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. 2021 Jan 14;16(1):e0245003. doi: 10.1371/journal.pone.0245003

The effect of antenatal care on perinatal outcomes in Ethiopia: A systematic review and meta-analysis

Kasiye Shiferaw 1,*, Bizatu Mengiste 2,#, Tesfaye Gobena 3,#, Merga Dheresa 1,#
Editor: Georg M Schmölzer4
PMCID: PMC7808692  PMID: 33444374

Abstract

Background

The estimated annual global perinatal and neonatal death is four million. Stillbirths are almost equivalent to neonatal mortality, yet they have not received the same attention. Antenatal care is generally thought to be an effective method of improving pregnancy outcomes, but its effectiveness as a means of reducing perinatal mortality has not been evaluated in Ethiopia. Therefore, we will identify the pooled effect of antenatal care on perinatal outcomes in Ethiopia.

Methods

Medline, Embase, Cinahl, African journal online and Google Scholar was searched for articles published in English language between January 1990 and May 2020. Two independent assessors selected studies and extracted data from eligible articles. The Risk of Bias Assessment tool for Non-Randomized Studies was used to assess the quality of each included study. Data analysis was performed using RevMan 5.3. Heterogeneity and publication bias were assessed using I2 test statistical significance and Egger's test for small-study effects respectively. The random effect model was employed, and forest plot was used to present the risk ratio (RR) with 95% confidence interval (CI).

Results

Thirteen out of seventeen included studies revealed antenatal care utilization had a significant association with perinatal outcomes. The pooled risk ratio by the random-effects model for perinatal death was 0.42 (95% CI: 0.34, 0.52); stillbirth 0.34 (95% CI: 0.25, 0.46); early neonatal death 0.85 (95% CI: 0.21. 3.49).

Conclusion

Women who attended at least one antenatal care visit were more likely to give birth to an alive neonate that survives compared to their counterpart. Therefore, the Ethiopian Ministry of health and other stakeholders should design tailored interventions to increase antenatal care utilization since it has been shown to reduce perinatal mortality.

Introduction

Globally, an estimated four million perinatal and neonatal deaths occur annually [13]. In addition, an estimated 2.6 million babies were stillborn in 2015, only a 19% decrease since 2000. Ninety eight percent of stillbirth occurred in low and middle income countries (LMICs) and 77% of these occurred in the south Asia and Sub-Saharan Africa (SSA), thus showing little progress in SSA [2]. Majority of the stillbirths (60%) occurred during the antepartum period were mainly due to untreated maternal infection, hypertension, and poor fetal growth [2], which are preventable. The perinatal mortality rate across SSA was 35 per 1000 live births [4]. In Ethiopia, there are high proportions of stillbirths and early neonatal deaths [5,6], being one of the top ten countries with highest stillbirth numbers, and the high perinatal mortality rate (33 per 1000 live births) is coupled with high percent of low birth weight babies (13% of babies weighing less than 2500 grams at birth) [2,7,8].

The increase in perinatal mortality is more likely due to increased stillbirths and reduced antenatal visits [9]. ANC is a vital intervention for successful maternal and child health, globally [10]. Attending less than 50% of recommended or inadequate ANC visits was associated with adverse pregnancy outcomes [1117]. Stillbirths are a reflection of ANC accessibility and utilization [18]. Women with no ANC had significantly increased risk of stillbirths [19]; mortality and morbidity of mothers and newborns was reduced for those who had optimal utilization of ANC services [20]. Furthermore, the risk of developing neonatal mortality was decreased for women who received as little as one ANC follow up [2127], but the effect on perinatal outcomes is unknown.

Studies revealed that low birth weight (LBW) was associated with not attending at least five to eight ANC visits, not receiving any ANC during the first trimester and not having access to certain ANC contents [2830]; LBW is a contributing factor to stillbirths [31]. However, there are conflicting results on the effectiveness of ANC interventions on maternal and newborn health outcomes [3236]. There are inconsistencies in the studies regarding the benefits of ANC in reducing perinatal mortality [17,3640]; studies revealed perinatal mortality was not affected by no and inadequate ANC [41]; other studies showed improved ANC did not reduce perinatal or neonatal mortality [42]. Benefits of ANC were reported by some but not all care programs regarding perinatal mortality [43]; however, ANC has not been compellingly shown to improve birth outcomes [44]. Furthermore, the focused ANC model is associated with more perinatal deaths than models comprised of at least eight ANC contacts [45].

Reduction in an availability and utilization’s gaps of ANC practice is needed to end preventable deaths of newborns [46]. Failure to improve birth outcomes by 2035 will result in an estimated 116 million deaths, 99 million survivors with disability [47], and an additional 52 million stillbirths [47,48]. There are no pooled estimates of the effect of ANC on perinatal outcomes in Ethiopia; therefore, we aimed to assess the effect of ANC on perinatal outcomes in Ethiopia in this systematic review and meta-analysis.

Methods

The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) checklist was used in the preparation of the systematic review methodology [49]. The systematic review was registered on the PROSPERO prospective register of systematic reviews after piloting the study selection process (registration number PROSPERO 2020: CRD42020188340).

Eligibility criteria

Assessment for eligibility was conducted and studies were included in this review if (i) the study involved a delivering/laboring women or newborn babies or women of child-bearing age or pregnant women or postpartum women; (ii) the study reported the outcomes (perinatal death, stillbirth, early neonatal death); (iii) the ANC utilization was considered as factors/exposure for the outcomes; (iv) the study was done in the perinatal period and the author(s) defined perinatal outcomes (perinatal mortality) as death of newborn between 28 weeks’ of gestation and seven days postpartum; (v) it was an observational study design (cross-sectional, case-control or cohort study design) and (v) English language article.

We excluded studies from the review that focused only on the number of ANC visits based on full-text assessment.

PICO. Population: Newborn after 28 weeks’ gestation and survived seven days postpartum.

Intervention: utilized at least one ANC visit.

Comparison: Newborns whose mothers received at least one ANC service as compared to newborns whose mothers did not.

Outcome: Newborn death during perinatal period (from 28 weeks’ of gestation to 7 days postpartum).

Information sources and search strategy

Medline (via PubMed), EMBASE, and CINAHL were searched for (S1S3 Tables) articles published in the English language between January 1990 and June 2020, using the keywords “antenatal care”, “prenatal care”, "maternity care", “maternal health care”, “obstetrics”, “maternal health services”, "pregnancy care", "perinatal mortality", "perinatal death", "early neonatal mortality", "early neonatal death" "stillbirth", "newborn mortality", "newborn death", "perinatal outcomes", “fetal death” "infant death", “infant mortality” AND "Ethiopia”. Moreover; we thorough literatures search was performed on Google Scholar and African Journal Online (AJOL). A search combining MeSH and key terms connecting population, intervention and outcomes of interest was performed.

Study selection

The study selection involved several steps. First, the title and abstract were selected independently by the review authors using the inclusion criteria. Second, after removing the duplicates, the full reports of all titles that met the inclusion criteria were independently identified by review authors. Third, the review authors screened the full text reports to decide whether the studies meet the eligibility criteria. Finally, any disagreements among review authors were resolved through discussion or review authors who did not participate in step one thru three decided whether to include or exclude the article. An attempt was made to meet study authors for additional information by email and in order to have put reasons for excluding studies (Fig 1).

Fig 1. Flowchart of search results for included studies.

Fig 1

Data extraction

Each studies’ relevance was checked based on their topic, objectives and methodology. Two independent reviewers (KS & BM) completed and verified the data extraction, using a standardized form with explicit inclusion and exclusion criteria. If not resolved by discussion of reviewers, the third or fourth author was consulted to decide on the disagreement. For each study, the first author’s last name, publication year, design, setting, sample size, study period, sample age, the definition of outcomes, population, outcome and comparison groups were documented.

In this review, our evaluation of perinatal outcomes related to the death of the newborn from 28 weeks’ of gestation to seven days postpartum (i.e., fetal death, stillbirth, and early neonatal death) were reported [5052]. Antenatal care ‘no ANC visit at all’ or ‘one or more ANC visit’ were the two classifications of the exposure variable. An attempt to contact study authors to request information, such as missing data, was made, if necessary and unfortunately there was no study which was excluded do to missing data.

Data items

Antenatal care is defined as ‘a woman having one or more health facility visits for a pregnancy check-up by a skilled attendant during her pregnancy’ [12,23,5358].

Focused ANC model is four visits providing essential evidence based interventions–a package to achieve the full life-saving potential that ANC promises for women and babies [59].

Perinatal outcomes/mortality refers to the number of stillbirths and deaths in the first week of life [23,42,60,61]. In this review, perinatal death (as study authors defined) or reviewers added the number of stillbirths and early neonatal deaths or available outcomes between stillbirths and early neonatal deaths to estimate overall perinatal outcomes/mortality rate.

Stillbirth was defined as fetal deaths after 28 weeks of gestation [5,62,63].

Skilled attendant refers to a midwife, doctor or nurse who has been educated, trained and accredited to manage normal pregnancies, childbirth and the immediate postnatal period and identify, manage and/or refer women and newborns with complications [64].

Early neonatal mortality was defined as neonatal deaths in the first week of life after being delivered in the age of viability (28 weeks of gestation and above) [5,56].

Individual study’s risk of bias

The review authors assessed all selected studies rigorously for inclusion in the review. The Risk of Bias Assessment Tool for Non-Randomized Studies (RoBANS) [65] was used to assess the quality of each included study. Studies were evaluated across six groups (selection bias, attrition bias, detection bias, performance bias, confounding bias and reporting bias). Each domain was assigned one of three possible groups for each of the involved studies: ‘low risk’, ‘high risk’ and ‘unclear’. RoBANS is shown in S4 Table.

Synthesis and analysis of data

Statistical analysis was carried out in RevMan version 5.3. A DerSimonian and Laird random effects model [66] was used to measure ANC’s overall effect on perinatal mortality and the risk ratio was measured with a 95% confidence interval. We calculated the I2 statistic which describes the percentage of total variation among studies to assess heterogeneity among studies. An I2 statistical value of 25%, 50% and 75% representing low, moderate and high heterogeneity respectively [67]. A p-value less than 0.05 was considered as statistically significant both for risk ratio and heterogeneity.

Sensitivity analysis was conducted to assess the stability of results and test individual study effects on the meta-analysis using leave one out method. Furthermore, possible sources of heterogeneity were explored using subgroup analysis. Egger's test for small-study effects was used to investigate potential publication bias (p-value > 0.1) [68].

Results

Search results

The initial search identified 1918 unique citations. Of these, 1824 and 53 were excluded on title/abstract alone and following full-text review respectively. Furthermore, 6 articles classified ANC based on number of visits [6974], 6 articles defined their outcomes differently [62,7579], 6 articles did not determine outcome at all [26,53,8083] and 6 articles had no ANC follow-up status [8489] and therefore they all were excluded. Lastly, 17 articles were retained for final review (Fig 1).

Characteristics of studies

The review included studies from all regions in Ethiopia; the majority were from Amhara and Oromia. Nine cross-sectional, six case-control and two cohort studies were included in the meta-analysis. The sample size of the studies ranged from 300 to 12560. Among the included studies, 5 and 12 were community-based and facility-based, respectively. A total of 51729 study samples were included, of which 2951 newborns died during the perinatal period, making the perinatal mortality rate 41 per 1000 total births (total deliveries, total stillbirths and total early neonatal deaths), excluding case-control studies in which total numbers of live births at the time of the study were unknown. Similarly, the stillbirth rate and early neonatal mortality rate were 38 per 1000 total births (stillbirths and live births) and 19 per 1000 live births. Table 1 displays the characteristics of the 17 included primary studies.

Table 1. Characteristics of studies revealing the effect of ANC on perinatal outcomes in Ethiopia.

No Authors Design Study setting Study period Sample size Population Sample age Outcomes variable Operational definition ANC status Perinatal outcomes
Yes No
1 Adane etal. 2014 [90] Cross-sectional study Facility-based February 2013 481 Laboring women <20, 20–35, 35+ Stillbirth Stillbirth was defined as the birth of an infant that has died in the womb or during intra-partum after 28 weeks of gestation. Yes 18 397
No 16 50
2 Goba et al. 2017 [91] Case-control study Facility-based study From February 1 to September 30, 2016 378 Delivering women <24, 25–34, 35+ Perinatal death Patients who experienced stillbirth or early neonatal death were classified as the case group and those whose neonates survived until discharge or for at least 7 days were control group. 0 visits 19 9
1–3 visits 89 149
≥4 visits 18 94
3 Roro et al. 2018 [92] Nested case-control study Community-based study Between March 2011 to December 2012 4438 Newborn babies 15–19, 20–24, 25–29, 30–34, 35+ Perinatal mortality Perinatal death is defined as the sum of stillbirth and early neonatal death. Yes 56 121
No 17 25
4 Welegebriel et al. 2017 [93] Case-control study Facility-based study From January 2011 to 2015 540 Mothers registered in for maternal health service utilization <20, 20–34, 35+ Stillbirth Not defined Yes 69 278
No 66 127
5 Worede and Dagnew 2019 [94] Unmatched case-control Facility-based study From 1st January to 30th April 2019 420 Delivering women <20, 20–34, 35+ Stillbirth Case is defined as fetal death after 28 weeks of pregnancy (either pre-partum or intra-partum stillbirth) Yes 47 284
No 37 52
6 Getiye and Fantahun 2017 [95] Unmatched case-control study Facility-based study From January 1/ 2014 to Dec 31/ 2014 1113 Delivering women 15–19, 20–24, 25–29, 30–34, 35+ Perinatal outcome Perinatal mortality is total number of deaths in the perinatal period Yes 354 724
No 22 13
7 Tilahun & Assefa 2017 [96] Cross-sectional study Facility-based Not specified 413 Delivering women <20, 20–34, 35–45 Stillbirth Not defined Yes 17 321
No 16 59
8 Berhie and Gebresilassie 2016 [97] Cross-sectional study Community-based study From September 2010 through June 2011 12,560 Women of child-bearing age 15–24, 25–34, 35+ Stillbirth Pregnancy losses occurring after seven completed months of gestation are defined as stillbirths. No ANC visit 273 3828
Visited at least once 118 3172
9 Tilahun and Gaym 2008 [98] Case-control study Facility-based From May 15, 2006 to August 15, 2006 390 Delivering mothers <20, 20–34, 35+ Perinatal Mortality Perinatal mortality (case) were mothers with a singleton pregnancy who were admitted to the labor ward and had a stillbirth or suffered an early neonatal death after delivery. Unbooked 43 14
Booked 87 246
10 Ballard et al. 2016 [99] Cross-sectional study Community-based Between May and December 2014 4442 Women of child-bearing age Not mentioned Stillbirth The stillbirth was delivering a dead neonate after a pregnancy lasting 7 months or more. Received ANC 42 2437
Not received ANC 53 1921
11 Eyob and Worku 2003 [100] Cross-sectional study Facility-based From lstJanuary 1995 to December 31, 1996 8986 Delivering mothers Not mentioned Perinatal death Not defined Unbooked 283 1770
Booked 301 6632
12 Worku et al. 2013 [14] Prospective cohort study Community-based From December 1, 2011 to August 31, 2012 727 Pregnant women <20, 20–34, 35+ Perinatal death Definition taken from WHO guideline monitoring emergency obstetric care Yes 13 240
No 23 451
13 Lakew et al. 2017 [101] Cross-sectional Community-based 2014 2555 Women of child-bearing age <24, 25–34, 35+ Stillbirth Stillbirth outcomes was characterized as the introduction of a newborn child that has passed on in the womb or amid intra-partum following 28 weeks of growth No ANC visit 9 138
ANC 1+ visit 7 231
14 Berhan 2014 [102] Retrospective cohort study Facility-based Between January 2006 and December 2011 9619 Women that gave birth <20, 20–34, 35+ Perinatal death Perinatal status defined the fetal or early neonatal survival (from 28 weeks of pregnancy age up to the first 7 days of newborn age) Yes 124 283
No 90 149
15 Chekol A., 2011 [103] Cross-sectional Facility-based From September 2008 to August 2009 581 Laboring women 15–19, 20–29, 30–42 Perinatal death It is fetal death starting from 28 weeks of gestational age and the death of new born in the first week of life, which comprises late fetal and early neonatal deaths. No 36 93
Yes 33 419
16 Aragaw Y., 2016 [104] Cross-sectional Facility-based From September 11, 2012 to 10, 2013 3786 Newborn babies <20, 20–34, 35+ Perinatal death Not defined Yes 204 2765
No 169 648
17 Mihiretu A. et al, 2017 [105] Cross-sectional Facility-based July, 2015 300 Mothers who gave birth <18, 18–34, 35+ Perinatal death Not defined Yes 10 142
No 42 107

Individual study’s risk of bias

The risk of bias assessment for all included studies is shown in Table 2. The risk of bias in selection of participants into the study was low for all studies. The bias due to missing or incomplete data was low in most of the studies, although a few studies have unclear explanation. The performance bias during measurement of exposure variable was low in fourteen and unclear in three studies. However, the risk of detection bias was high in all studies. The risk of confounding bias was low in thirteen, high in three and unclear in one study. The bias due to reporting of results was low in fifteen and unclear in two studies. See S4 Table.

Table 2. Individual studies risk of bias on effect of ANC on perinatal outcomes in Ethiopia.

Studies Selection bias Attrition bias Performance bias Detection bias Confounding bias Reporting bias
Adane et al. 2014 Low Low Low High Low Low
Ballard et al. 2016 Low Low Low High High Low
Berhan 2014 Low Low Unclear High High Low
Berhie and Gebresilassie 2016 Low Low Low High Low Low
Eyob and Worku 2003 Low Low Unclear High High Low
Getiye and Fantahun 2017 Low Low Low High Low Low
Goba et al. 2017 Low Low Unclear High Low Low
Lakew et al. 2017 Low Low Low High Low Low
Roro et al. 2018 Low Unclear Low High Low Low
Tilahun & Assefa 2017 Low Low Low High Low Low
Tilahun and Gaym 2008 Low Unclear Low High Low Low
Welegebriel et al. 2017 Low Unclear Low High Low Low
Worede and Dagnew 2019 Low Low Low High Low Low
Worku et al. 2013 Low Low Low High Unclear Low
Chekol A., 2011 Low Low Low High Low Low
Aragaw Y., 2016 Low Low Low High Low Unclear
Mihiretu A. et al, 2017 Low Low Low High Low Unclear

Pooled effect size of ANC on perinatal outcomes

Among the seventeen studies included in the analysis, thirteen studies with at least one ANC visit showed statistically significant associations with perinatal outcomes, whereas four studies had no statistically significant association. Similarly, the pooled effect size for perinatal death by the random-effect model was 0.42 (95% CI: 0.34, 0.52) for babies born to women who received at least one ANC follow-up as compared to newborns whose mothers did not receive any ANC follow-up (Fig 2). Furthermore, the pooled stillbirth and early neonatal death effect size by random effects model was 0.34 (95% CI: 0.25, 0.46) and 0.85 (95% CI: 0.21. 3.49) respectively.

Fig 2. Forest plot showing pooled effect of ANC on the perinatal outcomes in Ethiopia.

Fig 2

Heterogeneity of the studies

There was overall substantial heterogeneity across studies (I2 = 87%, p-value < 0.001), as well as within subgroups for sample size, design and place. Heterogeneity that was present in the overall meta-analysis was partially explained with stratification by study design and place. For example, in a subgroup analysis, cohort studies’ (RR = 0.83[95% CI: 0.67–1.02]; p-value = 0.45 for heterogeneity test, I2 = 0%) and community-based studies (RR = 0.64[95% CI: 0.51–0.80]; p-value = 0.23 for heterogeneity test, I2 = 29%) were not statistically heterogeneous (p-value > 0.10); however, heterogeneity was present when the subgroup analysis was performed by sample size (Table 3).

Table 3. Studies’ subgroup analysis modifying the effect of ANC on perinatal outcomes in Ethiopia.

Subgroup Random effects RR(95% CI) I-squared, p-value
Study design
Cross-sectional study 0.34(0.27–0.44) 78%, p-value < 0.001
Case-control study 0.45(0.33–0.61) 85%, p-value < 0.001
Cohort study 0.83(0.67–1.02) 0%, p-value = 0.45
Study place
Community-based study 0.64(0.51–0.80) 29%, p-value = 0.23
Facility-based study 0.36(0.28–0.46) 88%, p-value < 0.001
Sample size
< 500 0.29(0.22–0.38) 67%, p-value = 0.009
500–1000 0.53(0.26–1.05) 86%, p-value = 0.0006
> 1000 0.52(0.39–0.69) 90%, p-value < 0.001

Sensitivity analysis was performed for the outcome variable to observe a significant change in risk ratio and confidence interval. The meta-analysis resulted in no substantial difference in the overall risk ratio during the sequential removal of each study from the analysis. For instance, when a statistically insignificant study [14] and those study with wide confidence interval were excluded [101], the risk ratio of the effect of ANC did not change significantly or are within the confidence interval of pooled effect of ANC (0.32, 0.52).

An Egger's test for small-study effects showed no publication bias (p-value = 0.49). Therefore, there was no significant threat to the validity of the review.

Discussion

The purpose of this review was to evaluate the effectiveness of focused ANC as a means of reducing perinatal mortality among women (pregnant, delivering, postpartum, and mothers) in Ethiopia. Seventeen eligible primary studies were identified evaluating ANC with a range of populations including pregnant women, laboring women and postpartum mothers and their perinatal outcomes. Literature throughout Ethiopia support the benefits of ANC’s that provided by skilled attendants for the health of newborns. To improve ANC’s effectiveness, numerous approaches and strategies have been employed in LMICs [106108]. The focused ANC approach, developed in the 1990s by WHO has been implemented by most LMICs including Ethiopia [109,110].

The perinatal mortality and stillbirth rate were 41 and 38 per 1000 total births respectively in this meta-analysis which were slightly higher than the perinatal mortality rate in SSA (34.7 per 1000 total births) [4] however, lower than the pooled perinatal mortality rate (51.3 per 1000 total births) and slightly higher than stillbirth rate in Ethiopia (37 per 1000 total births) [6]. The review in SSA utilized only demographic health survey data whereas the pooled perinatal mortality in Ethiopia included both demographic health survey and study data. The difference may be attributed to not only a variation in the study nature, sample size, and setting but also maternal and child health utilization and access to quality maternal and newborn health services [6]. However, early neonatal mortality rate was 19 per 1000 live births in this review which was lower than systematic reviews found in Ethiopia (30 per 1000 live births).

A global multipartner movement to end preventable maternal and newborn deaths and stillbirths, setting a target for national stillbirths less than 12 per 1000 live births and will reduce death and disability continuously, ensuring no newborn is left behind in all countries by 2030 [2,19]; however, this review, along with the EDHS [5] and another systematic review in Ethiopia [6] revealed that the perinatal mortality has remained stable for two decades. Using this study’s perinatal mortality rate as a benchmark, the annual rate of reduction (ARR) must increase to achieve The Every Newborn Action Plan.

Pregnant women’s attendance of at least one ANC follow-up had a statistically significant effect on perinatal mortality. This study found a 58% and 66% lower risk of perinatal mortality and stillbirth among women who attended at least one ANC by a skilled attendant in Ethiopia. The basic finding of this study was even limited ANC (as little as one visit) leads to better newborn outcomes compared with no ANC, and encouraging pregnant women to seek ANC would significantly impact perinatal mortality rate (PMR) and would be an important strategy to incorporate in planning initiatives aimed at reducing PMR; this appears to be consistent with studies from another countries [56,111]. The finding was also in line with the global network’s population-based birth registry results in Africa, India, Pakistan and Guatemala [19]. A review in Asia also revealed a protective effect on perinatal mortality for women who used ANC and health facility delivery [39].

Antenatal care utilization and delivery at a health facility by a skilled attendant [112] who provides quality care are established as an intervention to reduce perinatal mortality [113115]. This may be due to the women receiving interventions during her pregnancy, [116118] which have a positive effect on lowering mortality; ANC also has an indirect impact since those women attending ANC are more likely to have a skilled birth attendant [39,112,119,120] hence, their newborns have access to basic neonatal resuscitation [121,122] which prevent perinatal mortality. Therefore, receiving high quality and an accessible health care services to reduce perinatal mortality is critical for pregnant women [123]. Skilled training of health care providers and resources of local primary healthcare facilities should be strengthened [124].

The factors associated with perinatal mortality (preterm labor, hypertensive disorders of pregnancy, intrauterine growth restriction, gestational diabetes) can be identified in the prenatal period, thus reinforcing the need to upgrade the continuum of care from initiation of ANC to complication management at health facilities [113,125].

A comprehensive database search was conducted to include all pertinent studies, and subgroup analysis was conducted to determine whether any specific study level factor described the outcomes. The large sample size of the analysis, could detect the effect of ANC on perinatal outcomes since the review included all studies conducted in Ethiopia. As a limitation, the systematic review and meta-analysis were based on English language and observational studies associated with inherent biases. We were unable to pool the overall effect of ANC for those studies that were based on the number of visits, since they did not define zero visits and therefore that were excluded. The study authors defined stillbirth and early neonatal death based on gestational age and the days of life of the newborn. The future research should focus on visits and specific ANC interventions that may affect perinatal outcomes.

Conclusion

This review showed that women who received at least one ANC follow-up by a skilled attendant were less likely to experience perinatal mortality than those who did not. Thus, increasing a woman’s ANC utilization by a skilled attendant is mandatory in Ethiopia to reduce perinatal mortality. Furthermore, to address perinatal mortality in the country, strategies should focus on women’s mobilization to seek ANC services and facility-based deliveries.

Supporting information

S1 Table. Searching using Medline via PubMed.

(DOCX)

S2 Table. Searching using EMBASE (via Ovid).

(DOCX)

S3 Table. Searching using CINAHL.

(DOCX)

S4 Table. Assessment of risk of bias for individual study (RoBANS).

(DOCX)

S1 File. Completed PRISMA checklist.

(DOC)

Acknowledgments

We would like to acknowledge Haramaya University for providing a scholarship and stipend. We also thank Tara Wilfong for her constructive comments and language edition.

Data Availability

All relevant data are within the manuscript and Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

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Decision Letter 0

Georg M Schmölzer

14 Sep 2020

PONE-D-20-22748

The effect of prenatal care on perinatal outcomes in Ethiopia: A systematic review and meta-analysis

PLOS ONE

Dear Dr. Kasiye Shiferaw,

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3. We noticed you have some minor occurrence of overlapping text with the following previous publications, which needs to be addressed:

https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0222566

https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-020-02880-5

https://nam.edu/wp-content/uploads/2016/09/Beyond-Survival-The-Case-for-Investing-in-Young-Children-Globally.pdf

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: I Don't Know

**********

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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**********

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Reviewer #1: Comments to the Authors:

The authors of this manuscript present a meta-analysis of nationally representative publications from Jan 1990 – June 2020, that reported on the effect of prenatal care on perinatal outcomes in Ethiopia. The study addresses a gap in knowledge in the stillbirth and early neonatal death rates in Ethiopia, which is not always reported in low and middle-income countries, but has important implications for overall reduction of the neonatal mortality rate (NMR), and provides a practical path for policymakers as they implement strategies to mitigate conditions that contribute to preventable morbidity and mortality in that country.

General comments:

1)The study was thoughtfully designed and executed. However, throughout the manuscript, there is need for correction of grammar, spelling and syntax. Changes in other areas of this manuscript will inform changes in the discussion section.

2) The basic premise of this study is to show that even limited prenatal care (as little as one visit) leads to better neonatal outcomes compared with no prenatal care, and encouraging pregnant women to seek prenatal care would significantly impact neonatal mortality rate (NMR) and would be an important strategy to incorporate in planning initiatives aimed at reducing NMR; this appears to be consistent with the experience of similar countries.

3) Since it appears that the authors had access to granularity of data, it would have added more weight to the manuscript if they also reported on causes of neonatal death and/or maternal risk factors contributing to stillbirths and early neonatal death (ENND) in this population. This is important for health providers and policymakers as it gives information about the burden of maternal/neonatal morbidity as they prioritize resources and develop targeted public health policies to optimize maternal and neonatal survival. Furthermore, the information is relevant not only for the current pregnancy, but also future pregnancies, since it informs the need for heightened surveillance for at-risk mothers as causative factors contributing to stillbirths and ENND may recur in a later pregnancy.

4) Definitions need to be more explicit, e.g. “stillbirths were identified according to WHO definition as fetal loss at or after 28 weeks gestation”, which would qualify as late and term stillbirths according to U.S. definition: early stillbirth – loss between 20-27 completed weeks of pregnancy; late stillbirth – loss between 28-36 completed weeks of pregnancy; term stillbirth – loss at 37 or more completed weeks of pregnancy.

5) For consistency – choose prenatal care (PNC) or antenatal care (ANC) throughout the manuscript.

Specific comments:

1. In the Abstract section: Lines 10 and 28 need to be clarified

2. In the Introduction section: Some of the content would be best addressed in the Discussion section. Also, please clarify lines 28-30.

3. In the Methods section: Please explain why “newborns after 28 weeks gestation” was chosen as the study population – is it consistency of WHO definition of stillbirth, accepted age of viability in Ethiopia, consistency with analyzed studies included in the meta-analyses, or some other reason?

4. In the Methods section: Authors should clarify inclusion criteria, especially item (i).

5. In the Methods section: Overall, the methodology is acceptable – authors were correct in their modelling by using random effects models for meta-analysis and sensitivity analysis in search of robustness of results. Study design, study population and sample size were well-described, however, sample age among/within the various studies of would have added weight to the manuscript.

6. In the Methods section: Operational definition: firstly, authors should indicate that the WHO stillbirth definition is being used. Secondly, in discussing skilled attendants and their diploma – what type/level of diploma did they achieve. Third, early neonatal death is sometimes defined as neonatal death in those born >1000g, occurring in the first 7 days of life. However, there is no consistent definition with regards to weight and gestational age cutoffs, only consistency is death in the first 7 days of life.

7. In the Results section: “Characteristics of included studies” – please explain why case control studies were excluded from determination of perinatal mortality rate. In addition, there appears to be confusion regarding definitions. If perinatal mortality refers to “stillbirths and death in the first week of life”, how can perinatal mortality rate be given as 39 per 1000 live births, or are the authors referring to NMR?

8. In the Results section: Despite substantial heterogeneity, the pooled effect size by the random effect model and tight confidence intervals were reassuring and speaks to the robustness of results.

9. In the Results section: Authors state that “visual observation of the funnel plot summary showed no publication bias”. On average, the ability to visually discern publication bias from funnel plots is poor; and the plot included with this manuscript does not represent a symmetric inverted funnel shape, but rather an asymmetric funnel that may suggest fundamental difference between studies of higher and lower precision, which appears to be consistent with the presented risk of bias assessments. The funnel plot does not substantially contribute to the manuscript and should be excluded.

10. In the Discussion section: “developing countries”, “low and middle-income countries” is preferred terminology.

11. In the Discussion section: Lines 22-28 – please clarify…is the author trying to indicate that the annual rate of reduction (ARR) needs to be much higher than the current ARR in order to achieve The Every Newborn Action Plan goal by 2030.

12. As mentioned earlier, there are sentences in the introduction, that would be better placed in the discussion.

Reviewer #2: This is a great paper that outlines the effects of antenatal care on newborn outcomes and it has a potential to highlight important predictors of newborn outcomes

First the paper states that they are looking into pregnancy outcomes - however as we read the paper we come to learn that the authors are interested in in newborns who have survived at least 7 days of life. But surprisingly the authors also have stillbirth as one of the outcomes and a stillbirth and neonatal death are not the same thing. It is also important to specify that the pregnancy outcomes of interest at neonatal outcomes right from the title

Methods - please review the prisma P 2015 version to see how you can reorganize the subheadings in the methods sections for easy flow

It was not clear in the selection criteria who did the selection and how it was done

As part of the search strategy submitting a table that gives the detailed search in the different databases would make it easy for those replicating the search to come up with the exact same search that you have - this can be submitted as a supplemental file

For the inclusion criteria it was not clear what study designs would be considered although when we move to risk bias analysis the authors mention non-randomized studies. However, it is great to see that two people conducted the data extraction and risk bias assessment

The operational definitions can be part of the introduction, however, it would be important to keep the ones that are relevant for the focus of the paper

When it came to the results it was difficult to understand which outcome was being reported it would be great to analyze the different outcomes separately - also conduct a qualitative synthesis to find out what the authors mean by perinatal death (as this will include both stillbirth and neonatal death). Analyze neonatal death and stillbirth separately and if you are including stillbirth as an outcome you may have revise the population in your PICO question

It was great to see the Prisma flow diagram as it helped understand the selection process

Reviewer #3: Overall, the manuscript was well organized, adding to existing literature. The authors did a good job at providing sufficient background information on the issue at hand, however I would advise to provide more clarity when providing worldwide statistics on the effectiveness of prenatal care versus those for Ethiopia, thus allowing for the discussion and conclusions of the manuscript to have a stronger impact on its readers. I feel the main title of the manuscript and then those for the tables and figures could have been stronger, though current titles do make sense. I do not have the appropriate knowledge base to determine whether the methods and statistical analyses used were most accurate for this type of research, however, the data provided in the Methods and Results sections matched the tables and figures provided. I caution authors to proofread carefully, paying close attention to capitalization and punctuation.

**********

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Reviewer #1: Yes: Janine Y Khan

Reviewer #2: Yes: Kaboni Whitney Gondwe

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Jan 14;16(1):e0245003. doi: 10.1371/journal.pone.0245003.r002

Author response to Decision Letter 0


16 Oct 2020

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

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https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Response- we have seen both guidelines and the manuscript was reorganized according these guidelines in the current version.

2. We suggest you thoroughly copyedit your manuscript for language usage, spelling, and grammar. If you do not know anyone who can help you do this, you may wish to consider employing a professional scientific editing service.

Whilst you may use any professional scientific editing service of your choice, PLOS has partnered with both American Journal Experts (AJE) and Editage to provide discounted services to PLOS authors. Both organizations have experience helping authors meet PLOS guidelines and can provide language editing, translation, manuscript formatting, and figure formatting to ensure your manuscript meets our submission guidelines. To take advantage of our partnership with AJE, visit the AJE website (http://learn.aje.com/plos/) for a 15% discount off AJE services. To take advantage of our partnership with Editage, visit the Editage website (www.editage.com) and enter referral code PLOSEDIT for a 15% discount off Editage services. If the PLOS editorial team finds any language issues in text that either AJE or Editage has edited, the service provider will re-edit the text for free.

Upon resubmission, please provide the following:

• The name of the colleague or the details of the professional service that edited your manuscript

• A copy of your manuscript showing your changes by either highlighting them or using track changes (uploaded as a *supporting information* file)

• A clean copy of the edited manuscript (uploaded as the new *manuscript* file)

Response- The native language speaker has seen the document very well. The address of the person who saw the manuscript is:

“Tara Wilfong MD, MPH

Associate Professor, College of Health and Medical Sciences

Haramaya University

Fulbright Alumni, Ethiopia

099 363 3861

twdoc@ufl.edu; tara.wilfong@fulbrightmail.org

The corrected manuscript was uploaded as recommended according to journal requirements.

3. We noticed you have some minor occurrence of overlapping text with the following previous publications, which needs to be addressed:

https://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0222566

https://bmcpregnancychildbirth.biomedcentral.com/articles/10.1186/s12884-020-02880-5

https://nam.edu/wp-content/uploads/2016/09/Beyond-Survival-The-Case-for-Investing-in-Young-Children-Globally.pdf

In your revision ensure you cite all your sources (including your own works), and quote or rephrase any duplicated text outside the methods section. Further consideration is dependent on these concerns being addressed.

Response- Thank you for the comments. The overlapping were checked in the current version and there were no overlapping. We tried to synthesize the idea as much as possible. We also used online free plagiarism checker to see if there is overlapping. We hope the problems in the previous version do not exist in the current version. Furthermore, it is our pleasure to correct if any such problems exist in the current version.

4. Please include a separate caption for each figure in your manuscript.

Response- The comment is accepted and incorporated in the current version.

Response to Reviewers

Reviewer #1: Comments to the Authors:

The authors of this manuscript present a meta-analysis of nationally representative publications from Jan 1990 – June 2020, that reported on the effect of prenatal care on perinatal outcomes in Ethiopia. The study addresses a gap in knowledge in the stillbirth and early neonatal death rates in Ethiopia, which is not always reported in low and middle-income countries, but has important implications for overall reduction of the neonatal mortality rate (NMR), and provides a practical path for policymakers as they implement strategies to mitigate conditions that contribute to preventable morbidity and mortality in that country.

General comments:

1)The study was thoughtfully designed and executed. However, throughout the manuscript, there is need for correction of grammar, spelling and syntax. Changes in other areas of this manuscript will inform changes in the discussion section.

Response- the comment is constructive and important for the clarity of the manuscript, hence the native language speaker has edited the manuscript. The grammar, spelling and syntax correction were made thoroughly in the manuscript.

2) The basic premise of this study is to show that even limited prenatal care (as little as one visit) leads to better neonatal outcomes compared with no prenatal care, and encouraging pregnant women to seek prenatal care would significantly impact neonatal mortality rate (NMR) and would be an important strategy to incorporate in planning initiatives aimed at reducing NMR; this appears to be consistent with the experience of similar countries.

Response- Thank you for understanding our manuscript very well. We incorporated the comment you suggested to the manuscript as it exactly explain the finding.

3) Since it appears that the authors had access to granularity of data, it would have added more weight to the manuscript if they also reported on causes of neonatal death and/or maternal risk factors contributing to stillbirths and early neonatal death (ENND) in this population. This is important for health providers and policymakers as it gives information about the burden of maternal/neonatal morbidity as they prioritize resources and develop targeted public health policies to optimize maternal and neonatal survival. Furthermore, the information is relevant not only for the current pregnancy, but also future pregnancies, since it informs the need for heightened surveillance for at-risk mothers as causative factors contributing to stillbirths and ENND may recur in a later pregnancy.

Response- You raised very important idea. As you mentioned, there are maternal, fetal and other factors that are contributing for perinatal deaths. Researchers did review ((Aminu et al. 2014 systematic literature review in low and middle income countries), (Reinebrant et al. 2017 systematic review globally) and (Berhan Y, and Berhan A, 2014 and Gedefaw et al. 2020 systematic review and meta-analysis in Ethiopia)) which identified very important determinant variables of pregnancy outcomes. These review have some gaps that we will address in the future review. But, the causative factors contributing to perinatal death (i.e. stillbirth and/or early neonatal death) covers vast concept to cover here and we plan to assess this part in another review. In this systematic review and meta-analysis, we need to know the effect of antenatal care on perinatal outcomes.

4) Definitions need to be more explicit, e.g. “stillbirths were identified according to WHO definition as fetal loss at or after 28 weeks gestation”, which would qualify as late and term stillbirths according to U.S. definition: early stillbirth – loss between 20-27 completed weeks of pregnancy; late stillbirth – loss between 28-36 completed weeks of pregnancy; term stillbirth – loss at 37 or more completed weeks of pregnancy.

Response- Thank you for the comment. In this review we took operational definition of study authors which is conceding with WHO definition. The study authors didn’t classify the stillbirth based on gestational age, hence we couldn’t identify these stillbirth as early, late or term, since we relied on study authors’ definition. As far as, the study authors used WHO definition (fetal loss at or after 28 weeks gestation), it may qualify late or term stillbirth.

5) For consistency – choose prenatal care (PNC) or antenatal care (ANC) throughout the manuscript.

Response- The comment is accepted; consistency very important and we chose the term ‘antenatal care’ throughout the manuscript instead of ‘prenatal care’.

Specific comments:

1. In the Abstract section: Lines 10 and 28 need to be clarified

Response- thank you. The comment is incorporated in the manuscript, we hope it is now clear in the current version.

2. In the Introduction section: Some of the content would be best addressed in the Discussion section. Also, please clarify lines 28-30.

Response- The comment is accepted, we moved one sentence ‘A global multipartner movement to end preventable maternal and newborn deaths and stillbirths, set a target for national stillbirth less than 12 per 1000 live births in all countries by 2030 [2, 10]’ to discussion section. As we go through the introduction there were no other sentences which we found important if moved to discussion section. We believe that introduction section sound well if these sentences retained. Furthermore, we reorganized the introduction section into four paragraphs for more clarity and precision.

3. In the Methods section: Please explain why “newborns after 28 weeks gestation” was chosen as the study population – is it consistency of WHO definition of stillbirth, accepted age of viability in Ethiopia, consistency with analyzed studies included in the meta-analyses, or some other reason?

Response- Thank you for this important question. The World Health Organization (WHO) has defined stillbirth as ‘fetal death late in pregnancy’, deferring the gestational age (GA) when a miscarriage becomes a stillbirth to country policy. Sometimes stillborn babies are not weighed, in these cases a gestational age of 28 completed weeks or a body length of 35 cm can be taken as equivalent to 1000 gram birth weight. As a result, Ethiopia adopted this definition and defined stillbirth as “fetal deaths after 28 weeks of gestation” which have being practiced in national guideline. Furthermore, 28 weeks of gestations is age of fetal viability in Ethiopia. The researchers also used this definition of stillbirth in Ethiopia. It very important if WHO definition of stillbirth that included gestational age and weight of the newborn were used, but in Ethiopia weight of the stillbirth baby is not measured routinely. As a result, we put this problems in our limitation as ‘the study authors’ definition were only based on gestational age of the newborn.’ in the discussion section.

4. In the Methods section: Authors should clarify inclusion criteria, especially item (i).

Response- Thank you. As study authors mentioned, the studies were done on different population i.e. delivering/laboring women or newborn babies or women of child-bearing age or pregnant women or postpartum women (Table 1). Therefore, all the studies that have assessed the outcomes and exposure of interest were included in this analysis. We rewrote the inclusion criteria (i) as ‘the study involved a delivering/laboring women or newborn babies or women of child-bearing age or pregnant women or postpartum women’. We have also made clear other inclusion criteria as recommended in the current version of the manuscript.

5. In the Methods section: Overall, the methodology is acceptable – authors were correct in their modelling by using random effects models for meta-analysis and sensitivity analysis in search of robustness of results. Study design, study population and sample size were well-described, however, sample age among/within the various studies of would have added weight to the manuscript.

Response- Thank you we have added ‘sample age’ to the manuscript as recommended.

6. In the Methods section: Operational definition: firstly, authors should indicate that the WHO stillbirth definition is being used.

Response- The comment is accepted. The definition was taken from WHO stillbirth definition in previous citations (already adopted from WHO definition). As we already mentioned above, Ethiopia adopted WHO definition which defined stillbirth as “fetal deaths after 28 weeks of gestation”. Furthermore, we cited WHO reference (from whom the definitions was adopted) in the current version of the manuscript.

Secondly, in discussing skilled attendants and their diploma – what type/level of diploma did they achieve.

Response- Thank you for the comments. We have substituted the previous definition with “Skilled attendant refers to a midwife, doctor, or nurse who been educated, trained and accredited to manage normal pregnancies, childbirth and an immediate postnatal period and identify, manage and/or refer women and newborns with complications” which is WHO definition of skilled attendant in the current version. The previous definition was taken from literature (Debelew et al. 2014 which defined skilled attendant as ‘Those who have trained to the level of Diploma and above was categorized as ‘‘skilled attendants’’).

Third, early neonatal death is sometimes defined as neonatal death in those born >1000g, occurring in the first 7 days of life. However, there is no consistent definition with regards to weight and gestational age cutoffs, only consistency is death in the first 7 days of life.

Response- Yes, we share your concern. As you already mentioned, the articles we included in this review defined early neonatal death as ‘death of newborn in the first 7 days of life’ regardless of the weight of the newborn. It would have been better if weight of the newborn in addition to age in days were used for the definition. We reviewed all the included studies whether they considered weight as criteria for definition as recommended. But, the articles were not mentioned the weight and gestational age cutoffs in their definitions of the early neonatal death. Furthermore, there were no studies that we excluded because of including or excluding weight >1000g in their definitions.

7. In the Results section: “Characteristics of included studies” – please explain why case control studies were excluded from determination of perinatal mortality rate. In addition, there appears to be confusion regarding definitions. If perinatal mortality refers to “stillbirths and death in the first week of life”, how can perinatal mortality rate be given as 39 per 1000 live births, or are the authors referring to NMR?

Response- We found your comment very important. We calculated stillbirth rate and early neonatal death rate separately (i.e. stillbirth rate, early neonatal mortality rate). Moreover, we calculated perinatal mortality rate adding stillbirth and early neonatal death to have overall estimation of perinatal mortality rate considering total live births (sample size in our case) as denominators. Most of the time case-control study design take case and control (the denominator is unknown) as a result it is not conducive to talk about magnitude or prevalence or rate of the disease. Similarly, previous review excluded case-control studies from rate calculation (e.g. Jena B.H., Biks G.A., Gelaye K.A. & Gete Y.K., 2020). However, the case-control study design that have total population (i.e. Roro et al. 2018 used nested case-control study design and the denominator is known) was included in the rate calculation.

We added this sentence to current version of manuscript “In this review, we took perinatal death (as study authors defined) or we added the numbers of stillbirths and early neonatal deaths (perinatal death during perinatal period) or we took available outcome between of stillbirths and early neonatal deaths to estimate overall perinatal outcomes/mortality rate.”

8. In the Results section: Despite substantial heterogeneity, the pooled effect size by the random effect model and tight confidence intervals were reassuring and speaks to the robustness of results.

Response- Thank you. We tried to subgroup the studies by study design, sample size and setting and the heterogeneity explained by study design and setting. But there were no significant change of heterogeneity of the analysis during subgrouping by sample size.

9. In the Results section: Authors state that “visual observation of the funnel plot summary showed no publication bias”. On average, the ability to visually discern publication bias from funnel plots is poor; and the plot included with this manuscript does not represent a symmetric inverted funnel shape, but rather an asymmetric funnel that may suggest fundamental difference between studies of higher and lower precision, which appears to be consistent with the presented risk of bias assessments. The funnel plot does not substantially contribute to the manuscript and should be excluded.

Response- Thank you. We share your concern “the ability to visually discern publication bias from funnel plots is poor”. As you suggested, we substituted the funnel plot with statistical method of assessment of publication bias (Egger's test for small-study effects). The Egger's test for small-study effects showed no statistical significance (H0=there is no small-study effect, H alternative=There is small-study effects, p-value was 0.49, therefore we failed to reject the H0), hence no publication bias in the manuscript. This finding match our funnel plot report of no publication bias.

10. In the Discussion section: “developing countries”, “low and middle-income countries” is preferred terminology.

Response- Thanking you for the comment, we substituted ‘developing countries’ with ‘low and middle-income countries’ throughout the manuscript in the current version.

11. In the Discussion section: Lines 22-28 – please clarify…is the author trying to indicate that the annual rate of reduction (ARR) needs to be much higher than the current ARR in order to achieve The Every Newborn Action Plan goal by 2030.

Response- Yes, thank you for the reconstruction of the sentence. we corrected the sentence as ‘however, this review, the EDHS [5] and review in Ethiopia [6] revealed that perinatal mortality remained stable in about two decade and considering our perinatal mortality rate as benchmark, the annual rate of reduction (ARR) needs to be much higher than the current ARR in order to achieve The Every Newborn Action Plan goal by 2030.’ in the current version of manuscript.

12. As mentioned earlier, there are sentences in the introduction that would be better placed in the discussion.

Response- We brought sentence ‘A global multipartner movement to end preventable maternal and newborn deaths and stillbirths, set a target for national stillbirth less than 12 per 1000 live births in all countries by 2030 [2, 10]’ to discussion section. We prefer the other sentences retained in the introduction section to better show the gaps.

Reviewer #2: This is a great paper that outlines the effects of antenatal care on newborn outcomes and it has a potential to highlight important predictors of newborn outcomes

First the paper states that they are looking into pregnancy outcomes - however as we read the paper we come to learn that the authors are interested in in newborns who have survived at least 7 days of life. But surprisingly the authors also have stillbirth as one of the outcomes and a stillbirth and neonatal death are not the same thing. It is also important to specify that the pregnancy outcomes of interest at neonatal outcomes right from the title

Response- Thank you for this credible idea, we share your concern “a stillbirth and neonatal death are not the same thing” and we defined perinatal outcomes as ‘In this review, we report our evaluation of perinatal outcomes related to death of newborn from 28 weeks’ of gestation to seven days postpartum (i.e. stillbirths and/or early neonatal deaths)’. Stillbirth was defined as fetal deaths after 28 weeks of gestation and early neonatal mortality was neonatal deaths in the first week of life after being delivered in the age of viability (28 weeks of gestation and above).

These definition was based on authors’ definition which is conceding with world health organization of these terms. We did the analysis separately for effect of ANC on stillbirth and early neonatal death as well. Ten studies saw effect of ANC on stillbirth which have showed statistically significant association. But, only two study were saw effect of ANC on early neonatal death and have no statistically significant association. Therefore, perinatal outcomes/mortality in our case is the stillbirth and/or early neonatal death to have overall estimates. The following sentence included in the current version of manuscript after your recommendation “In this review, we took perinatal death (as study authors defined) or we added the numbers of stillbirths and early neonatal deaths or we took available outcome between of stillbirths and early neonatal deaths to estimate overall pooled perinatal outcomes/mortality rate.”

Methods - please review the prisma P 2015 version to see how you can reorganize the subheadings in the methods sections for easy flow

Response- Okay. We reorganize it in the current version.

It was not clear in the selection criteria who did the selection and how it was done

As part of the search strategy submitting a table that gives the detailed search in the different databases would make it easy for those replicating the search to come up with the exact same search that you have - this can be submitted as a supplemental file

Response- Okay, the search strategies for EMBASE, and CINAHL were added to previous search strategy of PubMed that was submitted as additional fines (S1-S3 Table).

For the inclusion criteria it was not clear what study designs would be considered although when we move to risk bias analysis the authors mention non-randomized studies. However, it is great to see that two people conducted the data extraction and risk bias assessment

Response- Thank you. We included observational study design such as cross-sectional, case-control and cohort study. We have also added study designs to inclusion criteria in the current version of the manuscript.

The operational definitions can be part of the introduction, however, it would be important to keep the ones that are relevant for the focus of the paper

Response- We thank you for the comment. Since the PRISMA guideline recommend separate operational definition, we put it in the method section as you recommended (keep the ones that are relevant for the focus of the paper).

When it came to the results it was difficult to understand which outcome was being reported it would be great to analyze the different outcomes separately - also conduct a qualitative synthesis to find out what the authors mean by perinatal death (as this will include both stillbirth and neonatal death). Analyze neonatal death and stillbirth separately and if you are including stillbirth as an outcome you may have revise the population in your PICO question

Response- Thank you. We did separate analysis for stillbirth and early neonatal death as you recommended. The current PICO is more comprehensive that included both stillbirth and early neonatal death. It included fetal or newborn deaths during perinatal period both stillbirth and early neonatal deaths. The population is ‘newborn after 28 weeks’ gestation and survived seven days postpartum.’

It was great to see the Prisma flow diagram as it helped understand the selection process

Response-Thank you. The PRISMA flow diagram was shown in Fig 1.

Reviewer #3: Overall, the manuscript was well organized, adding to existing literature. The authors did a good job at providing sufficient background information on the issue at hand, however I would advise to provide more clarity when providing worldwide statistics on the effectiveness of prenatal care versus those for Ethiopia, thus allowing for the discussion and conclusions of the manuscript to have a stronger impact on its readers.

Response- Thank you. We added the effectiveness of ANC globally ‘ANC is relevant intervention for successful maternal and child health, globally’. The available information on effectiveness of ANC are studies with varying or inconsistent information on the area which mandate further research or pooling the existing studies. The pooled effect of ANC on neonatal mortality worldwide and in sub-Saharan Africa showed positive association as we mentioned in the introduction section. But, we as far as our knowledge is concerned there were no pooled estimates results showing effect of ANC on perinatal outcome in sub-Saharan Africa and Ethiopia.

I feel the main title of the manuscript and then those for the tables and figures could have been stronger, though current titles do make sense.

Response- Thank you for the comments. The title of the manuscript decided by the review authors after thorough discussion. Moreover, it has been registered on ‘PROSPERO’ as “The effect of ANC on perinatal outcome in Ethiopia” which best describe our review title. We afraid if we modify the title of the review it may not obey the registration principles and overlap with other review title. But, the title of the tables and figures were modified as you recommended it.

I do not have the appropriate knowledge base to determine whether the methods and statistical analyses used were most accurate for this type of research, however, the data provided in the Methods and Results sections matched the tables and figures provided. I caution authors to proofread carefully, paying close attention to capitalization and punctuation.

Response- Okay, thank you. Native Language speaker has seen the manuscript and we hope the capitalization and punctuation problems are now corrected.

Attachment

Submitted filename: Response to Reviewers.docx

Decision Letter 1

Georg M Schmölzer

30 Oct 2020

PONE-D-20-22748R1

The effect of antenatal care on perinatal outcomes in Ethiopia: A systematic review and meta-analysis

PLOS ONE

Dear Dr. Kasiye Shiferaw,

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PLOS ONE

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: (No Response)

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Reviewer #1: Yes

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Reviewer #1: Yes

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Reviewer #1: The authors of this manuscript have addressed many of the comments satisfactorily and overall the manuscript has a nice flow with improved clarity of writing. However, there are still syntax, punctuation and spelling errors (minor concern that is easily corrected), but more importantly, the authors continue to conflate perinatal mortality, neonatal mortality and stillbirths. A stillbirth is not a live birth. This remains a major flaw in the manuscript and should be corrected.

Of note - WHO and UNICEF The Every Newborn Action Plan: Goals for reducing newborn mortality and preventing stillbirths:

Goal 1. End preventable newborn deaths.

By 2030, all countries will have reached the target of 12 or less newborn deaths per 1000 live births and will continue to reduce death and disability, ensuring that no newborn is left behind.

Goal 2. Ending preventable stillbirths

By 2030, all countries will have reached the target of 12 or fewer stillbirths per 1000 total births and will continue to improve equity.

OR (updated),

Goal 1. End preventable newborn deaths.

By 2035, all countries will reach the target of 10 or less newborn deaths per 1000 live births and continue to reduce death and disability, ensuring that no newborn is left behind.

Goal 2. Ending preventable stillbirths

By 2035, all countries will reach the target of 10 or less stillbirths per 1000 total births and continue to close equity gaps.

Specific comments:

1. In the Introduction section: Lines 68-69 and line 228. It would be helpful for international readers if the “focused ANC model” referenced a few times in the manuscript is explained.

2. In the Introduction section: Line 70. “Reduction in the gaps reductions” – needs to be clarified.

3. In the Methods section: Line 129. Authors appear to suggest that an attempt was made to obtain missing data from its source, but not always successful – authors should add a statement as to how missing data was handled in the analysis.

4. In the Methods section: Lines 174-178. Authors should separate newborn deaths and stillbirths. Hence, clarify and probably show numbers used as numerator and denominator for each of the following: Stillbirth rate per 1000 total births = number of stillbirths/total number of births, whereas neonatal mortality rate per 1000 live births = number of neonatal deaths/total number of live births. As currently stated in the manuscript, there is an unresolved discrepancy in reporting. See also Line 231.

5. In the Results section: Line 248-249. “…58% and 66% lower risk of perinatal mortality and stillbirth among women who attended at least one ANC..” – these percentages may need to be modified after recommendations in Comment #4.

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Reviewer #1: Yes: Janine Y Khan

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PLoS One. 2021 Jan 14;16(1):e0245003. doi: 10.1371/journal.pone.0245003.r004

Author response to Decision Letter 1


17 Dec 2020

Response to reviewers

Comments

Reviewer #1

The authors of this manuscript have addressed many of the comments satisfactorily and overall the manuscript has a nice flow with improved clarity of writing. However, there are still syntax, punctuation and spelling errors (minor concern that is easily corrected),

Response- The comments were corrected in the main document. Thank you.

but more importantly, the authors continue to conflate perinatal mortality, neonatal mortality and stillbirths.

Response- We found your comment astonishing. We learnt a lot from you frankly. We defined these terms in the operational definition part. As you said these terms are not the same. We cautiously analyzed these findings in current version of the manuscript. We have explained this concern in detail below on response we provided to specific comment #4.

Of note - WHO and UNICEF The Every Newborn Action Plan: Goals for reducing newborn mortality and preventing stillbirths:

Goal 1. End preventable newborn deaths.

By 2030, all countries will have reached the target of 12 or less newborn deaths per 1000 live births and will continue to reduce death and disability, ensuring that no newborn is left behind.

Goal 2. Ending preventable stillbirths

By 2030, all countries will have reached the target of 12 or fewer stillbirths per 1000 total births and will continue to improve equity. OR (updated),

Goal 1. End preventable newborn deaths.

By 2035, all countries will reach the target of 10 or less newborn deaths per 1000 live births and continue to reduce death and disability, ensuring that no newborn is left behind.

Goal 2. Ending preventable stillbirths

By 2035, all countries will reach the target of 10 or less stillbirths per 1000 total births and continue to close equity gaps.

Response- Thank you, it is nice recommendation. We took goal 1 End preventable newborn deaths.

By 2030, all countries will have reached the target of 12 or less newborn deaths per 1000 live births and will continue to reduce death and disability, ensuring that no newborn is left behind in our manuscript as we explained it in the current version. We agreed all goals are reducing the newborn death and making sure all countries are achieving the goal.

Specific comments:

1. In the Introduction section: Lines 68-69 and line 228. It would be helpful for international readers if the “focused ANC model” referenced a few times in the manuscript is explained.

Response- Thank you for the comment. We defined it as ‘Focused ANC model is four visits providing essential evidence based interventions – a package to achieve the full life-saving potential that ANC promises for women and babies.’

2. In the Introduction section: Line 70. “Reduction in the gaps reductions” – needs to be clarified.

Response- The comment was accepted. Thank you. The repeated phrase was removed in the new version of the manuscript. We rewrote the sentence.

3. In the Methods section: Line 129. Authors appear to suggest that an attempt was made to obtain missing data from its source, but not always successful – authors should add a statement as to how missing data was handled in the analysis.

Response- As you know missing data is challenging most of the time. We tried to request for further information when we thought the data lack clarity and/or missing and unfortunately there was no study which was excluded due to clarity and/or missing data.

4. In the Methods section: Lines 174-178. Authors should separate newborn deaths and stillbirths. Hence, clarify and probably show numbers used as numerator and denominator for each of the following: Stillbirth rate per 1000 total births = number of stillbirths/total number of births, whereas neonatal mortality rate per 1000 live births = number of neonatal deaths/total number of live births. As currently stated in the manuscript, there is an unresolved discrepancy in reporting. See also Line 231.

Response- Thank you for the comments. Stillbirth rate is calculated using numerator of number of stillbirths and denominators of number of births (dead or alive) whereas early neonatal mortality is calculated using numerator of neonatal death and denominator of live birth during 7 days of life.

Number of stillbirths per 1000 births (live and stillbirths). It was 38 per 1000 total births (stillbirths and live births) in our review.

Early neonatal mortality rate is the death of neonate per 1000 live births within 7 days of life. The rate was 19 per 1000 live birth after correction was made based on your recommendation.

Similarly, the denominator used for perinatal mortality rate (PMR) determination was total births after 28 weeks of gestation. Since the majority of the studies included reported PMR as per 1000 total births, data presented in some primary studies with a denominator of total live births were changed into total births by determining new PMR taking into account the reported total deliveries, total still births and total early neonatal deaths. Therefore, the perinatal mortality rate in this finding was 41 per 1000 total births (total deliveries, total still births and total early neonatal deaths) as we mentioned in the previous version.

5. In the Results section: Line 248-249. “…58% and 66% lower risk of perinatal mortality and stillbirth among women who attended at least one ANC..” – these percentages may need to be modified after recommendations in Comment #4.

Response- Thank you for the comments. There is no any relationship between these percentages and definitions of these terms (comments #4). These percentages were taken from risk ratio which were found from random effect model calculation. Hence the risk ratio for perinatal mortality and stillbirths were 0.42 and 0.34 making 58% (1-0.42) and 66% (1-0.34) percentages. We did this because experts recommend explaining finding in percentage, rather putting as obsolete number.

Attachment

Submitted filename: Response to Reviewers.docx

Decision Letter 2

Georg M Schmölzer

21 Dec 2020

The effect of antenatal care on perinatal outcomes in Ethiopia: A systematic review and meta-analysis

PONE-D-20-22748R2

Dear Dr. Kasiye Shiferaw,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Georg M. Schmölzer

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Georg M Schmölzer

28 Dec 2020

PONE-D-20-22748R2

The effect of antenatal care on perinatal outcomes in Ethiopia: A systematic review and meta-analysis

Dear Dr. Shiferaw:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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on behalf of

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Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Searching using Medline via PubMed.

    (DOCX)

    S2 Table. Searching using EMBASE (via Ovid).

    (DOCX)

    S3 Table. Searching using CINAHL.

    (DOCX)

    S4 Table. Assessment of risk of bias for individual study (RoBANS).

    (DOCX)

    S1 File. Completed PRISMA checklist.

    (DOC)

    Attachment

    Submitted filename: Response to Reviewers.docx

    Attachment

    Submitted filename: Response to Reviewers.docx

    Data Availability Statement

    All relevant data are within the manuscript and Supporting Information files.


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