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 (S1–S3 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.

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 [50–52]. 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’ [12,23,53–58].

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].

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 [69–74], 6 articles defined their outcomes differently [62,75–79], 6 articles did not determine outcome at all [26,53,80–83] and 6 articles had no ANC follow-up status [84–89] 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.

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.