Tetanus toxoid immunization Coverage and associated factors in Ethiopia: A systematic review and meta-analysis.

Background: Tetanus is a bacterial disease caused by the bacterium Clostridium tetanus which is a highly fatal, non-communicable, and toxin-mediated disease. Globally, both maternal and neonatal tetanus is a public health problem due to low maternal tetanus toxoid vaccination. The main strategies for the prevention of maternal and neonatal tetanus at birth were vaccination of the mothers with a protective dose of tetanus toxoid and clean delivery. Ethiopia has the highest neonatal mortality and morbidity related to tetanus in the world due to low tetanus toxoid immunization coverage and a higher number of home-deliveries. The main aim of this systematic review and meta-analysis was to estimate the pooled tetanus toxoid immunization coverage and associated factors in Ethiopia. Methods: The primary studies for this review were searched from PubMed/MEDLINE online, Science Direct, and Hinari databases. We retrieved 212 records; of these, 199 articles were excluded due to different reasons, and 13 studies were included in the systematic review and this meta-analysis. The data were extracted in Microsoft Excel format and exported to STATA Version 14.0 statistical software for analysis. Heterogeneity was evaluated by the I 2 test. A random-effect meta-analysis model was used to estimate the pooled coverage of two or more tetanus toxoid immunization and its associated factors. Egger’s weighted regression and Begg’s rank correlation test were used to assess publication bias at a 5% signicance level. Result: The pooled estimate of at least two dose of tetanus toxoid immunization coverage was 52.6% (95% CI 41.4%–63.8%). Ante-natal care (ANC) visits [OR = 7.8 (95% CI; 3.2, 19.2)], media exposure [OR = 8.3 (95% CI; 2.1. 33.3), distance from the health facility [OR = 2.635 (95% CI; 1.1, 6.6)], educational status of mothers [OR = 0.225 (95% CI; 0.105, 0.483) and husband educational status [OR = 0.184 (95% CI; 0.104, 0.323)] were signicantly associated factors for tetanus toxoid immunization coverage in Ethiopia. Conclusion: The tetanus toxoid immunization coverage among childbearing women was low in Ethiopia. Strengthening maternal health service utilization (ANC, institutional delivery) to the nearest health facility including in health posts and empowering education is recommended to increase tetanus toxoid immunization coverage. Additionally, awareness creation on the advantage of taking tetanus toxoid immunization should be emphasized.


Introduction
Tetanus is a bacterial disease caused by the bacterium Clostridium tetanus which is a highly fatal, noncommunicable, and toxin-mediated disease [1,2]. Due to unhygienic deliveries and low tetanus toxoid (TT) immunization, women and their newborns are at higher risk of acquiring tetanus [3][4][5][6][7]. Globally, both maternal and neonatal tetanus (MNT) is a public health problem due to low maternal TT immunization [8]. Annually, 3.3 million neonatal deaths occur, of which neonatal tetanus shares a high number particularly in developing countries where home delivery is common [9]. Every year 15,000-30, 000 maternal deaths occurred due to tetanus related to the delivery process [10]. The WHO report showed that 90% of maternal and neonatal tetanus occurred in South East Asian (SEA) and Sub-Saharan African (SSA) countries, and almost all cases ended with death [11].
The main strategies for the prevention of maternal and neonatal tetanus (MNT) at birth were vaccination of the mothers with a protective dose of tetanus toxoid (TT) immunization and clean delivery [3,12,13]. Nearly 94% of Page 3/18 neonatal mortality related tetanus can be reduced through the immunization of pregnant women or women of childbearing with at least two doses of tetanus toxoid immunization (TT 2+ ) [14]. The World Health Organization (WHO) recommends 5 consecutive doses of tetanus toxoid (TT) vaccination for childbearing women (CBAW) per schedule to protect the birth against tetanus [1].
In many countries, at least two doses of the TT vaccination can be given to pregnant women during antenatal care (ANC) visits [15]. TT 2+ immunization coverage among pregnant mothers ranges from India 27% [16] to Ghana 71% [17]. It could be concluded that most countries could not reach the WHO Global Immunization target of at least 90% of national TT vaccination coverage and at least 80% of TT vaccination coverage in every district [18,19].
Previous studies identi ed factors such as age of the mothers, educational status, marital and occupational status, joint health decision with husband, distance from health facilities, wealth index, fear of side effects, fear of sterility, ANC follow-up, use of modern family planning, parity, information about TT vaccination, knowledge, attitude and awareness of mothers towards TT vaccination for low TT immunization coverage [14,16,18,[20][21][22][23].
TT immunization status also differs from urban to rural mothers as well as region to region in different countries [24,25].
Despite the country's effort of interventional policy to meet the WHO goals towards Maternal and Neonatal Tetanus Elimination (MNTE) through extended immunizations and campaigning of Tetanus Toxoid, Ethiopia continues to have the highest neonatal tetanus mortality and morbidity in the world due to low TT immunization coverage and a higher number of home-deliveries [26,27]. Although, the country was planned to reach 86% coverage of the national tetanus protective at birth (PAB) by 2015, only 49% of the pregnant mothers received at least two dose of tetanus toxoid vaccination as of the EDHS 2016 report [27,28].
Different independent and fragmented studies have been conducted to assess TT immunization coverage in Ethiopia despite their reports showing great disproportion across the region in the country. Thus, reliable and summarized information is essential to re ne government policies, strategies, and interventions. Hence, the main aim of this systematic review and meta-analysis was to estimate the pooled coverage of at least two dose of tetanus toxoid immunization and associated factors in Ethiopia. Therefore, this review can have vital importance to show summarized evidence and suggest possible applicable strategies for planning, decision making, and resource allocation in the health care system of Ethiopia.

Identi cation and selection of studies
Published and unpublished research reports describing tetanus toxoid immunization coverage and associated factors in Ethiopia were reviewed. Relevant studies were searched from PubMed/MEDLINE online, Science Direct, and Hinari databases. Gary literature was also identi ed from Google and Google Scholar. All searches were conducted from July 1 st to August 25 th /2020. The term 'tetanus toxoid' was searched in different variations such as tetanus toxoid immunization coverage/utilization/, protective dose of tetanus toxoid immunization, tetanus toxoid immunization status, tetanus toxoid vaccination uptake, and protection of last live birth against neonatal tetanus. The key terms used to retrieve primary studies were (Utilization OR coverage OR vaccination uptake OR immunization status AND (Tetanus toxoid) AND Ethiopia). We also used key terms of (Factors OR determinants OR risk factors OR correlates) AND (Tetanus toxoid) AND Ethiopia to search literature regarding factors associated with the utilization of tetanus toxoid immunization in Ethiopia. Data were extracted from reports of articles. All literature available until August 25, 2020, was identi ed and evaluated for their eligibility to be included in the systematic review and meta-analysis using prepared eligibility assessment criteria. The systematic review and meta-analysis were carried out in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines [29].

Eligibility criteria
Observational studies with original data reporting the coverage of TT 2+ immunization and its associated factors conducted in Ethiopia from 2010-2020 were included. In this review, we included articles published in English.
Studies that had unclear outcomes and poor quality were excluded. Qualitative studies were not included in this meta-analysis. Regarding publication, both published and unpublished articles were included in this review.

Data extraction
We used a standardized data extraction format prepared in Microsoft Excel to extract all the necessary data. The extraction format contains different columns including the name of the rst author, publication year, region of the country where the study was conducted, sample size, response rate, and coverage of TT 2+ immunization for the rst objective. For the second objective (factors associated with TT 2+ immunization), the data extraction format was prepared in the form of a two -by-two table.

Outcome measurements
This study has two main objectives. The rst objective was the pooled coverage of TT 2+ immunization in Ethiopia. The second objective was the factors associated with TT 2+ immunization. The utilization of TT 2+ vaccination was calculated by dividing the number of mothers ever taking at least two dose of TT by the total number of mothers who were included in the study and multiplied by one hundred (100). For the second objective, the odds ratio was used to measure the level of the association between TT 2+ immunization coverage and its associated factors. The odds ratio was calculated from primary studies using two by two tables.

Quality assessment
The qualities of primary studies were assessed using the Newcastle-Ottawa Scale [30]. The tool has three main parts. The rst part has ve components used to assess the methodological quality of each study. The second part assesses the comparability of primary studies, and the nal part of the tool measures the quality of the original articles concerning their statistical analysis. Two authors independently evaluated the qualities of original articles by using quality assessment guidelines, and articles with high quality (a minimum score of 6 out of 10 scores) were included in this review. Any difference between the two authors during the quality assessment of primary studies was solved by taking the average of the two assessment scores.

Statistical procedure
The extracted data from the Microsoft Excel format were exported to STATA Version 14.0 (software) for analysis.
The characteristics of the original articles were described using a table as well as a forest plot. Statistical heterogeneity was evaluated by the I 2 test, which shows the level of heterogeneity between studies [31]. The percentage of variability due to heterogeneity rather than sampling error or chance in effect estimate was determined through the I 2 test. Basically, the I 2 test does not depend on the number of studies incorporated into the study. A random-effect meta-analysis model was used to estimate the pooled utilization of TT 2+ immunization and its associated factors. The pooled effect size was conducted in the form of prevalence and odds ratio. Furthermore, we also employed a leave-one-out sensitivity analysis to identify the possible source of heterogeneity in the pooled meta-analysis. Subgroup analysis was also performed by a region where the study was conducted to minimize the random variations in the point estimates of the primary studies. Egger's weighted regression and Begg's rank correlation test were used to assess publication bias at a 5% signi cance level [32,33]. P<0.05 was considered statistically signi cant publication bias.

Search results
There were a total of 212 primary records retrieved during the literature search from the Midline/PubMed, Hinari, Science Direct, Google, and Goole Scholar databases. Approximately 79 articles were excluded due to duplication, and 102 studies were also excluded after reviewing their titles and abstracts as we found these articles as unrelated to our objective. Then, the remaining 31 articles were assessed by reading their full-text text based on the criteria. After the full-text review, 18 articles were further excluded due to the difference in the study population and outcome. Finally, 13 primary studies were included in this meta-analysis (Fig.1).

Characteristics of the included articles
In this review, 13 primary studies with a total of 13,731 study participants were included. The studies were conducted from 2010 to 2020 and were retrieved from ve regions of the country: 4 from the southern region, 3 from Amahara, 3 from Oromia, 1 from Tigray, 1 from Somalia, and another study was based on EDHS data [34][35][36][37][38][39][40][41][42][43][44][45][46]. All of these studies included in this review were community-based cross-sectional studies with sample sizes ranging from 239 to 7193 participants as reported from studies done in Bahir Dar and studies from EDHS data respectively [34,39]. Six studies were conducted in urban area and the other six were conducted in rural area. The highest coverage of TT 2+ immunization was reported from Debre Tabor town in the Amhara region 79.0% [39], and the least was from the Meinit-Shasha district in the southern region 13.9% [41] (Table 1). . This meta-analysis also revealed that the pooled coverage of two or more TT immunization was slightly higher in urban women (56.7 %, (95% CI; 40.2, 73.1)) than in rural urban women 49.0% (95% CI; 34.4, 63.7) ( Figure 5).  6).
Three primary studies included in our meta-analysis reported that media exposure (TV, radio) was signi cantly associated with TT 2+ immunization [34,40,43]. To see the association between media exposure and tetanus toxoid vaccination coverage, 8,289 study participants were included in the analysis. Accordingly, at least two dose of tetanus toxoid immunization among women having media exposure was 8.3 times higher than women having no media exposure [OR = 8.3 (95% CI; 2.1. 33.3) (Figure 7).
Distance from home to health facility was identi ed as a factor associated with two or more tetanus toxoid immunization among three primary studies with a total of 1933 study participants [38,43,44]. Women who walked less than 1 hour to reach health facilities were 2.6 times more likely to take tetanus toxoid immunization than mothers who walked greater than or equal to 1 hour to reach the health facility [OR = 2.635 (95% CI; 1.1, 6.6)] (Figure 8).
The educational status of the mothers was signi cantly associated with tetanus toxoid immunization coverage among ve primary studies included in our analysis [37,38,40,42,43]. A total of 2884 mothers were included in the analysis to examine the association of the educational status of the mothers and tetanus toxoid immunization. Mothers who had never attended formal education were 77.5% less likely to receive two or more doses of TT injection than educated mothers [OR = 0.225 (95% CI; 0.105, 0.483) (Figure 9).
Three primary studies reported that the husband's educational status was associated with receiving two or more dose of tetanus toxoid immunization with a total sample of 1957 mothers [37,38,40]. Accordingly, women whose husbands had no formal education were 81.6% less likely to receive two or more tetanus toxoid immunization as compared to women having educated husbands [OR = 0.184 (95% CI; 0.104, 0.323)] ( Figure 10).

Discussion
Neonatal and maternal tetanus is still a major public health problem especially in developing countries, but can be easily prevented through immunization of childbearing women with at least two dose of tetanus toxoid immunization. This systematic review and meta-analysis was conducted to show the pooled coverage of two or more dose of tetanus toxoid immunization and associated factors in Ethiopia. To the best of our knowledge, this is the rst systematic review and meta-analysis in Ethiopia.
In this meta-analysis, the pooled coverage of tetanus toxoid immunization at least two dose was 52.6% (95% CI 41.4, 63.8). This nding was consistent with a report from studies conducted in Kenya 52.0% and Pakistan 55.6% [18,47]. It was low compared to studies conducted in different developing countries such as Ghana 71% [48], India 68% [16], and Sierra Leone 82.1% [49]. The possible explanation for this difference might be due to geographical differences, sociocultural variation and maternal and child health service utilization.
However, the pooled coverage of at least two dose of tetanus toxoid immunization in this meta-analysis was higher compared to reports of studies conducted in Rivers State, Nigeria 37.1% [50] and Nigeria 40.8% [51]. The reason for this difference might be due differences in sociocultural characteristics, knowledge, attitudes, and awareness of mothers toward immunization. The other explanation for this difference may be the difference in the educational status of the mothers and their husbands.
This meta-analysis also identi ed different associated factors for tetanus toxoid immunization. Accordingly, ANC visits, media exposure, distance of health facilities, educational status of mothers, and their husbands were signi cantly associated with tetanus toxoid immunization status among women in Ethiopia. Tetanus toxoid immunization coverage was 7.8 times higher among mothers attending ANC follow-up compared to their counterparts. This nding was supported by studies conducted in Kenya [21] and Pakistan [18].Tetanus toxoid immunization was one component of ANC and counselling about the importance of TT immunization and other services during pregnancy.
Women who had media exposure were 8.3 times more likely to receive two or more dose of tetanus toxoid immunization than women who had no media exposure. A similar nding was reported from a study conducted in Indonesia [52]. The possible explanation for the association of media exposure with tetanus toxoid immunization might be that media may provide important information that can increase women's knowledge of the advantage of tetanus toxoid immunization. The odds of receiving two or more tetanus toxoid immunization was 2.6 times higher among women walking less than 1 hour to reach health facility than among women walking more than 1 hour to reach the nearest health facility. This might be because women in the household are responsible for multiple tasks that make them busy to receive tetanus toxoid immunization since TT vaccination requires repeated visits to health facilities.
Uneducated women in this meta-analysis were 77.5% less likely to immunize at least two dose of tetanus toxoid vaccine than educated women. This is consistent with studies conducted in Bangladesh [53] and France [54].
This could be because education increases women's knowledge, attitude, and awareness regarding the health bene t of tetanus toxoid immunization. Similarly, women having an educated husband were 81.6% more likely to receive two or more tetanus toxoid immunization than women having an illiterate husband. This might be because educated husbands have better knowledge and awareness of the advantage of TT immunization that could push their wives to take tetanus toxoid immunization. Furthermore, educated husbands may give more freedom to their wives to receive tetanus toxoid vaccination compared to non-educated husbands.

Limitation of the study
The limitation of this systematic review and meta-analysis was that all included primary studies were crosssectional study designs which made it di cult to establish cause-effect relationships.

Conclusion
This systematic review and meta-analysis showed that tetanus toxoid immunization coverage among childbearing age women in Ethiopia was low compared to the WHO global immunization target. It was higher in urban than rural women. Absence of ANC visits, no media exposure, distant health facilities, and low educational status were factors for low coverage for tetanus toxoid immunization. Strengthening maternal health service utilization such as ANC to the nearest health facility including in health posts is recommended to increase the coverage of tetanus toxoid immunization. Great emphasis on awareness creation about the advantage of taking tetanus toxoid immunization through media and education should be given.

Declarations
Ethics approval Not applicable

Consent for publication
Not applicable Availability of data and materials The data used for this study are available here. It will be shared upon request and will be obtained by email to the corresponding author using "nigussiejemberu@gmail.com. Or jemberu2123@gmail.com".
Competing interests Figure 1 Flow chart of the selection process for the studies included in the analysis.

Figure 2
Page 15/18 Forest plot for the pooled coverage of tetanus toxoid immunization in Ethiopia, 2020.  sub-group analysis of tetanus toxoid immunization coverage in Ethiopia, 2020 Page 16/18

Figure 5
Tetanus toxoid immunization coverage between rural and urban women in Ethiopia, 2020. Association of anti-natal care visit with tetanus toxoid immunization coverage in Ethiopia, 2020.

Figure 7
Association of media exposure with tetanus toxoid immunization coverage in Ethiopia, 2020. Association of distance of health facility with tetanus toxoid immunization coverage in Ethiopia, 2020.

Figure 9
Association of mothers' educational status with tetanus toxoid immunization coverage in Ethiopia, 2020.

Figure 10
Association of husband educational status with maternal tetanus toxoid immunization coverage in Ethiopia, 2020.