Congenital anomalies are a significant burden on global health, causing substantial morbidity and mortality in early life (1, 2). They are described as abnormalities of either structure or function that develop during intrauterine life and can be detected during pregnancy, at birth, or occasionally later in infancy. Congenital anomalies may appear as malformations, deformations, disruptions, sequences, dysplasias, or variants, each with distinct characteristics and root causes (3). Although the exact etiology of around half of congenital anomalies is unknown, known causes include chromosomal abnormalities, single gene errors, multifactorial inheritance, environmental teratogens, and micronutrient shortages (4). Even though the under-5 death rate is declining, congenital defects continue to be a major cause of neonatal and under-5 deaths (4). Congenital abnormalities have a substantial impact on mortality in Europe; they are responsible for up to 49% of deaths in children aged 1%–9% and 71% of deaths in neonates (5). Furthermore, Congenital abnormalities are a major burden in low-income nations; they account for 2.8% of neonatal admissions and 8.6 per 1,000 births, with a 33.2% neonatal death rate (6).

Congenital anomalies cause long-lasting disability and health problems. These conditions can lead to extended hospital stays, recurrent infections, neurological and psychological issues, and the need for significant surgical intervention. As other causes of death among children under five declines, the burden of congenital anomalies is increasing. This underscores the importance of improved prenatal care, screening, and nutrition for pregnant women (4, 7).

The US Public Health Service advised daily folic acid supplementation with 0.4 mg for all women who potentially become pregnant when persistent evidence of the protective benefit of folic acid supplementation against NTDs appeared (8). International recommendations advise women to take 0.4 mg of folic acid supplements from the time they are trying to conceive (at least 4 weeks) until 12 weeks into their pregnancy (4). Many women still do not take the recommended folic acid supplements during pregnancy, especially those from lower socioeconomic backgrounds, despite legislation in various nations regarding this matter (9, 10).

The need for micronutrients increases substantially during pregnancy, but they become particularly crucial in the first trimester when organogenesis is most active (11). The growth and development of the fetus are impacted by the nutritional status both before and after conception, and deficits raise the chance of birth abnormalities (12). Along with iron (13), iodine (14), and vitamin D (15), folate deficiency is one of the most prevalent micronutrient deficits among women in reproductive age (11).

Both experimental and observational studies have shown the efficacy of folic acid supplementation throughout periconception and pregnancy in lowering the risk of neural-tube abnormalities in offsprings (16–18). Besides, numerous studies have investigated the potential links between folic acid and multivitamins and other birth defects, including urinary tract defects, congenital heart defects, limb reduction defects, and other structural developmental anomalies (19–21). However, based on our current understanding, the overall impact of folic acid intake on congenital anomalies has not been thoroughly explored in prior research. Hence, the aim of this systematic review and meta-analysis is to assess the pooled influence of folic acid consumption on congenital abnormalities.

By integrating investigations conducted between 2011 and March 2023, this comprehensive meta-analysis, to the best of our understanding, represents an exhaustive scholarly endeavor that delineated the cumulative impact of maternal supplementation of folic acid on the occurrence of congenital anomalies. It was determined that folic acid supplementation substantially diminished the prevalence of congenital anomalies in the offspring, as evidenced by the overall and majority of the subgroup analysis findings of the present systematic review and meta-analysis (OR, 0.23; CI, 0.16–0.32). The outcomes of this systematic review and meta-analysis revealed that the vulnerability to various forms of birth defects might be reduced by 77% through the administration of folic acid supplements immediately prior to and during the initial trimester of pregnancy.

Vitamin B9, or folic acid, is a water-soluble vitamin that is essential to the body. It is crucial during times of fast growth, such as infancy, adolescence, and pregnancy, as it plays a role in the synthesis of DNA and RNA, the body's genetic material (46). Folate deficiency plays in atherosclerotic cardiovascular disease, neurological and neuropsychiatric disorders, congenital defects, and carcinogenesis. Folate has been identified as having great potential to prevent a wide range of disorders through folate supplementation (47).

Through a number of different processes, folate deprivation during pregnancy can raise the chance of congenital abnormalities. First and foremost, folate is essential for the synthesis and repair of DNA, as well as for healthy cell division and tissue development throughout the embryonic stage (48). A folate deficit can cause disruptions in DNA synthesis and repair systems, which can increase susceptibility to genetic mutations and cause genomic instability. This can have an impact on the development of different organs and tissues. Furthermore, through its effects on histone modifications, microRNA expression, and DNA methylation patterns, folate plays a critical role in epigenetic control (49). Gene expression patterns related to organogenesis, tissue differentiation, and embryonic development can be dysregulated by a folate deficit. The development of congenital anomalies like heart problems, limb abnormalities, and facial dysmorphisms can be facilitated by these changes in gene expression profiles, which can interfere with normal developmental processes (50, 51).

Moreover, oxidative stress and inflammation brought on by a folate shortage are linked to the pathophysiology of congenital abnormalities (47). Because folate plays a crucial role in the metabolism of homocysteine, a lack of it can raise homocysteine levels, which can cause oxidative damage to tissues and cells. Through apoptosis induction, tissue morphogenesis impairment, and interference with cellular signaling pathways, oxidative stress and inflammation can cause developmental disruptions in embryos. Furthermore, a lack of folate has a negative effect on neurodevelopment, which is necessary for healthy neuronal migration, proliferation, and differentiation. A lack of folate can cause abnormalities in the development of the brain, which can lead to congenital malformations such hydrocephalus, microcephaly, and intellectual impairments (46). These complex pathways demonstrate the extensive effects of folate deprivation on the development of the embryo and the elevated risk of congenital defects.

As previously discussed, there is a higher chance of birth abnormalities in children born to pregnant mothers who do not get enough folic acid. Doses of folic acid supplements for pregnant mothers usually vary based on personal health status, food consumption, and particular physician advice. Nonetheless, the standard recommendation for all pregnant mothers is to take a 400–800 microgram (mcg) prenatal vitamin every day, ideally beginning at least one month before to conception and continuing through the first trimester of pregnancy (52). Besides, Centers for Disease Control and Prevention (CDC) advises all women of reproductive age to take 400 mcg of folic acid daily from dietary supplements or fortified meals. The CDC recommends that pregnant women take 600 micrograms of folic acid each day in the form of supplements in addition to eating foods high in folate.

This systematic review and meta-analysis possess inherent limitations, akin to any other study. Consequently, it is imperative to consider these limitations when analyzing the data. The initial constraint of this review was its restriction to English articles or reports, which means that findings from publications in different languages could potentially influence our own findings.

Moreover, the expected report may be impacted by the diversity in study designs, sample sizes, study locations, and publication years. Thus, the interpretation of these study findings should take into account this variability.

Furthermore, the assessment encompassed investigations from a limited number of nations due to the scarcity of available data on the correlation between congenital malformations and congenital anomalies. The study's strength was the greatest effort made to locate papers from various databases and grey literatures, as well as the thorough analysis carried out to compute pooled estimates.

Inconclusion, according to the current systematic review and meta-analysis, there is a significant correlation between maternal folic acid supplementation and the risk of congenital anomalies. The risk is lowered by 77% for those who take folic acid. Furthermore, research indicates that a substantial proportion of reproductive-age women, especially those in underdeveloped nations, may not use or consume foods enriched with folic acid. Therefore, we advise the implementation of a large-scale cohort study to examine the impact of maternal periconceptional folic acid supplementation on the incidence of different forms of congenital anomalies in mothers residing in low-income communities or nations.