Folic acid supplementation during preconception period in sub-Saharan African countries: A systematic review and meta-analysis

Mekuriaw Nibret Aweke; Elsa Awoke Fentie; Muluken Chanie Agimas; Lemlem Daniel Baffa; Ever Siyoum Shewarega; Aysheshim Kassahun Belew; Esmael Ali Muhammad; Berhanu Mengistu

doi:10.1371/journal.pone.0318422

. 2025 Jan 31;20(1):e0318422. doi: 10.1371/journal.pone.0318422

Folic acid supplementation during preconception period in sub-Saharan African countries: A systematic review and meta-analysis

Mekuriaw Nibret Aweke ^1,^*, Elsa Awoke Fentie ², Muluken Chanie Agimas ³, Lemlem Daniel Baffa ¹, Ever Siyoum Shewarega ⁴, Aysheshim Kassahun Belew ¹, Esmael Ali Muhammad ¹, Berhanu Mengistu ¹

Editor: Jai K Das⁵

PMCID: PMC11785287 PMID: 39888921

Abstract

Introduction

Neural tube defects (NTDs) are serious congenital anomalies of the central nervous system caused by disruptions in early embryonic development. The prevalence is about twice as common in low- and middle-income countries and more prevalent in sub-Saharan Africa. Folic acid deficiency is a major risk factor and common during pregnancy. However, limited research on preconception folic acid supplementation in this region highlights the need for systematic reviews and targeted interventions to improve maternal and fetal health.

Methods

We conducted a systematic literature search in EMBASE, MEDLINE, Scopus, CINAHL, Google Scholar, and Google for studies on the proportion of folic acid supplementation during the preconception period, covering publications up to January 2024. Study quality was assessed using the Newcastle-Ottawa Scale. Heterogeneity was evaluated with Cochrane Q and I² statistics, and small study effects were tested with Egger’s test at a 5% significance level. The certainty of evidence was assessed using the GRADE approach. A random-effects model was used to estimate the pooled proportion of FA supplementation during the preconception period in sub-Saharan African countries.

Result

This systematic review included 28 studies with a total of 12,562 participants. The highest (45.2%) and lowest (1.9%) proportion of folic acid supplementation during preconception period were recorded in the southern and Amhara regions of Ethiopia, respectively. The estimated pooled proportion of folic acid supplementation among women in Sub-Saharan Africa (SSA) during preconception period was (14.10%; 95% CI: 11.22–16.98) with significant heterogeneity between studies (I² = 97.71%, p = 0.001). In sub-group analysis based on corresponding countries the highest estimated folic acid supplementation proportion during preconception period was found in studies conducted in Kenya ((22%; 95% CI: 19%-25%), I² = 97.7%), followed by studies conducted in Ghana (20%; 95% CI: 7%-33%), I² = 96.9%). The majority of the studies included in the analysis are of high quality, with quality scores ranging from 7 to 8. The certainty of evidence was assessed using the GRADE approach, resulting in a low overall rating.

Conclusion

The results of this systematic review and meta-analysis indicated that folic acid supplementation during preconception period is significantly low among mothers in sub-Saharan African countries, despite being one of the best approaches to improve birth outcomes. Therefore, healthcare organizations, governments, policymakers, and other stakeholders involved in folic acid supplementation must collaborate on developing strategies to improve its uptake during the preconception period.

Introduction

Neural tube defects (NTDs) are serious congenital anomalies that affect the central nervous system, arising from disruptions in the early embryonic development process responsible for closing the neural tube [1]. Various types of NTDs, including anencephaly, spina bifida, encephalocele, craniorachischisis, and iniencephaly, cause significant mortality, morbidity, long-term disability, and substantial psychological and economic impacts [2,3].

Globally, neural tube defects (NTDs) occur in about 1 in 1,000 pregnancies, making them the second most common congenital anomaly. Annually, they result in 300,000 affected births, 88,000 deaths, and 8.6 million disability-adjusted life years (DALYs) [4–6]. The burden of NTDs has been documented to be approximately twice as high in low- and middle-income countries (LMICs) compared to high-income countries [7].

Various studies conducted in LMICs have found that the prevalence of NTDs ranges from 11.7 to 50.74 per 10,000 births, highlighting a significant burden on different segments of the population [8,9]. In sub-Saharan Africa (SSA), NTDs are prevalent congenital anomalies, impacting around 1 to 3 births per 1000 annually, with an overall prevalence of about 21.4% [10]. A systematic review of 58 studies across 16 African countries found the NTD burden in Africa was 32.95 per 10,000 births, with Eastern Africa at 111.13 and Southern Africa at 11.43 per 10,000 births [11]. Another meta-analysis in Africa reported a pooled prevalence of 50.71 per 10,000 births, highlighting the impact of folic acid (FA) supplementation and maternal exposures on NTDs in the region [9]. Fetuses with anencephaly usually die either before birth or shortly thereafter [12]. Neural tube defects (NTDs) impose a significant economic burden. For instance, the CDC estimated the lifetime cost of spina bifida care at $791,900 in 2014 [13].

The etiology of NTDs is not fully understood, but factors such as genetic predisposition, maternal nutrition, environmental influences, and insufficient folic acid intake during early pregnancy are implicated [14]. Folic acid insufficiency is an important risk factor for NTDs and is common during pregnancy because dietary intake is insufficient to cover daily needs, even with a balanced diet [15]. Folate insufficiency exceeds 40% in many countries with available data, particularly affecting several African nations [16].

Multiple studies have highlighted that most NTDs can be prevented through effective FA supplementation during preconception [17]. Epidemiological evidence indicates that FA supplementation during preconception period reduces the incidence of NTDs when continued for a minimum of three months during pregnancy [18].

Folate is a water-soluble vitamin that is important in DNA synthesis, cell replication, and growth [19]. There are two strategies for improving FA intake prior to pregnancy: one involves fortifying the general food supply with folate, while the other entails targeted folate supplementation for individuals [20]. The WHO recommends women of reproductive age take 0.4 mg of folic acid daily, starting 2–3 months before conception and continuing through the 12th week of pregnancy [21,22]. High doses (4–5 mg per day of FA) are commonly recommended for those with certain underlying risk factors for NTDs and can reduce the risk of recurrent NTDs by more than 70 percent [21]. An alternative recommendation suggests weekly iron and folic acid supplements for women of reproductive age, especially in populations with anemia rates over 20% [23].

Folic acid supplementation is recommended before conception because NTDs occur very early in pregnancy, often before a woman knows she is pregnant [24]. Therefore, it is crucial to have adequate FA levels in the system before becoming pregnant. Since most pregnancies are unplanned, many countries have implemented FA fortification of staple foods for the prevention of NTDs [25].

Folic acid supplementation not only prevents NTDs but also reduces the occurrence of congenital cardiac and urologic anomalies [26]. Adequate folic acid intake before conception and through the 12th week of pregnancy is linked to reduced spontaneous abortions, preterm births, small-for-gestational-age babies, and improved pregnancy outcomes [27]. Despite established recommendations and benefits, folic acid supplementation before conception remains suboptimal, particularly in resource-limited settings [28]. The use of guidelines and recommendations for preconceptional FA supplementation varies globally, leading to differences in supplementation practices [29]. Several studies have indicated that taking FA before pregnancy is crucial for the health of both the mother and the fetus, particularly SSA countries [30]. There is a significant gap in the literature regarding folic acid supplementation during the preconception period in Sub-Saharan Africa. This systematic review and meta-analysis aims to estimate its proportion, serving as a crucial indicator for governments, health professionals, and policymakers to monitor progress, implement targeted interventions, and reduce the burden of NTDs at both individual and national levels.

2. Methods

2.1 Study protocol and registration

This systematic review and meta-analysis was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement guideline [31] and the study protocol was registered in the PROSPERO International Prospective Register of Systematic Reviews under the registration number CRD42024503924.

2.2 Inclusion and exclusion criteria

In this systematic review and meta-analysis, we included all studies conducted on the proportion of FA supplementations during the preconception period in SSA countries that were written in English. Quantitative studies, including cross-sectional, cohort, and case-control designs, were included based on the Population, Exposure, Comparator, Outcome (PECO) framework (Table 1). We included journal articles, theses, and dissertations without imposing restrictions based on publication date or age criteria. In contrast, studies utilizing qualitative methodologies were excluded due to the specific nature of the review and the chosen analytical approach. Studies done on pregnant women were only included if they had taken folate during preconception.

Table 1. Criteria for inclusion of quantitative studies based on the Population, Exposure, Comparator, Outcome (PECO) framework.

Criteria	Details
Population (P)	Women of all age group in Sub-Saharan African (SSA) countries Excludes women with diabetes, epilepsy, or prior neural tube defect-affected births
Exposure (E)	folic acid (FA) supplementation during the preconception period
Comparator (C)	Not applicable
Outcome (O)	Proportion of folic acid supplementation during the preconception period

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Exclusion criteria encompassed studies lacking data on the percentage of women engaging in any FA supplementation specifically during the preconception period as well as studies reporting zero prevalence. Additionally, experimental, case report or case series studies were excluded, along with studies where reported data were inadequate for estimating proportion (S1 Appendix). Furthermore, studies focusing on women with diabetes, epilepsy, or prior neural tube defect-affected births were excluded due to differing FA recommendations and potentially closer monitoring by healthcare providers during pregnancy.

2.3. Search strategy

The search strategy for this review involved using both MeSH terms and key terms related to preconception care and folic acid such as preconception care, preconception, pre-conception, periconception, peri-conception, before conception, folic acid, folate, vitamin, pteroylglutamic acid, folic acid supplementation, folic acid administration, folic acid adherence, folinic acid and vitamin B9. Terms were combined by using the Boolean operator OR and themes were combined using AND as explained in (S1 Table). Studies published in the English language up to January 2024 were retrieved from EMBASE, MEDLINE, Scopus, CINAHL, and manually on Google and Google Scholar. The search for unpublished studies included Google and institutional repositories(namely Addis Ababa University, Jimma University, Hawassa University, Haramaya University and Bahir Dar University). The literature search was last conducted on January 29, 2024 ensuring that the most recent and relevant studies were considered.

2.4. Study selection

We reviewed and evaluated studies from various sources to ensure a comprehensive analysis. All duplicate studies were removed, and full-text studies were downloaded. All the studies reviewed through different electronic databases were combined, exported, and managed using RAYYAN web-based software [32]. Titles and abstracts were first screened based on specific criteria to exclude irrelevant studies. Those that passed this stage underwent full-text screening, where their design, methodology, sample size, and key findings were assessed for relevance and suitability. The eligibility of each study was independently evaluated by two reviewers (BM & EA). Any significant differences in their assessments were resolved through discussion and consultation with other reviewers (MN & AK). Subsequently, the data were exported to the EndNote reference manager to facilitate the management and organization of citations.

2.5 Data extraction

The selected studies were carefully reviewed, and data were extracted using a pre-piloted data extraction form developed by the authors. Subsequently, data extraction was carried out using Microsoft Office Excel. All-important data extracted from each study included name of author, year of publication, study design, sub-Africa region, study period, country, study setting, publication type, sampling method(random/non-random), population characteristics, response rate, sample size (N) and overall proportion (S2 Appendix). We contacted one study author to obtain missing data to ensure comprehensive analysis. Data extraction was performed independently by three authors (E.S., A.K., and L.D.). Any discrepancies or inconsistencies were resolved through discussion and consensus.

2.6 Assessment of the quality of the included studies

Three reviewers (M.N., B.M and M.C.) assessed the methodological quality and eligibility of the identified articles using the Newcastle-Ottawa Quality Assessment Scale adapted for cross-sectional studies [33]. Disagreements among reviewers were resolved through discussion. This assessment scale evaluates several factors, including the representativeness of the sample, sample size adequacy, non-response rate, validity of measurement tools, comparability of subjects in different outcome groups, outcome assessment, and statistical testing. The quality assessment score for each study ranges from 0 to 10, with classifications including "Very Good" (9–10 points), "Good" (7–8 points), "Satisfactory" (5–6 points) and "Unsatisfactory" (0 to 4 points).

2.7 Evidence certainty assessment

In accordance with Cochrane’s guidelines, we evaluated the certainty of the evidence related to preconception FA supplementation, synthesizing findings from the included studies. This evaluation utilized the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) framework, considering factors such as study design, inconsistency, indirectness, imprecision, and potential publication bias, as outlined in the GRADE handbook [34]. The assessment was adapted to proportion estimates, with the certainty of evidence categorized as high, moderate, low, or very low. The results were presented in a Summary of Findings (SoF) table, generated using the GRADE approach [35]. The certainty of evidence was assessed independently by E.A. and M.C., with any disagreements resolved through consensus.

2.8 Statistical analysis

The extracted data were transferred to STATA/MP version 17.0 software (Stata Corp LLC, College Station, TX, USA) for analysis. The pooled proportion of FA during preconception period was analyzed using the random effects model with DerSimonian-Laird model weight. Heterogeneity in meta-analysis is commonly inevitable due to variations in study quality, sample size, methodology, and outcome measurements across studies. Statistical assessment of significant heterogeneity was conducted using the Cochrane Q-test and I² statistics. The interpretation of the I² test statistics < 50, 50–75%, and > 75% was declared as low, moderate, and high heterogeneity, respectively [36]. To reduce variance in estimated points between primary studies, subgroup analyses were performed based on sub-Africa regions, countries, year of publication, study setting, sampling methods, and study population (various articles include pregnant individuals, others encompass mothers who have delivered, while some incorporate women in their childbearing years). Also, sensitivity analyses were done to assess the influence of included studies on pooled estimates. Publication bias was evaluated both graphically and using Egger’s statistical test. A statistically significant result from Egger’s test (P-value < 0.05) would indicate the presence of a small study effect, which would then be addressed using non-parametric trim and fill analysis with the random effects model. We then proceed to explore the origins of heterogeneity using a meta-regression model, incorporating publication year and sample size as covariates.

3. Results

3.1 Selection and Identification of studies

Through a comprehensive and systematic exploration of literature, this systematic literature search identified 1,259 potential studies through electronic search and other sources. After eliminating the duplicates (n = 327), we reviewed 929 studies by title and abstract and eliminated 734 irrelevant studies. We reviewed the full texts of the remaining 195 articles for eligibility. Of these, 166 studies were not eligible, and 29 studies were eligible for inclusion in our review. After assessing the full texts of the remaining articles, an additional 1 article was excluded due to poor quality.

Finally, 28 studies that met the eligibility criteria were included in the final analysis (Fig 1).

3.2 Characteristics of included studies

This systematic review included 28 studies with a total of 12,562 participants [7,37–64]. All the studies utilized in this meta-analysis were cross-sectional and were conducted from 2014 to 2024 across various countries within the SSA region. From all studies 12 (42.86%) were conducted in Ethiopia [37,40,42,46,47,49–51,53–55,62], seven (25.0%) were from Nigeria [7,38,41,48,52,61,63], four (14.29%) from Ghana [43–45,59], and two (7.14%) were from Sudan [56,58] and Kenya [57,60], and one study (3.6%) was conducted in Cameroon [39]. Among those the highest sample size was observed in studies conducted in Sudan [58] which was equal to 1000 and the lowest was found in Nigeria 50 [38]. Out of 28 studies included in this review and analysis, eight (28.57%) were conducted on community-based and 20 (71.43%) were facility-based studies. The articles examined in this study encompass various participant groups, such as pregnant women, women of childbearing age, and postnatal mothers. Out of all the articles, the participants of eight studies (28.57%) were women of childbearing age, 16 studies (57.1%) centered on pregnant mothers, and four studies (14.3%) included postnatal mothers (Table 2). The majority of the studies included in the analysis were of high quality, with quality scores ranging from seven to eight (S2 Table).

Table 2. Characteristics of the included studies and their proportion of preconceptional FA supplementation in SSA, 2024.

S.No	Author	Publication year	Study design	Africa region	Country	Study setting	Population	Location/Scale	Number of Facilities/scales	Sample size	Reported prevalance (%)
1	Adebo et al.	2017	cross sectional	West Africa	Nigeria	institutional based	pregnant women	Facilities	3	300	3.0
2	Amaje et al.	2022	cross sectional	East Africa	Ethiopia	community based	pregnant women	District	4	677	12.7
3	Anzaku A.	2014	cross-sectional	West Africa	Nigeria	institutional based	pregnant women	Facility	1	595	4.8
4	Asresu et al.	2019	cross sectional	East Africa	Ethiopia	community based	delivered mothers	District	1	564	15.7
5	Ayele A. et al.	2022	cross-sectional	East Africa	Ethiopia	community based	childbearing age women	District	1	504	8.6
6	Boakye Y. et al.	2018	cross-sectional	West Africa	Ghana	institutional based	pregnant women	Facility	1	200	34.0
7	Dessie et al.	2017	cross-sectional	East Africa	Ethiopia	institutional based	pregnant women	Facility	1	422	1.9
8	Ekem et al.	2018	cross-sectional	West Africa	Nigeria	institutional based	pregnant women	Facility	1	453	3.8
9	Fetena N.et al.	2023	cross-sectional	East Africa	Ethiopia	community based	pregnant women	District	1	393	11.3
10	Gedefaw et al.	2018	cross-sectional	East Africa	Ethiopia	institutional based	delivered mothers	province	1	222	9.0
11	Gelgalu et al.	2021	cross-sectional	East Africa	Ethiopia	institutional based	pregnant women	Facility	5	455	11.0
12	Girma et al.	2023	cross-sectional	East Africa	Ethiopia	institutional based	pregnant women	Facility	1	385	31.2
13	Habte et al.	2021	cross-sectional	East Africa	Ethiopia	community based	delivered mothers	District	1	600	45.2
14	Hassan et al.	2024	cross-sectional	East Africa	Sudan	institutional based	1st trimaster Preg	Facility	1	720	3.8
15	Lawal T.	2014	cross-sectional	West Africa	Nigeria	institutional based	childbearing age women	Facility	2	602	2.5
16	Akinajo et al.	2019	Cross sectional	West Africa	Nigeria	institutional based	pregnant women	Facility	1	50	32.0
17	Alemajo et al.	2022	cross sectional	West Africa	Cameroon	institutional based	pregnant women	Facility	2	393	5.1
18	Alsammani et al.	2021	cross sectional	East Africa	Sudan	institutional based	pregnant women	Facility	1	1048	3.2
19	Asumadu et al.	2020	cross-sectional	West Africa	Ghana	institutional based	delivered mothers	Facility	1	363	6.9
20	Beyuo T et al.	2021	cross-sectional	West Africa	Ghana	institutional based	pregnant women	Facility	1	120	10.8
21	Fekene et al.	2020	cross-sectional	East Africa	Ethiopia	community based	childbearing age women	District	1	680	7.8
22	Gamshe E and DDB	2021	cross-sectional	East Africa	Ethiopia	institutional based	pregnant women	Facility	3	333	30.2
23	Joyce C. et al.	2018	cross-sectional	East Africa	Kenya	institutional based	childbearing age women	Facility	1	384	19.8
24	Mohammed B.et al.	2019	cross-sectional	West Africa	Ghana	institutional based	pregnant women	Facility	18	303	28.7
25	Mukhalisi A et al.	2022	cross-sectional	East Africa	Kenya	community based	Couples	District	1	422	23.7
26	Nwaolisa H. et al	2021	cross-sectional	West Africa	Nigeria	institutional based	pregnant women	Facility	1	165	38.0
27	Olowokere, A.E et. al	2015	cross-sectional	West Africa	Nigeria	institutional based	childbearing age women	Facility	11	375	30.4
28	Setegn Alie M et al.	2022	cross-sectional	East Africa	Ethiopia	community based	childbearing age women	District	1	624	5.3
29	Ubong Akpan Okon et al.	2020	cross-sectional	West Africa	Nigeria	institutional based	childbearing age women	Facility	11	606	10.4

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3.3 Proportion of preconception FA supplementation

The proportion of preconception FA supplementation ranged from 1.9% to 45.2% among the included studies. The highest (45.2%) and lowest (1.9%) proportion of FA supplementation during preconception period were recorded in the southern and Amhara regions of Ethiopia, respectively [47,55]. The pooled proportion using the fixed effect model showed significant heterogeneity among the studies. Therefore, we performed the analyses using the random effects model. Using the random effects model, the estimated pooled proportion of FA supplementation among women during preconception period in SSA was 14.10% (95% CI: 11.22–16.98) with significant heterogeneity between studies (I² = 97.7%, p = 0.001). The pooled proportion of FA supplementation during preconception period was presented using a forest plot (Fig 2).

3.4 Subgroup analysis

A subgroup analysis was done by classifying studies based on corresponding countries in SSA to compute and relate the proportion of preconception FA supplementation focusing on various characteristics. Sub-group analysis was done by study location (sub-Africa region and country), study period, and based on types of participants. From the 28 studies, the highest estimated FA supplementation proportion during preconception period was found in studies conducted in Kenya ((22%; 95% CI: 19%-25%), I² = 97.7%), followed by studies conducted in Ghana ((20%; 95% CI: 7%-33%), I² = 96.9%) (Fig 3).

The proportion estimates were categorized based on the study period, with studies conducted up to 2019 and those conducted after 2019. However, there was no noticeable difference in proportion estimates between the two study periods (Fig 4).

We examined articles involving different participant categories of mothers including pregnant women, childbearing-age women, and postnatal mothers. Among these groups, the highest estimated proportion of FA supplementation was observed among studies with postnatal mothers as participants (19.2%; 95% CI: 3.8%, 34.5%) with level of heterogeneity (I² = 98.9%) (Fig 5).

Subgroup analyses indicated that the proportion of FA supplementation before pregnancy showed similar magnitude variations across regions implying a consistent pattern across the sub-regions of Africa (Fig 6).

3.5 Heterogeneity and sensitivity analysis

In our systematic review and meta-analysis, we addressed heterogeneity in study results by initially using a fixed-effects model and subsequently by using a random-effects model to accommodate variability. Despite conducting sensitivity analyses, subgroup analyses, and meta-regression analyses, significant heterogeneity persisted, leading to further investigation. Upon conducting a meta-regression analysis, we found that the year of publication did not influence heterogeneity. However, we discovered that the sample size had a statistically significant relation to the presence of heterogeneity, as shown in Table 3.

Table 3. Meta-regression analysis of factors with heterogeneity of the proportion of preconceptional FA supplementation in SSA, 2024.

Heterogeneity source	Coefficient	Std. err.	P-value
Sample size	-.023446	.0080509	0.004
Publication year	.7000846	.5774253	0.225
_cons	-1389.062	1165.572

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Sensitivity analysis was performed to assess the impact of each individual study on the overall proportion estimate. Remarkably, removing any single study did not result in a statistically significant change to the pooled proportion estimate. Additionally, we conducted sensitivity analyses excluding studies of poor quality. Even after excluding these lower-quality studies, there were no significant changes to the estimated proportion (Fig 7).

3.6 Publication bias

In our meta-analysis, evidence of publication bias was observed through funnel plots and tests, indicating asymmetrical distribution (Fig 8).

Trim and fill analysis was conducted to estimate the effect sizes of missed studies and adjust for publication bias (Fig 9).

Egger’s and Begg’s tests were performed, showing considerable evidence of publication bias (Table 4).

Table 4. Egger’s of publication bias of included studies in the systematic review and meta-analysis of preconceptional FA supplementation in SSA, 2024.

Std_Eff	Coefficient	Std. err.	t	P>\|t	[95% conf.	interval]
slope	.0443915	.2695872	0.16	0.870	-5097529	.5985359
bias	2.98436	.4336036	6.88	0.000	2.093075	3.875644

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3.7 Evidence certainty

Overall, the certainty of the evidence regarding the pooled proportion estimates assessed by the GRADE approach was low (Table 5). Although the majority of the included studies were of high quality, significant heterogeneity was observed, with an I² value exceeding 97.7%. The directness of the evidence was rated as direct, and the precision of the proportion estimate was satisfactory. However, evidence of publication bias contributed to downgrading the certainty. Consequently, while the evidence offers valuable insights into the proportion of preconception folic acid supplementation among women in Sub-Saharan Africa, it is essential to recognize the limitations and uncertainties inherent in the findings.

Table 5. Certainty assessment for included outcomes for the proportion of preconception FA supplementation among women in Sub-Saharan Africa.

Outcome	Study design	Source	Risk of bias	Inconsistency	Directness	Imprecision	Publication bias	Proportion (CI)	Certainty
Preconception folic acid supplementation	Observational studies	28	Low¹	Serious²	Direct³	low⁴	Very low⁵,	14.10%(11.2216.98)	Low

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¹Rated as low because most studies included were of high quality.

²Rated as Serious due to significant heterogeneity (I² > 97.7%).

³ Rated as direct as there is a clear link between preconception folic acid intake and the outcome.

⁴Rated as low due to narrow confidence intervals.

⁵ publication bias present and rated as low but handled with trim and fill analysis.

4. Discussion

The current systematic review provides evidence of an estimated pooled proportion of FA supplementation during the preconception period in SSA countries. The study synthesizes data from 28 cross-sectional studies conducted between 2014 and 2024, involving 12,562 participants, with significant contributions from Ethiopia (42.9%) and Nigeria (25%). The proportion of preconception FA supplementation reported in included studies varied widely, ranging from 1.9% to 45.2%. In the meta-analysis utilizing a random-effects model, the subgroup and meta-regression analysis. Additionally, the quality assessment of the included studies showed that the majority were of high quality, demonstrating robust methodologies and reliable data.

The quality of evidence for preconception folic acid supplementation, evaluated with the GRADE approach, was rated as low. This is primarily due to notable differences between studies and some concerns about publication bias, despite the fact that most of the included studies were of high quality. Subgroup analysis by African region reveals closely similar findings between Eastern and Western African countries.

Despite implementing various strategies such as targeted health education initiatives, policy reforms, and healthcare provider training programs, the subgroup analysis found no significant change in the proportion of FA supplementation across different study periods. This implies a concerning trend indicating a persistent lack of improvement in FA utilization and failure to align with WHO recommendations which suggests a critical need for reevaluation and potential enhancement of current intervention approaches to effectively address barriers hindering optimal FA before pregnancy across SSA countries. This meta-analysis showed that the highest estimated proportion FA supplementation during preconception period was found in studies conducted in Kenya (22%). Another reason for this variation might be due to the small number of articles from Kenya and these small studies may overestimate the true effect size of FA supplementation during the preconception period. It is plausible that the observed variability in FA supplementation during preconception period rates across countries could be linked to the educational levels, cultural norms, and different activities and efforts to increase the supplementation of FA before conception.

In subgroup analysis based on study participants, the highest estimated proportion of FA supplementation was observed among studies involving postnatal mothers (19.2%). The observed variation in FA supplementation proportion during preconception period may be attributed to the positive influence of postnatal care (PNC) services. Mothers who receive postnatal services have higher health-seeking behavior for their health and their newborns [65]. This increased awareness and active engagement with healthcare services potentially plays a pivotal role in fostering improved adherence to preconception care practices, including the essential supplementation of FA.

Our findings demonstrate a higher proportion of preconceptional FA supplementation compared to a study conducted in Egypt, where only 8.8% of women reported taking FA supplements before pregnancy [66]. The discrepancy in proportion might be attributed to the time period of the conducted studies. In recent years, various mechanisms have been implemented, especially in low-income countries, to enhance awareness and access to FA supplementation. Many studies included in this meta-analysis were conducted after 2014, reflecting these advancements, which likely contributed to an increased proportion of preconceptional FA use observed in more recent studies compared to those conducted earlier. Another reason for this discrepancy could stem from variations in research methodology and the distinct characteristics of the population groups studied.

In addition, Toivonen et al. showed that the proportion of FA supplementation during the preconception period in Africa was 0% [28], which is lower than from our estimated pooled proportion. The discrepancy might be due to the previous review including only three studies from the African region, potentially underestimating the true proportion of FA supplementation during the preconception period. Another contributing factor to the variation in proportion estimates could be attributed to several factors, including changes in healthcare policies, economic conditions, and awareness campaigns.

The findings of this study indicate a significantly lower proportion of preconceptional FA supplementation compared to a study conducted in Lebanon, where 48% of participants reported using FA supplements before pregnancy [67]. This discrepancy underscores variations in health behaviors and practices across different populations, influenced by factors such as healthcare access, awareness campaigns, socioeconomic status, and cultural norms related to maternal health.

Similarly, our findings showed a significantly lower proportion compared to a study conducted in Vietnam, where FA use before pregnancy was reported to be 24.5% [68]. The lower proportion of FA supplementation in SSA compared to Vietnam can be attributed to factors such as less strong public health initiatives, socioeconomic disparities, and varying cultural practices that health seeking behavior. In the prior study, a significant majority of participants, exceeding 77%, had planned pregnancies which drove them to actively seek preconception care services including FA supplementation [69,70].

Likewise, studies conducted across various high-income nations have indicated a higher proportion of preconceptional FA intake compared to the current findings. For instance, a systematic review and meta-analysis conducted in 2018 reported that in North America, the proportion of preconceptional FA supplementation ranged from 32% to 51% [28]. Similarly, research conducted in China, Iran, and Vietnam documented proportion rates of 52.1%, 54.5%, and 24.9%, respectively [68,71,72]. These differences in supplementation rates across regions can be attributed to various factors, such as disparities in healthcare policies, availability of supplements, and the effectiveness of public awareness campaigns.

In high-income countries, comprehensive health education and awareness programs for childbearing women are provided through well-resourced healthcare systems, public health campaigns, and mandatory prenatal care guidelines. Greater awareness and education about the importance of preconceptional health and nutrition in high-income countries contribute significantly to the higher proportion of FA supplementation [73]. In contrast, low-income nations face significant barriers such as financial constraints and limited access to healthcare facilities, which pose challenges to women seeking essential healthcare services [74].

The findings highlight a critical need for targeted public health strategies aimed at improving access, awareness, and utilization of FA supplementation across Sub-Saharan Africa. In conclusion, the findings provide valuable insights into the proportion of preconception folic acid supplementation among women in Sub-Saharan Africa. However, based on the GRADE framework, the overall quality of evidence is rated as low. These limitations underscore the need for caution in interpreting the results and highlight the necessity for further research to improve the reliability of findings in this important area.

5. Strengths and limitations of the review

This systematic review and meta-analysis is the first comprehensive assessment of preconceptional FA supplementation in SSA, highlighting several strengths. This review is notably strong in its broad scope, covering a wide range of studies from different countries and regions within SSA. It includes both published and unpublished articles in its systematic review and meta-analysis across the continent. Subgroup analysis was performed to minimize statistical heterogeneity. While our study highlights the state of FA supplementation during preconception period in SSA, it is important to acknowledge several limitations. The lack of studies representing all countries across SSA may restrict its ability to be generalized to the entire region. Significant heterogeneity and potential publication bias require cautious interpretation. Additionally, comparing findings is challenging due to a lack of regional and global systematic reviews.

6. Conclusions and recommendations

The systematic review and metaanalysis revealed alarmingly low rates of FA supplementation during the preconception period in SSA. Addressing this critical issue necessitates coordinated efforts from policymakers, healthcare providers, and community stakeholders. Key strategies should focus on increasing awareness among women of reproductive age and healthcare professionals about the benefits of FA supplementation. Furthermore, integrating FA supplementation into existing maternal and child health programs, strengthening partnerships with pharmaceutical companies, and advocating for policy reforms to ensure affordable access to supplements are crucial steps toward improving maternal and child health outcomes in the region.

Future research should prioritize longitudinal studies and qualitative investigations into cultural factors, alongside assessing targeted interventions. These efforts are essential for effectively addressing disparities and enhancing maternal and child health outcomes in the region. Updated proportion estimates of FA supplementation before pregnancy are crucial for informing policymakers, health planners, communities, as well as governmental and non-governmental organizations.

Supporting information

S1 Table. PRISMA checklist.

(DOCX)

pone.0318422.s001.docx^{(28.5KB, docx)}

S2 Table. Keywords and searching methodology.

(DOCX)

pone.0318422.s002.docx^{(18KB, docx)}

S3 Table. Methodological quality assessment of included studies using Newcastle-Ottawa Scale (NOS) for preconceptional FA supplementation in SSA, 2024.

(DOCX)

pone.0318422.s003.docx^{(18KB, docx)}

S1 Appendix. Individual studies with exclusion.

(DOCX)

pone.0318422.s004.docx^{(223.1KB, docx)}

S2 Appendix. Data extraction form with data extractors name and date.

(XLSX)

pone.0318422.s005.xlsx^{(61.5KB, xlsx)}

Acknowledgments

The authors would like to thank all authors of studies included in this systematic review and meta-analysis. Additionally, we extend our gratitude to Aklilu Endalamaw for his valuable support throughout the study.

Abbreviations

CI: Confidence Interval
FA: Folic Acid
PRISMA: Preferred Reporting System for Meta-Analysis and Systematic Review
NTDs: Neural Tube Defects
SSA: Sub-Saharan Africa
WHO: World Health Organization

Data Availability

The data used in this study are from the Ethiopian Mini Demographic and Health Survey (miniDHS) 2019 and can be requested from the DHS Program at https://dhsprogram.com/Data/ following the procedures outlined in the Materials and Methods section of the paper. Access to these data is granted upon registration and approval by the DHS Program.

Funding Statement

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

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

**********

4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: No

Reviewer #2: No

**********

5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The manuscript under review addresses a critical question of folic acid supplementation in sub-sharan Africa. The methodolgy, analysis and results are relevant, however, the paper requires careful reconsideration and possibly re-writing the introduction and the discussion sections to strengthen the manuscript. Some specific points to consider are highlighted below:

Abstract:

1. Add the number of studies and participants included in the review in the results section of the abstract.

Introduction:

1. NTDs has been spelled out more than once. Spell out once when used for the first time and then use the acronym for the rest of the manuscript.

2. Some of the references in the introduction are very old. I suggest replacing these with the more recent references.

3. I found the introduction very weak. There are quite a few recent relevant references assessing the existing evidence, guidelines, and policies around folic acid supplementation. I suggest that the authors look at these papers and add some of the relevant references in their introduction to make a stronger case for the review:

- Quinn M, Halsey J, Sherliker P, Pan H, Chen Z, Bennett DA, Clarke R. Global heterogeneity in folic acid fortification policies and implications for prevention of neural tube defects and stroke: a systematic review. EClinicalMedicine. 2024 Jan 1;67.

- Viswanathan M, Urrutia RP, Hudson KN, Middleton JC, Kahwati LC. Folic acid supplementation to prevent neural tube defects: a limited systematic review update for the US preventive services task force.

- Barry MJ, Nicholson WK, Silverstein M, Chelmow D, Coker TR, Davis EM, Donahue KE, Jaén CR, Li L, Ogedegbe G, Rao G. Folic acid supplementation to prevent neural tube defects: US Preventive Services Task Force reaffirmation recommendation statement. Jama. 2023 Aug 1;330(5):454-9.

- De‐Regil LM, Peña‐Rosas JP, Fernández‐Gaxiola AC, Rayco‐Solon P. Effects and safety of periconceptional oral folate supplementation for preventing birth defects. Cochrane database of systematic reviews. 2015(12).

4. Add some references (if available) on country specific prevalance rates of NTDs in Africa.

5. The acronym for sub-sahraan Africa (SSA), folic acid (FA) and low- middle- income countries (LMICs) have been used inconsistently throughout the manuscripot. I would suggest that the authors spell it out when used for first time in the darft and then consistently use the acronym throughout.

Methods:

1. Not sure what this sentence under 'study selection' means: "articles examining the prevalence and determinants of folic acid supplementation during preconception period was gathered from various". From the objectives and results, it seems that only prevalance was assessed. I am not sure whether the authors ahve also looked at the determinants? and if they have, this has not be reported anywhere in the draft.

2. Not sure what this sentence means: "A quantitative cross-sectional study design was employed to enhance clarity and significance." Do you mean that the eligibility for study selection was cross-sectional study design? If yes, then state this clearly.

3. Suggest authors add a table or a figure depicting the regions and the respective countries included in sub-saharan Africa. It would add clarity for the readers as teh regions and respective countries have been disucssed and analysed in the resultss and discussion sections.

4. Studydesign is stated twice under data extraction.

Results:

1. I cant see the full characterictis of the inlcuded studies table (probably because it was in a landscape mode) so I am not sure if my comments are relevant. But I would suggest that the authors delete the columns on study period, center, sampling method, and response rate. I would also suggest that the authors add the columns on sample size and study results (reported prevalance) in the study characteristics table.

2. I would suggets that the authors remove the study quality column from the study characteristics table and add a separate section on study quality.

Discussion:

I would suggest that the authors re-organise the discussion section starting with summarising the reveiw findings, quality of the included studies, comparing the review findings with other studies/reviews, strengths and limitations of the review and research and practice implications.

I would suggest that the authors compare the study findings with studies conducted in similar context. For eaxmple, reference 59 is a study from Italy and hence widely differs in context. However, authors can broadly discuss the differences in the folic acid supplementation prevalance between high income and low- middle- income countries.

Reviewer #2: Thank you for giving me the opportunity to review your paper. I think you paper requires thorough read. Methodology is not clear, few sentances are repetitive, there are grammatical errors and information looks scattered.

Abstract:

Introduction:

Seems very long for an abstract.

Just a suggestion: instead of reporting global estimates of NTDs I would suggest writing the estimates from Sub Saharan Africa.

I dont think daily dosage is required here.

Methods:

Please add on what type of studies did you include? Last date of search? if GRADE was conducted and how was quality of included studies conducted (if you did any of these)

Results:

Line 44: not sure what do you mean by 'individual studies' here.

Line 46: subgroup analysis based on?

Line 49: remove double brackets from the end

Quality of included studies in missing

Introduction

If you have introduced the abbreviation once, then you dont have to introduce it again and again. e.g., NTDs.

Methods:

I would suggest to rearrange some headings. After registration, you should talk about the eligibility criteria and then search strategy and study selection and so on.

Line 117: you have stated that you search institutional repositories. Please state which were those?

Line 120: Please check punctuation: "supplementation, and folic acid administration. folic acid adherence, folinic acid, and vitamin B9."

Line 127-129: This sentence is very vague "A quantitative cross-sectional study design was employed to enhance clarity and significance'

Line 127: 'omitted' is not an appropraite word to use here

I think you need to revisit this paragraph. It requires language editing

Linme 127-129: " A quantitative cross-sectional study design was employed to enhance clarity and significance. In contrast, studies utilizing qualitative methodologies were omitted due to the specific nature of the review and the analytical approach selected for this review" I think this should be discussed under section 2.4.

Line 131: I understand you used RAYYAN then why did you exported data on Endnote?

Section 2.3 says study selection but it doesnt talks clearly about it. You have not written about title/abstract and full text screening. How conflicts were managed? Lacks lot of important information.

Section 2.4: A lot of important information is missing. I am confused. Did you include cross sectional studies and grey literature or only cross sectional studies.

Line 136: better to use the word 'included' rather than incorporated.

Suggest adding a Table on PECO criteria

Line 146: suggest using the word 'resolved' instead of 'fixed'

Line 153 and 155: please avoild using such vague words/phrases: 'the required information' 'important parameters'

Line 157: study setting in repeated twice

Line 156: If you are only including cross-sectional studies then why are you collecting data on study designs.

Line 162: Add reference of Stata

Line 166-168: The sentances are repetitive.

A lot of missing information in methods sections: did you conduct cross-referencing. did you felt need of contacting authors for missing data. You stated that you searched institutional website there is no mention of inclusion of reports in the eligibility criteria.

Why did you not assess the quality of evidence using GRADE?

On what basis did you conduct the sensitivity analysis? high heterogeneity or low quality of studies? How did you "assess the influence of individual studies on pooled estimates"?

Results:

Please Format your headings: "3.1 selection and Identification of studies"

Why did you exclud study based on poor quality? You could have done a sensitivity analysis for it

Line 198: spell out 2. Suggest spelling out numbers <10

Please dont use the word 'individual studies'.. you can say 'included studies'

Table 1 doesn't fit the page and is not clear. what does NS mean? what is R. rate? response rate?

Not sure why did you do subgroup analysis based on study period? What would you get from it?

Quality of included studies MISSING! in text.

Discussion:

I would suggest that you should summarise your study findings in the first para and then discuss about other studies

Lines 270-274: Can be moved later in the discussion under strengths.

Lines 289-291: not sure why are you comparing prevalence of Italy with your results? There is no link. These are two different regions/countries. You can compare with LMICs buy why with Italy?

You have not discussed on how quality of studies can affect the findings of your study?

Conclusion would come after limitations and strengths

Figure 1:

Why were studies excluded based on title and abstract twice?

General Comments:

Did you find studies on peri-conception? if yes, then I would suggest doing a subgroup analysis based on preconception and periconception supplementation.

Why did you included studies on pregnant women when you intention was preconception? Did they collect reterospective data?

What were the ages of the included participants? suggest doing a subgroup analysis bases of age and see the prevalence in young people

Did you do sensitivity analysis based on low quality of studies? if not then suggest doing that too.

**********

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

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PLoS One. 2025 Jan 31;20(1):e0318422. doi: 10.1371/journal.pone.0318422.r002

Author response to Decision Letter 0

20 Jul 2024

Date: July 19, 2024

To: PLOS ONE, Editorial Office

Subject: Submitting a Revised Version of Manuscript and Point-by-Point Response

Manuscript ID: PONE-D-24-13717

Title: Folic Acid Supplementation During Preconception Period in Sub-Saharan African Countries: A Systematic Review and Meta-Analysis

Dear Editorial Office,

We are pleased to submit the revised version of our manuscript titled "Folic Acid Supplementation During Preconception Period in Sub-Saharan African Countries: A Systematic Review and Meta-Analysis" (Manuscript ID: PONE-D-24-13717). In response to the academic editor and reviewers' comments and suggestions, we have made substantial revisions to improve the clarity and quality of our manuscript. We believe these changes have strengthened our study, and we are grateful for the constructive feedback provided.

Enclosed with this letter, please find our detailed point-by-point response to the reviewers' comments. Each comment has been addressed meticulously, and the corresponding revisions are highlighted in the manuscript for your convenience.

We appreciate the opportunity to revise and resubmit our work to PLOS ONE. We look forward to your positive response.

Regards,

Authors

Point-by-Point Response to the Academic Editor and Reviewers' Comments

1. Comments from the Academic Editor and Responses

Academic Editor’s Comments:

1. Please ensure that your manuscript meets PLOS ONE's style requirements

Authors’ Response:

Dear Editor,

Thank you for the opportunity to submit our manuscript. We have meticulously ensured that our manuscript meets all PLOS ONE style requirements.

2. We noticed you have some minor occurrences of overlapping text with the following previous publication(s), which needs to be addressed

Authors’ Response:

Dear Editor,

We appreciate your attention to this matter and have promptly addressed and resolved the minor occurrences of overlapping text with the previous publication.

3. Please complete your Competing Interests on the online submission form to state any Competing Interests

Authors’ Response:

Dear Editor,

Thank you for the reminder. We have completed the Competing Interests section on the online submission form and included it with the cover letter.

4. We note that you have referenced (unpublished) on page 6. Please remove this from your References and amend this to state in the body of your manuscript: (ie “Bewick et al. [Unpublished]”) as detailed online in our guide for authors

Authors’ Response:

Dear Editor,

We apologize for the confusion caused. Upon review, we confirm that there is no unpublished citation on page six, and there is no reference named Bewick et al. in the manuscript. Sorry for any confusion this may have caused.

5. Please include captions for your Supporting Information files at the end of your manuscript

Authors’ Response:

Dear Editor,

Thank you for your recommendation. We have included captions for all Supporting Information files at the end of our manuscript as requested.

________________________________________

2. Comments from Reviewer #1 and Responses

Reviewer’s Comments:

1. Abstract: Add the number of studies and participants included in the review in the results section of the abstract.

Authors’ Response:

Dear Reviewer,

Thank you for your suggestion. We have revised the abstract to include the number of studies and participants included in the review as requested.

2. Introduction: NTDs has been spelled out more than once. Spell out once when used for the first time and then use the acronym for the rest of the manuscript.

Authors’ Response:

Dear Reviewer,

Thank you for your feedback. We have revised this in the manuscript and spelled out "NTDs" in the introduction once and used the acronym thereafter throughout the manuscript unless the term comes at the beginning of the statement.

3. Some of the references in the introduction are very old. I suggest replacing these with more recent references.

Authors’ Response:

Dear Reviewer,

Thank you for your suggestion. We replaced the older references in the introduction with more recent ones to ensure the currency of the information. Thank you once again for your valuable suggestion.

4. I found the introduction very weak. There are quite a few recent relevant references assessing the existing evidence, guidelines, and policies around folic acid supplementation. I suggest that the authors look at these papers and add some of the relevant references in their introduction to make a stronger case for the review

Authors’ Response:

Dear Reviewer,

Thank you for your suggestion. We appreciate the feedback and have reviewed recent relevant literature to strengthen the introduction by incorporating recent relevant references related to folic acid supplementation. The revised version of the manuscript incorporated the suggested updated articles and sources. This will enhance the robustness of our review.

5. Add some references (if available) on country-specific prevalence rates of NTDs in Africa.

Authors’ Response:

Dear Reviewer,

Thank you for the suggestion. We have incorporated recent relevant references on country-specific prevalence rates of neural tube defects in Africa to provide a more comprehensive introduction, aligning with existing evidence and guidelines on folic acid supplementation.

6. The acronym for sub-Saharan Africa (SSA), folic acid (FA), and low-middle-income countries (LMICs) have been used inconsistently throughout the manuscript. I would suggest that the authors spell it out when used for the first time in the draft and then consistently use the acronym throughout

Authors’ Response:

Dear Reviewer,

Thank you for your feedback. We have corrected it and ensured consistency in the use of acronyms such as SSA (Sub-Saharan Africa), FA (folic acid), and LMICs (low- and middle-income countries) throughout the manuscript.

7. Not sure what this sentence under 'study selection' means: "articles examining the prevalence and determinants of folic acid supplementation during the preconception period were gathered from various". From the objectives and results, it seems that only prevalence was assessed. I am not sure whether the authors have also looked at the determinants? and if they have, this has not been reported anywhere in the draft.

Authors’ Response:

Dear Reviewer,

We apologize for any confusion caused by the initial statement. The manuscript has been updated to accurately reflect our findings. The revised statement now reads:

"A comprehensive collection of articles assessing the prevalence of folic acid supplementation during the preconception period was gathered from various sources."

Thank you again.

8. Not sure what this sentence means: "A quantitative cross-sectional study design was employed to enhance clarity and significance." Do you mean that the eligibility for study selection was cross-sectional study design? If yes, then state this clearly.

Authors’ Response:

Dear Reviewer,

Thank you for your query regarding the statement "A quantitative cross-sectional study design was employed to enhance clarity and significance." We apologize for any confusion caused by this sentence. The intention of this statement was to clarify that our review specifically included studies employing quantitative methodologies, while excluding those using qualitative approaches. We revised the statement in the manuscript to explicitly state: “Quantitative studies were included to enhance clarity and significance.”

9. Suggest authors add a table or a figure depicting the regions and the respective countries included in Sub-Saharan Africa. It would add clarity for the readers as the regions and respective countries have been discussed and analyzed in the results and discussion sections

Authors’ Response:

Dear Reviewer,

Thank you for your valuable suggestion to add a table or figure depicting the regions and respective countries included in Sub-Saharan Africa. We have now included a table in the main manuscript under the characteristics of the studies section. This table outlines the regions of Sub-Saharan Africa and the respective countries within each region.

10. Study design is stated twice under data extraction

Authors’ Response:

Dear Reviewer,

Thank you for your observation. We have removed the duplicate mention of "study design" under the data extraction section.

11. Result: I can’t see the full characteristics of the included studies table (probably because it was in a landscape mode) so I am not sure if my comments are relevant. But I would suggest that the authors delete the columns on study period, center, sampling method, and response rate. I would also suggest that the authors add the columns on sample size and study results (reported prevalence) in the study characteristics table

Authors’ Response:

Dear Reviewer,

Thank you for your feedback regarding the table of included studies. We apologize if the landscape format made it difficult to view the entire table. Based on your suggestions, we made the following adjustments:

o We have deleted the columns on study period, center, sampling method, and response rate.

o We have added columns for sample size and study results (reported prevalence).

12. I would suggest that the authors remove the study quality column from the study characteristics table and add a separate section on study quality.

Authors’ Response:

Dear Reviewer,

Thank you for your feedback regarding the study characteristics table. We agree that separating the study quality information into its own section would enhance clarity. As such, we removed the study quality column from the study characteristics table and have prepared a separate section dedicated to study quality assessment. Thank you once again for your recommendation.

13. I would suggest that the authors re-organise the discussion section starting with summarising the reveiw findings, quality of the included studies, comparing the review findings with other studies/reviews, strengths and limitations of the review and research and practice implications.

Authors’ Response:

Dear Reviewer, Thank you for your valuable suggestion regarding the re-organization of the discussion section. We appreciate your feedback and agree that restructuring the section will enhance the clarity and coherence of our manuscript. In the discussion section, we summarized key findings, evaluated study quality, compared results with existing literature, and assessed methodological strengths and limitations. We concluded by discussing implications for future research and clinical practice.

14. I would suggest that the authors compare the study findings with studies conducted in similar context. For eaxmple, reference 59 is a study from Italy and hence widely differs in context. However, authors can broadly discuss the differences in the folic acid supplementation prevalance between high income and low- middle- income countries.

Authors’ Response:

Dear Reviewer, Thank you for your valuable feedback. We agree that Reference 59, a study from Italy, differs significantly in context compared to our study setting. To address this, we have broadened our discussion to compare folic acid supplementation prevalence between high-income and low- to middle-income countries. Although studies in this area are limited, we have made efforts to address this gap through a comprehensive search of existing literature. Thank you once again for your insightful suggestion.

3. Comments from Reviewer #2 and Responses

Reviewer’s Comments:

1. Introduction: Seems very long for an abstract. Just a suggestion: instead of reporting global estimates of NTDs I would suggest writing the estimates from Sub Saharan Africa. I dont think daily dosage is required here.

Authors’ Response:

Dear Reviewer, Thank you for your feedback. We have focused on Sub-Saharan Africa estimates of NTDs and omitted daily dosage details to make the abstract more concise. Thank you for your suggestions.

2. Methods: Please add on what type of studies did you include? Last date of search? if GRADE was conducted and how was quality of included studies conducted (if you did any of these).

Dear Reviewer, Thank you for your feedback. We have revised the methods section to include more details about the types of studies included, the last date of the search, and the quality assessment process using Newcastle-Ottawa Scale. Thank you for your suggestions.

3. Results: Line 44: not sure what do you mean by 'individual studies' here.

Line 46: subgroup analysis based on?

Line 49: remove double brackets from the end.

quality of included studies in missing

Authors’ Response:

Thank you for your feedback.

Line 44: We apologize for any confusion caused. We have now clarified our statement.

Line 46: We conducted subgroup analysis based on corresponding countries.

Line 49: Thank you for your observation. We have removed the unnecessary information.

We employed the Newcastle-Ottawa Scale for quality assessment, as highlighted in the abstract and we have included it the main document.

Thank you once again for your careful review and for improving the abstract section.

4. Introduction If you have introduced the abbreviation once, then you dont have to introduce it again and again. e.g., NTDs.

Authors’ Response:

Dear Reviewer, Thank you for your feedback. We have corrected it and ensured consistency in the use of abbreviations, such as NTDs, once introduced.

5. Methods: I would suggest to rearrange some headings. After registration, you should talk about the eligibility criteria and then search strategy and study selection and so on

Authors’ Response:

Dear Reviewer, Thank you for your suggestion. We have rearranged the headings to discuss eligibility criteria immediately following registration, followed by the search strategy, study selection, and subsequent sections. Thank you for guiding us in improving the organization of our methods section.

6. Line 117: you have stated that you search institutional repositories. Please state which were those?

Authors’ Response:

Dear Reviewer, Thank you for your comment. We have searched the institutional repositories of several universities, namely Addis Ababa University, Jimma University, Hawassa University, and Bahir Dar University. Thank you for your attention to this detail and your valuable feedback.

7. Line 120: Please check punctuation: "supplementation, and folic acid administration. folic acid adherence, folinic acid, and vitamin B9."

Authors’ Response:

Dear Reviewer, Thank you for your comment.

Line 120: We have corrected the punctuation as follows: “preconception care, preconception, pre-conception, periconception, peri-conception, before conception, folic acid, folate, vitamin, pteroylglutamic acid, folic acid supplementation, folic acid administration, folic acid adherence, folinic acid and vitamin B9”.Thank you for bringing this to our attention and for your careful review.

8. Line 127-129: This sentence is very vague "A quantitative cross-sectional study design was employed to enhance clarity and significance'

Authors’ Response:

Dear Reviewer,

Thank you for your feedback.

Line 127-129: We acknowledge the vagueness of the sentence "A quantitative cross-sectional study design was employed to enhance clarity and significance." We revised this statement to provide more specific details about our study design. Thank you for your thoughtful review and suggestions for improving clarity in our manuscript.

9. Line 127: 'omitted' is not an appropriate word to use here

Dear Reviewer, Thank you for your feedback. Line 127: We acknowledge that "omitted" is not appropriate in this context. We have revised the wording accordingly to accurately describe our methodology. Thank you for bringing this to our attention and for your careful review.

10. I think you need to revisit this paragraph. It requires language editing

Authors’ Response:

Dear Reviewer, Thank you for yo

Attachment

Submitted filename: Response to Reviewers.docx

pone.0318422.s006.docx^{(41KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0318422.r003

Decision Letter 1

Jai K Das

6 Sep 2024

PONE-D-24-13717R1Folic acid supplementation during preconception period in sub-Saharan African countries: A systematic review and meta-analysisPLOS ONE

Dear Dr. Aweke,

Please submit your revised manuscript by Oct 21 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Jai K Das

Academic Editor

PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Partly

Reviewer #2: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: No

Reviewer #2: No

**********

6. Review Comments to the Author

Reviewer #1: The review title and objectives suggest that the authors aimed to review the prevalance of folic acid supplementation during preconception period which is defined as the period of time before pregnancy occurs. However, the authors have used terms for 'periconception' as well in their search strategy. Moreover, the included studies had a variety of target population "eight studies (28.57%) were women of childbearing age, 16 studies 257 (57.1%) centered on pregnant mothers, and four studies (14.3%) included postnatal mothers." Majority of these studies (16 studies) included pregnant women and does not follow the eligibiltiy crirteria for inclusion which is preconception supplementation. The only studies eligible for inlcusion as per the authors eligibility criteria are studies that targeted either women of reproductive age or postnatal women. I would suggets that the authors clarify the definition of "preconception" used for this review to reflect the correct eligibility and inclusion.

Reviewer #2: Manuscript require thorugh read anf formatting edits. There are places were there is no space between text, references, and brackets e.g., Line 108: individuals(7).The ; Line 82: In sub-Saharan Africa(SSA).

Punctuation is not used appropriately e.g. like 127: .(28). - Remove extra full stops where evere required.

Please read your manuscript thoroughly and make the required edits where necessary.

Abstract:

Introduction is still very long. Please reduce some text

- Line 31: Remove extra brackets and full stop

- Line 40: Add space between of and FA

Line 152: This line is very confusing where you say that you are including ALL journal articles. However you are excluding qualitative studies. I get what you are trying to say here but its still very confusing. "We included all types of studies published as journal articles, theses, and dissertations without imposing restrictions based on publication date or age criteria."

Section 2.2 (Line 150): First write what was included and then write what was excluded. This brings more clarity.

line 149: Which quantitative studies did you include? please state. List all the study designs which you intended to included and in results you can state that you only found cross-sectional studies

Section 2.3:

- Line 164: "were taken" is not an appropriate work to use here

- In this section first talk about making the search strategy by using Mesh terms and key words. Then talk about databases searched

Section 2.4:

Line 176: Unclear

Line 177: "The search was not constrained by the publication year; hence, articles published until January 2024, were considered for review eligibility." You have already mentioned the last publication date in section 2.3. The remaining details on restrictions should be moved to section 2.3.

Line 180: The information is not making any sense to me. As 'systematic review" everything should be done systematically. Even contacting authors comes after data extraction. Not before screening. Please read some good published systematic reviews and suggest rewritting your methodology.

Line 186: This should come before title abstract screening.

Section 2.6 will come before 2.5

Section 2.6:

Did you summarise data in Excel or you conducted data extraction in excel? Please clarify

Did you cross-reference studies for missing studies?

Through NewCastle you assess the quality of included studies. Through GRADE you assess quality of evidence. both are two different things. However, I would suggest to use GRADE. Let us know if you dont have the capacity to do GRADE.

Results:

Line 231: "We reviewed the full texts of the remaining 195 articles for eligibility, 163 studies were not eligible, and 32 studies were identified." what do you mean by 32 were identified?

- Rephrase line 238

- Line 259: I think it should be table 2?

Please place all the tables appropriately.

Table 2: Suggest showing this in a graph and move table 2 to supplementary file.

Table 3: You said that you included pregnant women because they reterospectively collected data then how are those cross-secrional studies. wont those be reterospective cohort studies? Or these were cross-sectional who collected data based on recall. I just want to have an understanding on what type of studies were these.

- You are talking about sensitivity analysis in Section 3.5 and then the actual analysis comes in Section 3.7. I would suggest moving Section 3.7 to Section 3.5

- Line 357-360: There is no connection of discussing quality of studies of your review after discussing the intervention from existing evidence. Suggest moving it afetr line 341 and try to be more cohesive.

- Line 361: I think you discussion need more working. First, Talk about the evidence coming from you study, including the subgroup, sentivity and quality of studies. then compare with other studies conducted in Africa followed by studies conducted in LMIC and HIC countries. Then talk about stengths and limitations.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

PLoS One. 2025 Jan 31;20(1):e0318422. doi: 10.1371/journal.pone.0318422.r004

Author response to Decision Letter 1

20 Sep 2024

Academic editor’s comments Authors’ responses

Submit a revised version of the manuscript that addresses the points raised during the review process

Authors’ responses

Dear editor,

Thank you for the opportunity to submit our manuscript.

we have thoroughly addressed and incorporated all of the reviewers' comments and suggestions into the revised version. We greatly appreciate the time and effort the editorial team have invested in reviewing our work, and we believe that these revisions have strengthened the manuscript.

2. Comments from reviewer #1 and responses

Reviewer’s comments

The review title and objectives suggest that the authors aimed to review the prevalance of folic acid supplementation during preconception period which is defined as the period of time before pregnancy occurs. However, the authors have used terms for 'periconception' as well in their search strategy. Moreover, the included studies had a variety of target population "eight studies (28.57%) were women of childbearing age, 16 studies 257 (57.1%) centered on pregnant mothers, and four studies (14.3%) included postnatal mothers." Majority of these studies (16 studies) included pregnant women and does not follow the eligibiltiy crirteria for inclusion which is preconception supplementation. The only studies eligible for inlcusion as per the authors eligibility criteria are studies that targeted either women of reproductive age or postnatal women. I would suggets that the authors clarify the definition of "preconception" used for this review to reflect the correct eligibility and inclusion.

Authors’ responses

Dear reviewer,

Thank you for your valuable feedback We understand your concern regarding the search terms we used and the target populations of the included studies.

We used the term "periconception" in our search strategy because some studies report folic acid supplementation during the preconception period separately, even though the studies were conducted during the periconception phase. By including "periconception," we aimed to ensure that we captured all relevant studies, particularly those that might have reported preconceptional folic acid intake under the broader term "periconception.” So, we specifically selected only those that reported on folic acid supplementation during the preconceptional(before pregenency) period.

Regarding the inclusion of studies involving pregnant, we included studies with pregnant participants because they assessed folic acid (FA) intake during the preconception period by asking women about their supplementation practices before the pregnancy based on recall. Even though these studies involve pregnant women at the time of the survey, they provided valuable information about preconceptional FA intake. However, we did not include studies that reported FA supplementation during pregnancy. Our aim was to focus specifically on preconceptional FA supplementation to ensure the relevance of the data.

Thank you for your detailed review and for highlighting these points. We appreciate your insights and hope this clarifies our approach.

3. Comments of reviewer #2 and responses

Reviewer’s comments

Manuscript require thorugh read anf formatting edits. There are places were there is no space between text, references, and brackets e.g., Line 108: individuals(7).The ; Line 82: In sub-Saharan Africa(SSA). Punctuation is not used appropriately e.g. like 127: .(28). - Remove extra full stops where evere required.

Please read your manuscript thoroughly and make the required edits where necessary.

Authors’ responses

Dear reviewer,

Thank you for your feedback. We have reviewed and corrected the formatting issues, including spacing between text, references, and brackets, and adjust punctuation errors such as extra full stops.

We appreciate your assistance and will make the necessary edits.

Reviewer’s comments

Abstract:

Introduction is still very long. Please reduce some text

- Line 31: Remove extra brackets and full stop

- Line 40: Add space between of and FA

Authors’ responses

Dear reviewer,

Thank you for your carful review and your relevant comments. According to the suggestions we reduced the texts from the introduction of abstract section and we have corrected the errors of and we removed in appropriate punctuations. Thanks again for your suggestions.

Thank you for requesting the clarity of the confusing stetment. We have rewrite the statement as the following and we hope it is clear.

“We included journal articles, theses, and dissertations without imposing restrictions based on publication date or age criteria.”

Reviewer’s comments

Section 2.2 (Line 150): First write what was included and then write what was excluded. This brings more clarity.

line 149: Which quantitative studies did you include? please state. List all the study designs which you intended to included and in results you can state that you only found cross-sectional studies.

Authors’ responses

Dear reviewer.

Thank you for your valuable comments and suggestions. We have corrected the order of the statements, first specifying the included studies and then the excluded ones. We included cross-sectional, cohort, and case-control studies, but ultimately found only cross-sectional studies in our review.

We mentioned the included study designs in the main document.

Thank you again for your efforts to improve the manuscript.

Reviewer’s comments

Section 2.3:

- Line 164: "were taken" is not an appropriate work to use here

- In this section first talk about making the search strategy by using Mesh terms and key words. Then talk about databases searched.

Authors’ responses

Dear reviewer,

Thank you for your comment. We have written the stetment according to the comment as the following.

“Studies published in the English language up to January 2024 were retrieved from EMBASE, MEDLINE, Scopus, CINAHL, and manually on Google and Google Scholar.”

In addition in this section first we mentioned about mesh terms and key words then we explained about data base search. Thank you for again for your important comments.

Reviewer’s comments

Section 2.4:

Line 176: Unclear

Authors’ responses

Dear Reviewer,

Thank you for your comment.

We apologize for the confusion caused by the unclear statement. We have corrected it in the main document as follows:

“We systematically reviewed and evaluated studies from various sources to ensure a comprehensive analysis.”

Reviewer’s comments

Authors’ responses

Dear reviewer,

Thank you for your comment. We agree that we have already explained this under section 2.3 and we have removed the statement from Line 177, as the details about publication year constraints are already explained in Section 2.3.

Reviewer’s comments

Authors’ responses

Dear reviewer,

Thank you for your feedback. We acknowledge that contacting authors should occur after data extraction in a systematic review. We have corrected the arrangement of stetments and we mentioned contacting Authors for missed data were under the data extraction section.

Reviewer’s comments

Line 186: This should come before title abstract screening

Authors’ responses

Dear reviewer,

Thank you for your valuable suggestion. To maintain the sequence of the review process, we moved the statement from Line 86 to precede the abstract and title screening stetments.

Reviewer’s comments

Section 2.6 will come before 2.5

Authors’ responses

Dear reviewer,

Thank you for your feedback. We have revised the manuscript to present the section 2.6 before section 2.5.

Thank you again for your relevant suggestions.

Reviewer’s comments

Section 2.6:

Did you summarise data in Excel or you conducted data extraction in excel? Please clarify

Authors’ responses

Dear reviewer,

Thank you for your question. We apologize for the confusion that cuase in the writing this process. We conducted the data extraction using Microsoft Office Excel and we clarify it in the main document this process.

Reviewer’s comments

Did you cross-reference studies for missing studies?

Authors’ responses

Dear reviewer.

Thank you for the feedback. We have cross-referenced the included studies to ensure no relevant studies were missed.

Reviewer’s comments

Authors’ responses

Dear reviewer,

Thank you for your valuable feedback. We have carefully assessed the certainty of evidence using the GRADE approach, as requested. The evaluation was conducted independently by two authors (E.A. and M.C.), with any disagreements resolved by consensus. This process has been clearly documented in the revised manuscript. We appreciate your suggestion, which has helped improve the clarity and transparency of our study.

Reviewer’s comments

Results:

Line 231: "We reviewed the full texts of the remaining 195 articles for eligibility, 163 studies were not eligible, and 32 studies were identified." what do you mean by 32 were identified?

Authors’ responses

Dear Reviewer,

Thank You for your request regarding to the clarity of the stetment. We corrected the stetment in the main document as the following;

“We reviewed the full texts of the remaining 195 articles for eligibility. Of these, 163 studies were not eligible, and 32 studies were eligible for inclusion in our review”

Reviewer’s comments

Rephrase line 238

Authors’ responses

Dear reviewer,

Thank You for your suggestion. We rephrased the statement as the following;

“We excluded three studies from the analysis: two conducted in Ethiopia(36, 37) and one in Uganda(38), because they reported a prevalence of folic acid supplementation during the preconception period as zero percent (0%).”

Reviewer’s comments

- Line 259: I think it should be table 2?

Please place all the tables appropriately.

Table 2: Suggest showing this in a graph and move table 2 to supplementary file.

Authors’ responses

Dear Reviewer,

Thank you for your suggestion. We have moved Table 2, which covers the quality of the study, to the supplementary file and placed the other tables in their appropriate locations as needed. We appreciate your guidance.

Reviewer’s comments

Dear reviewer,

Thank you for your clarification request. The studies were cross-sectional whose target population were pregnant women. However, this study collected data by asking pregnant women to recall and report their folic acid (FA) supplementation history from before they became pregnant.

Reviewer’s comments

You are talking about sensitivity analysis in Section 3.5 and then the actual analysis comes in Section 3.7. I would suggest moving Section 3.7 to Section 3.5

Authors’ responses

Dear reviewer,

Thank you for pointing that out. To improve the flow, we have moved Section 3.7 to Section 3.5, aligning the sensitivity analysis with its results for improved coherence.

Reviewer’s comments

Authors’ responses

Dear reviewer,

Thank you for the suggestion. We moved the discussion on study quality to follow after line 341 to enhance coherence and ensure a better connection with the preceding content on the intervention.

Reviewer’s comments

Authors’ responses

Dear reviewers,

Thank you for your valuable suggestions. We have thoroughly revised the discussion section. We have incorporated evidence from our study, including subgroup analysis, sensitivity, and study quality, followed by comparisons with African studies and research from LMICs and HICs. We have also addressed the strengths and limitations of our work. We appreciate your helpful comments and feedback.

We appreciate the reviewer's and editor’s thoughtful comments and suggestions, which have significantly contributed to enhancing the clarity and robustness of our manuscript.

Attachment

Submitted filename: Response to Reviewers.docx

pone.0318422.s007.docx^{(32KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0318422.r005

Decision Letter 2

Jai K Das

11 Nov 2024

PONE-D-24-13717R2Folic acid supplementation during preconception period in sub-Saharan African countries: A systematic review and meta-analysisPLOS ONE

Dear Dr. Aweke,

Please submit your revised manuscript by Dec 26 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Jai K Das

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

I would like to thank the authors for conducting this systematic review and thoroughly revising the manuscript based on the feedback from the reviewers. I have some additional concerns which are stated below:

Please specify that in the methods and results that studies done on pregnant women were only included if they had taken folate during preconception and also clarify that the studies only included these women or was there a mix.

I would suggest not to use the word ‘prevalence’ and rather use ‘proportion’ as there were studies included which were conducted in facilities and did not have a sampling frame to assess prevalence and even a few community studies would have done so. The authors need to define whether the studies covered few geographic locations or were nation level.

The introduction is lengthy and should be shortened

In the results and the PRISMA diagram – specify that how many studies were included from grey literature

Specify how many authors were contacted for missing information

Why two studies reporting zero prevalence were excluded from the analysis as they have reported the proportion, and this can add to the meta-analysis. If there is any specific reason, then the authors should state that.

In the table of included studies – please also specify the scale of the included studies – whether from one village, district, province or national and if from facilities – then how many facilities were covered.

Can the authors add a sub-group by urban/rural

Please thoroughly check the manuscript for language and grammar

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Reviewer #1: The authors have responded to the concerns raised over the last two rounds of review. I am happy with the editors recommendations if authors can make the edits to the eligibility criteria specifying that only data from studies where outcomes were specific to preconception supplementation were included. As the readers might get a bit confused looking at the 'participants' column in the characteristics studies.

Reviewer #2: Minor:

Table 1: add brackets around C after Comparison

Line 188: remove extra full stops.

Line 187: 'data' should be in lowercase

Check spacing: sampling method(random/non-random)

Table 5: I did inquire initially about using Gradepro for GRADE. I would suggest giving low/moderate/serious etc ranking for each domain and providing the explanation of each ranking as footnotes.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

**********

PLoS One. 2025 Jan 31;20(1):e0318422. doi: 10.1371/journal.pone.0318422.r006

Author response to Decision Letter 2

19 Nov 2024

Date: Nov 13, 2024

To: Plos One, Editorial Office

Subject: Submitting a revised version of manuscript and point by point response

Manuscript ID: PONE-D-24-13717R1

I am pleased to resubmit our revised manuscript titled, "Folic acid supplementation during preconception period in sub-Saharan African countries: A systematic review and meta-analysis" (ID: PONE-D-24-13717R1). We have carefully considered and addressed the reviewers' valuable comments, making revisions that we believe have strengthened the clarity and quality of the manuscript.

This work highlights an important public health issue, and we are grateful for the opportunity to improve it based on the feedback provided. We hope it now meets the high standards of PLOS ONE and look forward to your assessment. Thank you for your time and consideration.

Regards,

Authors

Point by point response to the Academic editor and reviewer’s comments

1. Comments from the academic editor and responses

Response

Dear editor,

Thank you for your helpful feedback. Upon carefully reviewing the reference list, we found that two issues needed to be address the following citation was mistakenly cited in the manuscript:

Gbemileke A, Atta AO, Abolade T, Adegoke F, Arogundade E, Kung'u J, Beckworth C. Assessing women's knowledge on benefits of iron and folic acid and its consumption during pregnancy in northern Nigeria. Annals of Nutrition and Metabolism. 2023;79:636.

we have correct reference that should have been included is:

‘Adebo OO, Dairo DM, Ndikom CM, Adejumo PO. Knowledge and uptake of folic acid among pregnant women attending a secondary health facility in Nigeria. British Journal of Midwifery. 2017 Jun 2;25(6):358-64.’

This reference is accurate and has now been included in the updated reference list. Thank you for your understanding and continued guidance.

Editor comment

Please specify that in the method results studies done one pregenent women were only included if they had taken folate during preconception and clarify that the studies only included these women or were there a mix.

Authors response

Dear Editor,

Thank you for your clarification question and recommendation to clarify this clearly in the manuscript. We have only included studies with pregenent women participants when they were take folate before pregnency/during preconception period.

Editors request

I would suggest not to use ‘prevalence’ and rather use ‘proportion’ as there were studies included which were conducted in facilities and did not have a sampling frame to assess prevalence and even few community studies would have done so. The authors need to define weather the studies covered few geographic locations or were national level.

Authors response

Dear editor,

Thank you for your suggestion to use proportion rather than prevalence due to the nature of the included studies. we have accepted and using proportion is more convenient than proportion. So we have corrected it accordingly. Thank you again for your valuable suggestion.

Editor request

In the result and prisma diagram specify how many studies were included from grey litrature

Authors response

Dear Editor,

Thank you for your request to specify the number of grey literatures in PRISMA flow diagram.

We have specified the number of grey literatures included to this SRMA study in the PRISMA flow diagram.

Thank you again for your valuable comments.

Editors request

The introduction is lengthy and to be shortened

Authors response

Dear Editor,

Thank you for your recommendation to shorten the introduction section. We have made it shorten with removing unnecessary words and phrases to make stronger and more informative introduction. Thank you again for your suggestion

editors request

Why two studies zero prevalence were excluded from the analysis as they have reported the proportion and this can add to the meta-analysis. if there is specific reason the authors should state that.

Authors response

Dear Editor

Thank you for your concern and request regarding to exclusion zero prevalence studies.

We excluded studies reporting zero prevalence from the analysis because, after closer reviewing them, we found that folic acid (FA) intake wasn’t the main focus of these studies. While they reported zero prevalence for FA intake, this wasn’t a central finding for their research, which made us concerned about how relevant and reliable that data would be for our meta-analysis. Additionally, the sample size and the methods used in these studies could have led to inaccurate reporting of zero prevalence. Including them could have introduced bias and affected the overall results, so we decided to exclude them to ensure the accuracy and reliability of our findings.

Editors request

Authors response

Dear Editor,

Thank you for your insightful suggestion to specify the scale/level of the included studies. We have now clarified the scale/level for each study, and for those conducted in health facilities, we have included the number of facilities in the table.

Once again, we appreciate your valuable feedback.

Editors request

Can the authors add a sub-group by urban/rural

Authors response

Dear Editor,

Thank you for your suggestion to conduct a sub-group analysis by urban/rural. However, since most of the studies were conducted in health facilities with participants from both urban and rural areas, we were unable to perform the sub-group analysis.

Editors request

Please thoroughly check the manuscript for language and grammar

Authors response

Dear Editor,

Thank you for your suggestion to review the manuscript for language and grammar errors. We have carefully reviewed and corrected the manuscript and remain open to any additional suggestions or comments regarding any missed errors.

2. Comments from reviewer #1 and responses

Reviewer’s comments

Authors’ responses

Dear Reviewer,

Thank you for your crucial and helpful comments throughout the review process. Regarding the study participants, we have clarified that all the included studies focused on women were included only if women took folate before pregnancy. Thank you again for your valuable feedback.

3. Comments from reviewer #2 and responses

Table 1: add brackets around C after Comparison

Line 188: remove extra full stops.

Line 187: 'data' should be in lowercase

Check spacing: sampling method(random/non-random)

Authors' response

Dear Reviewer,

Thank you for your comments and suggestions throughout the review process. Based on your feedback, we have corrected the typographical errors by removing extra full stops, adding brackets, changing the "D" in "data" to lowercase, and removing double spacing. We appreciate your valuable comments and suggestions.

Reviewers comment

Table 5: I did inquire initially about using Gradepro for GRADE. I would suggest giving low/moderate/serious etc ranking for each domain and providing the explanation of each ranking as footnotes.

Authors response

Dear reviewer,

Thank you for your inquiry. Based on your recommendation and the GRADE assessment criteria, we have revised the table and added footnotes with explanation of each ranking.

We appreciate the reviewer's and editor’s thoughtful comments and suggestions, which have significantly contributed to enhancing the clarity and robustness of our manuscript.

Attachment

Submitted filename: Response to Reviewers.docx

pone.0318422.s008.docx^{(23.4KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0318422.r007

Decision Letter 3

Jai K Das

22 Dec 2024

PONE-D-24-13717R3Folic acid supplementation during preconception period in sub-Saharan African countries: A systematic review and meta-analysisPLOS ONE

Dear Dr. Aweke,

Please submit your revised manuscript by Feb 05 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Jai K Das

Academic Editor

PLOS ONE

Journal Requirements:

Additional Editor Comments:

i would like to thank the authors for the revisions. I have one remaining comment about the three studies reporting zero prevalence being excluded from the analysis.

The authors should either exclude these studies altogether from the review or give the reason in the manuscript for not including them in the meta-analysis and if folic acid (FA) intake wasn’t the main focus of these studies, then why were they included. Also I am not clear how the authors assessed if the sample size and the methods used in these studies were not accurate (as the Newcastle-Ottawa Scale ratings do not suggest so) and how was this ascertained for all the studies that were included. i did have a look at it and did not see any compelling issues as preconception care was assessed in these studies and IFA was one component assessed. Please elaborate on this.

[Note: HTML markup is below. Please do not edit.]

PLoS One. 2025 Jan 31;20(1):e0318422. doi: 10.1371/journal.pone.0318422.r008

Author response to Decision Letter 3

24 Dec 2024

Date: December 24, 2024

To: PLOS ONE Editorial Office

Subject: Resubmission of Revised Manuscript (ID: PONE-D-24-13717R1)

Dear Editors,

We are pleased to resubmit our revised manuscript, "Folic Acid Supplementation During the Preconception Period in Sub-Saharan African Countries: A Systematic Review and Meta-Analysis" (ID: PONE-D-24-13717R1). We have carefully addressed the editor's comments and made revisions to enhance the manuscript's clarity and quality. Thank you for the opportunity to improve our work, and we look forward to your assessment.

Sincerely,

The Authors

Authors response: Thank you for your feedback. We have reviewed the references and replaced the incomplete citation, "Organization WH. Global health estimates (GHE)–Cause-specific mortality. 2015. 2015," with the complete and relevant reference:

Flores A, Vellozzi C, Valencia D, Sniezek J. Global burden of neural tube defects, risk factors, and prevention. Indian Journal of Community Health. 2014;26(Suppl 1):3.

We also replaced

World Health Organization. Prevention of neural tube defects. Department of Making Pregnancy Safer Switzerland: World Health Organization. 2006

with the more relevant and complete citation:

Gomes S, Lopes C, Pinto E. Folate and folic acid in the periconceptional period: recommendations from official health organizations in thirty-six countries worldwide and WHO. Public Health Nutrition. 2016 Jan;19(1):176-89.

We have replaced the incomplete reference:

The GRADE handbook H. Schünemann, J. Brożek, G. Guyatt and A. Oxman Cochrane Collaboration London, UK 2013

with the complete and updated citation:

Guyatt GH, Thorlund K, Oxman AD, Walter SD, Patrick D, Furukawa TA, Johnston BC, Karanicolas P, Akl EA, Vist G, Kunz R. GRADE guidelines: 13. Preparing summary of findings tables and evidence profiles—continuous outcomes. Journal of Clinical Epidemiology. 2013 Feb 1;66(2):173-83.

While we have ensured accuracy, we will accept if any incomplete references remain that may make tracking difficult.

Academic editor’s comments:i would like to thank the authors for the revisions. I have one remaining comment about the three studies reporting zero prevalence being excluded from the analysis.

Authors response: Dear Editor,

Thank you for your insightful feedback and for pointing out this issue. We excluded the three studies with zero prevalence. These studies reporting zero prevalence were excluded from the review because their primary focus was not on folic acid (FA) intake during the preconception period. While these studies report zero prevalnce during preconception, FA supplementation was only a minor component, which could significantly influence the results and potentially compromise the reliability of the review findings.

Excluding these studies from review strengthens the specificity and reliability of our systematic review and meta-analysis in estimating FA supplementation during the preconception period. We have updated the manuscript accordingly and appreciate your guidance in helping us improve the quality of our work.

Thank you once again for your support to enhance the manuscript.

Attachment

Submitted filename: Response to Reviewers.docx

pone.0318422.s009.docx^{(20.1KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0318422.r009

Decision Letter 4

Jai K Das

30 Dec 2024

PONE-D-24-13717R4Folic acid supplementation during preconception period in sub-Saharan African countries: A systematic review and meta-analysisPLOS ONE

Dear Dr. Aweke,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. I would like to thank the authors for all the hard work and making the revisions and addressing most comments but I taking am still not clear on why the three studies with zero-prevalence are being excluded as the reasons that 'primary focus was not on folic acid (FA)' and a 'minor component' are not strong enough reasons as previously they were included in the review though not in meta-analysis. Also the exclusion criteria of your review does not specify exclusion on these reasons. The quality assessment done by the authors for the three studies is also not very different from the other studies and especially the domain of 'Assessment of outcome'. So I would suggest to include these three or provide a strong reason (within the pre-set exclusion criteria) and how it varies from all the other included studies.

Please submit your revised manuscript by Feb 13 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

We look forward to receiving your revised manuscript.

Kind regards,

Jai K Das

Academic Editor

PLOS ONE

Journal Requirements:

[Note: HTML markup is below. Please do not edit.]

PLoS One. 2025 Jan 31;20(1):e0318422. doi: 10.1371/journal.pone.0318422.r010

Author response to Decision Letter 4

1 Jan 2025

To: PLOS ONE Editorial Office

Subject: Resubmission of Revised Manuscript (ID: PONE-D-24-13717R1)

Dear Editors,

Sincerely,

The Authors

Academic editor’s comments

I would like to thank the authors for all the hard work and making the revisions and addressing most comments but I taking am still not clear on why the three studies with zero-prevalence are being excluded as the reasons that 'primary focus was not on folic acid (FA)' and a 'minor component' are not strong enough reasons as previously they were included in the review though not in meta-analysis. Also the exclusion criteria of your review does not specify exclusion on these reasons. The quality assessment done by the authors for the three studies is also not very different from the other studies and especially the domain of 'Assessment of outcome'. So I would suggest to include these three or provide a strong reason (within the pre-set exclusion criteria) and how it varies from all the other included studies.

Authors’ responses

Dear Editors We appreciate your thoughtful comments and suggestion. The decision to exclude these three studies was not only 'primary focus was not on folic acid (FA)' and a 'minor component but also based on the fact that their results were extremely low, reporting zero values, which are considered outliers in this context.

Including these studies in the meta-analysis would not allow for a standard pooled estimate, as zero values lead to a negative standard deviation, which is not acceptable. To resolve this, a continuity correction formula would need to be applied, but doing so would still introduce bias by modifying the numbers inappropriately. Therefore, to maintain the robustness and integrity of the study, we decided to exclude these studies. We have added the exclusion criteria to the Methods section for greater clarity and transparency. However, we remain open to your suggestions and are happy to reconsider the approach if necessary. Thank you again for your insightful comments and suggestions.

Journal Requirements:

Authors’ responses

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PLoS One. doi: 10.1371/journal.pone.0318422.r011

Decision Letter 5

Jai K Das

16 Jan 2025

Folic acid supplementation during preconception period in sub-Saharan African countries: A systematic review and meta-analysis

PONE-D-24-13717R5

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PLoS One. doi: 10.1371/journal.pone.0318422.r012

Acceptance letter

Jai K Das

18 Jan 2025

PONE-D-24-13717R5

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Associated Data

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

Supplementary Materials

S1 Table. PRISMA checklist.

(DOCX)

pone.0318422.s001.docx^{(28.5KB, docx)}

S2 Table. Keywords and searching methodology.

(DOCX)

pone.0318422.s002.docx^{(18KB, docx)}

S3 Table. Methodological quality assessment of included studies using Newcastle-Ottawa Scale (NOS) for preconceptional FA supplementation in SSA, 2024.

(DOCX)

pone.0318422.s003.docx^{(18KB, docx)}

S1 Appendix. Individual studies with exclusion.

(DOCX)

pone.0318422.s004.docx^{(223.1KB, docx)}

S2 Appendix. Data extraction form with data extractors name and date.

(XLSX)

pone.0318422.s005.xlsx^{(61.5KB, xlsx)}

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Data Availability Statement

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PERMALINK

Folic acid supplementation during preconception period in sub-Saharan African countries: A systematic review and meta-analysis

Mekuriaw Nibret Aweke

Elsa Awoke Fentie

Muluken Chanie Agimas

Lemlem Daniel Baffa

Ever Siyoum Shewarega

Aysheshim Kassahun Belew

Esmael Ali Muhammad

Berhanu Mengistu

Roles

Abstract

Introduction

Methods

Result

Conclusion

Introduction

2. Methods

2.1 Study protocol and registration

2.2 Inclusion and exclusion criteria

Table 1. Criteria for inclusion of quantitative studies based on the Population, Exposure, Comparator, Outcome (PECO) framework.

2.3. Search strategy

2.4. Study selection

2.5 Data extraction

2.6 Assessment of the quality of the included studies

2.7 Evidence certainty assessment

2.8 Statistical analysis

3. Results

3.1 Selection and Identification of studies

Fig 1. PRISMA flow diagram of article selection for systematic review and meta-analysis of FA supplementation during preconception period in sub-Saharan African countries.

3.2 Characteristics of included studies

Table 2. Characteristics of the included studies and their proportion of preconceptional FA supplementation in SSA, 2024.

3.3 Proportion of preconception FA supplementation

Fig 2. Forest plot of FA supplementation during preconception period in sub-Saharan African countries.

3.4 Subgroup analysis

Fig 3. Sub-group by country pooled proportion of FA supplementation during preconception period in SSA countries.

Fig 4. Sub-group by year pooled proportion of folic acid supplementation during preconception period in SSA countries.

Fig 5. Sub-group by participant categories pooled proportion of FA supplementation during preconception period in SSA countries.

Fig 6. Sub-group by African region pooled proportion of FA supplementation during preconception period in SSA countries.

3.5 Heterogeneity and sensitivity analysis

Table 3. Meta-regression analysis of factors with heterogeneity of the proportion of preconceptional FA supplementation in SSA, 2024.

Fig 7. Sensitivity analysis of FA supplementation during preconception period in SSA countries.

3.6 Publication bias

Fig 8. Funnel plot result of FA supplementation during preconception period in SSA countries.

Fig 9. Trim and fill analysis of FA supplementation during preconception period in SSA countries.

Table 4. Egger’s of publication bias of included studies in the systematic review and meta-analysis of preconceptional FA supplementation in SSA, 2024.

3.7 Evidence certainty

Table 5. Certainty assessment for included outcomes for the proportion of preconception FA supplementation among women in Sub-Saharan Africa.

4. Discussion

5. Strengths and limitations of the review

6. Conclusions and recommendations

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Jai K Das

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Author response to Decision Letter 0

Decision Letter 1

Jai K Das

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Author response to Decision Letter 1

Decision Letter 2

Jai K Das

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Author response to Decision Letter 2

Decision Letter 3

Jai K Das

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Author response to Decision Letter 3

Decision Letter 4

Jai K Das

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Author response to Decision Letter 4

Decision Letter 5

Jai K Das

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