Folic Acid: Small Pill, Big Protection for Your Baby

N.Jayasree*; Vijayalakshmi Cholavaram; O.Susmitha; SK.Davood; K.Ruchitha

Department of Pharmacy Practice, Swathi College of Pharmacy, Nellore, Andhra Pradesh.

*Correspondence: nandipallijayasree3814@gmail.com

DOI: https://doi.org/10.71431/IJRPAS.2025.4902  

INTRODUCTION

Folic acid, also referred to as folate or vitamin B9, is a water-soluble micronutrient that plays an essential role in numerous biochemical processes in the human body. It exists in several interconvertible forms, including folate, dihydrofolate, and tetrahydrofolate. Functioning as a coenzyme, it participates in one-carbon transfer reactions, which are fundamental for the synthesis of nucleotides, amino acids, and other key bio-molecules. In addition, folic acid is vital for red blood cell production and optimal neurological function.

During pregnancy, the requirement for folic acid increases substantially due to its critical role in embryonic development, particularly in facilitating proper neural tube formation and closure. These effects are mediated in part through epigenetic mechanisms. Maternal plasma folate concentrations typically decline to nearly half of pre-pregnancy levels over the course of gestation, a reduction largely attributed to physiological haemodilution, renal adaptations, and hormonal changes.

According to Toteja et al. [1], approximately 62.8% of pregnant women in India have serum folic acid levels below 3 ng/mL, reflecting a widespread deficiency. The prevalence is particularly high among vegetarian women, whose diets are often rich in phytates—anti nutritional factors that hinder folic acid absorption. Further evidence from southern India indicates that folic acid deficiency often coexists with vitamin B12 and iron deficiencies, together affecting more than half of women of reproductive age. These concurrent deficiencies represent a significant public health concern, prompting recommendations for combined micronutrient supplementation as an effective preventive strategy [2]. Several studies have investigated the link between folate deficiency and adverse pregnancy outcomes, including spontaneous abortion, recurrent pregnancy loss, and stillbirth. For example, a Swedish study found that low blood folate levels were an independent risk factor for spontaneous abortion, while higher folate concentrations were associated with a non-significant reduction in risk [3,4]. However, the interpretation of these findings is constrained by methodological limitations, including small sample sizes, unmeasured confounding variables, and study populations that may not reflect broader demographic profiles. As a result, the evidence connecting folate deficiency with recurrent miscarriage remains inconclusive.

Research examining the relationship between folic acid supplementation and preeclampsia has produced inconsistent findings. While some investigations have reported a potential protective effect, indicating a reduced risk of preeclampsia and gestational hypertension with supplementation [5,6], others—such as the study conducted by Li et al.—have found no significant association [7].

Observational evidence has also indirectly suggested a possible role of folate status in the timing of labour. Low folate concentrations have been linked to an increased incidence of spontaneous preterm birth, which may result from abnormal inflammatory responses triggered by infection or haemorrhage [8–10]. Folic acid plays a key role in maintaining immune competence, and deficiency can impair both cell-mediated and humoral immune responses [11]. Individuals with inadequate folate levels often exhibit diminished bactericidal capacity and reduced phagocytic activity of polymorphonuclear leukocytes, thereby increasing susceptibility to infections [12]. Furthermore, some studies indicate that folic acid supplementation can enhance immune function and lower concentrations of inflammatory markers, including α1-acid glycoprotein and C Reactive protein.

AIM OF THE REVIEW

 Considering the diverse and, at times, contradictory findings in existing literature, the present review was undertaken to provide a clearer understanding of the role of folate in pregnancy. Emphasis is placed on its relationship with foetal growth restriction (FGR), miscarriage, preeclampsia, placental abruption, and preterm labour. The objective is to synthesise available evidence, identify gaps in current knowledge, and highlight areas where further research is required to guide clinical practice and public health policy.

BENEFITS:

Folic Acid and Neural Tube Defects (NTDs):

Neural tube defects (NTDs), such as spina bifida, anencephaly, and encephalocele, are serious congenital malformations caused by the incomplete closure of the neural tube during early embryonic development [13]. These conditions not only lead to high rates of perinatal mortality globally but also contribute to long-term infant morbidity that can extend into adulthood [14]. Among all birth defects, NTDs are among the most expensive to manage. However, they are unique in that over two-thirds of cases can be prevented through sufficient folic acid intake before conception and during the first trimester of pregnancy. NTDs are common and devastating central nervous system abnormalities, with anencephaly and spina bifida accounting for more than 90% of all cases. Anencephaly is characterized by the absence of major portions of the brain, skull, and scalp, while spina bifida involves the protrusion of the spinal cord and/or meninges through an opening in the spine.These defects typically develop before a woman even realizes she is pregnant and are associated with significant physical, emotional, and financial burdens. Anencephaly usually results in stillbirth or death shortly after birth, whereas spina bifida can lead to lifelong disabilities, such as paralysis, incontinence, learning difficulties, and increased mortality, despite advances in medical treatment [13].

Clinical research has provided strong evidence that folic acid significantly reduces the risk of both first-time and recurrent NTDs. The most compelling support comes from the Medical Research Council (MRC) double-blind randomized trial. In this study, women with a previous NTD-affected pregnancy were assigned to receive either 4 mg of folic acid, a multivitamin without folic acid, a multivitamin with 4 mg folic acid, or a placebo. Supplements were taken before conception and continued through the first trimester. The study showed that women who received folic acid experienced a roughly 72% reduction in the recurrence of NTDs, while no significant reduction was observed in the group receiving vitamins without folic acid, confirming folic acid’s protective effect. Based on this evidence, the World Health Organization (WHO) recommends that women of reproductive age maintain red blood cell (RBC) folate concentrations above 400 ng/mL (906 nmol/L) to achieve the maximum prevention of NTDs [14].

Research on NTDs serves as a valuable model for designing future clinical trials aimed at evaluating the preventive benefits of folic acid in other conditions.

Folic Acid and Oro facial Clefts (OFC):

Oro facial clefts (OFC), which include clefts of the lip and/or palate, are among the most common congenital abnormalities and arise from a combination of genetic and environmental factors. While there is some evidence suggesting a possible preventive role of folic acid in OFCs, several critical questions remain unresolved. These include whether folic acid definitively prevents OFCs, whether it affects initial occurrence, recurrence, or both, whether it helps prevent cleft lip with or without cleft palate (CL/P), isolated cleft palate (CP), or both, and whether low or high doses of folic acid are most effective.

Research so far has shown mixed results, especially concerning whether low or high doses of folic acid reduce the primary risk of OFCs. Most case-control observational studies that suggest a preventive effect appear to involve low to moderate doses (<1 mg) of folic acid, although many did not specify or measure the actual dose used. One observational study did report a reduction in isolated cleft palate (CP) with high dose folic acid supplementation, though it found no significant effect on cleft lip with or without palate (CL/P).

Furthermore, some studies have suggested that insufficient folic acid intake during pregnancy may increase the risk of cleft palate specifically. Oro facial clefts develop when the tissues of the lip and/or roof of the mouth fail to fuse properly during foetal development, typically between the 6th and 9th weeks of gestation. Treatment generally involves multiple stages of reconstructive surgery, starting around 3 months of age and continuing through adolescence. Despite surgical repair, individuals may experience lasting complications affecting speech, hearing, appearance, and psychological health, all of which can significantly impact overall well-being.

Orofacial clefts (OFCs), including cleft lip with or without cleft palate (CL/P) and isolated cleft palate (CP), are among the most frequent congenital anomalies. These defects result from a complex interplay of genetic and environmental factors. OFCs develop when the tissues of the Lip and/or palate fail to fuse properly during early foetal development, typically between the 6th and 9th weeks of gestation.

Even after surgical repair, individuals with OFCs often face long-term complications, such as persistent ear infections, speech difficulties, facial deformities, and dental problems. Cleft lip and/or palate occurs in approximately 1 in 700 live births. Cleft lip, with or without cleft palate, is more common in males, whereas isolated cleft palate is more frequently observed in females. The prevalence of OFCs varies by ethnicity and geographic region.

The causes of OFCs are multifactorial. Genetic studies have shown a higher occurrence of clefts in monozygotic twins compared to d dizygotic twins and in families with a history of congenital anomalies. Environmental risk factors also play a role and include maternal exposure to tobacco smoke, alcohol, certain medications (especially anticonvulsants like diazepam, phenytoin, and phenobarbital), illicit drug use, viral infections, and nutritional loss During embryogenesis, between 14 and 60 days. days post-conception, the face forms through a carefully coordinated process involving gene expression, cell migration, differentiation, and programmed cell death(apoptosis). By day 48, the upper lip is typically fully formed, and by day 60, the fusion of the palatal shelves is complete. Disruptions in any of these tightly regulated events—due to genetic mutations or harmful environmental exposures—can lead to cleft lip and/or palate.

Recent research has explored the role of epigenetics in OFC development. For example, a study by Khan MFJ et al. (2018) suggested that altered DNA methylation patterns might interfere with lip fusion, highlighting the need for further large-scale studies.

OFCs can be classified into isolated (non-syndromic) and non-isolated (syndromic) forms. Isolated forms, which account for the majority of CL/P cases, occur without other structural or developmental abnormalities. In contrast, syndromic cases—linked to over 450 different conditions—may involve chromosomal abnormalities, single-gene disorders, environmental influences, or unidentified syndromes.

Although CL/P and CP are sometimes studied separately due to their different embryological origins and recurrence risks, many studies combine them because they often share genetic and epidemiological risk factors. Recently, researchers have begun to investigate sub phenotypes within clefts to gain deeper insights into their causes. OFCs pose a significant burden on individuals and families, affecting not only health but also emotional, social, and economic well-being. They are among the most prevalent birth defects, often requiring long-term multidisciplinary care.

There is some suggestive evidence that folic acid supplementation may reduce the risk of both occurrence and recurrence of Orofacial clefts. However, more research is needed to determine optimal dosing, timing, and specific sub-types affected.

Evidence suggests that folic acid supplementation, particularly at higher doses, may help prevent the recurrence of orofacial clefts (OFCs) when taken before conception and throughout pregnancy. While 0.4 mg of folic acid is well-established for preventing the first occurrence of neural tube defects (NTDs), a higher dose of 4 mg has proven effective in preventing recurrence. Given the substantial physical, emotional, and financial impact of clefts on individuals and families—and considering the low cost and safety of folic acid—there is a compelling case for conducting randomized clinical trials comparing the effectiveness of high versus low doses of folic acid in preventing cleft recurrence.

Cleft lip and/or palate has a multifactorial origin, involving both genetic predispositions and environmental exposures. This complex aetiology provides a valuable opportunity to explore gene-environment interactions and develop effective preventive strategies. The potential role of vitamin supplementation in reducing the risk of cleft lip and palate has been hypothesized for over four decades. Studies reviewed by Czeizel and Munger have supported the idea that folic acid and other vitamins—such as vitamin A and B6—may influence cleft formation. These findings underscore the need for continued research into the effects of vitamins and environmental factors in cleft prevention and highlight the potential of nutritional interventions to reduce risk.

Notably, results from Hungarian trials have indicated that low doses of folic acid may not be sufficient to prevent the occurrence of oral clefts, whereas high doses show greater promise for preventing recurrence. This mirrors the NTD prevention model, where low doses reduce first-time occurrence and high doses reduce recurrence. Such findings suggest that higher folic acid doses may be necessary to effectively prevent both initial and repeat instances of oral clefts.

Furthermore, exposure to folic acid antagonists—such as certain anti-epileptic drugs and dihydrofolate reductase inhibitors—has been associated with a twofold increase in the risk of oral clefts. Animal studies also support folic acid's protective, anti-teratogenic effects. For instance, Peer et al. demonstrated that folic acid injections reduced cortisone-induced cleft palates in mice by 69%, with an even greater reduction (82%) observed when combined with vitamin B6. Similarly, folic acid supplementation reduced the incidence of cleft palate caused by retinoic acid in mice by up to 92%, and co-supplementation with methionine enhanced this protective effect. Folic acid was also found to reduce procarbazine-induced clefts in rats, with potential effects based on dose and gender. Despite these promising findings, only a limited number of interventional studies have been conducted in the past 50 years to evaluate the effect of folic acid on the recurrence of OFCs in women who previously had a child affected by the condition. This highlights the urgent need for well-designed, large-scale clinical trials to fully assess the preventive potential of high-dose folic acid supplementation in this context.

Across various studies investigating folic acid supplementation and the recurrence of orofacial clefts (OFC), reported reductions regardless of statistical significance have ranged from approximately 24% to 100%. In one early study by Conway (1958), none of the 59 births to women with a prior history of OFC experienced a recurrence after receiving a multivitamin containing 0.5mg of folic acid. In contrast, a recurrence rate of 5.1% was observed among 78 births to mothers who did not receive supplementation.

Peer et al. (1964) found a 53% reduction in OFC recurrence among 176 women who took a multivitamin plus 5 mg of folic acid and 10 mg of vitamin B6 during the first trimester of pregnancy, compared to a control group of 418 mothers.

Building on this work, Briggs (1976) extended Peer’s study and observed a 35% overall reduction in OFC recurrence. Notably, there was a more substantial 65% reduction in the recurrence of cleft lip with or without palate (CL/P).In another influential study, Tolarova (1982) reported an 84% reduction in CL/P recurrence among 80 women who received a multivitamin and 10 mg of folic acid beginning three months before conception and continuing through three months post conception. This was compared to a control group of 202 women (p = 0.02).

 Later, Tolarova and Harris (1995) used a larger sample—including women affected by or at risk of CL/P—and the same intervention as the 1982 study. They found a 66% reduction in CL/P recurrence.

 A synthesis by Johnson and Little (2008) estimated an overall 67% reduction in CL/P recurrence based on the collective findings of these studies. While these estimates are primarily descriptive—due to variations in study design, sample size, and intervention protocols—they are valuable for informing hypotheses and expected treatment outcomes in future clinical trials.

Overall, these studies suggest a promising preventive effect of high-dose folic acid on the recurrence of orofacial clefts.

Folic Acid and Ischemic Heart Diseases:

Elevated levels of plasma homocysteine (tHcy) have been linked to various chronic vascular conditions, including peripheral vascular disease, cerebrovascular disease, coronary artery disease, and even cognitive decline. More recently, elevated homocysteine has also been associated with vascular complications during pregnancy, such as pre-eclampsia. Several intervention studies have demonstrated that folic acid supplementation can effectively lower plasma homocysteine levels. In light of this, large-scale randomized clinical trials are currently underway to assess whether reducing homocysteine through folic acid supplementation can lead to a decrease in cardiovascular events. These trials primarily involve individuals who already have pre-existing cardiovascular disease. The minimum effective dose of folic acid needed to lower homocysteine levels is also being evaluated as part of these ongoing studies.

Folic Acid and Homocysteine Reduction in Ischemic Heart Disease:

Determining the minimum effective dose of folic acid for lowering homocysteine levels remains a debated but critical issue, particularly in shaping food fortification policies, as concerns grow about the potential negative effects of excessive folic acid intake. Earlier studies have evaluated how varying doses of folic acid influence homocysteine levels, but findings have been inconsistent. One such study involving patients with ischemic heart disease (IHD) examined daily folic acid doses ranging from 0.2 mg to 1 mg and observed a dose-dependent reduction in homocysteine, with the greatest effect—a 23% decrease—seen at 0.8 mg/day. However, this study did not consider baseline homocysteine levels prior to treatment, which may have affected the outcomes.

In a 2011 study by Tighe et al., the efficacy of 0.2 mg, 0.4 mg, and 0.8 mg/day of folic acid was compared over six months. The results showed that even the lowest dose of 0.2 mg/day significantly reduced homocysteine levels when taken consistently over time. Increasing the dose beyond this threshold did not provide any additional significant benefit, suggesting that lower doses could be sufficient. Furthermore, it is possible that doses even below 0.2 mg/day might be effective if taken over a longer duration.

Another study that categorized participants based on their baseline homocysteine levels estimated that 0.4 mg/day was enough to achieve 90% of the maximum homocysteine-lowering effect. These findings, along with data from 23 other studies, were included in a meta-analysis that adjusted for pretreatment homocysteine concentrations.

In conclusion, evidence indicates that daily folic acid doses as low as 0.2 mg can effectively reduce homocysteine levels when administered for six months. Higher doses may not offer additional benefits and could even pose long-term risks, reinforcing growing concerns about excessive folic acid exposure. Earlier trials may have overestimated the necessary dosage due to shorter intervention periods that did not allow for full response to lower doses.

Unmetabolized Folic Acid (UMFA):

Folic acid is a synthetic form of folate that, once consumed, is normally converted in the body by the enzyme dihydrofolate reductase into dihydrofolate and then into tetrahydrofolate—forms identical to those produced from natural dietary folate. However, when folic acid is taken in large oral doses, this conversion process can become saturated. As a result, unmetabolized folic acid can accumulate in the bloodstream.

This build-up of unmetabolized folic acid (UMFA) occurs only with synthetic folic acid intake and is not seen after consuming naturally occurring folate from food sources. The metabolism, function, and long-term biological effects of UMFA remain poorly understood. Some researchers have proposed potential health concerns related to UMFA, but conclusive evidence is still lacking.

There is growing concern that the presence of unmetabolized folic acid (UMFA) in the bloodstream may contribute to the potential risks associated with high folic acid intake. Research indicates that the enzymatic processes responsible for converting folic acid into its active forms-specifically reduction and methylation-are dose dependent. When oral intake of folic acid exceeds a certain threshold, these metabolic pathways become saturated, resulting in the accumulation of UMFA in the serum alongside the usual metabolite, 5-methyltetrahydrofolate.

Studies have demonstrated that UMFA can appear in the bloodstream at oral doses as low as 200–266 µg. More recent findings suggest that even regular consumption of typical, physiological amounts of folic acid can lead to the gradual build-up of UMFA in the blood. Furthermore, research has shown that passive intake of folic acid from fortified foods by pregnant women can result in the presence of UMFA in foetal cord blood. However, while these studies have assessed short-term responses, the long-term impact of continuous folic acid exposure on UMFA levels remains unexplored. One well-documented safety issue is folic acid’s ability to mask the early hematologic signs of pernicious anaemia, both in experimental and clinical settings.

Masking of Vitamin B12 Deficiency Anaemia:

Historically, a major concern regarding folic acid supplementation has been its potential to mask anaemia caused by vitamin B12 deficiency. Case reports from the 1940s to 1960s suggested that consuming ≥5000 µg of folic acid per day could prevent the development of anaemia, a key early symptom of B12 deficiency. This masking effect could delay diagnosis, allowing neurological complications related to untreated B12 deficiency to progress unnoticed. It is now well recognized that diagnosing vitamin B12 deficiency should not rely solely on haematological indicators, as they may be unreliable. Instead, diagnosis and treatment response should be based on a range of biomarkers reflecting vitamin B12 status. In 1998, the Institute of Medicine (IOM) concluded that there was no definitive evidence that folic acid causes neurotoxicity in humans. Several studies, both before and after the introduction of folic acid fortification, have also found little evidence that recommended intake levels lead to masking or worsening of B12-related neurological damage.

Nonetheless, the 2007 guidelines from the Mother risk program and the Society of Obstetricians and Gynaecologists of Canada recommend a daily folic acid intake of 5mg for women with certain medical or social risk factors—such as minority status, epilepsy, obesity,  substance use, poor adherence to medications, or lack of contraception. This recommended dose significantly exceeds the commonly accepted tolerable upper intake level (TUL) of 1.0 mg per day. The 5 mg/day recommendation stands out because it is far above the standard levels advised in most other countries. The TUL was established primarily due to concerns that excessive folic acid could obscure the diagnosis of pernicious anaemia, potentially allowing irreversible neurological damage from untreated vitamin B12 deficiency to occur.

The amount of folic acid required to correct anaemia related to vitamin B12 deficiency has been estimated at approximately 5.0 mg per day. Based on this, the Institute of Medicine (IOM) established the tolerable upper intake level (TUL) for folic acid at a conservative 1 mg per day—one-fifth of the dose needed to mask B12 deficiency—acknowledging this limit was somewhat arbitrary.

Today, vitamin B12 levels can be routinely and easily tested in individuals with unexplained neurological symptoms. Furthermore, studies conducted after the introduction of folic acid fortification have shown no significant impact on population B12 levels. Importantly, fortification has not led to an increase in cases of vitamin B12 deficiency occurring without accompanying anemia.These findings are significant for two main reasons. First, the concern about masking B12 deficiency is often cited as a major safety issue in debates over widespread folic acid supplementation. In fact, this concern was a primary reason the United Kingdom chose not to proceed with mandatory folic acid fortification in 2002. Similar hesitations have been seen in countries like Australia and Switzerland, where the issue remains under debate.

Second, the TUL was a critical factor in shaping folic acid fortification policy in the United States. The level of fortification was carefully set so that most individuals would receive an additional 0.1 mg (100 µg) of folic acid daily, while ensuring that nearly no one would exceed the 1.0 mg/day threshold.

Folic Acid and Cancer:

Folate appears to have a dual role in cancer—it can either prevent or promote cancer development, depending on the timing of intake. In North America, intrauterine exposure to folic acid has significantly increased due to mandatory food fortification and widespread supplement use, raising concerns about a potential link to increased breast cancer risk in offspring.

Emerging evidence suggests that one unintended consequence of folic acid fortification may be a heightened risk of colorectal cancer in some populations. This risk is likely influenced by the complex nature of folate-dependent one-carbon metabolism, as well as individual genetic variability in the enzymes involved in folate pathways.

Folic acid may support the early stages of certain malignant processes. For example, following the introduction of mandatory folic acid fortification, hospitalization rates for colon cancer in individuals aged 45 and older more than doubled. Similarly, findings from the Norwegian Vitamin Trial and the Western

Norway B Vitamin Intervention Trial revealed that supplementation with 800 mcg/day of folic acid, vitamin B12, and vitamin B6 for over three years was associated with a 21% increase in lung cancer risk.

Further analysis of these studies, which were originally intended to assess whether high-dose folic acid and vitamin B12 could reduce cardiovascular mortality by lowering plasma homocysteine levels, highlighted potential cancer-related risks associated with high doses of synthetic folic acid.

Supplementation with high doses of folic acid has unexpectedly been associated with increased risks of cancer and overall mortality. It's important to note, however, that the doses used in the two major Norwegian trials were twice as high as the internationally recommended intake for pregnancy. Despite these findings, there is a lack of comprehensive, systematic studies examining the long-term safety of high dose folic acid use. The absence of evidence should not be mistaken for evidence of safety.

Currently, no single agency holds the responsibility for overseeing the long-term safety of folic acid fortification programs. The lack of coordinated safety monitoring creates uncertainty regarding which health outcomes are the most sensitive indicators of risk. This issue has become increasingly urgent for researchers, policymakers, and industry stakeholders—especially in countries like the United States, where folic acid fortification has been mandatory for years and public health messaging has consistently promoted its benefits.

Several studies have raised concerns that folate might have pro-carcinogenic properties. Folate plays a unique role in the body by contributing to the synthesis of purines and thymidine, which are essential for DNA replication. Because of this, antifolate drugs such as methotrexate are used in cancer treatment to inhibit cell growth. A meta-analysis of six large-scale, prospective folic acid supplementation trials—selected from over 1,100 studies—found that cancer incidence was higher among participants receiving folic acid than those who did not. The relative risk was 1.21 (95% CI: 1.05–1.39). These findings suggest that any future folic acid supplementation trials should include robust systems to monitor cancer incidence and other potential side effects.

CAUSES OF FOLATE DEFICIENCY, RISK FACTORS & PREVENTION

CAUSES:

Folate is a water-soluble vitamin, meaning it dissolves in water and is not stored infat cells. As a result, the body cannot store large amounts of it, and any excess is excreted in urine. This makes it essential to consume folate regularly through your diet. Several factors can lead to folate deficiency [15].

1. Poor Diet:

The most common cause is a diet lacking in fresh fruits, vegetables, and fortified cereals. Additionally, overcooking food can destroy folate. Without a sufficient intake of folate-rich foods, levels can drop within a few weeks.

2. Medical Conditions:

·         Certain health conditions can impair folate absorption in the digestive tract, including: Crohn’s disease

·         Celiac disease.

·         Some forms of cancer

·         Advanced kidney disease requiring dialysis

3. Genetic Factors:

Some individuals have a genetic mutation that affects the conversion of folate into its active form, methyl folate. This impairs the body’s ability to use folate efficiently, even if dietary intake is adequate.

RISK FACTORS:

·         Excessive alcohol consumption

·         Pregnancy

·         Being of reproductive age

·         Regular intake of overcooked foods

·         Diets lacking in essential vitamins

·         Underlying medical conditions like sickle cell disease

·         Low socioeconomic status, Older adults, particularly those in long-term care

              facilities

·         Genetic variations in the MTHFR gene

·         Conditions that impair nutrient absorption, such as celiac disease or inflammatory bowel disease, Use of certain medications that interfere with folate metabolism.

PREVENTION:

To prevent folate deficiency, it’s important to maintain a balanced and nutritious diet. Foods rich in folate include:

·         Leafy green vegetables like spinach and broccoli

·         Brussels sprouts

·         Peas

·         Citrus fruits

·         Tomato juice

·         Eggs

·         Beans and legumes

·         Mushrooms

·         Asparagus

·         Organ meats like kidney and liver

·         Poultry and pork

·         Shellfish

·         Wheat bran

·         Fortified breakfast cereals

The recommended daily intake of folate is 400 micrograms. Individuals who may become pregnant are advised to take a folate supplement, as it is essential for healthy foetal development. People with certain MTHFR gene variants should avoid foods fortified with folic acid, as these genetic differences can impair the conversion of folic acid into its active form, methyl folate [16-17].

LIMITATIONS:

1. Masking of Vitamin B12 Deficiency:

Folic acid can conceal the symptoms of vitamin B12 deficiency, which is particularly concerning for pregnant women and those of childbearing age. If left undiagnosed, vitamin B12 deficiency may lead to irreversible neurological damage, and excessive folic acid can delay its detection.

2. Possible Increased Risk of Autism:

Some studies have suggested a potential association between elevated folic acid levels during pregnancy and a heightened risk of autism spectrum disorder (ASD) in children. One study reported that mothers with folate levels exceeding four times the recommended amount had twice the risk of having a child with ASD.

3. Possible Effects on Brain Development.

DISCUSSION AND CONCLUSION:

Findings from the current study imply that insufficient folic acid levels...These findings emphasize the importance of adhering to nutritional guidelines for folic acid supplementation during pregnancy to help prevent such complications. Folic acid supplementation before conception and during the first trimester of pregnancy is essential for preventing neural tube defects (NTDs), such as spina bifida and anencephaly, in the developing foetus. Beginning supplementation early is a vital measure to reduce the risk of these serious birth abnormalities. The literature demonstrates that folic acid is indispensable for normal embryonic a placental development, with clear benefits for preventing neural tube defects. However, evidence linking folate status to broader obstetric outcomes, such as preeclampsia, miscarriage, preterm birth, and immune-related pregnancy complications, remains inconsistent. Variability in study designs, population characteristics, and assessment methods contributes to conflicting results. This underscores the need for large-scale, well-controlled studies to clarify causal relationships and inform optimal supplementation strategies during pregnancy.

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