The impact of antenatal care on neonatal mortality in sub-Saharan Africa: A systematic review and meta-analysis

Publication date: 2019

RESEARCH ARTICLE The impact of antenatal care on neonatal mortality in sub-Saharan Africa: A systematic review and meta-analysis Tesfalidet TekelabID1,2*, Catherine Chojenta1, Roger Smith3, Deborah LoxtonID1 1 Research Centre for Generational Health and Ageing, Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia, 2 College of Medical and Health sciences, Wollega University, Nekemte, Oromia, Ethiopia, 3 The Mothers and Babies Research Centre at the Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia * ttesfalove@gmail.com Abstract Background Newborns are at greatest risk of dying at and shortly after the time of birth. Newborn mortal- ity remains an urgent concern and is an important indicator of child health, development and well-being. Studies examining the effectiveness of antenatal care on maternal and newborn health outcomes have provided conflicting results. The aim of this review and meta-analysis was to determine the pooled effect of antenatal care on neonatal mortality in sub-Saharan Africa. Methods We searched PubMed, Medline, EMBASE, CINAHL and Google Scholar from September to November 2016 and then updated our search on April 13, 2019. Two independent review- ers extracted data from eligible studies. The quality of each included study was assessed using the Risk of Bias Assessment tool for Non-Randomized Studies (RoBANS). The results were reported based on risk ratio (RR) with 95% confidence intervals (CI) using a random-effects model. Results Eight hundred and ninety eight studies were initially identified. During screening, 23 studies were found to be relevant for data extraction. Of these, only twelve studies fulfilled the inclu- sion criteria and were included in the analysis. In five of the twelve studies included in the analysis, antenatal care service utilization had a significant association with neonatal mortal- ity. The pooled risk ratio by the random-effects model was 0.61 (95% CI: 0.43, 0.86) for neo- nates born to women who received at least one antenatal care visit by a skilled provider as compared to neonates born to women who did not receive antenatal care. PLOS ONE | https://doi.org/10.1371/journal.pone.0222566 September 13, 2019 1 / 15 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Tekelab T, Chojenta C, Smith R, Loxton D (2019) The impact of antenatal care on neonatal mortality in sub-Saharan Africa: A systematic review and meta-analysis. PLoS ONE 14(9): e0222566. https://doi.org/10.1371/journal. pone.0222566 Editor: Umberto Simeoni, Centre Hospitalier Universitaire Vaudois, FRANCE Received: May 29, 2018 Accepted: September 3, 2019 Published: September 13, 2019 Copyright: © 2019 Tekelab et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the manuscript and Supporting Information files. Funding: The authors received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist. Conclusion This review indicates that utilization of at least one antenatal care visit by a skilled provider during pregnancy reduces the risk of neonatal mortality by 39% in sub-Saharan African countries. Thus, in order to accelerate progress towards the reduction of newborn deaths, all pregnant women should receive antenatal care during pregnancy. Introduction Newborns are at greatest risk of dying at and shortly after the time of birth. Newborn mortality remains an urgent concern and is an important indicator of child health, development and well-being. Globally, child mortality is an unfinished agenda of the Millennium Development Goals (MDG4) and remains unacceptably high with approximately 11 deaths occurring every minute[1]. In 2015, there was progress in reducing child mortality by 3.9%. However, there has been slow progress in the reduction of neonatal mortality compared to post-neonatal mor- tality (the number of newborns dying between 28 and 364 days of age): 47% compared with 58% globally [1–4]. Neonatal mortality accounts for 44% of total under five deaths globally. For many newborns, their day of birth is also their day of death. On the day of birth almost one million neonatal deaths occur and close to two million neonates die in the first seven days of life [1, 5]. To achieve the Sustainable Development Strategies (SDS) by 2030, all countries have aimed to reduce neonatal mortality to 12 or fewer neonatal deaths per 1,000 live births and to ten or fewer by 2035. Therefore, newborn mortality has received greater attention in this post Millennium Development Goals era [6–8]. Even though under-five child mortality decreased in all regions of low-income countries, these countries are experiencing an increase in the proportion of newborn morbidity and death[1]. Every day in Africa, 3,100 newborns die within 28 days of birth. Studies report that in most countries in sub-Saharan Africa (SSA), the leading causes of newborn deaths were infections such as tetanus, sepsis and pneumonia, preterm birth complications and birth asphyxia [9–11]. SSA showed progress in the reduction of under-five mortality, by having a 4.1% annual rate of reduction between 2000 and 2016. However, neonatal mortality is still high [1, 4, 12]. This is thought to reflect, at least in part, non-use or underutilization of mater- nal health care services. About half of women and their babies in SSA do not receive skilled care during pregnancy, childbirth and the postnatal period [12, 13]. Effective and timely maternal health care before conception, as well as during pregnancy and childbirth, could save nearly 3 million newborns in high burden countries. Most neonatal deaths could be prevented by direct interventions [8, 14, 15]. Evidence suggests that two thirds of neonatal deaths could be prevented if all pregnant mothers and newborns had access to cost-effective and direct interventions as well as receiving care from skilled health care providers during pregnancy and childbirth [8, 16, 17]. Antenatal care (ANC) can be defined as the care provided by skilled health care providers to pregnant women and adolescent girls in order to ensure the best health conditions for both mother and baby during pregnancy [18]. Researchers examining the effectiveness of ANC interventions on maternal and newborn health outcomes have provided conflicting results [19–22]. In two recent systematic reviews conducted in both high- and low-income countries, it was shown that there is insufficient evidence of the effect of antenatal care on the reduction of newborn mortality [21, 23]. Both of these reviews, conducted only among socially disadvan- taged and vulnerable women and compared lower number of ANC with the standard model The impact of antenatal care on neonatal mortality in sub-Saharan Africa PLOS ONE | https://doi.org/10.1371/journal.pone.0222566 September 13, 2019 2 / 15 (depending on the number of visits). However, in studies conducted in India and Indonesia, positive effects of ANC in preventing newborn deaths were indicated [24–26]. These studies used interventions such as supplementation of iron tablets during pregnancy. ANC interven- tions must be integral to any quality improvement in outcomes for both mothers and new- borns. ANC addresses the most prevalent health issues that affect mothers and newborns [19– 21, 27]. For instance, ANC helps health care providers to identify diseases such as hyperten- sion, haemorrhage and diabetes mellitus, and treat conditions that could affect the wellbeing of the mother and baby. In a recently published document, the World Health Organisation (WHO) now recom- mends a minimum of eight ANC visits to improve neonatal outcomes and to provide a more positive and women-centred experience for pregnant women [18]. It is estimated that ANC alone reduces neonatal mortality by 10–20% [20, 28], though the utilization of those services in SSA is inadequate [29]. Thus, considering the different and conflicting results concerning the effect of ANC on neonatal mortality in SSA [30–35], there is a need for assessing studies from SSA, where most maternal and newborn morbidity and mortality occur [10, 36]. A sys- tematic review and meta-analysis is therefore necessary to critically evaluate relevant studies to provide up to date evidence about the effect of ANC on neonatal mortality. The aim of this sys- tematic review and meta-analysis was to determine the pooled impact of ANC on neonatal mortality in sub-Saharan Africa. Methods Study selection The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was used in the formulation of the systematic review methodology [37]. The systematic review was registered on the PROSPERO prospective register of systematic reviews after piloting the study selection process (registration number PROSPERO 2016: CRD42016049143). Studies were assessed for inclusion through a title and abstract review. Articles were selected from electronic database searches; a list of relevant studies was identified and the full text of the studies was obtained for further assessment. Reference lists of selected articles were assessed in order to identify other potential studies of interest. Search strategy We searched the following databases from September to November 2016 and re-ran the search from March 23 to April 13, 2019 on PubMed, Medline, EMBASE, CINAHL and Google Scholar (S1 Table). We used the keywords “perinatal mortality”, “perinatal death”, “neonatal mortality”, “neonatal death”, “newborn mortality”, “newborn death”, “antenatal care”, “prena- tal care”, “maternal health care”, “sub-Saharan Africa”, and “Africa south of the Sahara”. Grey literature was searched for on Google Scholar and ProQuest. While grey literature was searched, no studies included in the grey literature met the eligibility criteria of the current review. PICO criteria Population. Live born neonates age less than 28 days. Intervention. At least one antenatal care service utilization. Comparison. Neonates born to women who received at least one antenatal care service as compared to neonates born to women who did not receive antenatal care. Outcome. Newborn death during the first 28 days of life. The impact of antenatal care on neonatal mortality in sub-Saharan Africa PLOS ONE | https://doi.org/10.1371/journal.pone.0222566 September 13, 2019 3 / 15 Study inclusion criteria Study design and language. All studies of any design were included if they met the fol- lowing criteria: (i) the study involved a mother who gave birth without any specific risk factors; (ii) the study was conducted in the perinatal period (early neonatal mortality) if the authors defined a death during the first seven days of life and neonatal mortality if the authors defined a death during the first 28 days of life (iii); the study reported on the risk of perinatal or neona- tal mortality; (iv) utilization of antenatal care was considered as a possible factor for neonatal mortality; and (v) the article was published in English. Exclusion criteria. Studies that focused only on the number of ANC visits were excluded from the review. Studies were excluded on the basis of a full-text assessment and the main characteristics of these excluded studies are shown in S1 File. Data extraction The relevance of the studies were checked based on their topic, aims and methodology. Two independent reviewers (TT & CC) completed the data extraction, using a standardized form with clear inclusion and exclusion criteria. Disagreement between the reviewers was resolved by discussion between the authors or by consulting the third author. For each study, we recorded the first author’s last name, year of publication, study setting, study design, study period, sample size, response rate, population, outcome definition, comparison groups and effect estimate. The outcome variables were perinatal and neonatal mortality. Neonatal mortal- ity was defined as a death occurring during the first four weeks (28 days) after the birth of a live baby [38]. The exposure variable ANC was classified as ‘no ANC visit’ and ‘one or more ANC visits’. Where necessary, we contacted study authors to request further information, such as missing data. Quality assessment All studies selected for inclusion in the review were assessed rigorously by review authors. The quality of each included study was assessed using the Risk of Bias Assessment tool for Non- Randomized Studies (RoBANS) [39]. Studies were assessed across six categories (selection bias, confounding bias, performance bias, detection bias, attrition bias and reporting bias). Each domain was allocated one of three possible categories for each of the included studies: ‘low risk’, ‘high risk’, and ‘unclear’. RoBANS is shown in S2 Table. Data synthesis and analysis Statistical analysis was carried out in Stata 11. The overall effect of ANC on neonatal mortality was carried out by using a DerSimonian and Laird random effects model [40] and risk ratio was measured with 95% CI. To assess heterogeneity among studies, we calculated the I2 statis- tic, which describes the percentage of total variation among studies due to heterogeneity rather than to chance. An I2 statistical value of 30% to 60% may represent moderate heterogeneity, whereas 50% to 90% may represent substantial heterogeneity and 75% to 100% may represent considerable heterogeneity [41]. The ‘leave-one-out’ method was used to conduct a sensitivity analysis in order to evaluate the stability of the results and to test whether any single study had an influence on the meta- analysis. Moreover, subgroup analyses were conducted to explore possible sources of heterogeneity. Potential publication bias was investigated by visual inspection of funnel plots and Egger’s linear regression test [42, 43]. The impact of antenatal care on neonatal mortality in sub-Saharan Africa PLOS ONE | https://doi.org/10.1371/journal.pone.0222566 September 13, 2019 4 / 15 Operational definition A woman who received ANC was defined as ‘a women having at least one health facility visit for a pregnancy check-up by skilled attendants during pregnancy’. For instance, the included studies defined ANC as: • Having a health facility visit for a pregnancy check-up by skilled attendants during preg- nancy [31]; • Care given during pregnancy by a skilled birth attendant [44, 45]; and • At least one visit with a skilled birth attendant during pregnancy [32–34, 46]. Neonatal death. Death of a newborn during the first 28 days of life. Results Search results As shown in Fig 1, our study search yielded 1,179 published articles on neonatal mortality. After removing duplicates, 898 records remained, of which 792 were excluded during the ini- tial screening as their titles were not relevant. We then assessed the abstracts of 106 studies before excluding 83 more studies. Finally, after applying the inclusion and exclusion criteria, eight studies were included. Four studies were added after updating the search. Therefore, a total of twelve studies were included in the review. Study characteristics The review included studies from seven countries. The design of the studies were five cohort studies, two case-control studies and five cross-sectional studies [31–35, 44–50]. The sample size ranged from 238 to 27,147. Three fourths of the studies were community-based studies and the remaining three were facility-based studies. The publication year of the included stud- ies ranged from 2009 to 2019. A total of 79,990 live births were included, of which 2,107 died within 28 days of birth, making the weighted neonatal mortality rate 26.3 per 1,000 live births (Table 1). Risk of bias The assessment of the risk of bias in all studies included are shown in Table 2. The risk of bias in the selection of participants was low in all studies, except in one study which is unclear. However, the risk of confounding bias was high in ten studies, but low in two studies which adjusted for major confounding variables during analysis. The risk of performance bias due to an inadequate measurement of risk factors was low in seven studies, which described exposure or risk factors clearly; it was unclear in three studies and high in two studies. The risk of detec- tion bias due to an inadequate measurement of outcome was low in eight studies and high in the remaining studies. The risk of attrition bias due to an inadequate handling of incomplete outcome data was low in ten studies, unclear in one and high in one study. The risk of report- ing bias was low in all studies due to selective reporting of the outcomes. See S2 Table. Pooled effect size of antenatal care on neonatal mortality Among the twelve studies included in the analysis, five showed statistically significant associa- tions between ANC services utilization and neonatal mortality, and seven showed non-signifi- cant effects. The pooled effect size by the random-effects model was 0.61 (95% CI: 0.43, 0.86) The impact of antenatal care on neonatal mortality in sub-Saharan Africa PLOS ONE | https://doi.org/10.1371/journal.pone.0222566 September 13, 2019 5 / 15 Fig 1. Flow chart showing identification, screening and inclusion of studies for systematic review and meta-analysis of the impact of antenatal care on neonatal mortality in sub-Saharan Africa. https://doi.org/10.1371/journal.pone.0222566.g001 The impact of antenatal care on neonatal mortality in sub-Saharan Africa PLOS ONE | https://doi.org/10.1371/journal.pone.0222566 September 13, 2019 6 / 15 Table 1. Characteristics of studies included in the systematic review and meta-analysis of the impact of antenatal care on neonatal mortality in sub-Saharan Africa. First author & year of publication Country Study setting Study design Study period Outcome definition Antenatal care definition Sample size Received ANC Not received ANC Live births Neonatal deaths Live births Neonatal deaths Engmann C, 2009 Democratic Republic of Congo Facility- based Cross-sectional from RCT June 2005 and January 2007 Death of a live born infant at or before 7 days of life At least one visit with a skilled birth attendant during pregnancy 8257 7604 231 355 24 Diallo AH, 2011 Burkina Faso Community- based Prospective cohort study from RCT June 2006 to May 2007 Death of any live born infant within 28 days of his/ her birth Use of health services during pregnancy[61] 895 626 28 238 12 Nankabirwa V, 2011 Uganda Community- based Prospective cohort study from RCT January 2006 to May 2008 Number of newborn deaths in the first 7 days of life Women who attended health facilities to receive care during pregnancy by a skilled birth attendant 835 600 12 235 6 Debelew GT, 2014 Ethiopia Community- based Prospective cohort study September 2012 to December 2013 Death of an infant before 28 completed days Having at least one health facility visit for a pregnancy check- up by skilled attendants during pregnancy 3604 2645 78 819 32 Welaga P, 2013 Ghana Community- based Cross-sectional January 2003 to 2009 Not specified Care during pregnancy with a skilled birth attendant [62] 18237 12460 301 5291 123 Kolola T, 2016 Ethiopia Community- based Case-control January to May 2015 Deceased newborns within 28 days of birth Health facility visits during pregnancy 336 313 72 23 12 Ezeh OK, 2014 Nigeria Community- based Cross-sectional 2003 and 2008 Death of a neonate between birth and 1 month of life Care provided by a skilled health worker during pregnancy [63] 27147 9421 232 6316 169 Engmann C, 2012 Ghana Community- based Cross-sectional January 2002 to December 2008 Death of a live born infant at or before 7 days of life Care with a skilled birth attendant during pregnancy 20497 11939 179 5372 87 Arunda M, 2017 Kenya Community- based Cross-sectional May 7 to October 20, 2014 Death of a baby before reaching 28 days (one month) of age Mother visited a skilled provider for check-ups and pregnancy- related advice during pregnancy 14,190 13414 167 539 24 (Continued) The impact of antenatal care on neonatal mortality in sub-Saharan Africa PLOS ONE | https://doi.org/10.1371/journal.pone.0222566 September 13, 2019 7 / 15 for neonates born to women who received at least one ANC visit as compared to neonates born to women who did not receive ANC (Fig 2). Sources of heterogeneity There was substantial heterogeneity across studies overall (I2>92%, P value for heterogeneity <0.001), as well as within subgroups for study design, study region, sample size and study place. In a subgroup analysis, a significant reduction of neonatal mortality was observed in case-control studies (RR = 0.62 [95% CI 0.48–0.80]; P = 0.57 for the heterogeneity test, I2 = 0.0%,). When the included studies were stratified based on study region, the heterogeneity dis- appeared in the study done in West Africa (P for heterogeneity = 0.84, I2 = 0.0%); however, Table 1. (Continued) First author & year of publication Country Study setting Study design Study period Outcome definition Antenatal care definition Sample size Received ANC Not received ANC Live births Neonatal deaths Live births Neonatal deaths Orsido TT, 2019 Ethiopia Facility- based Retrospective cohort October 2015 to October 2017 Death of a newborn within 28 days Having at least one health facility visit for a pregnancy check- up by skilled birth attendant 964 719 79 86 80 Kidus F, 2019 Ethiopia Community- based Case-control February 1 to December 30, 2013 Newborn death within 28 days Pregnancy care received from skilled providers [64] 238 131 47 97 67 Farah AE, 2018 Ethiopia Facility- based Retrospective cohort August 2014 to May 2017. Newborn death within 28 days Pregnancy care received from skilled providers [64] 792 666 37 81 8 https://doi.org/10.1371/journal.pone.0222566.t001 Table 2. Risk of bias of included non-randomized studies on impact of antenatal care on neonatal mortality in sub-Saharan Africa. Author/Year Selection of participant (selection bias) Confounding variables (confounding bias) Measurement of exposure (performance bias) Measurement of outcomes (detection bias) Incomplete outcome data (attrition bias) Selective outcome reporting (reporting bias) Diallo AH, 2011 Low High Low High Unclear Low Engmann C, 2009 Low High Unclear High Low Low Nankabirwa V, 2011 Low High Low High Low Low Debelew GT, 2014 Low Low Low Low Low Low Kidus F, 2019 Low Low High Low Low Low Welaga P, 2013 Low High High Low Low Low Kolola T, 2016 Low High Low High Low Low Ezeh OK, 2014 Low High Low Low High Low Engmann C, 2012 Low High Unclear Low Low Low Arunda M, 2017 Unclear High Low Low Low Low Orsido TT, 2019 Low High Low Low Low Low Farah AE, 2018 Low High Unclear Low Low Low https://doi.org/10.1371/journal.pone.0222566.t002 The impact of antenatal care on neonatal mortality in sub-Saharan Africa PLOS ONE | https://doi.org/10.1371/journal.pone.0222566 September 13, 2019 8 / 15 heterogeneity was still present in studies done in East Africa (P for heterogeneity<0.001, I2 = 88.5%; Table 3). Visual observation of the funnel plot symmetry, the Egger test (P = 0.273) and Begg’s Test (P = 0.444) showed no publication bias (Fig 3). These findings indicate no major threat to the validity of the review. Discussion This systematic review and meta-analysis assessed the pooled effect of ANC on neonatal mor- tality in SSA. The review is the first of its kind to be done in SSA and clearly shows the benefit to neonatal outcomes of ANC. Previous studies did not report the pooled effect of ANC on newborn health and focused only on the effect of health facility delivery on neonatal mortality [51, 52]. The current review provides important information to policy makers who are work- ing in the area of maternal and infant health care in SSA by delivering robust evidence to eval- uate policies related to ANC and newborn mortality. This review may help to strengthen ANC policies and programs, which may improve newborn health in SSA. Moreover, ANC will cre- ate an opportunity for women and their newborns to receive different interventions, including immunization and other necessary pregnancy related information on preventive measures that may have an impact on preventing newborn death. Attendance of at least one ANC appointment had a statistically significant effect on neona- tal mortality. We found a 39% lower risk of neonatal mortality among women who attended at Fig 2. Overall pooled estimates of the impact of antenatal care on neonatal mortality in sub-Saharan Africa. https://doi.org/10.1371/journal.pone.0222566.g002 The impact of antenatal care on neonatal mortality in sub-Saharan Africa PLOS ONE | https://doi.org/10.1371/journal.pone.0222566 September 13, 2019 9 / 15 least one ANC visit in SSA. All of the included studies in this review were from different parts of SSA. Therefore, the review provides the most comprehensive evidence for countries in SSA to promote the importance of ANC for the health of newborns. This finding is in line with other studies done in low- and middle-income countries [30, 51, 53, 54]. A survival analysis in Fig 3. Funnel plot of the studies included in the meta-analysis of the impact of antenatal care on neonatal mortality in sub- Saharan Africa. https://doi.org/10.1371/journal.pone.0222566.g003 Table 3. Sub-group analysis of studies included in meta-analysis of impact of antenatal care on neonatal mortality in sub-Saharan Africa. Sub-group Random effects RR(95%CI) I-squared, P-value Study design Cohort 0.56(0.26–1.21) 91.1%, P<0.001 Case-control 0.62(0.48–0.80) 0.0%, P = 0.57 Cross-sectional 0.68(0.47–1.0) 89.8%, P< 0.001 Study region West Africa 0.96(0.85–1.09) 0.0%, P = 0.84 East Africa 0.48(0.30–0.77) 88.5%,P<0.001 Central Africa 0.47(0.31–0.70) - Sample Size <500 0.62(0.48–0.80) 0.0%, P = 0.57 500–1000 0.52(0.21–1.27) 88.9%, P<0.001 >1000 0.69(0.50–0.96) 87.2%,P<0.001 Study place Facility-based 0.36(0.18–0.73) 87.1%,P<0.001 Community-based 0.73(0.57–0.93) 78.3%,P<0.001 https://doi.org/10.1371/journal.pone.0222566.t003 The impact of antenatal care on neonatal mortality in sub-Saharan Africa PLOS ONE | https://doi.org/10.1371/journal.pone.0222566 September 13, 2019 10 / 15 low- and middle-income countries found a 55% lower risk of neonatal mortality among women who met the previous WHO recommendations of four ANC visits, and a 32% lower risk among those who had at least one ANC visit [30]. Similarly, in an analysis of the Indone- sian Demographic and Health Survey, it was reported that use of postnatal care was not associ- ated with neonatal survival, but ANC reduced the risk of neonatal death by 51% [53]. This may be due to the mother receiving important advice during the pregnancy and receiving iron, folic acid and tetanus immunizations, which also have a positive effect in reducing neo- natal mortality. In addition, ANC has indirect benefits since women attending ANC are more likely to have their delivery assisted by a skilled birth attendant or give birth in health facilities [53]. According to a recent United Nations Children’s Fund (UNICEF) report, the majority of newborn deaths are easily preventable with simple, cost-effective interventions administered during pregnancy and childbirth [55]. However, there is a high degree of variability in the use and quality of maternal health care services provided to pregnant women and their newborns. Many women and newborns miss out on key interventions that can save their lives [55]. In previous literature, it has been indicated that causes of newborn deaths in Africa could be min- imized or prevented through ANC interventions such as tetanus vaccination and iron supple- mentation provided during pregnancy [9, 56–59]. In this review, we found the most common causes of neonatal mortality were birth asphyxia, infection, preterm birth and birth injury. These findings are consistent with other studies conducted elsewhere [12, 60]. This may be due to non-use of maternal health care services during pregnancy and childbirth. The other reason may be a lack of counselling during pregnancy to prevent maternal and newborn com- plications and inadequate use of ANC interventions. The findings of this systematic review and meta-analysis need careful consideration, bearing in mind its limitations. Firstly, the findings are based on the data extracted from observational studies that are associated with inherent biases. Secondly, the included studies were limited to English only, which may result in missing studies that could have been published in other languages. Thirdly, there was inconsistent classification of ANC visits in the included studies, so it was difficult to show the pooled effect size of each ANC visit (based on the number of visits). Fourthly, we are unable to show the impact of specific ANC interventions on neonatal mortality because there is insufficient information in rela- tion to how ANC was defined and which specific interventions were performed in the included studies. This points to the need for more research in this area to establish which aspects of ANC are the most important for infant outcomes. Despite these limitations, we conducted a comprehensive search of databases to include all relevant studies, and sub- group analyses were conducted to determine whether any specific study-level factor explained the results. Conclusion This review on the impact of ANC on neonatal mortality in SSA found that women who received one ANC visit by a skilled provider were less likely to experience neonatal mortality than those who did not. Thus, to accelerate progress towards the reduction of newborn deaths, all pregnant women should receive ANC by a skilled provider. Moreover, the health care pro- vider should provide counselling to pregnant women during ANC visits to increase health facility delivery and this in turn may reduce neonatal mortality by preventing sepsis and by managing and treating preterm birth. Stakeholders should develop strategies to increase the utilization of ANC. The impact of antenatal care on neonatal mortality in sub-Saharan Africa PLOS ONE | https://doi.org/10.1371/journal.pone.0222566 September 13, 2019 11 / 15 Supporting information S1 File. Excluded articles and reason. (DOCX) S2 File. Completed PRISMA Checklist impact of ANC on neonatal mortality. (DOC) S1 Table. Search method used in Medline. (DOCX) S2 Table. The Risk of Bias Assessment tool for RoBANS. (DOCX) Acknowledgments We would like to acknowledge the University of Newcastle for providing a scholarship and sti- pend. Our sincere gratitude also goes to the University of Newcastle librarian Debbie Booth. Finally, we thank Dr. Ryan O’Neill and Natalia Soeters for language and grammar editing. Author Contributions Conceptualization: Tesfalidet Tekelab, Catherine Chojenta, Deborah Loxton. Data curation: Tesfalidet Tekelab. Formal analysis: Tesfalidet Tekelab. Investigation: Tesfalidet Tekelab. Methodology: Tesfalidet Tekelab, Catherine Chojenta, Roger Smith, Deborah Loxton. 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