Effects of vaccinations of newborn on neonatal mortality: A systematic review and meta-analysis of randomized controlled trials studies in low and low- to middle-income countries

Effects of vaccinations of newborn on neonatal mortality: A systematic review and meta-analysis of randomized controlled trials studies in low and low- to middle-income countries | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Effects of vaccinations of newborn on neonatal mortality: A systematic review and meta-analysis of randomized controlled trials studies in low and low- to middle-income countries Fillmon Kidus Ebuy, Fitwi Melles Hagos, Tsegaye Getachew Mekonnen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8218455/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Newborn vaccination can significantly lower neonatal mortality by protecting against infectious disease and offering nonspecific protective effects, which may include in all-cause mortality. Studies conducted on new born vaccination and neonatal mortality in low and low-to middle-income countries have shown inconsistency results. Therefore, the objectives of this study were to produce concrete pooled evidence and to identify the source of inconsistency in the studies’ results. Methods : The protocol of this study was registered in the International Prospective Register of Systematic Review with registration number CRD420251164676. Moreover, this study adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Studies were identified through databases searchs in PubMed, MEDLINE, Embase, and Google Scholar. All the meta-analyses were conducted via Review manager 5.4.1. Statistical tests were conducted by applying random effect model of pooled effect measures, heterogeneity, subgroup analyses and sensitivity analyses. Furthermore, risk bias, publication bias ,and certainty evidence assessments were performed. Results: Nine studies, with total sample size 40772 were included in the review, on the basis of established criteria. The pooled effect measure revealed that vaccination of newborns with BCG only or BCG-plus-OPV or OPV alone significantly decrease the risk of neonatal mortality by 22% [HR= 0.78 , 95% CI (0.67 - 0.90), P <0.001]. Moreover, heterogeneity was detected with the Higgins I 2 statistical test [I 2 = 61%], and the Cochran's Q statistical test [Q=20.44, DF= 8, P = 0.009]. Sample size, intervention type, and study setting variation were the sources of the heterogeneity. The sensitivity analysis indicated that the absence of influential studies was plausible. Furthermore, the study revealed the absence of publication bias. The certainty evidence of the studies was high grade. Conclusions: The study results showed that newborns vaccinated with BCG alone or BCG-plus-OPV, or OPV alone had a 22% lower risk of neonatal death. Moreover, the source of inconsistency in the included studies was due to variation in sample size, intervention type, and study setting. Therefore, all stakeholders should promote increasing coverage of new born vaccination. Future research should focus on other newborn vaccines such as hepatitis B. PROSPERO Protocol registration : CRD420251164676 Immunology Neonatal mortality Vaccination BCG OPV heterogeneity risk bias sensitivity Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Background According to the World Health Organization(WHO) definition, neonatal mortality is the death of a live -born neonates within the first 28 days of life. The neonatal period, it is the most insecure period for a child's survival and most children are risk of death. With an average global rate of 17 deaths per 1,000 live births in 2023, a 53% decrease from the 37 fatalities per 1,000 live births in 1990. [ 1 ]. Compared to postneonatal under5 mortality, neonatal mortality decreased more slowly between 1990 and 2022. Furthermore, unless immediate action is taken, 64 nations will not meet the Sustainable Development Goals(SDG) objective for newborn death by 2030, and the gains have decreased dramatically since 2010 [ 2 ]. Sub-Saharan Africa was responsible for only 30% of live births worldwide in 2022, but 57% (2.8 million) of all under5 fatalities worldwide. With 27 neonatal deaths per 1000 live births, sub-Saharan Africa has the highest neonatal mortality rate globally. Compared with Australia and New Zealand, which have the lowest mortality rates, the probability of dying in the first month of birth is eleven times higher in sub-Saharan Africa [ 2 ]. Central and southern Asia have the second highest number of deaths, with 21 neonatal deaths per 1000 live births [ 1 ]. The probability of dying before the 28th day of life for a child born in the nation with the highest mortality rate was approximately 60 times higher than that of the country with the lowest mortality rate[ 2 ]. Neonatal infections, congenital abnormalities, premature birth, and birth problems (such as hypoxia or trauma) continue to be the main causes of neonatal mortality. Conditions and diseases linked to inadequate quality care at birth or skilled care and treatment shortly after birth and in the first few days of life are experienced by children who pass away within the first 28 days of life [ 2 ]. The first few weeks following birth are when infectious morbidity and mortality are at their peak [ 3 , 4 ].The primarily unaffected phenotype of neonatal immune cells and unique immunological challenges at birth, which necessitate discrimination between a wide range of foreign antigens linked to primary commensal colonization as well as harmless self-antigens and non-inherited maternal antigens, indicating vulnerability. Overall, a combination of these physiological limitations is likely responsible for susceptibility to severe illness[ 5 , 6 ]. One of the most economical methods of illness prevention is still vaccination. Millions of infants receive vaccinations against poliomyelitis, hepatitis B, TB, tetanus, pertussis, and diphtheria averting with an estimated 2.5 million fatalities per year [ 7 ]. Vaccination has been far less successful in the first month of life, although it has undoubtedly helped older infants and children [ 3 , 4 ]. To speed up the priming of protective immunological components, the World Health Organization advises vaccination against polio, hepatitis B, and tuberculosis as soon as possible after delivery (less than 24 hours) [ 8 ]. Similarly, maternal immunization provides vertically transferred immunity to prevent infection by specific pathogens [ 8 ]. However, new data indicate that a variety of pathogens are responsible for newborn infections in lower- and lower-middle-income countries [9,10.11]. Notably, there are currently no vaccines in clinical use that protect against any of these infections. Furthermore, even with the application of state-of-the-art diagnostic techniques, the triggering pathogen was not found in more than 70% of cases of clinically suspected infection [ 10 , 11 ]. The percentage of causative pathogens that immunization misses is probably higher than is currently understood, even though some of these undetected instances might not be true infections. Alternative approaches are therefore needed to improve early- life immunity against a broad range of diseases. To optimize early-life immunity, we describe the principles underlying the vaccination of newborns and their mothers, including the increasingly acknowledged pathogen-agnostic benefits that emphasize the necessity of viewing the mother-newborn relationship as a single immunological unit [ 10 , 11 ]. The lack of existing immunization programs resulted in neonatal mortality reductions equivalent to those observed in older infants and children, considering that neonates are capable of robust vaccine responses. First, the microorganisms that cause serious infections in the first few weeks of life are not specifically targeted by the immunizations now given to newborns. Even while polio, hepatitis B, and tuberculosis can be contract in the first few weeks of life, these illnesses typically show clinical symptoms outside of the newborn period. Vaccines against pathogens and several other germs that do cause severe infection in the first weeks, either unavailable or have not yet been attempts in neonates[ 12 ]. Second, infections can cause morbidity and mortality within the first few days after delivery,buy it frequently takes weeks to prime a protective adaptive immune response in primarily unaffected newborn cells (12). Strategies aimed at producing protective neonatal adaptive immune components are difficult because of the discrepancy between the time it takes to prime protective pathogen-specific immunity and the time which infections arise [ 3 , 4 ]. Previous RCTs(randomized controlled trials) have shown inconsistent results. Some studies from lower and lower- to middle- income countries have shown statistically significant associations and other studies have revealed the absence of a statistical significant association between vaccination of newborns and neonatal mortality [ 13 – 21 ]. Previously, a meta-analysis was conducted on the effect of only BCG vaccination on neonatal mortality[ 22 ]. However, our study concurrently scrutinized the effects of vaccinations of newborns with only BCG, or BCG -plus- OPV, or OPV alone on neonatal mortality. The main aims of this study were to determine the pooled effect measure and assess the source of inconsistency in the results regarding effect of vaccination of newborns on neonatal mortality. Therefore, it is essential to conduct a systematic review and meta-analysis of studies to produce concrete evidence regarding the effect of vaccination of newborns on neonatal mortality for all stakeholders, health workers and policy makers in low and low-middle-income countries in order to implement and improve coverage of the new new born immunization programs. Methods Study settings, study design and registration The studies included in this systematic review and meta-analysis were from low and low -to middle-income countries such as Guinea Bissau and India. The study design applied was systematic review and meta-analysis. Furthermore, this study adhered to the PRISMA statement (Preferred Reporting Items for Systemic Review and Meta-Analysis) guidelines to process the review [ 23 ]. Moreover, the protocol of this systematic review and meta-analysis was registered in PROSPRO (International Prospective Register of Systematic Review)with registration number CRD420251164676. Eligibility criteria Study type : The inclusion criterion for studies was RCTs, which were published in English between January, 2015 and November, 2025. The exclusion criteria were studies with abstracts only, studies published not in English, and studies conducted in developed countries. Study population : The inclusion criterion for the study population was that all neonates lived for 28 completed days of life and that all neonates died during the 28 completed days of life. The exclusion criteria was that all neonates lived and died after the 28 days of new born life. Outcome of interest : The inclusion criterion for the outcome of the study was death of neonates within the 28 completed days of life. The exclusion criterion was neonatal death occurring after the 28 days of new born. Exposure of interest : The inclusion criterion for the exposure was vaccination of newborn with BCG(Bacillus Calamity Groin) alone or OPV (Oral Polio Vaccine) alone or BCG-plus-OPV. The exclusion criteria were vaccination of newborns with BCG alone or OPV alone or BCG- plus- OPV after 28 completed days newborn life. Information source and search strategy A systematic electronic database search was conducted in PubMed, MEDLINE, Embase, and Google Scholar. The search approach included terms related to exposure, outcome, participants ,and study design. We applied the following search strategy in PubMed and MEDLINE as follow: (((vaccination) OR (immunization)) AND (neonatal mortality)) AND (randomized controlled trial). In Google Scholar : “vaccination” “immunization” “neonatal-mortality” “randomized controlled trials” Study selection process Two unbiased reviewers(FK and FM) initially scanned abstracts and titles to select potential full-text articles for further analysis. Following approval of the title and abstract, the full texts of the studies were accessed via linked databases and carefully reviewed for inclusion by the two reviewers. Studies that were published by the same researchers and look at the same factor were evaluated for any duplicate data on the basis of the year of publication and the subject regions. Data Extraction Process The included studies were retrieved and calibrated via an Excel data extraction form that the researcher created on the basis of the pilot review. Two reviewers(FK and FM) were independently extracted data from the eligible research studies in order to assess quality of studies and synthesize the data. A third reviewer(TG) was then be consulted in order to identify and resolve any differences. measurement. Any missing data were requested via email from the authors of the study. Data items (outcome) : The outcome domain and definition were neonatal mortality, which is the death of a newborn child within 28 completed days of newborn life. Data items(other variable) The following detail information was obtained, author, study site, study population exposure details, study design, information on risk of bias assessment, sample size, confounding, effect size, and standard error. Study risk of bias assessment To investigate the impact of eliminating low-quality research, the quality assessment's overall findings were employed in data synthesis for a prearranged sensitivity analysis, by evaluating the quality of research via the RoB2 tool(Cochran risk of bias 2) [ 24 ]. Two reviewers(FK and FM) were independently assessed the risk of bias in the included studies. In order to settle any disputes between the two reviewers about the possibility of bias in certain research, a third reviewer(TG) was participated in the conversation. The RoB2 method is applied across five domains : bias arising from the randomization process, bias due to deviation from intended interventions, bias due to missing outcome of data, bias in the measurement of the outcome, and bias in the selection of reported results. Synthesis methods Pooled effect and heterogeneity test All analyses were conducted with Review Manager(RevMan) 5.4.1 software. When heterogeneity was confirmed, a random effects model with a p value < 0.05 was used. We provided a summary of effects for each study by computing thehazard ratio(HR), which is the recommended method for RCT data, with a 95% confidence interval and p-value for the outcome. To assess the degree of inconsistency among studies, methodological differences were assessed via Cochrane's Q statistics and Higgins’ I² statistics. An I² value greater than 50% and a P value < 0.05 was considered statistical significant heterogeneity[ 25 ]. Subgroup analysis Subgroup analysis was used to scrutinize the influence of variables on the combined effect size and source of the heterogeneity among studies. If the P value was < 0.005 the subgroup differences considered significant. Sensitivity analysis By eliminating one study at a time, the leave-one-out meta-analysis is a technique that analyzes the impact of each individual study on the total effect size. By continually performing a meta-analyses and adding a new study on the basis of its sample size, cumulative meta-analysis was used to evaluate the influence of the larger studies on the effect size. Publication bias assessment Begg's modified funnel plot was used when five or more studies are scrutinized the association of a certain component [ 26 ]. To fill in the gaps in knowledge about the methodologies used in the included research and to obtain missing data, we contacted the authors via the email addresses listed in the publications. Certainty evidence assessment The GRADE technique [ 27 ] was used to evaluate the degree of certainty, and GRADEpro [ 28 ]software was applied to illustrate the results. Criteria used to assess the certainty of evidence results include number of studies ,research design, risk of bias, inconsistencies, indirectness, imprecision, publication bias, confounding ,large effect size, and dosage response prediction. Results Study selection Between September 10, 2025, and October 10, 2025, a literature review was carried out using databases from Google Scholar, Embase, MEDLINE, and PubMed. We discovered 2777 articles, pertaining to this review topic between January 2015 and October 10, 2025. After eliminating duplicate record retrievals, 2621 records remained; 2590 of them were removed during the first evaluation because of their irrelevant titles. The full texts of the remaining 31 documents were reviewed and confirmed. Out of the 31 records that were evaluated for eligibility, 22 studies [ 29 – 50 ] were disqualified because they were identified to have no similarity on in terms of exposure, outcome or study design. Nine full-text research papers [ 13 – 21 ]were obtained and added to the review on the basis of predetermined criteria (Fig. 1 ). Study characteristics The studies included in the review were from Guinea Bissau and India. All of the studies included were randomized controlled trials design. A total of 40772 participants were involved in the studies. The sampling method the studies employed was random assignment. All studies used an intervention of BCG only or BCG-plus-OPV or OPV alone(Table 1 ). Risk of bias assessment The overall risk of bias for the study and for each study included was demonstrated a lower risk(Fig. 2 ). Results of synthesis Pooled results and heterogeneity test Since the studies were heterogeneous, we preferred a random effects model for the meta-analysis. The overall pooled effect measure revealed that n ewborn vaccination with BCG alone or BCG-plus-OPV or OPV alone was statistically significantly associated with a decreased risk of neonatal mortality [HR = 0.78, 95% CI (0.67–0.90), P < 0.001]. The Higgins I 2 statistical test, revealed that [I 2 = 61%], and the Cochran's Q statistical test reported that [Q = 20.44, DF (degree of freedom) = 8, P = 0.009]. These results unveiled the statistical significance of heterogeneity among the studies(Fig. 3 ). Subgroup analysis Subgroup analysis studies from Guinea Bissau revealed a statistically significant correlation between vaccinations of newborn and neonatal mortality(P = 0.002). However, studies from India showed that this difference was not statistical significant(P = 0.34). The test for subgroup differences indicated that no statistical significant differences with substantial heterogeneity [ Q test = 3.02, df = 1, P = 0.08, I 2 = 66%](Fig. 4 ). A statistically significant correlation was discovered for both the parallel and clustered RCTs designs (P = 0.007) and (p = 0.009) respectively. The subgroup difference test also showed not statistical significant and presence of heterogeneity[Q test = 2.12, DF = 1, P = 0.15, I 2 = 52.9%] (Fig. 5 ). Intervention with BCG only and BCG-plus-OPV was not statistically significantly associated with neonatal mortality(P = 0.06). However; intervention with OPV statistically significantly associated with the risk of neonatal mortality ( P = 0.03). Overall, the subgroup difference test indicated that not statistically significant differences, with an absence of heterogeneity[ Q = 0.56, DF = 2, P = 0.76, I 2 = 0] (Fig. 6 ). With respect to sample size, When sample size 10,000 a statistically significant association was detected (P = 0.007) and (P = 0.03) respectively. Overall the subgroup difference test demonstrated not statistically significant differences, with an absence of heterogeneity studies[ Q = 0.54, df = 2, P = 0.76, I 2 = 0%](Fig. 7 ). Sensitivity analysis According to the results of our sensitivity analysis, the point-estimated effect size of HR that was obtained when one study excluded from the meta-analysis fell within the confidence interval of the meta-analysis's pooled effect size, illustrated a statistically significant association between newborn vaccination with BCG alone or BCG-plus-OPV or OPV alone and neonatal death. Moreover, the heterogeneity was within the range of the pooled meta-analyses of all the studies. All the leave-one-out study meta-analyses revealed statistically significant heterogeneity, with a minimum range of[ I 2 = 55%] and a maximum range of[I 2 = 65% ].The effect measure range for the leave-one-out study meta-analysis was between [HR = 0.73, 95% CI (0.61–0.81)]. and [HR = 0.81, 95% CI (0.70–0.94)], which was within the range of pooled meta-analysis of the full studies(Table 3). Publication biases assessment Begg’s funnel plot showed that, the results were symmetrical and indicative of the absence of publication bias (Fig. 8 ). Certainty of evidence assessment On the basis of the GRDAE technique, the certainty evidence assessment overall conclusion indicated that it was highly certain. Discussion This study is the systematic review and meta-analysis conducted in low and low-to middle-income countries with an intervention of involving the vaccination of newborns with BCG alone or BCG-plus-OPV or OPV alone. On the basis of the results of the study, the overall risk of bias assessment was evaluated as a lower risk. In line with this, newborns vaccinated with BCG alone or BCG-plus-OPV, or OPV alone statistically significantly had a 22% lower risk of neonatal death than those not vaccinated newborn. The heterogeneity test indicated that a sign of statistically significant heterogeneity among studies included the in the review. With respect to subgroup analysis, study setting, exposure type and sample size variation were the sources of heterogeneity among studies. The results of the sensitivity analysis were illustrated consistent and no study was significantly affected the original pooled meta-analysis. The study reported that Begg's funnel plot was symmetrical, indicating the absence of publication bias. Moreover, the studies’ assessment of certainty evidence was revealed, it was highly certain. The main aims of this study were to produce concrete pooled evidence and to identify the source of inconsistency in the studies’ results. On the basis of RoB 2 risk of bias assessment, the study showed a lower risk bias. However, a similar meta-analysis study conducted in low and higher-income countries reported high risk of bias, in contrast to our study[ 13 ]. This might be due to the fact that, the studies included were different from our studies. The factors behind the low risk of bias were that the studies adequately addressed the potential source of bias across the five domains of RoB2 tool. The process for assigning participants to groups was truly random, the study maintained the intended interventions for most participants, data for specific outcomes were available for all participants, the method used to measure the outcome was appropriate, the outcome assessors were adequately blind to intervention group, and there was no evidence of selective reporting of favorable findings. Generally, the studies conducted to high methodological standards with a least amount of systematic error. Therefore, this judgment means the study provides reliable and trustworthy estimate of the intervention effect. With regard to pooled effect measure, newborns vaccinated with BCG alone or BCG + OPV, or OPV alone statistically significantly had a 22% lower risk of neonatal death compared to those not vaccinated new born [HR = 0.78, 95% CI(0.67–0.90), P < 0.001]. A similar study conducted in low and high- income countries with an intervention involving BCG only reported congruent results[ 13 ]. This might be because newborn vaccination can significantly lower neonatal mortality by protecting against infectious disease and offering nonspecific protective effects which may include in all-cause mortality. Live vaccines ,particularly BCG and OPV,provide border protection against unrelated infections, not their target disease. These off-target effects able to train the newborn’s innate immune system to respond more effectively to a wide range of common severe infections, such as respiratory illness and diarrhea, which are are major causes of neonatal death in low income settings(16). However, other scientific reports have also shown that vaccination has been far less successful in the first month of life, although it has undoubtedly helped older infants and children. The first reason is that the microorganisms that cause serious infections in the first few weeks of life are not specifically targeted by the immunizations now given to newborns. Second, infections can cause morbidity and mortality within the first few days after delivery,but it frequently takes weeks to prime a protective adaptive immune response in primarily unaffected newborn cells[ 3 , 4 , 12 ]. According to the results of the Cochrane's Q statistical test [Q = 20.44, df = 8, P = 0.009] and Higgins I 2 statistical test [I 2 = 61%] showed statistically significant substantial heterogeneity. A similar study from low and high-income countries with BCG only intervention illustrated c findings that were consistent with our study[ 50 ]. The subgroup analysis also indicated that the study setting, exposure type, and sample size variation were the sources of heterogeneity among the studies. This might because, heterogeneity in meta-analysis might be caused by differences between studies often referred to as clinical diversity (differences in populations, and interventions, and outcomes) and methodological issues (different study designs, measurement tools, and potential biases). These differences cause variability in study results that is greater than what would be expected by chance. This finding indicates that the results these studies are not consistent and that it and be difficult to draw a single, reliable conclusion from the combined results[ 51 ]. However, to mitigate the inconsistency in studies results the studies a random effects model was used for the meta-analysis, which helped to increase the reliability of the results. The results of the sensitivity analysis were consistent and no study significantly affected the original pooled meta-analysis. Therefore, the meta-analysis of the leave-one-out study produced a solid and credible result. No similar study was found with sensitivity analysis result for comparison. However, this finding was a true evidence that the overall conclusion of the meta-analysis was not dependent on the data from any single study. In line with this, there was no individual studies that disproportionately skewed the meta-analysis results. Moreover, the body of evidence was consistent and the combined result was a stable average of multiple results. The results of the meta-analysis increase confidence because the results are more credible and trustworthy, as they are not subjected the influence of single data point. With respect to publication bias, Begg's funnel plot was symmetrical, which was indicative of the absence of publication bias. There were no similar studies reporting publication bias for comparison. However, this might be true due to the fact that, the meta-analysis study identified and included six studies as statistically significant [ 13 – 14 , 16 , 19 – 21 ] and three studies as not statistically significant [ 15 , 17 – 18 ] association between newborn immunization and neonatal mortality. Similarly studies reported that, the absence of publication bias is interpreted as a study collection being representative of the research landscape, with both positive and negative statistical significance being published without bias. The absence of publication bias was very important, as the published literature more accurately reflected of the true state of evidence allowing researchers to draw more reliable and valid conclusions from the meta-analysis as the overall effect estimate was less likely to be skewed by unpublished studies[ 52 ]. The GRADE certainty evidence assessment revealed high- quality evidence. However, no similar study with a GRADE certainty assessment has been conducted for comparison. Nevertheless, high certainty means that the confidence in the evidence’s quality is high suggesting that the findings from a systematic review or meta-analysis are reliable and robust. This high rating indicates a strong belief in the effect estimate because the evidence is typically from high quality studies such as RCT studies and has not been significantly downgraded owing to factors such as bias, inconsistency or imprecision.Generally, a high grade provides a strong foundation for making clinical recommendation[ 53 ]. This meta-analysis had limitations and strengths. The limitation of this review was presence of substantial heterogeneity among the identified studies.However, the study tried to mitigate the heterogeneity among the studies statistically by applying a random effects model approach for meta-analysis. The reader of this article should consider that this heterogeneity might have an impact on the reliability of the pooled results the meta-analysis. Despite the above limitations, the study has several strengths. Those strengths were the study had low risk of bias, absence of publication bias, the sensitivity analysis was plausible, and the GRADE assessment was highly certain. These strengths are very imperative for obtaining reliable, robust, representative, generalizable, and clinically recommendable findings. Conclusions In conclusion, the meta-analysis result showed that newborns vaccinated with BCG alone or BCG-plus-OPV, or OPV alone had a 22% lower risk of neonatal death. In line with this, the source of inconsistency in the studies included in the meta-analysis was due to variation in sample size, intervention type, and study setting. Therefore, stakeholders, health workers, policymakers should promote and increase coverage of newborn vaccinations with BCG or BCG-plus-OPV or OPV as key components of child survival strategies to avert the high neonatal mortality. Future research should focus on RCTs study on other new born and maternal vaccinations such as Hepatitis B. Abbreviations BCG :Bacilius Calmiti Goroin, DF : Degree of Freedom, Embase : Excerpta medica data base, GRADE: Grading of Recommendations Assessment Development and Evaluation, HR : Hazard Ratio, LCI :Lower Confidence Interval, MEDLINE: Medical Literature Analysis and Retrieval System ,NM: Neonatal Mortality, OPV : Oral Polio Vaccine, PROSPERO: International Prospective Register of Systemic Review , RoB2 : Cochran’s Risk of Bias 2, SDG: Sustainable Development Goals, SE : Standard Error , UCI: Upper Confidence Interval, WHO: World health organization Declarations Ethical approval and consent to participate Not applicable Consent for publication Not applicable Availability of data and materials All the data generated during this meta-analysis and review are included in this manuscript with in the figure, tables, and supplementary material. Competing interests The authors declare that they have no competing interests. Funding Not applicable Authors' contributions FK was responsible from inception to design, literature search , analysis, and interpretation of data and preparing the manuscript. FM was participated as second independent reviewer, data extraction, and risk bias assessment. TG was participated as third independent reviewer, data extraction, risk bias assessment, and approve the final manuscript. All author read and approved the final manuscript. Acknowledgment The authors would like to thank all the authors and publishers of original studies. Authors’ Information FK: Benshangul Gumuz Regional Health Bureau, Epidemiologist, independent researcher and Disease Surveillance specialists, Assosa, Benshangul Gumuz Region, Ethiopia. FM: United Nation Children's Fund, Big Catch UP(BCU), Strategic Planning and programme Management, New York, USA. TG : Ethiopian Public Health Institute , Researcher, Addis Ababa, Ethiopia. References UNICEF (2025) Unicef data. 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PMID: 25210141; PMCID: PMC4340366 Biering-Sørensen S, Andersen A, Ravn H, Monterio I, Aaby P, Benn CS (2015) Early BCG vaccine to low-birth-weight infants and the effects on growth in the first year of life: a randomised controlled trial. BMC Pediatr 15:137. 10.1186/s12887-015-0452-2 PMID: 26416147; PMCID: PMC4587923 Aaby P, Andersen A, Martins CL, Fisker AB, Rodrigues A, Whittle HC, Benn CS (2016) Does oral polio vaccine have non-specific effects on all-cause mortality? Natural experiments within a randomised controlled trial of early measles vaccine. BMJ Open 6(12):e013335. 10.1136/bmjopen-2016-013335 PMID: 28011813; PMCID: PMC5223718 Prentice S, Nassanga B, Webb EL, Akello F, Kiwudhu F (2021) Delayed BCG Study Team. BCG-induced non-specific effects on heterologous infectious disease in Ugandan neonates: an investigator-blind randomised controlled trial. Lancet Infect Dis 21(7):993–1003. 10.1016/S1473-3099(20)30653-8 Epub 2021 Feb 17. PMID: 33609457; PMCID: PMC8222005 Roth AE, Benn CS, Ravn H, Rodrigues A, Lisse IMetal (2010) Effect of revaccination with BCG in early childhood on mortality: randomised trial in Guinea-Bissau. BMJ 340:c671. 10.1136/bmj.c671 PMID: 20231251; PMCID: PMC2839082 Michael Borenstein (2023) How to understand and report heterogeneity in a meta-analysis: The difference between I-squared and prediction intervals.Integrative Medicine Research. 12(4):101014. https://doi.org/10.1016/j.imr.2023.101014 Lin L, Chu H (2018) Quantifying publication bias in meta-analysis. Biometrics 74(3):785–794. 10.1111/biom.12817 Epub 2017 Nov 15. PMID: 29141096; PMCID: PMC5953768 Manya Prasa (2024) Introduction to the GRADE tool for rating certainty in evidence and recommendations.Clinical. Epidemiol Global Health 25(101484):2213–3984. https://doi.org/10.1016/j.cegh.2023.101484 Tables Table 1. Characteristics of studies included on effect of vaccination of new born on neonatal mortality, 2015-2025 Author, Year Region/location Study Design Sample Size Sampling Method Effect Measure Outcome Intervention Biering etal [13], 2018 Guinea Bissau Paralell RCT 6583 Random assignment HR NM BCG Denmark Lund etal [14], 2015 Guinea Bissau Paralell RCT 7012 Random assignment HR NM BCG+OPV Schaltz etal [15], 2021 Guinea Bissau Paralell RCT 3353 Random assignment HR NM BCG Thysen etal [16], 2024 Guinea Bissau Clustred RCT 2226 Random assignment HR NM BCG Japan+OPV Ferederic etal[17],2024 Guinea Bissau paralell RCT 8752 Random assignment HR NM BCG Russia Joyramanetal[18], 2019 India Paralell RCT 972 Random assignment HR NM BCG Russia+ OPV Adhsivam etal [19],2025 India Paralell RCT 5420 Random assignment HR NM BCG Danish +OPV Timmermann [20], 2015 Guinea Bissau Pralell RCT 2209 Random assignment HR NM BCG Nanque etal [21], 2024 Guinea Bissau Clustred RCT 10175 Random assignment HR NM OPV Table 2. Sensitivity analysis on effect of vaccination of new born on neonatal mortality, 2015 -2025 Excluded studies HR P value 95%LCI 95%UCI I 2 Q test value Q test p value Adhsivam etal[19], 2019 0.75 0.003 0.62 0.91 65% 20.25 0.005 Beiring etal[13], 2018 0.81 0.006 0.70 0.94 55% 15.58 0.03 Frederic etal[17],2024 0.73 0.001 0.61 0.89 60% 17.34 0.02 Joyoraman etal[18],2019 0.73 <0.001 0.62 0.87 59% 17.05 0.02 Lund etal[14], 2015 0.80 0.004 0.69 0.93 60% 17.42 0.01 Nanque etal[21], 2024 0.79 0.004 0.67 0.93 62% 18.47 0.01 Schaltz etal[15], 2021 0.76 <0.001 0.64 0.89 65% 20.20 0.005 Thysen etal16],2024[ 0.80 0.002 0.69 0.92 59% 17.26 0.02 Timmemannetal[20],2015 0.80 0.002 0.69 0.92 60% 17.37 0.02 N= total number of studies Notice : the presented study on each raw is excluded study from the over all included studies in the analysis(N - one study excluded ) Additional Declarations The authors declare no competing interests. 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08:43:50","extension":"xml","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":148353,"visible":true,"origin":"","legend":"","description":"","filename":"rs82184550structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-8218455/v1/1a8909e0f22d553adaf5bcaa.xml"},{"id":97131789,"identity":"47aae0fd-06ad-4ffa-82ba-7e182ee743c8","added_by":"auto","created_at":"2025-12-01 08:43:50","extension":"html","order_by":22,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":161603,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8218455/v1/46f02023bb8acf0f45ffa2c6.html"},{"id":97131760,"identity":"2d3c49ee-45f8-4843-9375-943685f9b22f","added_by":"auto","created_at":"2025-12-01 08:43:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":371344,"visible":true,"origin":"","legend":"\u003cp\u003eFlow Chart of study search result adapted from PRISMA to study on effect of vaccination of new born on neonatal mortality, 2015-2025\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8218455/v1/1061557370c5cffaa33c1e4d.png"},{"id":97131764,"identity":"f0d2c658-de17-4ee5-b514-f600e217a77d","added_by":"auto","created_at":"2025-12-01 08:43:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":375276,"visible":true,"origin":"","legend":"\u003cp\u003eRisk of bias assessment using cochran’s RoB 2 tool on effect of vaccination of new born on neonatal mortality, 2015-2025\u003c/p\u003e","description":"","filename":"Picture2.pngvaccination.png","url":"https://assets-eu.researchsquare.com/files/rs-8218455/v1/74ac45d309918ab6541d63c3.png"},{"id":97141328,"identity":"c323ac7c-84dd-436f-859a-5b474147204b","added_by":"auto","created_at":"2025-12-01 10:06:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":95134,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot of on effect of vaccination of new born on neonatal mortality, 2015-2025\u003c/p\u003e","description":"","filename":"Picture3.pngvaccination.png","url":"https://assets-eu.researchsquare.com/files/rs-8218455/v1/caa885988ea2bff86f632f77.png"},{"id":97131761,"identity":"ab91cb73-f7a9-4d94-b37a-f05d3f0df2d6","added_by":"auto","created_at":"2025-12-01 08:43:49","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":131376,"visible":true,"origin":"","legend":"\u003cp\u003eSub group analysis of study location on effect of vaccination of new born on neonatal mortality, 2015-2025\u003c/p\u003e","description":"","filename":"Picture4.pngvaccination.png","url":"https://assets-eu.researchsquare.com/files/rs-8218455/v1/885158ceae0cf11639db43e6.png"},{"id":97131762,"identity":"4a2d5a6e-0cb2-4375-8a6a-7e30824dce7b","added_by":"auto","created_at":"2025-12-01 08:43:49","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":131540,"visible":true,"origin":"","legend":"\u003cp\u003eSub group analysis of type of RCT design on effect of vaccination of new born on neonatal mortality, 2015-2025\u003c/p\u003e","description":"","filename":"Picture5.pngvaccination.png","url":"https://assets-eu.researchsquare.com/files/rs-8218455/v1/d039e22c1ed4f6076ab523f6.png"},{"id":97142951,"identity":"37bd3143-b2be-4581-8ccb-6971f19e259f","added_by":"auto","created_at":"2025-12-01 10:08:09","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":145574,"visible":true,"origin":"","legend":"\u003cp\u003eSub group analysis of intervention type on effect of vaccination of new born on neonatal mortality, 2015-2025\u003c/p\u003e","description":"","filename":"Picture6.pngvaccination.png","url":"https://assets-eu.researchsquare.com/files/rs-8218455/v1/38ab549ed542797e4e3ab35a.png"},{"id":97142273,"identity":"89f67d1c-6581-4b1e-849d-678495fe9865","added_by":"auto","created_at":"2025-12-01 10:07:28","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":144662,"visible":true,"origin":"","legend":"\u003cp\u003eSub group analysis of sample size on effect of vaccination of new born on neonatal mortality, 2015-2025\u003c/p\u003e","description":"","filename":"Picture7.pngvaccination.png","url":"https://assets-eu.researchsquare.com/files/rs-8218455/v1/013c65bd758241dd23675cc9.png"},{"id":97131766,"identity":"74b3e1a0-13f6-42f6-ba9b-5bea6eda81ed","added_by":"auto","created_at":"2025-12-01 08:43:49","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":27376,"visible":true,"origin":"","legend":"\u003cp\u003eBegg’s funnel plot on effect of vaccination of new born on neonatal mortality, 2015-2025\u003c/p\u003e","description":"","filename":"Picture8pngvaccination.png","url":"https://assets-eu.researchsquare.com/files/rs-8218455/v1/0c3974340c739fe6a4a014d1.png"},{"id":97248570,"identity":"6da69279-7025-4f28-8f24-35968b5cd378","added_by":"auto","created_at":"2025-12-02 13:03:33","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2499066,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8218455/v1/236ff5cf-151a-4142-ab7c-95a32729be34.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eEffects of vaccinations of newborn on neonatal mortality: A systematic review and meta-analysis of randomized controlled trials studies in low and low- to middle-income countries\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eAccording to the World Health Organization(WHO) definition, neonatal mortality is the death of a live -born neonates within the first 28 days of life. The neonatal period, it is the most insecure period for a child's survival and most children are risk of death. With an average global rate of 17 deaths per 1,000 live births in 2023, a 53% decrease from the 37 fatalities per 1,000 live births in 1990. [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Compared to postneonatal under5 mortality, neonatal mortality decreased more slowly between 1990 and 2022. Furthermore, unless immediate action is taken, 64 nations will not meet the Sustainable Development Goals(SDG) objective for newborn death by 2030, and the gains have decreased dramatically since 2010 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eSub-Saharan Africa was responsible for only 30% of live births worldwide in 2022, but 57% (2.8\u0026nbsp;million) of all under5 fatalities worldwide. With 27 neonatal deaths per 1000 live births, sub-Saharan Africa has the highest neonatal mortality rate globally. Compared with Australia and New Zealand, which have the lowest mortality rates, the probability of dying in the first month of birth is eleven times higher in sub-Saharan Africa [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Central and southern Asia have the second highest number of deaths, with 21 neonatal deaths per 1000 live births [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The probability of dying before the 28th day of life for a child born in the nation with the highest mortality rate was approximately 60 times higher than that of the country with the lowest mortality rate[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eNeonatal infections, congenital abnormalities, premature birth, and birth problems (such as hypoxia or trauma) continue to be the main causes of neonatal mortality. Conditions and diseases linked to inadequate quality care at birth or skilled care and treatment shortly after birth and in the first few days of life are experienced by children who pass away within the first 28 days of life [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe first few weeks following birth are when infectious morbidity and mortality are at their peak [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].The primarily unaffected phenotype of neonatal immune cells and unique immunological challenges at birth, which necessitate discrimination between a wide range of foreign antigens linked to primary commensal colonization as well as harmless self-antigens and non-inherited maternal antigens, indicating vulnerability. Overall, a combination of these physiological limitations is likely responsible for susceptibility to severe illness[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eOne of the most economical methods of illness prevention is still vaccination. Millions of infants receive vaccinations against poliomyelitis, hepatitis B, TB, tetanus, pertussis, and diphtheria averting with an estimated 2.5\u0026nbsp;million fatalities per year [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eVaccination has been far less successful in the first month of life, although it has undoubtedly helped older infants and children [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. To speed up the priming of protective immunological components, the World Health Organization advises vaccination against polio, hepatitis B, and tuberculosis as soon as possible after delivery (less than 24 hours) [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Similarly, maternal immunization provides vertically transferred immunity to prevent infection by specific pathogens [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, new data indicate that a variety of pathogens are responsible for newborn infections in lower- and lower-middle-income countries [9,10.11]. Notably, there are currently no vaccines in clinical use that protect against any of these infections. Furthermore, even with the application of state-of-the-art diagnostic techniques, the triggering pathogen was not found in more than 70% of cases of clinically suspected infection [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The percentage of causative pathogens that immunization misses is probably higher than is currently understood, even though some of these undetected instances might not be true infections. Alternative approaches are therefore needed to improve early- life immunity against a broad range of diseases. To optimize early-life immunity, we describe the principles underlying the vaccination of newborns and their mothers, including the increasingly acknowledged pathogen-agnostic benefits that emphasize the necessity of viewing the mother-newborn relationship as a single immunological unit [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe lack of existing immunization programs resulted in neonatal mortality reductions equivalent to those observed in older infants and children, considering that neonates are capable of robust vaccine responses. First, the microorganisms that cause serious infections in the first few weeks of life are not specifically targeted by the immunizations now given to newborns. Even while polio, hepatitis B, and tuberculosis can be contract in the first few weeks of life, these illnesses typically show clinical symptoms outside of the newborn period. Vaccines against pathogens and several other germs that do cause severe infection in the first weeks, either unavailable or have not yet been attempts in neonates[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Second, infections can cause morbidity and mortality within the first few days after delivery,buy it frequently takes weeks to prime a protective adaptive immune response in primarily unaffected newborn cells (12). Strategies aimed at producing protective neonatal adaptive immune components are difficult because of the discrepancy between the time it takes to prime protective pathogen-specific immunity and the time which infections arise [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePrevious RCTs(randomized controlled trials) have shown inconsistent results. Some studies from lower and lower- to middle- income countries have shown statistically significant associations and other studies have revealed the absence of a statistical significant association between vaccination of newborns and neonatal mortality [\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17 CR18 CR19 CR20\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Previously, a meta-analysis was conducted on the effect of only BCG vaccination on neonatal mortality[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, our study concurrently scrutinized the effects of vaccinations of newborns with only BCG, or BCG -plus- OPV, or OPV alone on neonatal mortality. The main aims of this study were to determine the pooled effect measure and assess the source of inconsistency in the results regarding effect of vaccination of newborns on neonatal mortality. Therefore, it is essential to conduct a systematic review and meta-analysis of studies to produce concrete evidence regarding the effect of vaccination of newborns on neonatal mortality for all stakeholders, health workers and policy makers in low and low-middle-income countries in order to implement and improve coverage of the new new born immunization programs.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy settings, study design and registration\u003c/h2\u003e\u003cp\u003eThe studies included in this systematic review and meta-analysis were from low and low -to middle-income countries such as Guinea Bissau and India. The study design applied was systematic review and meta-analysis. Furthermore, this study adhered to the PRISMA statement (Preferred Reporting Items for Systemic Review and Meta-Analysis) guidelines to process the review [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Moreover, the protocol of this systematic review and meta-analysis was registered in PROSPRO (International Prospective Register of Systematic Review)with registration number CRD420251164676.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eEligibility criteria\u003c/h3\u003e\n\u003cp\u003e\u003cb\u003eStudy type\u003c/b\u003e : The inclusion criterion for studies was RCTs, which were published in English between January, 2015 and November, 2025. The exclusion criteria were studies with abstracts only, studies published not in English, and studies conducted in developed countries.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStudy population\u003c/b\u003e : The inclusion criterion for the study population was that all neonates lived for 28 completed days of life and that all neonates died during the 28 completed days of life. The exclusion criteria was that all neonates lived and died after the 28 days of new born life.\u003c/p\u003e\u003cp\u003e\u003cb\u003eOutcome of interest\u003c/b\u003e: The inclusion criterion for the outcome of the study was death of neonates within the 28 completed days of life. The exclusion criterion was neonatal death occurring after the 28 days of new born.\u003c/p\u003e\u003cp\u003e\u003cb\u003eExposure of interest\u003c/b\u003e : The inclusion criterion for the exposure was vaccination of newborn with BCG(Bacillus Calamity Groin) alone or OPV (Oral Polio Vaccine) alone or BCG-plus-OPV. The exclusion criteria were vaccination of newborns with BCG alone or OPV alone or BCG- plus- OPV after 28 completed days newborn life.\u003c/p\u003e\n\u003ch3\u003eInformation source and search strategy\u003c/h3\u003e\n\u003cp\u003eA systematic electronic database search was conducted in PubMed, MEDLINE, Embase, and Google Scholar. The search approach included terms related to exposure, outcome, participants ,and study design. We applied the following search strategy in PubMed and MEDLINE as follow: (((vaccination) OR (immunization)) AND (neonatal mortality)) AND (randomized controlled trial). In Google Scholar : \u0026ldquo;vaccination\u0026rdquo; \u0026ldquo;immunization\u0026rdquo; \u0026ldquo;neonatal-mortality\u0026rdquo; \u0026ldquo;randomized controlled trials\u0026rdquo;\u003c/p\u003e\n\u003ch3\u003eStudy selection process\u003c/h3\u003e\n\u003cp\u003eTwo unbiased reviewers(FK and FM) initially scanned abstracts and titles to select potential full-text articles for further analysis. Following approval of the title and abstract, the full texts of the studies were accessed via linked databases and carefully reviewed for inclusion by the two reviewers. Studies that were published by the same researchers and look at the same factor were evaluated for any duplicate data on the basis of the year of publication and the subject regions.\u003c/p\u003e\n\u003ch3\u003eData Extraction Process\u003c/h3\u003e\n\u003cp\u003eThe included studies were retrieved and calibrated via an Excel data extraction form that the researcher created on the basis of the pilot review. Two reviewers(FK and FM) were independently extracted data from the eligible research studies in order to assess quality of studies and synthesize the data. A third reviewer(TG) was then be consulted in order to identify and resolve any differences. measurement. Any missing data were requested via email from the authors of the study.\u003c/p\u003e\u003cp\u003e\u003cb\u003eData items (outcome)\u003c/b\u003e : The outcome domain and definition were neonatal mortality, which is the death of a newborn child within 28 completed days of newborn life.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eData items(other variable)\u003c/strong\u003e\u003cp\u003eThe following detail information was obtained, author, study site, study population exposure details, study design, information on risk of bias assessment, sample size, confounding, effect size, and standard error.\u003c/p\u003e\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStudy risk of bias assessment\u003c/h2\u003e\u003cp\u003eTo investigate the impact of eliminating low-quality research, the quality assessment's overall findings were employed in data synthesis for a prearranged sensitivity analysis, by evaluating the quality of research via the RoB2 tool(Cochran risk of bias 2) [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Two reviewers(FK and FM) were independently assessed the risk of bias in the included studies. In order to settle any disputes between the two reviewers about the possibility of bias in certain research, a third reviewer(TG) was participated in the conversation. The RoB2 method is applied across five domains : bias arising from the randomization process, bias due to deviation from intended interventions, bias due to missing outcome of data, bias in the measurement of the outcome, and bias in the selection of reported results.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSynthesis methods\u003c/h3\u003e\n\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003ePooled effect and heterogeneity test\u003c/h2\u003e\u003cp\u003eAll analyses were conducted with Review Manager(RevMan) 5.4.1 software. When heterogeneity was confirmed, a random effects model with a p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was used. We provided a summary of effects for each study by computing thehazard ratio(HR), which is the recommended method for RCT data, with a 95% confidence interval and p-value for the outcome. To assess the degree of inconsistency among studies, methodological differences were assessed via Cochrane's Q statistics and Higgins\u0026rsquo; I\u0026sup2; statistics. An I\u0026sup2; value greater than 50% and a P value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistical significant heterogeneity[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eSubgroup analysis\u003c/h2\u003e\u003cp\u003eSubgroup analysis was used to scrutinize the influence of variables on the combined effect size and source of the heterogeneity among studies. If the P value was \u0026lt;\u0026thinsp;0.005 the subgroup differences considered significant.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eSensitivity analysis\u003c/h2\u003e\u003cp\u003eBy eliminating one study at a time, the leave-one-out meta-analysis is a technique that analyzes the impact of each individual study on the total effect size. By continually performing a meta-analyses and adding a new study on the basis of its sample size, cumulative meta-analysis was used to evaluate the influence of the larger studies on the effect size.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003ePublication bias assessment\u003c/h2\u003e\u003cp\u003eBegg's modified funnel plot was used when five or more studies are scrutinized the association of a certain component [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. To fill in the gaps in knowledge about the methodologies used in the included research and to obtain missing data, we contacted the authors via the email addresses listed in the publications.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003eCertainty evidence assessment\u003c/h2\u003e\u003cp\u003eThe GRADE technique [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] was used to evaluate the degree of certainty, and GRADEpro [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]software was applied to illustrate the results. Criteria used to assess the certainty of evidence results include number of studies ,research design, risk of bias, inconsistencies, indirectness, imprecision, publication bias, confounding ,large effect size, and dosage response prediction.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eStudy selection\u003c/h2\u003e\u003cp\u003eBetween September 10, 2025, and October 10, 2025, a literature review was carried out using databases from Google Scholar, Embase, MEDLINE, and PubMed. We discovered 2777 articles, pertaining to this review topic between January 2015 and October 10, 2025. After eliminating duplicate record retrievals, 2621 records remained; 2590 of them were removed during the first evaluation because of their irrelevant titles. The full texts of the remaining 31 documents were reviewed and confirmed. Out of the 31 records that were evaluated for eligibility, 22 studies [\u003cspan additionalcitationids=\"CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38 CR39 CR40 CR41 CR42 CR43 CR44 CR45 CR46 CR47 CR48 CR49\" citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e] were disqualified because they were identified to have no similarity on in terms of exposure, outcome or study design. Nine full-text research papers [\u003cspan additionalcitationids=\"CR14 CR15 CR16 CR17 CR18 CR19 CR20\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]were obtained and added to the review on the basis of predetermined criteria (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eStudy characteristics\u003c/h2\u003e\u003cp\u003eThe studies included in the review were from Guinea Bissau and India. All of the studies included were randomized controlled trials design. A total of 40772 participants were involved in the studies. The sampling method the studies employed was random assignment. All studies used an intervention of BCG only or BCG-plus-OPV or OPV alone(Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eRisk of bias assessment\u003c/h2\u003e\u003cp\u003eThe overall risk of bias for the study and for each study included was demonstrated a lower risk(Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003eResults of synthesis\u003c/h2\u003e\u003cdiv id=\"Sec20\" class=\"Section3\"\u003e\u003ch2\u003ePooled results and heterogeneity test\u003c/h2\u003e\u003cp\u003eSince the studies were heterogeneous, we preferred a random effects model for the meta-analysis. The overall pooled effect measure revealed that \u003cb\u003en\u003c/b\u003eewborn vaccination with BCG alone or BCG-plus-OPV or OPV alone was statistically significantly associated with a decreased risk of neonatal mortality [HR\u0026thinsp;=\u0026thinsp;0.78, 95% CI (0.67\u0026ndash;0.90), P\u0026thinsp;\u0026lt;\u0026thinsp;0.001]. The Higgins I\u003csup\u003e2\u003c/sup\u003e statistical test, revealed that [I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;61%], and the Cochran's Q statistical test reported that [Q\u0026thinsp;=\u0026thinsp;20.44, DF (degree of freedom)\u0026thinsp;=\u0026thinsp;8, P\u0026thinsp;=\u0026thinsp;0.009]. These results unveiled the statistical significance of heterogeneity among the studies(Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec21\" class=\"Section2\"\u003e\u003ch2\u003eSubgroup analysis\u003c/h2\u003e\u003cp\u003eSubgroup analysis studies from Guinea Bissau revealed a statistically significant correlation between vaccinations of newborn and neonatal mortality(P\u0026thinsp;=\u0026thinsp;0.002). However, studies from India showed that this difference was not statistical significant(P\u0026thinsp;=\u0026thinsp;0.34). The test for subgroup differences indicated that no statistical significant differences with substantial heterogeneity [ Q test\u0026thinsp;=\u0026thinsp;3.02, df\u0026thinsp;=\u0026thinsp;1, P\u0026thinsp;=\u0026thinsp;0.08, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;66%](Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eA statistically significant correlation was discovered for both the parallel and clustered RCTs designs (P\u0026thinsp;=\u0026thinsp;0.007) and (p\u0026thinsp;=\u0026thinsp;0.009) respectively. The subgroup difference test also showed not statistical significant and presence of heterogeneity[Q test\u0026thinsp;=\u0026thinsp;2.12, DF\u0026thinsp;=\u0026thinsp;1, P\u0026thinsp;=\u0026thinsp;0.15, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;52.9%] (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eIntervention with BCG only and BCG-plus-OPV was not statistically significantly associated with neonatal mortality(P\u0026thinsp;=\u0026thinsp;0.06). However; intervention with OPV statistically significantly associated with the risk of neonatal mortality ( P\u0026thinsp;=\u0026thinsp;0.03). Overall, the subgroup difference test indicated that not statistically significant differences, with an absence of heterogeneity[ Q\u0026thinsp;=\u0026thinsp;0.56, DF\u0026thinsp;=\u0026thinsp;2, P\u0026thinsp;=\u0026thinsp;0.76, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0] (Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eWith respect to sample size, When sample size\u0026thinsp;\u0026lt;\u0026thinsp;5000 was not statistically significantly associated with newborn vaccination and neonatal mortality ( P\u0026thinsp;=\u0026thinsp;0.15). However, when sample size was 5000-10,000 and \u0026gt;\u0026thinsp;10,000 a statistically significant association was detected (P\u0026thinsp;=\u0026thinsp;0.007) and (P\u0026thinsp;=\u0026thinsp;0.03) respectively. Overall the subgroup difference test demonstrated not statistically significant differences, with an absence of heterogeneity studies[ Q\u0026thinsp;=\u0026thinsp;0.54, df\u0026thinsp;=\u0026thinsp;2, P\u0026thinsp;=\u0026thinsp;0.76, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%](Fig.\u0026nbsp;\u003cspan refid=\"Fig9\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e\u003ch2\u003eSensitivity analysis\u003c/h2\u003e\u003cp\u003eAccording to the results of our sensitivity analysis, the point-estimated effect size of HR that was obtained when one study excluded from the meta-analysis fell within the confidence interval of the meta-analysis's pooled effect size, illustrated a statistically significant association between newborn vaccination with BCG alone or BCG-plus-OPV or OPV alone and neonatal death. Moreover, the heterogeneity was within the range of the pooled meta-analyses of all the studies. All the leave-one-out study meta-analyses revealed statistically significant heterogeneity, with a minimum range of[ I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;55%] and a maximum range of[I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;65% ].The effect measure range for the leave-one-out study meta-analysis was between [HR\u0026thinsp;=\u0026thinsp;0.73, 95% CI (0.61\u0026ndash;0.81)]. and [HR\u0026thinsp;=\u0026thinsp;0.81, 95% CI (0.70\u0026ndash;0.94)], which was within the range of pooled meta-analysis of the full studies(Table\u0026nbsp;3).\u003c/p\u003e\u003cdiv id=\"Sec23\" class=\"Section3\"\u003e\u003ch2\u003ePublication biases assessment\u003c/h2\u003e\u003cp\u003eBegg\u0026rsquo;s funnel plot showed that, the results were symmetrical and indicative of the absence of publication bias (Fig.\u0026nbsp;\u003cspan refid=\"Fig10\" class=\"InternalRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec24\" class=\"Section2\"\u003e\u003ch2\u003eCertainty of evidence assessment\u003c/h2\u003e\u003cp\u003eOn the basis of the GRDAE technique, the certainty evidence assessment overall conclusion indicated that it was highly certain.\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study is the systematic review and meta-analysis conducted in low and low-to middle-income countries with an intervention of involving the vaccination of newborns with BCG alone or BCG-plus-OPV or OPV alone. On the basis of the results of the study, the overall risk of bias assessment was evaluated as a lower risk. In line with this, newborns vaccinated with BCG alone or BCG-plus-OPV, or OPV alone statistically significantly had a 22% lower risk of neonatal death than those not vaccinated newborn. The heterogeneity test indicated that a sign of statistically significant heterogeneity among studies included the in the review. With respect to subgroup analysis, study setting, exposure type and sample size variation were the sources of heterogeneity among studies. The results of the sensitivity analysis were illustrated consistent and no study was significantly affected the original pooled meta-analysis. The study reported that Begg's funnel plot was symmetrical, indicating the absence of publication bias. Moreover, the studies\u0026rsquo; assessment of certainty evidence was revealed, it was highly certain. The main aims of this study were to produce concrete pooled evidence and to identify the source of inconsistency in the studies\u0026rsquo; results.\u003c/p\u003e\u003cp\u003eOn the basis of RoB 2 risk of bias assessment, the study showed a lower risk bias. However, a similar meta-analysis study conducted in low and higher-income countries reported high risk of bias, in contrast to our study[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. This might be due to the fact that, the studies included were different from our studies. The factors behind the low risk of bias were that the studies adequately addressed the potential source of bias across the five domains of RoB2 tool. The process for assigning participants to groups was truly random, the study maintained the intended interventions for most participants, data for specific outcomes were available for all participants, the method used to measure the outcome was appropriate, the outcome assessors were adequately blind to intervention group, and there was no evidence of selective reporting of favorable findings. Generally, the studies conducted to high methodological standards with a least amount of systematic error. Therefore, this judgment means the study provides reliable and trustworthy estimate of the intervention effect.\u003c/p\u003e\u003cp\u003eWith regard to pooled effect measure, newborns vaccinated with BCG alone or BCG\u0026thinsp;+\u0026thinsp;OPV, or OPV alone statistically significantly had a 22% lower risk of neonatal death compared to those not vaccinated new born [HR\u0026thinsp;=\u0026thinsp;0.78, 95% CI(0.67\u0026ndash;0.90), P\u0026thinsp;\u0026lt;\u0026thinsp;0.001]. A similar study conducted in low and high- income countries with an intervention involving BCG only reported congruent results[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. This might be because newborn vaccination can significantly lower neonatal mortality by protecting against infectious disease and offering nonspecific protective effects which may include in all-cause mortality. Live vaccines ,particularly BCG and OPV,provide border protection against unrelated infections, not their target disease. These off-target effects able to train the newborn\u0026rsquo;s innate immune system to respond more effectively to a wide range of common severe infections, such as respiratory illness and diarrhea, which are are major causes of neonatal death in low income settings(16). However, other scientific reports have also shown that vaccination has been far less successful in the first month of life, although it has undoubtedly helped older infants and children. The first reason is that the microorganisms that cause serious infections in the first few weeks of life are not specifically targeted by the immunizations now given to newborns. Second, infections can cause morbidity and mortality within the first few days after delivery,but it frequently takes weeks to prime a protective adaptive immune response in primarily unaffected newborn cells[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAccording to the results of the Cochrane's Q statistical test [Q\u0026thinsp;=\u0026thinsp;20.44, df\u0026thinsp;=\u0026thinsp;8, P\u0026thinsp;=\u0026thinsp;0.009] and Higgins I\u003csup\u003e2\u003c/sup\u003e statistical test [I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;61%] showed statistically significant substantial heterogeneity. A similar study from low and high-income countries with BCG only intervention illustrated c findings that were consistent with our study[\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. The subgroup analysis also indicated that the study setting, exposure type, and sample size variation were the sources of heterogeneity among the studies. This might because, heterogeneity in meta-analysis might be caused by differences between studies often referred to as clinical diversity (differences in populations, and interventions, and outcomes) and methodological issues (different study designs, measurement tools, and potential biases). These differences cause variability in study results that is greater than what would be expected by chance. This finding indicates that the results these studies are not consistent and that it and be difficult to draw a single, reliable conclusion from the combined results[\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. However, to mitigate the inconsistency in studies results the studies a random effects model was used for the meta-analysis, which helped to increase the reliability of the results.\u003c/p\u003e\u003cp\u003eThe results of the sensitivity analysis were consistent and no study significantly affected the original pooled meta-analysis. Therefore, the meta-analysis of the leave-one-out study produced a solid and credible result. No similar study was found with sensitivity analysis result for comparison. However, this finding was a true evidence that the overall conclusion of the meta-analysis was not dependent on the data from any single study. In line with this, there was no individual studies that disproportionately skewed the meta-analysis results. Moreover, the body of evidence was consistent and the combined result was a stable average of multiple results. The results of the meta-analysis increase confidence because the results are more credible and trustworthy, as they are not subjected the influence of single data point.\u003c/p\u003e\u003cp\u003eWith respect to publication bias, Begg's funnel plot was symmetrical, which was indicative of the absence of publication bias. There were no similar studies reporting publication bias for comparison. However, this might be true due to the fact that, the meta-analysis study identified and included six studies as statistically significant [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e] and three studies as not statistically significant [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] association between newborn immunization and neonatal mortality. Similarly studies reported that, the absence of publication bias is interpreted as a study collection being representative of the research landscape, with both positive and negative statistical significance being published without bias. The absence of publication bias was very important, as the published literature more accurately reflected of the true state of evidence allowing researchers to draw more reliable and valid conclusions from the meta-analysis as the overall effect estimate was less likely to be skewed by unpublished studies[\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe GRADE certainty evidence assessment revealed high- quality evidence. However, no similar study with a GRADE certainty assessment has been conducted for comparison. Nevertheless, high certainty means that the confidence in the evidence\u0026rsquo;s quality is high suggesting that the findings from a systematic review or meta-analysis are reliable and robust. This high rating indicates a strong belief in the effect estimate because the evidence is typically from high quality studies such as RCT studies and has not been significantly downgraded owing to factors such as bias, inconsistency or imprecision.Generally, a high grade provides a strong foundation for making clinical recommendation[\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis meta-analysis had limitations and strengths. The limitation of this review was presence of substantial heterogeneity among the identified studies.However, the study tried to mitigate the heterogeneity among the studies statistically by applying a random effects model approach for meta-analysis. The reader of this article should consider that this heterogeneity might have an impact on the reliability of the pooled results the meta-analysis. Despite the above limitations, the study has several strengths. Those strengths were the study had low risk of bias, absence of publication bias, the sensitivity analysis was plausible, and the GRADE assessment was highly certain. These strengths are very imperative for obtaining reliable, robust, representative, generalizable, and clinically recommendable findings.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, the meta-analysis result showed that newborns vaccinated with BCG alone or BCG-plus-OPV, or OPV alone had a 22% lower risk of neonatal death. In line with this, the source of inconsistency in the studies included in the meta-analysis was due to variation in sample size, intervention type, and study setting. Therefore, stakeholders, health workers, policymakers should promote and increase coverage of newborn vaccinations with BCG or BCG-plus-OPV or OPV as key components of child survival strategies to avert the high neonatal mortality. Future research should focus on RCTs study on other new born and maternal vaccinations such as Hepatitis B.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBCG :Bacilius Calmiti Goroin, DF : Degree of Freedom, Embase : Excerpta medica data base, GRADE: Grading of Recommendations Assessment Development and Evaluation, HR : Hazard Ratio, LCI :Lower Confidence Interval, MEDLINE: Medical Literature Analysis and Retrieval System ,NM: Neonatal Mortality, OPV : Oral Polio Vaccine, PROSPERO: International Prospective Register of Systemic Review , RoB2 : Cochran\u0026rsquo;s Risk of Bias 2, SDG: Sustainable Development Goals, SE : Standard Error , \u0026nbsp; UCI: Upper Confidence Interval, WHO: World health organization\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthical approval and consent to participate \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent for publication \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;All the data generated during this meta-analysis and review are included in this manuscript \u0026nbsp;with in the figure, tables, and supplementary material.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompeting interests \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The authors declare that they have no competing interests. \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFunding \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not applicable\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;FK was responsible from inception to design, literature search , analysis, and interpretation of data and preparing the manuscript. FM was participated as second independent reviewer, data extraction, and risk bias assessment. TG was participated as third independent reviewer, data extraction, risk bias assessment, and approve the final manuscript. All author read and approved the final manuscript. \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcknowledgment\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The authors would like to thank all the authors and publishers of original studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; Information\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;FK: Benshangul Gumuz Regional Health Bureau, Epidemiologist, independent researcher and Disease Surveillance specialists, Assosa, Benshangul Gumuz Region, \u0026nbsp;Ethiopia. FM: United Nation Children\u0026apos;s Fund, Big Catch UP(BCU), Strategic Planning and programme Management, New York, USA. \u003csup\u003e\u0026nbsp;\u003c/sup\u003e TG : Ethiopian Public Health Institute , Researcher, Addis Ababa, Ethiopia. \u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eUNICEF (2025) Unicef data. Monitoring the situation of children and women. March\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWHO (2024) New born mortality. Key facts\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang H, Liddell CA, Coates MM, Mooney MD, Levitz CE (2014) Global, regional, and national levels of neonatal, infant, and under-5 mortality during 1990\u0026ndash;2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. ;384(9947):957\u0026thinsp;\u0026ndash;\u0026thinsp;79. doi: 10.1016/S0140-6736(14)60497-9. Epub 2014 May 2. 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Biometrics 74(3):785\u0026ndash;794. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/biom.12817\u003c/span\u003e\u003cspan address=\"10.1111/biom.12817\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003eEpub 2017 Nov 15. PMID: 29141096; PMCID: PMC5953768\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eManya Prasa (2024) Introduction to the GRADE tool for rating certainty in evidence and recommendations.Clinical. Epidemiol Global Health 25(101484):2213\u0026ndash;3984. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.cegh.2023.101484\u003c/span\u003e\u003cspan address=\"10.1016/j.cegh.2023.101484\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1. Characteristics of studies included on effect of vaccination of new born on neonatal mortality, 2015-2025\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"left\" width=\"1048\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Author, \u0026nbsp; \u0026nbsp;Year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 135px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Region/location\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; Study Design\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003eSample Size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 146px;\"\u003e\n \u003cp\u003e\u0026nbsp; Sampling Method\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 110px;\"\u003e\n \u003cp\u003eEffect Measure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eOutcome\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 148px;\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp;Intervention\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003eBiering etal [13], 2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 135px;\"\u003e\n \u003cp\u003eGuinea Bissau\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 118px;\"\u003e\n \u003cp\u003eParalell RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e6583\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 146px;\"\u003e\n \u003cp\u003eRandom assignment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 110px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 148px;\"\u003e\n \u003cp\u003eBCG Denmark\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003eLund etal [14], 2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 135px;\"\u003e\n \u003cp\u003eGuinea Bissau\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 118px;\"\u003e\n \u003cp\u003eParalell RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e7012\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 146px;\"\u003e\n \u003cp\u003eRandom assignment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 110px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 148px;\"\u003e\n \u003cp\u003eBCG+OPV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003eSchaltz etal [15], 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 135px;\"\u003e\n \u003cp\u003eGuinea Bissau\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 118px;\"\u003e\n \u003cp\u003eParalell \u0026nbsp;RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e3353\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 146px;\"\u003e\n \u003cp\u003eRandom assignment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 110px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 148px;\"\u003e\n \u003cp\u003eBCG\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003eThysen etal [16], 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 135px;\"\u003e\n \u003cp\u003eGuinea Bissau\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 118px;\"\u003e\n \u003cp\u003eClustred RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e2226\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 146px;\"\u003e\n \u003cp\u003eRandom assignment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 110px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 148px;\"\u003e\n \u003cp\u003eBCG Japan+OPV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003eFerederic etal[17],2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 135px;\"\u003e\n \u003cp\u003eGuinea Bissau\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 118px;\"\u003e\n \u003cp\u003eparalell RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e8752\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 146px;\"\u003e\n \u003cp\u003eRandom assignment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 110px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 148px;\"\u003e\n \u003cp\u003eBCG \u0026nbsp; Russia\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003eJoyramanetal[18], 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 135px;\"\u003e\n \u003cp\u003eIndia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 118px;\"\u003e\n \u003cp\u003e\u0026nbsp;Paralell RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e972\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 146px;\"\u003e\n \u003cp\u003eRandom assignment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 110px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 148px;\"\u003e\n \u003cp\u003eBCG Russia+ OPV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003eAdhsivam etal [19],2025\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 135px;\"\u003e\n \u003cp\u003eIndia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 118px;\"\u003e\n \u003cp\u003eParalell RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e5420\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 146px;\"\u003e\n \u003cp\u003eRandom assignment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 110px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 148px;\"\u003e\n \u003cp\u003eBCG Danish +OPV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003eTimmermann [20], 2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 135px;\"\u003e\n \u003cp\u003eGuinea Bissau\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 118px;\"\u003e\n \u003cp\u003ePralell RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e2209\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 146px;\"\u003e\n \u003cp\u003eRandom assignment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 110px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 148px;\"\u003e\n \u003cp\u003eBCG\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 225px;\"\u003e\n \u003cp\u003eNanque etal [21], 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 135px;\"\u003e\n \u003cp\u003eGuinea Bissau\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 118px;\"\u003e\n \u003cp\u003eClustred RCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 95px;\"\u003e\n \u003cp\u003e10175\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 146px;\"\u003e\n \u003cp\u003eRandom assignment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 110px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 72px;\"\u003e\n \u003cp\u003eNM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 148px;\"\u003e\n \u003cp\u003eOPV\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp; Table 2. Sensitivity analysis on effect of vaccination of new born on neonatal mortality, 2015 -2025\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"105%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 29px;\"\u003e\n \u003cp\u003e\u0026nbsp;Excluded studies\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 6px;\"\u003e\n \u003cp\u003eHR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003e95%LCI\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e95%UCI\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 7px;\"\u003e\n \u003cp\u003eI \u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003eQ test value\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003eQ test p value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 29px;\"\u003e\n \u003cp\u003eAdhsivam etal[19], 2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 6px;\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.91\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 7px;\"\u003e\n \u003cp\u003e65%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e20.25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 29px;\"\u003e\n \u003cp\u003eBeiring etal[13], 2018\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 6px;\"\u003e\n \u003cp\u003e0.81\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003e0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 7px;\"\u003e\n \u003cp\u003e55%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e15.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 29px;\"\u003e\n \u003cp\u003eFrederic etal[17],2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 6px;\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003e0.61\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 7px;\"\u003e\n \u003cp\u003e60%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e17.34\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 29px;\"\u003e\n \u003cp\u003eJoyoraman etal[18],2019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 6px;\"\u003e\n \u003cp\u003e0.73\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 7px;\"\u003e\n \u003cp\u003e59%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e17.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 29px;\"\u003e\n \u003cp\u003eLund etal[14], 2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 6px;\"\u003e\n \u003cp\u003e0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 7px;\"\u003e\n \u003cp\u003e60%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e17.42\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 29px;\"\u003e\n \u003cp\u003eNanque etal[21], 2024\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 6px;\"\u003e\n \u003cp\u003e0.79\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.93\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 7px;\"\u003e\n \u003cp\u003e62%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e18.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 29px;\"\u003e\n \u003cp\u003eSchaltz etal[15], 2021\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 6px;\"\u003e\n \u003cp\u003e0.76\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003e0.64\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.89\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 7px;\"\u003e\n \u003cp\u003e65%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e20.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 29px;\"\u003e\n \u003cp\u003eThysen etal16],2024[\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 6px;\"\u003e\n \u003cp\u003e0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 7px;\"\u003e\n \u003cp\u003e59%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e17.26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 29px;\"\u003e\n \u003cp\u003eTimmemannetal[20],2015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 6px;\"\u003e\n \u003cp\u003e0.80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 11px;\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.92\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 7px;\"\u003e\n \u003cp\u003e60%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 9px;\"\u003e\n \u003cp\u003e17.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 12px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"bottom\" style=\"width: 29px;\"\u003e\n \u003cp\u003eN= total number of studies\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"7\" valign=\"bottom\" style=\"width: 70px;\"\u003e\n \u003cp\u003eNotice : the presented study on each raw is excluded study from the over all included studies in the analysis(N - one study excluded )\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Neonatal mortality, Vaccination, BCG, OPV, heterogeneity, risk bias, sensitivity","lastPublishedDoi":"10.21203/rs.3.rs-8218455/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8218455/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground: Newborn vaccination can significantly lower neonatal mortality by protecting against infectious disease and offering nonspecific protective effects, which may include in all-cause mortality. Studies conducted on new born vaccination and neonatal mortality in low and low-to middle-income countries have shown inconsistency results. Therefore, the objectives of this study were to produce concrete pooled evidence and to identify the source of inconsistency in the studies’ results.\u003c/h2\u003e\n\u003cp\u003eMethods : The protocol of this study was registered in the International Prospective Register of Systematic Review with registration number CRD420251164676. Moreover, this study adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Studies were identified through databases searchs in PubMed, MEDLINE, Embase, and Google Scholar. All the meta-analyses were conducted via Review manager 5.4.1. Statistical tests were conducted by applying random effect model of pooled effect measures, heterogeneity, subgroup analyses and sensitivity analyses. Furthermore, risk bias, publication bias ,and certainty evidence assessments were performed.\u003c/p\u003e\n\u003cp\u003eResults: Nine studies, with total sample size 40772 were included in the review, on the basis of established criteria. The pooled effect measure revealed that vaccination of newborns with BCG only or BCG-plus-OPV or OPV alone significantly decrease the risk of neonatal mortality by 22% [HR= 0.78 , 95% CI (0.67 - 0.90), P \u0026lt;0.001].\u0026nbsp; Moreover, heterogeneity was detected with the Higgins I\u003csup\u003e2\u003c/sup\u003e\u0026nbsp; statistical test [I\u003csup\u003e2\u003c/sup\u003e = 61%], and the Cochran's Q statistical test [Q=20.44, DF= 8, P = 0.009]. Sample size, intervention type, and study setting variation were the sources of the heterogeneity. The sensitivity analysis indicated that\u0026nbsp; the absence of influential studies was plausible. Furthermore, the study revealed the absence of publication bias. The certainty\u0026nbsp; evidence of\u0026nbsp; the\u0026nbsp; studies was high grade.\u003cbr\u003e\nConclusions:\u003cstrong\u003e \u003c/strong\u003e\u0026nbsp;The study results showed that newborns vaccinated with BCG alone or BCG-plus-OPV, or OPV alone had a 22% lower risk of neonatal death. Moreover, the source of inconsistency in the included studies was due to variation in sample size, intervention type, and study setting. Therefore, all stakeholders should\u0026nbsp; promote increasing coverage of new born vaccination. Future research should focus on other newborn vaccines such as hepatitis B.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ePROSPERO Protocol registration\u003cstrong\u003e :\u003c/strong\u003e CRD420251164676\u003c/p\u003e","manuscriptTitle":"Effects of vaccinations of newborn on neonatal mortality: A systematic review and meta-analysis of randomized controlled trials studies in low and low- to middle-income countries","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 08:43:45","doi":"10.21203/rs.3.rs-8218455/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6ab28bb4-6217-4745-bf22-4343ea3144e7","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":58690311,"name":"Immunology"}],"tags":[],"updatedAt":"2025-12-01T08:43:45+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-01 08:43:45","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8218455","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8218455","identity":"rs-8218455","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}