K. S., Wojdyla D., Say L., Gülmezoglu A. M., Look P. F. A. V., 2006).The first reviewer screened all titles and abstracts of papers identified by the literature search.The second reviewer handled duplicate screening on a random selection of found titles or abstracts.The disagreements were discusses between both reviewers.All studied that had been identified as potentially relevant were retrieved and read in full to determine eligibility for inclusion.
Data extractions were conducted by using a pre-defined data extraction template.Data that were extracted include design characteristics, study population and country, sample size, sample selection, age of participants, the exposure and outcome measures and results.

Primary Outcome
The primary outcome was pain and/ fever following infants immunization.Examples of validated observational measures for pain were a Douleur Aigue du Nouveau-ne (DAN) Scale, Facial Pain Rating Scale and Neonatal / Infant Pain Scale (NIPS), Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and cry duration.Examples of observational measures for fever were babies' fussiness and temperature reading more than and at 38°C.

Validity Assessment
The included trials were not masked to the reviewers (N.S. and S.H.S.).The methodological quality of each study was assessed by two (2) independent reviewers using the Crowe Critical Appraisal Tool (CCAT) (Donnelly, Hickey, Burns, Murphy, Doyle, 2015) to investigate internal validity (the extent to which the information is probably free of bias) with the following attributes.The CCAT was developed based on a wide number of previous critical appraisal tools, general research methods theory and reporting guidelines (Donnelley et. al., 2015).The tool was validated and undergone testing for reliability and validity (Donnelly et. al., 2015).The CCAT appraised papers included in the review in eight (8) categories.This tool uses scoring system in which each category is scored from zero (0) in which no evidence to five (5) in which highest evidence.Total scores of each study are presented as a percentage.The average scores of reviewers were reported.

Data Abstraction
Data from each eligible study were extracted individually on custom-made data-collection forms (designed specifically for each intervention) by two (2) reviewers (N.S. or S.H.S.), and the results were compared.The reviewers resolved any disagreements through discussion.

Study Characteristics
Characteristics of included studies as well as the country of being conducted were displayed in Table 2 (for effectiveness of breastfeeding) and 3 (for effectiveness of prophylactic Paracetamol and its safety).This study included research published in 1987 onwards.

Data Synthesis
Data syntheses were tabulated into study characteristics, quality and effects.The original review of summarizing the evidence from studies of variable design will provide details how the differences between study results were investigated and how they were summarized (Khan, 2003).
Authors of trials were not contacted for further details or provision of original data if the published report contained insufficient information.The study findings, as reported by the authors, were included in this review.
The data in this research cannot be pool due to not enough data regarding odd ratio or relative risk as well as confidence interval in each study.

Secondary Outcomes
Local and adverse reactions following infants immunization was reviewed in the study of prophylactic Pracetamol post infants vaccination.

Study Descriptions
Figure 1 presents a flow diagramme of the search strategy.After duplicates are removed the search retrieved 9504, of which 9481 are excluded (9400 on review of abstracts / title and a further 81 after full text papers assessment).23 of reviewed full text articles and 19 were excluded because outcome and exposure not measured.Among these, one (1) was excluded because the age was not within inclusion criteria.Finally, data from three (3) journal articles included in the systematic review.

Study Characteristics
Overall, there were three (3) studies that met the inclusion criteria and eligible for study of the effectiveness of breastfeeding as an analgesic property for pain following immunization in infants.These researches were conducted mainly in East Coast country region which include one (1) in Iran, one (1) in Jordan and one (1) in Turkey.Studies began in 2007 and the latest study was in 2013.These studies addressed two (2) of the intervention categories identified in the protocol: (i) breastfeeding or (ii) held in mothers' arms but not fed.All studies included age of babies not more than one (1) year.
The researcher included randomized control trial and quasi controlled trial that compared breastfeeding and combined interventions of interest with a placebo or control group for pain management during immunization in children aged from 0months to 1 year of age.Among these, there were two (2) studies that were randomized controlled trial and only one (1) study that was quasi controlled trial.The primary outcome measure for pain was made by health care worker or observer using observational methods; for example Douleur Aigue du Nouveau-ne (DAN) Scale, Facial Pain Rating Scale and Neonatal / Infant Pain Scale (NIPS), Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and cry duration.However, all of these studies did not mentioned the duration of breastfeeding.
Among these three (3) studies, one (1) did not contain information about receiving approval by institutional review board or ethics committee.On the other hand, two (2) of three (3) studies mentioned that they obtained approval from institutional ethics review board or committee.All of these studies mentioned that they obtained information consent from the mothers.

Methodologic quality of the included studies
The percentage of agreement on all key items for assessment of the methodologic quality of the three (3) studies was from 75% till 83%; disagreements were resolved by consensus.Three (3) trials which include 316 infants aged zero (0) to 12 months examined the analgesic effects of breastfeeding.
The reviews of all studies found significant benefit from breastfed in pain score and duration of crying as well as behavioral changes.Pain score of study by one (1) study revealed that significant lower pain score in which p<0.001 in study by Razek et. al., 2009 for experimental group (breastfeeding group) than control group (not breastfed).One study by Razek et. al. in 2009 noted that FPS for intervention group represents little more pain (38%) than control group which represents hurt even more Score 3 that indicate pain.Two (2) studies evaluated crying time and it was revealed that crying time was shorter in intervention group rather than control group (Razek et. al., 2009, Efe et. al., 2007).Other than that, among two (2) studies that evaluated behavioral changes in which heart rate and oxygen saturation, one (1) of them was found that statistically significant difference before and after immunization between intervention and control group (p< 0.005).The other one (1) study found that heart rate and oxygen saturation level almost same in both groups.
These studies showed that breastfeeding is effective as pain relief following immunization in infants

Study Descriptions
Figure 2 presents a flow diagram of the search strategy.After duplicates were removed the search retrieved 1176, of which 1165 were excluded (1100 on review of abstracts / title and a further 65 after full text assessment).11 of reviewed full text articles and two (2) were excluded because outcome and exposure not measured.Among these, five (5) were excluded because the age were not within inclusion criteria.Finally, data from four (4) journal articles were included in the systematic review.

Study Characteristics
Overall, there were four (4) studies were assessed as being of sufficient quality to be included in the review.These researches were conducted mainly in Europe and East Coast country region which include one (1) in Czech Republic, one (1) in United States of America (USA), one (1) in Germany and one (1) in Finland.Studies began in 1988 and the latest study was in 2013.
As mentioned before, these studies addressed two (2) intervention categories: (i) administration of prophylactic Paracetamol and (ii) non-prophylactic Paracetamol for fever following childhood immunization.
The researcher included all randomised controlled trial that compared prophylactic Paracetamol use and/ no prophylactic Paracetamol use post infants vaccination.The primary outcome measure for fever was made by parents completed the diary and/ questionnaires given by the researcher of the study, Age not within inclusion criteria Among these four (4) studies, three (3) of them mentioned that they obtained approval from institutional ethics review board or committee (Rose et al., 2013, Jackson et. al, 2011and Prymula et. al., 2009).All of these studies mentioned that they obtained information consent from parents and/ legal guardian except the study by Uhari et. al (1988) did not mentioned they obtained consent from guardians, however they had obtained Ethical Approval from Medical Faculty of Oulu University.

Methodologic quality of the included studies
The percentage of agreement on all key items for assessment of the methodologic quality of the four (4) studies were ranging from 65% till 88%; disagreements were resolved by consensus.Four (4) trials which include 1156 infants aged zero (0) to 12 months of age examined the antipyretic effect of Paracetamol.

Effect of prophylactic PCM for fever and pain following childhood immunization
All studies compared children receiving prophylactic or non-prophylactic PCM post vaccination.Fever was measured using body temperature ≥38C or >39.5C of axillary or rectal temperature, meanwhile baby condition was measured by the appearance of fussiness.
The reviews of two (2) studies found significant benefit from prophylaxis Paracetamol in fever (Rose et. al., 2013 andPrymula et. al., 2009) and only one (1) study found significant benefit from prophylaxis Paracetamol in fussiness (Jackson et. al., 2011).On the other hand, there was one (1) study found not signifiant benefit from prophylaxis Paracetamol in fever (Uhari et. al., 1988).

Local and adverse reactions following immunization
Other than that, recent one (1) study found that local systemic reactions were less frequent in prophylaxis group, but no significant difference between groups (Rose et. al., 2013).In contrast, there was none study showed that there was significant reductions in local systemic reactions of prophylactic group (Jackson et. al, 2011, Prymula et. al., 2009and Uhari et. al., 1988).
Besides, there was one (1) study stated that no vaccine-related serious adverse event reported (Rose et. al., 2013), and there was none study mentioned that prophylactic PCM can significantly reduced frequency and severity of common adverse reactions (Rose et. al, 2013, Jackson et. al, 2011, Prymula et. al., 2009and Uhari et. al., 1988).The study by Uhari et. al. in 1988 revealed that no significant difference in occurrence of minor adverse events.

Safety of prophylactic Paracetamol post infants vaccination
Other than that, there were two (2) studies evaluate the safety of prophylactic Paracetamol (Prymula et. al., 2009 andUhari et. al., 1988).These studies revealed different outcomes, in which study by Prymula et. al. in 2009 found that antibody responses to several antigens were reduced significantly, and the other study by Uhari et. al. in 1988 found that antibody titres to DTP bacteria of placebo and PCM not differ significantly.The study by Prymula et. al. in 2009 also noted that prophylactic Paracetamol at time of vaccination should not routinely recommended although febrile reactions significantly reduced since antibody responses to several antigens were reduced significantly.
Prophylactic Paracetamol had been studied to have beneficial effects as antipyretic property post vaccination in children.However this outcome is questionable since there were also studies that rejected the benefit of prophylactic Paracetamol.Other than that, there was one (1) study found that prophylactic Paracetamol may significantly reduced the antibody of infants (Prymula et. al., 2009).Additionally there was one (1) study by Jackson et. al. in 2011 was stopped because the result of study by Prymula et. al. in 2009.The study by Jackson et. al. in 2011 also noted that the potential benefit of Paracetamol prophylaxis in reducing the risk of fever and associated adverse events following contemporary infants immunizations appear to be outweighted by the potential harmful effects of Paracetamol prophylaxis on vaccine immune responses.

DISCUSSION
Paracetamol was use as an antipyeretic agent and analgesic post vaccination in infants.However, its use seems questionable since in theory the use of Paracetamol at early stage of fever may alter the vaccine function and causes vaccine less effective (Prymula, et. al, 2009).Theoretically, the use of Paracetamol may interferes natural body immune response by inhibiting Prostaglandins (PGs) which involve in natural human body defense mechanisms.Meanwhile, most vaccines injected to the child are originated from the live attenuated organism itself (organism that may cause infection) in which they work by replicating of the live organisms over days or weeks thus covering the immunity.
Prophylactic antipyretic of Paracetamol significantly reduced the febrile reactions of ≥38ºC after vaccinations.There were statistically significant differences in antibody responses between two groups in which lower in prophylactic Paracetamol group.Recent one (1) study showed that there were significant reductions in the local and systemic symptoms in prophylaxis group, but no significant difference between groups (Rose et. al., 2013).
Only two (2) trials studied the antibody response (Prymula et. al, 2009 andUhari, et. al. 1988), thus the data cannot be pooled.Studies used different doses/ schedules antipyretic administration as well as age of participants or timing of administration also markedly differed among studies.
There were none of studies that were identified in the literature search evaluated the effectiveness of oral analgesic in which Paracteamol for immunization pain (Shah, Taddio, Rieder, 2009).Pediatricians may recommend oral analgesics to parents as a pain-relieving intervention for vaccine injection pain (Shah et. al., 2009).However, no evidence was found to recommend the use of either agent as a method of pain relief for vaccine injections.There was no study of Paractemol effects on vaccine injection pain was identified, however this agent was widely used.Thus, a study that addresses this issue may be warranted.
This study found that breastfeeding before, during and after immunization reduced pain, as assessed using cry duration, DAN scale, FPS, NIPS, CHEOPS and or behavioral changes (heart rate and oxygen saturation.The proposed mechanisms of breastfeeding provides analgesia include (i) breastfeeding, (ii) maternal holding and skin to skin contact (Efe et. al., 2007).
The findings of systemic review were consistent with the effectiveness of breastfeeding as an analgesic property in reducing pain of injection immunization in neonates (Shah et. al., 2009).Breastfeeding is a natural, cost-neutral, time-efficient, and convenient intervention that could be easily adopted from the perspectives of health care providers and parents (Shah et. al., 2009).Other than nutritional and psychological value of breastfeeding, the analgesic properties may encourage more mothers to breastfeed (Shah et. al., 2009).

LIMITATION
Methodologic challenges and limitations of this review include the small number of studies for breastfeeding interventions, small sample size, limited age range of participants, limited number of vaccines evaluated and variability in pain assessments.The included trials used various methods of assessing pain in infants, which made it difficult to combine and contrast the results.

RECOMMENDATION FOR FUTURE RESEARCH
Finally, in deciding Paracetamol to be rational use following infants immunization, it may need for further research which include in depth quantitative and qualitative studies to identify specific problem and causes regarding this issue.
Based on the researcher's review, areas for future research were identified.The role of expressed breast milk has not been studies, and further research is needed.Finally, studies addressing whether the gap between research findings and clinical practice can be narrowed by communication and dissemination strategies aimed at practitioners, professional groups, and families will be important in establishing the common goal of pain-free, tolerable, and effective immunization for infants.
Future trials should focus on the timing (before, with or after) and route (oral or rectal) of administration of Paracetamol as well as on the subgroup of infants (term or preterm) for any correlation with the immune response.Future trials should focus on trial examining the prophylactic effect of Paracetamol post vaccination antibody response since there was lack of studies regarding this issue.The mechanism underlying the reduction in immune / antibody response should also be explored.Trials should also be conducted in developing countries where over-the-counter use of antipyretics (including prophylactic) are common.Other cofounding factors that might affect the antibody response such as infants sleep post-immunization should also be studied.

CONCLUSION
In identifying the problem in drug use, this preliminary research need to be conducted as guided by World Health Organization in deciding the relevancy of the supply of Paracetamol post all types of infants immunization.
The relevancy of giving Paracetamol post all types of vaccination may be questionable since the the safety issue of this intervention may be arised.
Although prophylactic antipyretic Paracetamol administration leads to relief of local and systemic symptoms after vaccinations, there was a reduction in antibody responses to some vaccine antigens.Future trials and surveillance programs should also aim at assessing the effectiveness of programs where prophylactic Paracetamol is given.The timing of administration of Paracetamol should be discusses with the parents after explaining the benefits and risks.
Breastfeeding before, during and after immunization are recommended for pain reduction as systematic review of this study showed its proven effectiveness.
) databases which accessed through EzProxy for Off Campus Access Online Database for International Islamic University Malaysia (IIUM) Students and Staffs in which

Figure 1 :
Figure 1: Flow diagramme of research strategy for effectiveness of breastfeeding as pain intervention post childhood vaccination

Figure 2 :
Figure 2: Flow diagramme of research strategy for effectiveness of prophylactic Paracetamol as fever reduction post childhood vaccination

Table 1 :
Keywords for Systematic Review

Table 3 :
Summary of Relevant Research on Effectiveness of Prophylactic Antipyretic Used as an Intervention to Decrease Fever in Infants and its Safety Issue