Preconception Folic Acid and Multivitamin Supplementation for the Prevention of Neural Tube Defect: An Umbrella Review of Systematic Review and Meta-analysis

Congenital abnormalities are a significant cause of morbidity, disability, and mortality in children as well as a significant contributor to healthcare costs. Neural tube defects (NTDs) are a frequent term for congenital abnormalities of the central nervous system, including anencephaly, encephalocele, and spinal bifida. The failure of neural tube fusion, which normally happens during the third and fourth weeks of conception, or on average 5–7 weeks following the first day of the previous menstrual period, is what causes these deformities [1, 2]. According to estimates from the World Health Organization (WHO), 270,000 fatalities globally are attributed to congenital abnormalities that occur during the first 28 days of life. Neural tube malformations are among the most prevalent and dangerous of these abnormalities [3].

The frequency of NTDs varies between 0.8 and 3 per 1,000 live births in the region. The global incidence is estimated to be 880 per day or 324,000 per year. Roughly two-thirds of the cases (225,000) came from low-income countries, 26% from middle-income countries (84,000), and 4% from high-income nations (15 cases) [3, 4]. Other well-known risk factors for NTDs include antiepileptic medications, pregestational diabetes, obesity, high fever, medical history, low folic acid, and other B-vitamins [2].

The development of the embryonic neural tube is regulated by genes, but nongenetic variables like vitamin status also play a role in the complex etiology of NTDs [5]. NTDs are more common in women who use antiepileptic medications, have obesity or diabetes, or present with symptoms of these conditions [6, 7]. In these higher risk categories, folate insufficiency may be a factor in the pathogenic processes that result in NTDs.

Folic acid is essential for a proper embryonic development because it plays a role in DNA synthesis and cell division. When the neural tube is still developing in the early stages of pregnancy, adequate folic acid intake is very crucial. NTDs are the consequence of partial neural tube closure or failure to develop in pregnant women with insufficient or low amounts of folic acid [8]. Folic acid is a kind of vitamin B9 and a water-soluble B vitamin. It is present in many different forms and occurs naturally in a large range of foods [9]. Folic acid is found in leafy greens, citrus fruits, almonds, beans, peas, shellfish, eggs, dairy products, meat, and chicken, among other foods. Conversely, folic acid comes in a synthetic form that is frequently found in supplements and dietary fortification [10, 11].

It is advised that women of childbearing age take 0.4 mg of folic acid supplement daily. But women who are at a higher risk – for example, those who have diabetes, are on antiepileptic medications, or have had pregnancies impacted by NTD in the past – are recommended to take more folic acid (0.8–5 mg daily) during the periconception phase [12]. Studies recommend that all women who are capable of becoming pregnant take folic acid or folic acid-containing multivitamin supplements starting 8–12 weeks before conception and continuing until 12 weeks after conception. This recommendation ensures that every pregnant woman begins her pregnancy with optimal levels of folic acid. By starting supplementation prior to conception, it allows time for folic acid stores to build up, increasing the chances of preventing NTDs during the critical early stages of fetal development [5, 6].

The worldwide prevalence of NTDs has fallen noticeably during the past 30 years. Preconception intake of folic acid reduces a women’s risk of having an infant affected by an NTD [10]. Folic acid intervention studies in pregnant women with prior NTD-affected pregnancies showed a 60–100% reduction in NTD risk with a later pregnancy. Observational studies of folic acid efficacy in preventing NTD in pregnant women without a prior NTD-affected pregnancy showed a 0–75% reduction in risk [13]. The comprehensive Canadian analysis of neural tube reduction after folic acid flour fortification has reported a 46% reduction. The observed reduction was greater for spinal bifida (53%) than for anencephaly (38%) and encephalocele (31%) [14]. In addition to the effectiveness of folic acid supplementation, the economic burden, profound emotional and psychological impact on individuals and their families, long-term impact on quality of life, treatment challenges for the long-term consequences of these defects, and the irreversible nature of the problem have compelled a focus on prevention strategies [7, 9, 15].

The WHO strongly recommended the implementation of preconception care (PCC) 5 years ago [16, 17]. PCC is crucial for promoting safe pregnancy outcomes and improving maternal health, but it has not yet become a universal practice worldwide, particularly in developing nations. The necessary medical attention is not received by more than 40% of pregnancies prior to pregnancy [18, 19]. Some studies from Europe, Canada, Iran, and Egypt reported poor PCC knowledge and practice among HCPs [13, 14, 20, 21]. The level of implementation of PCC in some of these African countries is varied [22‒24]. The adoption of newer evidence-based innovations for change, like PCC, is still the challenge of the continent [25, 26]. Despite the availability of a number of evidence-based PCC clinical guidelines and recommendations, many of the low-income countries have not yet introduced PCC in their national health systems [27].

The current state of FA and multivitamin supplementation to prevent NTD knowledge and practice for clinical application appears to differ greatly in terms of evidence. As a result, the subject of whether mother FA, multivitamin supplementation, and the risk of NTD are related is brought up. In order to answer this question, we have carried out an umbrella review of systematic reviews and meta-analyses in the current study. Our goal is to assess the relationship between preconception FA and multivitamin supplementation for reducing the risk of nontransferable diseases (NTDs) and to offer a solid scientific foundation for future medical research and decision-making regarding NTD prevention. In order to lower the incidence of NTDs, it is essential to comprehend the function that folic acid and multivitamin supplementation play during the preconception and early pregnancy period. The results of this study will add to the body of knowledge already in existence and give policymakers, academics, and healthcare professionals important new information about how to improve pregnancy outcomes.

This umbrella review was done following the methodology of umbrella review of existing SRM studies [28]. From checking PROSPERO, this umbrella review needed to be registered. We have submitted the registration protocol, which is under consideration in PROSPERO.

We searched systematic review and meta-analysis from the following databases: PubMed, Embase, Scopus, Web of Sciences, Cochrane Database of Systematic Reviews, Scopus, and Google Scholar in a global context on 23/11/2023 G.C. Were searched SRM which reported the effect of preconception folic acid and/or multivitamin supplementation for prevention of NTD in a global context using PICO (Population, Intervention, Comparison/Control and Outcome) frameworks. The search included MeSH terms and keywords, and combinations. All databases were searched broadly using keywords that are the combinations of PICO framework. A manual search of references in previous systematic reviews was also undertaken. A snowball searching of the references of all relevant papers for linked articles was also performed. Using those key terms, we used the Boolean operator “OR” (to connect key terms/phrases within the same concept), “AND” (to connect key terms/phrases between two concepts), and “NOR” to filter out. In addition, we used truncation (*), adjacency searching (ADJn), and wildcard symbols to find variations in spelling and variant word endings on the Ovid databases. Moreover, we applied relevant limits (filters) such as a limit to human studies and published in English language only. Search terms includes: (Preconception OR pre-conception OR pre-natal) AND (Multivitamin OR vitamin OR mineral OR micronutrient OR antioxidant OR anti-oxidant OR diet) AND (Neural Tube Defect OR NTD OR Birth Defect OR Congenital Defect OR Congenital Anomaly OR Anencephaly, OR spinal bifida OR spinal occulta OR encephalocele OR meningomyelocele OR meningocele OR neureninteric cyst OR acrania OR exencephaly OR spinal dysraphism) AND (meta-analysis OR systematic review OR review).A sample of the literature search strategy, PubMed search strategy, developed using a combination of MeSH terms and free texts is presented as a supplementary file (online suppl. Table 1; for all online suppl. material, see https://doi.org/10.1159/000539803). In addition to the systematic database searching, article searching was done using the reference list of the included studies and the “cited by” and “related articles” function of PubMed.

The retrieved SRMs were exported to the reference manager software, Endnote version 8, to remove duplicate studies. Two investigators (B.B. and M.A.) independently screened the selected studies using their titles and abstracts before retrieval of full-text papers. We used prespecified inclusion criteria to screen the full-text articles further. Those SRMs had reported the effect of folic acid and multivitamins for the prevention of NTD and published in the English language in a global context. For a study to be considered as a systematic review or meta-analysis, it should have to meet the following predefined criteria:

• 1.

  Presented a defined literature search strategy.

• 2.

  Appraised included studies using a relevant tool.

• 3.

  Followed a standard approach in pooling studies and providing summary estimates.

Studies were excluded due to any of the following reasons: (a) no report on the measures of interest for this study; (b) language other than English; and (c) narrative reviews, editorials, correspondence, abstracts, and methodological studies. The screening and selection of studies were conducted in two stages. First, title and abstract screening were done, and then full-text reviewing was done. Disagreements were discussed during a consensus meeting with other reviewers for the final selection of studies to be included in the umbrella review.

All published, unpublished, and systematic reviews and meta-analyses assess the effect of preconception folic acid and multivitamin supplementation for preventing NTD in the offspring. We would have included studies reported as abstracts only and those with full-text manuscripts.

Participants who have taken folic acid and multivitamin supplementation during the preconception period, regardless of whether the pregnancy was single or multiple, and irrespective of their gestational age, were considered.

Folic acid and multivitamin supplementation were administered to women before pregnancy and compared with a placebo, no treatment, or an alternative agent to improve outcomes. We included studies where different regimens for helping folic acid and multivitamins were compared.

The incidence of NTD among intervention groups (whose mothers have taken folic acid and multivitamins) compared to the control groups (whose mothers didn’t take folic acid and multivitamins) will be estimated.

Global.

Both published and unpublished articles reported the effect of the outcome of interest.

Methodological quality of all included reviews was assessed by two independent reviewers using the Assessment of Multiple Systematic Reviews (AMSTAR) tool [29, 30]. It consists of 11 questions that measure the quality of the approaches used for pooling the empirical studies included in the review and summarizing their estimates. The tool has been validated and frequently used for appraisal of the quality of SRM works. The quality scoring was done out of 11, with scores 8–11, 4–7, and <3 indicating high, medium, and low qualities, respectively. The decision as to whether or not to include a review can be made based on meeting a predetermined proportion of all criteria or on certain criteria being met. Decisions about a scoring system or any cutoff for exclusion was made in advance and agreed upon by all reviewers before critical appraisal commences. We have checked the quality of the included primary/original research studies in each of the research syntheses that have been included in the umbrella review.

Data from the included SRM studies were extracted using a standardized data abstraction form, developed in an excel spreadsheet. For each SRM study, the following data were extracted: (a) identification data (first author’s last name and publication year), (b) review aim and type, (c) incidence of NTD (%), (d) folic acid and multivitamin estimate (odds ratio [OR] or relative risk [RR] with 95% confidence intervals [CI]), (f) number of primary studies included within each SRM study and their respective design type, (g) total number of sample size included, (h) publication bias assessment methods and scores, (i) quality assessment methods and scores, (j) data synthesis methods (random or fixed-effects model), and (k) the authors’ main conclusion of the SRM study (Table 1).

After the data were extracted using Microsoft Excel format, we imported the data to STATA version 17.0 statistical software for further analysis. Both narrative and qualitative approaches were used to summarize the estimates of the included reviews. When two or more estimates were provided on the same topic, we presented the estimates’ range and calculated a summary (pooled) estimate. Using the binomial distribution formula, standard error was calculated for each study. We pooled the overall magnitude estimates of the effects of folic acid and multivitamin supplementation by a random-effects meta-analysis [36]. The pooled effect with 95% CI was presented using forest plots.

We examined the heterogeneity between the studies using Cochrane’s Q statistics (χ²), inverse variance (I²), and p values [37]. In this study, the I² statistic value of zero indicates true homogeneity, whereas 25%, 50%, and 75% represent low, moderate, and high heterogeneity, respectively [30, 38]. For the data identified as heterogeneous, we conducted our analysis using the DerSimonian-Laird random-effects model analysis. The subgroup analysis was conducted by the type of supplement (folic acid or multivitamin). Sensitivity analysis was employed to see the effect of a single study on the overall estimation. Publication bias was checked by the funnel plot and more objectively through Egger’s regression test [39].

A total of 1,280 reviews were identified: 1,272 from different databases and 8 from other sources. After duplication removed, a total of 711 articles remained (569 removed by duplication). Finally, 126 studies were screened for a full-text review, and 10 SRMs with 296,816 participants were included for the final analysis (Fig. 1; online suppl. Table 2).

Ten systematic review and meta-analysis reported the pooled effect of preconception supplementation of either folic acid or multivitamin for the prevention of NTD [31‒35, 40]. Five of the included reviews were done on the effect of folic acid for the prevention of NTD [31, 35, 40]. Most of the included reviews were aimed at the prevention of occurrence of NTD. The minimum and maximum number of included studies in these included SRMs were 3 (36) and 41 (37), respectively. Five included SRMs were conducted to assess the effect of folic acid and multivitamin supplementation for the prevention of NTD occurrence [33‒35] (Table 1).

Ten included SRMs have reported the effect of either folic acid or multivitamin supplementation for the prevention of NTD during the prenatal period [31‒35, 40]. The estimate of effect of either folic acid or multivitamin supplementation for the prevention of NTD was ranged from 0.03 (95% CI: 0.0, 0.06) [31] to 0.67 (95% CI: 0.58, 0.77) [32]. The random-effects model analysis from those trials revealed that the pooled effect of either folic acid or multivitamin supplementation for the prevention of NTD globally is found to be 0.43 (95% CI: 0.29, 0.58) (I² = 93.50%; p ≤ 0.001). This indicates that prenatal folic acid or multivitamin supplementation was associated with a 57% reduction in NTD in their offspring (Fig. 2). The level of heterogeneity was significant as evidenced by high I² (93.50%), a significant p value (p ≤ 0.001), and an asymmetric Galbraith plot (Figure 2; online suppl. Fig. 1).

Subgroup analysis was done through stratification by the type of supplementation. Based on this, the pooled effect of either folic acid or multivitamin supplementation for the prevention of NTD was found to be 0.23 (0.09, 0.37) in the folic acid group, while this estimate is 0.63 (0.53, 0.72) among studies with multivitamin supplementation and 0.61 (0.46, 0.75) in groups who took both folic acid and multivitamin (Fig. 3).

Subgroup analysis was also done through stratification by the aim of the trials (primary or secondary prevention). Based on this, the pooled effect of either folic acid or multivitamin supplementation for the prevention of NTD was found to be 0.50 (0.34, 0.66) in SRMs aimed at the occurrence prevention (primary prevention) group, while this estimate is 0.20 (−0.01, 0.41) among SRMs which aimed at reoccurrence (secondary) prevention and 0.61 (0.46, 0.75) among those SRMs aimed to assess the effect folic acid or multivitamin for prevention of both occurrence and reoccurrence (Fig. 4).

Subgroup analysis was also done through stratification by the design of included studies. Based on this, the pooled effect of either folic acid or multivitamin supplementation for the prevention of NTD was found to be 0.45 (0.03, 0.87) in SRMs of observational studies, while this estimate is 0.43 (0.32, 0.54) among SRMs of randomized controlled trials (RCTs) (Fig. 5).

A funnel plot showed asymmetrical distribution (online suppl. Fig. 2). The Egger’s regression test value was 0.015, which indicated the presence of publication bias (online suppl. Fig. 3). Due to the presence of publication bias, we employed a trim-and-fill analysis. However, there is no change in the pooled estimate after trim-and-fill analysis (online suppl. Fig. 4).

A leave-one-out sensitivity analysis was employed to identify the impact of the individual study on the pooled effect of preconception folic acid and multivitamin for the prevention of NTD. The results of this sensitivity analysis showed that the pooled finding was not dependent on a single study. Our pooled estimated effect of preconception folic acid and multivitamin for the prevention of NTD varied from 0.40 (0.17–0.63) to 0.49 (0.38–0.60) after the deletion of a single study (online suppl. Fig. 5).

This is the first umbrella review that we are aware of that examines the relationship between a mother’s prenatal multivitamin and folic acid consumption and her offspring risk of NTD. We pooled the data from 10 systematic reviews and meta-analyses in a global context, and the results of the overall analysis indicated a lower risk of NTD among offspring whose mothers took folic acid and multivitamin supplements before their pregnancies, as compared to those children whose mothers did not take the supplements. This might be due to the fact that the vital component of DNA replication and the metabolism of vitamins and amino acids, folic acid or folate (vitamin B9) serve as a substrate for several enzyme activities. Because of the fetus’s increasing needs, there is a rise in folate demands during pregnancy. It has been indicated that folic acid deficiency before and throughout the early stages of pregnancy (up to 1² weeks of gestation) increases the risk of NTDs, and periconception folic acid supplementation can significantly reduce this risk [41‒43]. If inadequate folic acid consumption in the early stages of pregnancy can cause NTDs, it may also cause milder forms of fetal brain damage that could show up in early childhood as delayed neurodevelopment or autism [44]. In fact, low folate levels are associated with a number of clinical disorders, including neurological and cardiovascular disorders as well as a higher risk of NTDs [45‒47]. In most cortical and subcortical areas, large quantities of methyl donors are necessary for neurogenesis and cell migration [48].

Neurogenesis and cell migration require considerable amounts of methyl donors in most cortical and subcortical locations [9, 49, 50]. The timing of a mother’s folate intake seems to be important; only when the supplements were taken prior to conception and in the early stages of pregnancy, between 4 weeks and 8 weeks after the start of pregnancy, did a child’s risk of NTDs decrease [51]. Although there is no definitive period for starting folic acid supplementation, most experts concur that starting 4–8 weeks prior to conception is the ideal time to begin FA. Given that neural tube closure takes place during the first 28 days following conception, this may have something to do with it [52, 53].

In this study, subgroup analysis indicates that the pooled effect of folic acid supplementation for the prevention of NTD was found to be 0.23 (0.09, 0.37). This is in line with previous studies. Supplementing with folic acid tablets during the periconceptional period lowers the risk of NTDs in offspring by over 50% [11, 54]. A multicenter case-control study found that consuming 0.4 mg of folic acid per day prior to conception decreased the chance of developing NTDs by about 60% [55]. Similarly, the meta-analysis studies reported that the effect of periconception folic acid supplementation for the primary prevention of NTDs showed a reduction of 62% in the incidence NTDs (RR 0.38; 95% CI: 0.29–0.51, I² = 27.9%, fixed model). According to a nonrandomized intervention study conducted in China, taking 0.4 mg of folic acid daily supplements prior to conception decreased the risk of NTDs by 41% and 79%, respectively, in northern and southern China [56]. Daily FA supplementation at any dose was associated with a 67% (adjusted OR = 0.33; 95% CI = 0.13, 0.76) reduced NTD risk among pregnancies with a family history of NTD [57]. However, despite citing the lack of information on the daily amount of supplemental folic acid intake in the survey as a limitation, a nationwide prospective birth cohort study in Japan found no significant correlation between preconception folic acid supplements and the incidence of NTDs [58, 59]. On the other hand, the pooled results for the primary prevention of NTDs using folic acid fortification also showed a reduction of 41% in primary occurrence of NTDs (RR 0.59; 95% CI: 0.520.68, I² = 88%, random model) [60]. The pooled results of three RCTs for the prevention of recurrent NTDs showed a reduction of 70% in the recurrence of NTDs (RR 0.30; 95% CI: 0.14–0.65, I² = 0%, fixed model) [61]. Congruently, the study result of medical research council vitamins using a nonblinded randomized trial also stated that folic acid supplementation (4 mg) around the time of conception was prevented recurrent NTDs by 72% with an RR of 0.28 (95% CI: 29 to 88%) [62]. Similarly, a population-based cohort research involving Mexican-American women whose previous pregnancies were affected by NTDs revealed that folic acid supplementation at a dose of 0.4 mg or higher before to conception was effective in avoiding recurrent NTDs [63].

Folic acid is extremely beneficial in preventing congenital abnormalities, particularly NTDs. The fast-developing fetus and the rise in the mother’s red blood cell count during pregnancy boost the need for folate, which is crucial for cell division and DNA synthesis. Its deficit may result from other medical conditions, hereditary issues, or inadequate nutritional consumption. A shortage in folate raises the plasma concentration of homocysteine, which is crucial for the development of several congenital abnormalities, including nontyping diabetes [11, 64].

For 2 to 3 months prior to conception, during the pregnancy, and for 4 to 6 weeks following delivery or until lactation is finished, women who do not have a personal or family history of NTDs or other folic acid-sensitive congenital anomalies must follow a healthy diet rich in folate-rich foods and take a daily oral multivitamin containing 0.4–1 mg of folic acid [11, 32, 50]. According to the study reported from the RCT of periconception supplementation with multivitamins including folic acid (0.8 mg) verified a substantial reduction in the occurrence of NTDs (OR, 0.07; 95% CI, 0.04–0.13) [65]. Correspondingly, the result of Hungarian cohort-controlled trial recognized that the primary prevention of NTDs with a periconception multivitamin supplementation containing folic acid (0.8 mg) was powerful and it would be possible to reduce the rate of NTDs from 3 per 1,000 to 0.3 per 1,000 [58]. A case-control study reported that women with any use of a folic acid-containing vitamin (<0.4 mg, 0.4–0.9, and 0.9 mg per day) in the 3 months before conception had a lower risk of having NTD affected pregnancy (OR = 0.65; 95% CI = 0.45–0.94). On the other hand, any level of folic acid use in the 3 months after conception resulted in a lowered risk as well (OR = 0.60; 95% CI = 0.46–0.79) [66]. Other a prospective study showed that women who were taking a vitamin containing folic acid of any dose before or during the first 2 weeks since the last menstrual period (before conception), 6 NTD cases occurred among 7,044 women, reflecting a 76% reduction in risk (PR = 0.24; CI = 0.09–0.66) compared with those who started supplements later [67].

The pooled effect of either folic acid or multivitamin supplementation for the prevention of NTD was found to be 55% and 57% reductions in SRMs of observational studies and RCTs. This slight variation due to the design of included studies in meta-analysis is discussed below. Analytic and nonanalytic (descriptive) study designs are the two categories into which study designs can be classified, according to the Centre for Evidence-Based Medicine. Quantifying the relationship between an intervention (such as a treatment) or a naturally occurring exposure and a result is the goal of analytical investigations. They can be separated into observational and experimental (i.e., RCT) research. Because the randomization process removes the connection between the intervention’s allocation and patient outcome, RCTs are the most effective study design for assessing the anticipated impact of an intervention. One must rely on observational analytical studies if the randomization of the intervention or exposure is not feasible; nevertheless, these studies typically have bias and confounding. The best study designs are observational analytical studies if the focus of the investigation is on unintended effects of interventions, or consequences of an intervention that were not planned or anticipated. This is true as long as there is no connection between the allocation of the intervention and the unintended effect. Moreover, observational study designs are frequently utilized in nonanalytic studies or descriptive studies [1, 2]. Compared to RCTs, observational studies offer a number of benefits, such as reduced costs, faster turnaround times, and a larger patient pool. However, the use of these studies in treatment comparisons has been restricted due to concerns about inherent bias. Observational studies are mostly employed in circumstances where RCTs would be impractical or unethical to determine risk factors and prognostic markers [1, 3, 4, 8]. In conclusion, there are intrinsic differences between RCTs and observational study designs, and each has advantages and disadvantages according to the study’s objectives.

The study covers a wide range of data sources and includes a substantial number of systematic reviews and meta-analysis, providing a comprehensive view of the effect of folic acid and/or multivitamin supplementation for the prevention of NTD. The research methodology follows PRISMA guidelines and is robust, ensuring that the included studies meet specific criteria for quality and relevance. The AMSTAR tool is appropriately used for quality assessment. Subgroup analyses by the type of supplement, aim of supplement, and type of included studies are conducted, enhancing the study’s depth. Despite these strengths, the study also has few limitations: as the included studies were not from all countries and this may affect the generalizability of the pooled result. This study result is also with the mild to moderate level of heterogeneity despite the authors tried to reduce it by using a weighted inverse variance random-effects model to pool the results and subgroup analysis. The gap in global policy implementation and challenges regarding preconception folic acid and multivitamin supplementation should be addressed with implementation research as it is beyond the scope of the current study.

This umbrella review of systematic review and meta-analysis found that prenatal folic acid or multivitamin supplementation was associated with a 57% reduction in NTD. Participants who took folic acid supplementation were associated with a slightly higher (77%) percentage of reduction in NTD compared with those who took multivitamins (37%). Reductions of 80% and 50% were observed for reoccurrence and occurrence prevention of NTD. Reductions of 57% and 55% of NTD have been found in SRM of RCTs and observational studies. This comprehensive umbrella review revealed that both folic acid and multivitamin were associated with significantly lower levels of NTD in children. Considering the incorporation of those supplements in NTD prevention strategies during the preconception period is recommended. More large-scale prospective cohort and RCTs are needed to understand the protective effect of multivitamins and/or folic acid on NTD risk addressing the molecular mechanisms and to determine the optimal dose, duration, and timing of maternal multivitamin/and folic acid intake for best child NTD risk reduction. All women in the reproductive age group who have preserved fertility should be advised about the benefits of folic acid in a multivitamin supplementation during medical wellness visits whether or not a pregnancy is contemplated.

This study is an umbrella review of published systematic review and meta-analysis, so it does not require ethical approval. As the study conducted based on the secondary published article, therefore, there are no patient and the public involvement in this study.

The authors have no conflicts of interests.

The authors did not receive any fund for publication.

All authors have been involved in all steps from conceptualization, data extraction, analysis, and manuscript writing. All authors edited the manuscript and approved its submission for publication.

All data generated or analyzed during this study are included in this published article.