Burden of Neural Tube Defects and Their Associated Factors in Africa: A Systematic Review and Meta-Analysis

Background Neural tube defects are a type of congenital anomaly caused by an abnormality in the development of the brain and spinal cord during embryogenesis. They cause high rates of mortality, morbidity, and lifelong disability. There are several studies carried out worldwide reporting different findings on the burden and associated factors. The aim of this study is to carry out a systematic review and meta-analysis of the burden of neural tube defects and their associated factors in Africa. Methods A total of 58 eligible articles were identified systematically using databases such as PubMed, Embase, African Journal Online Library, ProQuest, Cochrane, Google Scopus, Google Scholar, and Grey literature. Extracted data were analyzed using STATA 16.0 statistical software. The heterogeneity of studies was determined using the Cochrane Q test statistic and I2 test statistics with forest plots. A random effects model was used to examine the pooled burden of neural tube defects, subgroups of the region, subtypes of NTDs, sensitivity analysis, and publication bias. The association between NTDs and associated factors was studied using a fixed-effect model. Results Fifty-eight studies with a total of 7,150,654 participants in 16 African countries revealed that the pooled burden of neural tube defects was 32.95 per 10,000 births (95% CI: 29.77-36.13). The Eastern African region had the highest burden in the subgroup analysis, with 111.13 per 10,000 births (95% CI: 91.85–130.42). South African countries had the lowest burden, at 11.43 per 10,000 births (95% CI: 7.51–15.34). In subtype analysis, spina bifida had the highest pooled burden at 17.01 per 10,000 births (95 percent CI: 15.00-19.00), while encephalocele had the lowest at 1.66 per 10,000 births (95% CI: 1.12-2.20). Maternal folic acid supplementation (AOR: 0.38; 95% CI: 0.16-0.94), alcohol consumption (AOR: 2.54; 95% CI: 1.08-5.96), maternal age (AOR: 3.54; 95% CI: 1.67-7.47), pesticide exposure (AOR: 2.69; 95% CI: 1.62-4.46), X-ray radiation (AOR: 2.67; 95% CI: 1.05-6.78), and history of stillbirth (AOR: 3.18; 95% CI: 1.11-9.12) were significantly associated with NTDs. Conclusion The pooled burden of NTDs in Africa was found to be high. Maternal age, alcohol consumption, pesticide and X-ray radiation exposure, history of stillbirth, and folic acid supplementation were significantly associated with NTDs.


Introduction
Neural tube defects (NTDs) are a type of congenital anomaly caused by an abnormality in the development of the brain and spinal cord during embryogenesis [1], with nearly 300,000 cases worldwide annually [2]. The effects they cause in Africa are substantial. NTDs are the world's second most common birth defect (1 in 1000 live births) [3], with the highest rates in northern China (3.7/1000 live births) and Ireland (1.6 per 1000 live births) [4].
The prevalence and etiology of NTDs vary by population [5]. The rate of occurrence increases from the west to the east coast in the United States, with the Appalachian region having the highest frequency [3,4,6]. NTD affects approximately 1-3 per 1000 births in Africa each year [7]. The prevalence of NTD in Ghana is 1.6 per 1000 live births [8].
In Ethiopia, variable outcomes ranging from 30.87 to 42.5 per 1000 births were reported on the prevalence of neural tube defects. Improved maternal health, preconception care, folic acid supplementation, and routine fetal anomaly scanning may all help to detect congenital anomalies earlier in pregnancy. Permanent epidemiological surveillance is required to determine the true prevalence at the national and temporal trend levels [9][10][11].  Geneti et al. [9]  International Journal of Pediatrics 2.5. Methodological Quality Assessment. The quality of relevant articles was assessed using the Joanna Briggs Institute (JBI) critical evaluation tool [13]. Two of the authors (RW and MA) independently evaluated the quality of the full text selected for the meta-analysis. The tool includes ten items for case-control studies, forty for cross-sectional studies, and eight for cohort studies (additional file 3 and 4). Each study's items were scored as yes (1) or no (0). The quality of each study was graded based on the number of items judged "Yes" (1) as low risk < 60%, medium (60-80%), and high >80%.
2.6. Data Extraction. Following the inclusion of the relevant papers, the two reviewers (RW and MA) extracted all of the required data separately. To retrieve all qualified articles, a consistent data extraction tool was used with Microsoft Office Excel Software.
For the burden of NTDs, the data extraction tool includes the first author, publication year, country and subregion, study design, setting, sample size, and number of NTDs. The prevalence and number of cases for each of the NTD subtypes were also included. The data for NTD-related factors was extracted in two tables. The pooled odds ratio and its corresponding 95% confidence interval (CI) were calculated based on the original study report (additional file 5 and 6). Note: Weights are from random efects analysis statistical analyses. The heterogeneity of all included studies was assessed using I 2 statistics and the Cochrane Q test. In this meta-analysis, the test revealed significant heterogeneity among included articles (I 2 = 99:4 percent, P value = 0.00). As a result, a random effects model was used. The Egger test statistics were used to examine the publication bias. The pooled burden and odds ratios, as well as their respective 95% confidence intervals, were displayed using a forest plot. To determine the associated factors for NTDs, the data was entered into Review Manager Version 5, and pooled odds ratios (ORs) with a 95% confidence interval (CI) were calculated.

Operational Definition.
NTDs are a circumstance that influences all neonates with one of the following malformations: spina bifida, anencephaly, and encephalocele. The number of infants born with NTDs was divided by the total number of newborns and multiplied by a hundred to calculate the burden of neural tube defects.
Spina bifida is a congenital disorder caused by the spine and spinal cord not developing properly. In infants with spina bifida, a portion of the neural tube does not close or develop normally, leading to abnormalities in the spinal cord and spine bones. There are three types of spina bifida: myelomeningocele, meningocele, and occulta.
Anencephaly is a birth defect in which the baby's brain and skull bones do not fully form while it is inside the womb. As a result, the cerebral cortex in particular does not develop as quickly in the baby's brain.
Encephalocele is a rare type of congenital abnormality of the neural tube that affects the brain. An encephalocele is a sac-like protrusion or extension of the brain and the membranes that protect it through a hole in the skull.

Results
The numerous subheadings listed below describe the findings from this systematic review and meta-analysis.

Description of Study Selection.
A total of 547 studies on the burden of neural tube defects and associated factors in African countries were found in the Medline (PubMed), Cochrane, Embase, AJOL, ProQuest, Google Scopus, Google Scholars, ResearchGate, Basebieled scholarly, Wiley Online Library, and Google databases.
Ninety articles were removed due to duplication. After reviewing the titles and abstracts of the remaining 457 papers, it was determined that 375 were irrelevant to the study and were thus eliminated. In addition, 100 full-text papers were assessed for eligibility based on the established criteria. For the final systematic review and meta-analysis, 58 papers were selected that met the criteria ( Figure 1).  The overall burden of neural tube defects was determined using 48 studies from among the qualifying papers. Ten more studies were considered to be explored for associated factors of neural tube defects, including ten case-control studies.

Publication Bias.
As indicated by the asymmetrical distribution of funnel plot tests, there was a publication bias in the burden of neural tube defects among the included studies. The forest plot revealed that the experiments differed greatly. The studies showed significant heterogeneity (I 2 = 99:4%, P value ≤ 0.001) (Figure 3). Egger's test, too, revealed that publication bias is statistically significant (p value ≤ 0.001) (   (Figure 10). The frequency of encephalocele was highest at 5.16 (2.12, 8.19) in Eastern African countries and lowest at 0.56 (0.19, 0.93) in northern African countries (Figure 11).

Associated Factors of Neural Tube
Defects. This metaanalysis included maternal folic acid supplementation, parental consanguinity marriage, maternal alcohol consumption, maternal history of stillbirth, maternal pesticide exposure, maternal radiation exposure, maternal medical illness, infant sex, and mother's age > 35 years old as associate factors for neural tube defects, with ten papers [19-22, 28, 30, 32, 51, 54, 71] retrieved into the review. For sensitivity analysis, each variable was carefully examined. However, sensitivity analysis revealed that neither of the linked parameters was significant. A separate analysis was conducted for each variable.
(1) Maternal Age and Neural Tube Defects. From three [20,21,30] studies, we found that maternal age above 35 years of age during pregnancy was significantly associated with NTDs among newborn infants with odds ratio 3.54 (95% CI: 1. 67-7.47
(2) Maternal Alcohol Consumption and Neural Tube Defects. Three [22,28,30] studies showed that the women who had alcohol consumption during pregnancy were significantly associated with NTDs, odds ratio 2.54 (95% CI: 1.08-5.96). This indicated that infants of mother who had alcohol consumption were 2.54 times more likely to have babies with NTDs than women who had never consumed alcohol during pregnancy. The study showed moderate heterogeneity (I 2 = 52%, P <0.12) ( Figure 13). Hence, random model effect was computed.
(4) Maternal Exposure to Pesticide and Neural Tube Defects. This research looked at four studies [19,20,28,30] to assess the maternal exposure to pesticide and neural tube defects. The neural tube defect pooled odds ratio found that women who were exposed to pesticides during pregnancy were 2.69 times more likely to have a baby with neural tube defects (OR, 95 percent CI; 2.69 (1.62-4.46)). The study was considered with the heterogeneity test, which found low heterogeneity (I 2 = 0, P < 0:67) ( Figure 15). As a result, the fixedeffects model was adopted in this study.

International Journal of Pediatrics
Women who had been exposed to radiation were 2.67 times more likely to have infants with neural tube defects than women who had not been exposed to radiation (OR, 95% CI: 2.67 (1.05-6.78)). Low heterogeneity (I 2 = 0, P < 0:55) was found. This study utilized a fixed-effects model ( Figure 16).

(6) Paternal Consanguineous Marriage and Neural Tube
Defects. Based on the four studies [28,51,54,71], the link between parental consanguineous marriage and neural tube defects was rigorously analyzed. There was no difference in the combined odds ratio of neural tube defects between parents who were consanguineous and those who were not (OR 95 percent CI: 1.07 (0.40-2.91)). I 2 = 75% andP ≤ 0:001 revealed moderate heterogeneity. As a result, in the final analysis, the random effects model was used (Figure 17).

(8) Maternal Medical Illness and Neural Tube Defects.
The pooled odds ratio for neural tube defects between the two studies [21,28] found no difference between pregnant women with and without medical illness (OR, 95 percent CI: 1.38 (0.83-2.28)) ( Figure 19). The heterogeneity was then found to be low (I 2 = 35%, P < 0:20). The fixed effect was therefore assessed.
(9) Maternal History of Stillbirth and the Outcome. Three [20][21][22]28] studies revealed that women who had a stillbirth were 3.18 times more likely to have a newborn with neural tube defects than women who had not had a stillbirth, (95% CI: 1.11-9.12). The study discloses high heterogeneity (I 2 = 82%, P ≤ 0:001). As a result, a random effects model was contemplated (Figure 20).

Discussion
The burden of subtype analysis of neural tube defects was evaluated by region for the first time in Africa. The overall burden of NTDs was 32.95 per 10,000 infants (95% CI: 29.77-36.13). This finding is higher than the studies conducted in California which reported a prevalence of 9 per 10,000 births [73], low-and middle-income countries (11

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International Journal of Pediatrics per 10,000) [74], Africa (21.42 per 10,000) [69]. However, the overall burden found in this study is lower than the previous studies conducted in Africa which reported a prevalence value of 50.74 per 10,000 and India (45 per 10,000 and 42.48 per 10,000) [75][76][77]. This may be due to several factors, including variable birth record system, study design, and population size. Inclusion or exclusion criteria of articles among reviews may also have an effect in the findings. Furthermore, data loss and less organized system might also be a reason for the heterogeneity of the burden rate among the various studies.
The subgroup analysis of this study showed that the burden of NTDs among newborn infants significantly var-ies across the regions. The highest burden was observed in the eastern Africa region with a burden of 111.13 per 10,000 births (95% CI: 91.85, 130.42), and the lowest burden was in southern Africa, with 11.43 per 10,000 births (95% CI: 7.51, 15.34). This has been linked to varying folic acid supplementation trends. The eastern region had a higher burden. This may be due to a greater deficiency in folic acid supplementation with the staple foods lacking adequate amount of folic acid fortification. On the other hand, the reason for the lower burden in the southern countries may be due to better folic acid supplementation practices and fortification policies in their staple foods [78][79][80].   (2.12, 8.19) in eastern African countries and lowest at 0.56 (0.19, 0.93) in northern African countries. The current review showed that the burden of spina bifida was higher than a previous study conducted in Africa with a value of 13 per 10,000 births [81].
On the other hand the burden of anencephaly and encephalocele were lower than that of a previous study carried out in Africa, with a value of 14 per 10,000 and 2 per 10,000, respectively [82,83]. This variation in the burden of the subtypes of NTD may be due to the differences in defect identification and detection methods over time, as well as differences in location, income level, and institutional folic acid fortification policy [74,80,84].
In this study, 10 studies [19-22, 28, 30, 32, 51, 54, 71] were retrieved in order to identify protective and associated factors with NTDs in newborns. After reviewing 2,946 sample sizes, 946 cases and 1703 controls were investigated. Infants born to mothers over the age of 35 during pregnancy were 3.54 times more likely to have NTDs than infants born to mothers under the age of 35, according to the combined odds. A finding of this study, which a fetus with NTDs is more likely to have chromosomal abnormalities as maternal age increases, was consistent with a previous study that found a link between maternal age and infants born with NTDs that have chromosomal abnormalities [85]. Meiotic division restriction leads to increased aneuploidy [86,87]. Women with a history of alcohol use were 2.54 more likely to have infants with NTDs than women that had never consumed alcohol during pregnancy. This finding contradicts with the findings from studies that reported no link between maternal alcohol consumption and NTDs. This finding in the study has explained very well that this could be due to underreporting of alcohol consumption, which is directly related to the social stigma of drinking during pregnancy [88,89].
Women who had been exposed to radiation were 2.67 times more likely to have infants with neural tube defects than women who had not been exposed to radiation. This finding is in line with the study's findings of altered chromatin structure, altered gene expression, and DNA damage. It may be due to radiation's ability to alter global DNA methylation, which in turn can affect altered gene expression, altered chromatin structure, and DNA damage [90]. Apoptotic mutations caused by X-rays combine with neurodevelopment to increase the likelihood of NTD closure failure. Chronic low-dose radiation may affect the growth of neural progenitor cells and disrupt brain development [90].
The link between parental consanguineous marriage and NTDs has been extensively examined. There was no difference in the combined odds ratio of NTD among with and without consanguineous marriages. This observational study contradicts the findings of an Indian study that had reported that consanguinity increases the risk of NTD [91]. Consanguineous marriage alters the communal genetic frequency due to the gene residing in the family's genetic tree, which has a significant impact on NTD [92]. Study Figure 13: Forest plot depicting the association between maternal alcohol consumption and neural tube defects in Africa, 2022.  The results of the present study show no difference between male and female newborns in the burden of neural tube defects. These results go against a study [76] from India that found that newborn girls are more likely than newborn boys to have NTD.
It is unlikely that the outcome can be used to predict vulnerability to NTDs and was most likely caused by the rate of embryonic development. Due to females' slower rate of growth and the length of time spent undergoing neurulation, males appear to have made advancements in a few areas of the neurulation process, which increases the risk of NTDs [93]. The prevalence of NTDs was reduced due to extensive folic acid supplementation in both sexes [94]. Study   The pooled odds ratio for neural tube defects among the studies found no difference between pregnant women with and without medical illness, according to this metaanalysis. These findings are consistent with a study carried out in the United States [95], which found no difference in NTD prevalence between HIV-exposed pregnant women and the general population. On the other hand, it contradicts a previous study that found a higher risk of NTDs linked to fever during the first trimester of pregnancy [96]. In addition, a study done on Mexican-Americans had also reported that the occurrence of stressful life events was associated with NTD risk [97].
Women who had a history of stillbirth were 3.18 times more likely to have a newborn with neural tube defects than women who had not had a stillbirth. This finding is consistent with previous study that a previous miscarriage increases the risk of NTDs. The risk of recurrent stillbirth and termination pregnancies rises with NTD [98].
Reviewing the overall prevalence and contributing factors of neural tube defects among newborns in Africa has revealed significant advancements made possible by incorporating newer studies and up-to-date research to attract more attention and address a variety of studies. Therefore, the main aim of this systematic review and meta-analysis

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International Journal of Pediatrics was to estimate the burden of neural tube defects and their associated factors in Africa. In order to minimize the occurrence of neural tube defects in Africa, policymakers and program planners could use the findings of this review as a guide when developing suitable interventions. The evaluation could also be used as a starting point for future studies on associated subjects.

Strength and Limitations of the Study
Strength of the study is inclusion of cross-sectional, cohort, and case-control type of additional and current studies to increase attention and address many studies to show the burden of NTDs in Africa. On the other hand, as a limitation, only a few original studies have been conducted in some African regions and included in this review. The studies reviewed are hospital-based studies, which may likely limit the coverage of the study population to assess the overall burden of NTDs in Africa.

Conclusion
This review has revealed the burden of NTDs among newborn infants in African countries. The burden of NTDs varies in different regions of Africa and varies in relation with different risk factors. Folic acid supplementation is found as a protective factor of NTDs. The recommendation of this study is to implement a preconception folic acid therapy policy for all women of childbearing age, as well as a policy of mandatory food fortification is critical.

Abbreviations
NTDs: Neural tube defects CI: Confidence interval JBI: Joanna Briggs Institute MeSH: Medical subject headings.

Data Availability
The datasets used and/or evaluated in this study are available from the corresponding author upon reasonable request.