Folate Deficiency 

Folate Deficiency – 19 Interesting Facts

1. Folate deficiency is a condition associated with inadequate levels of folate (vitamin B₉) in body tissues ¹
2. Manifests as prenatal, systemic, or cerebral folate deficiency
3. Neural tube defects may be recognized by prenatal ultrasonography; biochemical assays (eg, quad screening) are used as secondary screening tools
4. Systemic folate deficiency manifests as megaloblastic anemia
5. Infantile cerebral folate deficiency presents in young children as irritability and sleep disturbances in early life (younger than 6 months) and progressive neurologic disturbances including seizures, visual disturbances, hearing loss, and impaired mental development in later life (older than 6 months) ²
6. Prenatal folate deficiency can be diagnosed by low maternal RBC folate levels (400 ng/mL [906 nmol/L] or less) ³
7. Standard therapy in developed countries is to prescribe folate supplementation to pregnant patients to prevent neural tube defects without measuring RBC folate level
8. In systemic folate deficiency, serum folate levels lower than 3 ng/mL (7 nmol/L) indicate folate deficiency, but an indeterminate zone exists from 3 to 4.5 ng/mL (7-10 nmol/L); serum folate level must be considered in context of full clinical picture ¹
9. Test infants and children suspected of having cerebral folate deficiency using cerebrospinal fluid 5-methyltetrahydrofolate assay; levels below reference range are diagnostic
10. Folic acid supplementation to treat prenatal and systemic deficiency is indicated for the following:
11. Patients with folate-deficient megaloblastic anemia due to dietary insufficiency, pregnancy, or drugs
12. Patients with malabsorptive states
13. Patients with chronic hemolytic states
14. Patients undergoing renal dialysis
15. Patients who are pregnant (as prophylaxis against neural tube defects and systemic folate deficiency)
16. Patients with cerebral folate deficiency require treatment with leucovorin
17. RBC transfusion is recommended for symptomatic patients with megaloblastic anemia or hemoglobin below 7 to 8 g/dL (8 g/dL if patient has preexisting cardiovascular disease) ⁴
18. Prognosis is good for children with cerebral folate deficiency if they are diagnosed and treated by age 6 months; prognosis is more guarded for those diagnosed later in life ²
19. Prenatal folate deficiency has a good prognosis in the developed world owing to universal folate supplementation for pregnant patients who receive prenatal care

Urgent Action

• Urgent transfusion is required to achieve a hemoglobin level above 8 g/dL for patient with severe anemia, particularly when cardiovascular disease is present and patient is symptomatic (eg, dyspnea, orthostatic hypotension, chest pain) ⁴

Pitfalls

• Risk of neural tube defects is elevated in infants of folate-deficient mothers, even if maternal folate deficiency is subclinical with no megaloblastic anemia ³
• In practice, isolated clinical folate deficiency is extremely rare in the developed world. Consider circumstances (eg, pregnancy, methotrexate therapy) that may lead to shortage or malabsorption of multiple nutrients when diagnosing folate deficiency

Introduction

• Folate deficiency is a condition associated with inadequate levels of folic acid (vitamin B₉) in the blood and body tissues ¹
  • Folate encompasses all biologically active forms of vitamin B₉
  • Folic acid is the synthetic form of vitamin B₉ used in supplements, fortified foods, and treatments
  • Folate is critical to various intracellular processes associated with cell growth ⁵
  • Folate deficiency is the most common megaloblastic anemia in pregnancy ⁶

Classification

• Prenatal folate deficiency ²
  • Subclinical folate deficiency in a pregnant patient
    • Patient has normal CBC results and no symptoms or signs of megaloblastic anemia
    • RBC folate level is 400 ng/mL or less (906 nmol/L), placing embryo or fetus at risk for neural tube defect ³
• Systemic folate deficiency ²
  • Patient has megaloblastic anemia associated with folate deficiency
• Cerebral folate deficiency ²
  • Neurologic syndrome features the following:
    • Low 5-methyltetrahydrofolate (active folate metabolite) concentration in cerebrospinal fluid
    • Folate metabolism and levels are normal outside nervous system
  • Infantile cerebral folate deficiency typically occurs due to a mitochondrial disorder ^2 7

Diagnosis

Clinical Presentation

History

• Prenatal folate deficiency ³
  • Patient is asymptomatic and pregnant
• Systemic folate deficiency presents with any of the following symptoms: ⁸⁹
  • Directly related to folate deficiency
    • Oral ulcers
    • Pain on swallowing
    • Upper abdominal pain
    • Nausea
    • Diarrhea
    • Anorexia
    • Cognitive impairment
    • Depression
    • Dementia
    • Irritability
    • Myelopathy
  • Related to marked megaloblastic anemia
    • Fatigue or lethargy
    • Dyspnea on exertion
    • Palpitations
    • Darkened urine
    • Symptoms of heart failure
      • Peripheral edema
      • Orthopnea
      • Nocturia
    • Syncope
• Infantile cerebral folate deficiency ²⁷
  • Manifesting at age 4 to 6 months ²
    • Irritability
    • Sleep disturbances
  • Manifesting at age 6 months to a few years ²
    • Visual disturbances (age approximately 3 years) ²
    • Progressive sensorineural hearing loss (age approximately 6 years) ²
    • Seizures
    • Impaired mental development

Physical examination

• Prenatal folate deficiency ³
  • No physical signs
• Systemic folate deficiency presents with any of the following signs: ¹⁸
  • Accompanying marked megaloblastic anemia
    • Asthenia
    • Hepatomegaly or splenomegaly
    • Tachypnea
    • Tachycardia
  • Directly related to folate deficiency
    • Hyperpigmentation of skin and mucous membranes
      • Especially dorsal fingers and toes, and palm and sole creases
    • Angular stomatitis
    • Mouth ulcers
• Infantile cerebral folate deficiency ²
  • Manifesting at age 4 to 6 months ²
    • Decelerated head growth
  • Manifesting at age 6 months to a few years ²
    • Psychomotor retardation
    • Cerebellar ataxia
    • Hypotonia
    • Pyramidal signs in lower extremities (eg, hyperreflexia, spasticity)
      • May progress to spastic quadriplegia with age
    • Dyskinesias (eg, choreoathetosis, ballismus) and epileptic seizures occur in one-third of patients ²
      • Seizures are myoclonic-astatic (myoclonic seizure followed immediately by an atonic seizure), absence, or tonic-clonic
• No clearly defined progression from inadequate tissue folate status to onset of megaloblastic anemia ¹
  • Along the ill-defined progression, deficiency can affect any tissue with rapidly proliferating cells (eg, gastrointestinal tract, bone marrow), leading to manifestations of subclinical deficiency in a host of body systems

Causes

• Dietary deficiency
  • Natural folates in food are vulnerable to a variable degree of degradation by cooking processes ¹
  • Folate status is likely to be poorer in people whose diets rely on foods not fortified with folic acid and those who eat low amounts of legumes, green leafy vegetables, citrus fruits, and/or whole grains ¹
• Increased rates of folate deficiency are seen in people with the following conditions: ¹⁰
  • Pregnancy and lactation (often combined with a poor diet)
  • Prematurity
  • Chronic hemolytic anemia
  • Malignancies (eg, leukemia, lymphoma, carcinoma)
  • Inflammatory conditions (eg, severe psoriasis, Crohn disease, exfoliative dermatitis)
  • Myelofibrosis
  • Malabsorption ¹¹
    • Celiac disease
    • Tropical sprue
    • Jejunal resection
  • Increased folate loss
    • Some skin diseases (eg, psoriasis, exfoliative dermatitis) ¹¹
    • Long-term hemodialysis and immediate postdialysis period ¹
  • Complex or uncertain mechanism ¹¹
    • Excessive ethanol use
      • In addition, caloric value of ethanol staves off hunger; people who use ethanol excessively develop deficiency of several micronutrients, including folate
      • Risk of developing folate deficiency is elevated with a daily ethanol intake that exceeds 80 g ¹
    • Anticonvulsant drugs (eg, carbamazepine, valproic acid, phenytoin, primidone, phenobarbital) ¹²
    • Cycloserine
    • Glutethimide
    • Oral contraceptive drugs
  • Acquired disrupted folate utilization
    • Drug interference with dihydropteroate synthetase or dihydrofolate reductase prevents synthesis of tetrahydrofolate; these drugs include: ¹¹
      • Methotrexate
      • Pyrimethamine
      • Triamterene
      • Trimethoprim
  • Inherited abnormalities of folate absorption and metabolism ¹¹
    • Severe MTHFR deficiency (5,10-methylenetetrahydrofolate reductase)
      • Presents early in life with severe developmental delay, seizures, and hypotonia; may present in childhood with gait abnormalities
      • Megaloblastic anemia is absent, but serum, cerebrospinal fluid, and RBC folate levels are low
    • Hereditary folate malabsorption
      • Causes cerebral folate deficiency
    • Glutamate FTCD deficiency (formiminotransferase cyclodeaminase)
      • Manifests with both megaloblastic anemia and neurologic effects, particularly delayed mental development

Risk factors and/or associations

Age

• Geriatric patients are at particular risk, possibly owing to medication use, altered demand, or other factors; these patients experience the highest incidence of folate deficiency ¹³
• Infantile cerebral folate deficiency manifests typically at age 4 to 6 months ²

Sex

• Pregnant patients have elevated risk of folate deficiency owing to elevated fetal folate requirements

Genetics

• Hereditary folate malabsorption ¹⁴
  • Autosomal recessive inheritance with variant in SLC46A1 gene encoding PCFT protein (proton-coupled folate transporter) (OMIM *611672, ¹⁵ #229050 ¹⁶)
• Glutamate FTCD deficiency ¹⁷
  • Autosomal recessive inheritance with variant in FTCD gene (OMIM *606806 ¹⁸)
• Severe MTHFR deficiency
  • Autosomal recessive inheritance with variant in MTHFR gene (OMIM *607093 ¹⁹)

Ethnicity/race

• Elevated rates of folate deficiency and neural tube defects have been reported in Latino populations ²⁰

Other risk factors/associations

• Low socioeconomic status ²
  • Especially associated with multivitamin deficiencies (including folate) during pregnancy, increasing risk of neural tube defects
• Liver disease ¹

Diagnostic Procedures

Primary diagnostic tools

• In patients with mild symptoms, can attempt folate replacement before doing detailed laboratory testing
• Laboratory tests are indicated for those patients whose history and physical examination are suggestive of folate deficiency and those who do not respond to supplementation, including:
  • CBC ⁸
  • Serum folate ^1 11
  • Selected patients
    • RBC folate ^1 11
    • Plasma homocysteine ^1 11
    • Plasma methylmalonic acid (when risk for vitamin B₁₂ deficiency is high) ¹¹
  • In infants or children with suspected cerebral folate deficiency ²¹
    • Cerebrospinal fluid assay for 5-methyltetrahydrofolate (active folate metabolite)
• Chronic hemolysis contributes to increased folate use. Order the following tests for hemolysis markers for patients showing symptoms or signs of megaloblastic anemia, especially those with jaundice and/or scleral icterus: ⁸
  • Serum lactate dehydrogenase
  • Indirect bilirubin
  • Haptoglobin
• In developed nations, isolated clinical folate deficiency is extremely rare ¹
  • Consider circumstances (eg, pregnancy, methotrexate therapy) that may lead to shortage or malabsorption of multiple nutrients when diagnosing folate deficiency

Laboratory

• CBC with peripheral smear ¹
  • Folate deficiency manifests as megaloblastic anemia, indicated by the following:
    • Decreased RBC count and hemoglobin level
    • RBC macrocytosis (mean corpuscular volume more than 100 fL) ⁸
      • Elevated mean corpuscular hemoglobin level
    • Elevated RBC distribution width
    • Hypersegmented neutrophils, defined by either of the following:
      • 5% of neutrophils or more with at least 5 lobes ^1 8
      • 1% of neutrophils or more with at least 6 lobes ⁸
    • Anisopoikilocytosis (RBCs of different shapes and sizes)
    • Ovalocytosis
    • Reticulocytopenia
      • Very important for differentiating megaloblastic anemia from other causes of hemolysis, which tend to be associated with increased reticulocytes
    • RBC inclusions, such as the following:
      • Howell-Jolly bodies
      • Punctate basophilia
      • Cabot ring bodies
• Serum folate assay ¹
  • First line assay to assess folate status
  • Folate level less than 3 ng/mL (7 nmol/L) is indicative of folate deficiency, because risk of megaloblastic anemia increases substantially below this level ¹
    • Significant indeterminate zone exists from 3 to 4.5 ng/mL (7-10 nmol/L) ¹
    • Low serum folate level is suggestive of deficiency; this is not a highly sensitive diagnostic assay
  • Generally, must consider serum folate level in context of full clinical picture
    • False-negative finding (folate level within reference range) can happen if test is done on blood drawn after patient takes oral folate
    • False-positive (folate level outside reference range) can happen in patients with any of the following conditions:
      • Anorexia nervosa
      • Acute ethanol consumption
      • Pregnancy
      • Anticonvulsant therapy
  • Serum folate level usually decreases within several weeks of folate deprivation, but it is not clear how low serum folate level must be to cause biologic and hematologic effects
• RBC folate assay
  • Indicated when there is strong clinical suspicion of folate deficiency (despite a serum folate level within reference range) and when folate deficiency is suspected during pregnancy; not routinely used
  • RBC folate level lower than 150 ng/mL (340 nmol/L) is used as a cutoff value for clinically categorizing patients as folate deficient ¹
  • Maternal RBC folate level of 400 ng/mL (906 nmol/L) or lower places fetus at risk of neural tube defects ³
  • Soon after dialysis, RBC folate generally is the preferred assay. For predialysis assessment, serum folate assay is preferable
• Plasma homocysteine assay ¹
  • Homocysteine levels are elevated in folate deficiency and also may be elevated in vitamin B₁₂ deficiency
  • Not routinely obtained, because it has strict technical and sampling requirements
  • Elevated plasma homocysteine level correlates with serum folate level dropping below approximately 4.5 ng/mL (10 nmol/L) ¹
  • Plasma homocysteine level higher than 15 μmol/L may indicate folate deficiency but must be assessed using local reference ranges ¹
• Plasma methylmalonic acid assay ¹
  • Indicated in patients with risk factors for vitamin B₁₂ deficiency, including:
    • Excessive ethanol use
    • Vegetarian or vegan diet
    • Helicobacter pylori, Giardia lamblia, or fish tapeworm infection
    • Malabsorption conditions, including:
      • Crohn disease
      • Tropical sprue
      • Celiac disease
    • Genetic disorders affecting vitamin B₁₂ metabolism or transport, including:
      • Transcobalamin deficiency
      • Imerslund-Gräesbeck syndrome (selective vitamin B₁₂ malabsorption with proteinuria)
  • Serum methylmalonic acid levels generally are within reference range in patients with folate deficiency; elevated methylmalonic acid levels suggest pathology is actually vitamin B₁₂ deficiency
• Cerebrospinal fluid 5-methyltetrahydrofolate (active folate metabolite) assay
  • Indicated in infants or children who are thought to have cerebral folate deficiency, particularly when serum folate levels are within reference range
  • Lower cerebrospinal fluid level than in controls within reference range confirms diagnosis
• Markers for hemolysis ⁸
  • Use in patients whose history and physical examination suggest possible megaloblastic anemia, either clinical or subclinical, particularly those with jaundice or scleral icterus
  • Serum lactate dehydrogenase level above reference range
  • Indirect bilirubin level above reference range (typically)
  • Haptoglobin level below reference range

Differential Diagnosis

Most common

• Based on finding of megaloblastic anemia
  • Vitamin B₁₂ (cobalamin) deficiency⁸
    • Vitamin deficiency causing disruption of folate recycling and leading to impaired purine synthesis
    • Similarities to folate deficiency
      • Megaloblastic anemia, which usually develops before neurologic manifestations
      • Elevated plasma homocysteine level
    • Contrasts to folate deficiency
      • Presentation often includes 1 or both of the following neurologic manifestations:
        • Subacute combined degeneration
          • Features deficits in dorsal column medial lemniscus tract with sparing of spinal-thalamic tract
          • Causes distal paresthesia and anesthesia and weakness of extremities
        • Peripheral neuropathy
      • Plasma methylmalonic acid level is elevated in vitamin B₁₂ deficiency but is within reference range in folate deficiency
    • Definitive diagnosis is made by assessing serum vitamin B₁₂ (cutoff for reference range is typically 200 pg/mL [148 pmol/L]) and methylmalonic acid levels ⁸
  • Primary bone marrow disorders²²
    • Myelodysplasia, leukemia, multiple myeloma, and other disorders in which blood cells are abnormal owing to genetic disruption of hematopoietic stem cells in bone marrow
    • Like folate deficiency, primary bone marrow disorders can present with megaloblastic-like macrocytosis
    • Unlike folate deficiency, erythroblasts show megaloblastic-like abnormalities that differ from classic features of megaloblastosis (large, oval with immature, lacy nucleus)
    • Definitive diagnosis is achieved by bone marrow biopsy assessed by a hematopathologist

Treatment

Goals

• Prenatal folate deficiency ²
  • Prevent neural tube defects
• Systemic folate deficiency
  • Correct megaloblastic anemia
• Cerebral folate deficiency ²¹
  • Reduce or eliminate neurologic symptoms
  • Prevent cerebral atrophy and continued neurologic deterioration

Disposition

Admission criteria

• Consider admitting symptomatic patients who have megaloblastic anemia and need transfusion if they are not manageable in the emergency department (due to transfusion difficulties or presence of significant comorbidity) ²³

Recommendations for specialist referral

• Refer patients whose megaloblastic anemia does not respond to folate replacement, or in whom diagnosis is questionable, to a hematologist
• Refer all pregnant patients with low serum folate level to an obstetrician/gynecologist if they do not already have one
• Promptly refer infants or children with suspected cerebral folate deficiency to a pediatric neurologist
• Consider nutritional consultation for all patients with nutritional folate deficiency

Treatment Options

Supplemental folic acid is appropriate therapy for most patients ¹

• Bioavailability of dietary folate is approximately 50% lower than that of supplemental folic acid ¹

Leucovorin (formyltetrahydrofolate, 5-formyltetrahydrofolate, folinic acid) ²

• 5-Formyl derivative of tetrahydrofolic acid that is easily reduced to tetrahydrofolate and other reduced folic acid derivatives; allows purine synthesis despite inhibition of dihydrofolate reductase
  • Dosing varies and should be determined by a specialist (eg, oncologist, medical toxicologist)
• Indicated in the following settings:
  • Toxicity induced by dihydrofolate reductase inhibitor (eg, methotrexate)
    • Includes planned toxicity in treatment regimens with methotrexate or 5-fluorouracil to allow doses of the agents that otherwise would not be possible
  • Cerebral folate deficiency
    • Neurologist or other neurology subspecialist provides treatment. Requires close monitoring owing to increased seizure risk

Transfusion with packed RBCs ⁴

• Recommended when patients become symptomatic or hemoglobin level decreases to 7 to 8 g/dL or lower (8 g/dL if patient has preexisting cardiovascular disease) owing to megaloblastic anemia ⁴

Drug therapy

• Folic acid ¹
  • Folate-deficient megaloblastic anemia due to dietary insufficiency, pregnancy, or drugs
    • Folic Acid Oral tablet; Infants: 1 mg PO once daily, initially. Reduce dose to 0.1 mg PO once daily when clinical symptoms have subsided and laboratory parameters have normalized.
    • Folic Acid Oral tablet; Children 1 to 3 years: 1 to 5 mg PO once daily, initially. Reduce dose to 0.1 to 0.3 mg PO once daily when clinical symptoms have subsided and laboratory parameters have normalized.
    • Folic Acid Oral tablet; Children and Adolescents 4 to 17 years: 1 to 5 mg PO once daily, initially. Reduce dose to 0.4 mg PO once daily when clinical symptoms have subsided and laboratory parameters have normalized.
    • Folic Acid Oral tablet; Pregnant or Lactating Persons: 1 mg PO once daily, initially. Reduce dose to 0.8 mg PO once daily when clinical symptoms have subsided and laboratory parameters have normalized.
    • Folic Acid Oral tablet; Adults: 1 to 5 mg PO once daily, initially. Reduce dose to 0.4 mg PO once daily when clinical symptoms have subsided and laboratory parameters have normalized.
  • Chronic hemolytic states and renal dialysis
    • Folic Acid Oral tablet; Adults: 5 mg PO once daily, initially. May increase the dose by 5 mg/day based on plasma homocysteine concentrations. Dose range: 5 mg PO once weekly to 15 mg PO once daily. Max: 15 mg/day.
  • Malabsorptive states
    • Folic Acid Oral tablet; Adults: 5 mg PO once daily. May increase the dose up to 15 mg PO once daily for 4 months.
  • Pregnant patients or persons planning to become pregnant with no personal or family history of any folic acid–sensitive anomalies (for neural tube defect prophylaxis)
    • Folic Acid Oral tablet; Adolescents: 0.4 to 0.8 mg PO once daily starting at least 1 month prior to conception and continuing through the first 2 to 3 months of pregnancy. May continue 0.4 mg PO once daily throughout pregnancy and for 4 to 6 weeks postpartum or as long as breastfeeding continues.
    • Folic Acid Oral tablet; Adults: 0.4 to 0.8 mg PO once daily starting at least 1 month prior to anticipated conception and continuing through the first 2 to 3 months of pregnancy.
  • Pregnant patients with previous pregnancy complicated by a neural tube defect
    • Folic Acid Oral tablet; Adolescents: 0.4 to 5 mg PO once daily starting 3 months prior to conception and continuing throughout pregnancy. May continue 0.4 mg PO once daily for 4 to 6 weeks postpartum or as long as breastfeeding continues.
    • Folic Acid Oral tablet; Adults: 4 mg PO once daily starting 3 months prior to conception and continuing until 12 weeks of gestational age.
    • This high-dose supplementation can be offered to females with medical or surgical conditions causing preconception low serum or RBC folate levels that persist despite 1 to 2 months of daily supplementation with 1 mg of folic acid ²⁴

Nondrug and supportive care

• Supplemental oxygen ²⁵
  • Appropriate for patients with anemia who are hypoxic
• Transfusion with packed RBCs ⁴
  • Recommended when patients experience symptoms (eg, fatigue, lightheadedness when upright or on standing, tachycardia, dyspnea) or when hemoglobin level decreases to 7 to 8 g/dL (8 g/dL if patient has preexisting cardiovascular disease) or lower, owing to megaloblastic anemia

Comorbidities

• Vitamin B₁₂ (cobalamin) deficiency ¹
  • Low serum folate level may be associated with low serum vitamin B₁₂ level
  • When treating such cases, start vitamin B₁₂ therapy before beginning folate therapy
• Thiamine deficiency ²⁶
  • Requires immediate treatment with parenteral thiamine
  • Common in patients who abuse ethanol
  • Recognized based on characteristic signs and symptoms, including:
    • Symmetrical peripheral neuropathy
    • In severe cases, signs associated with Wernicke encephalopathy (eg, ataxia, papilledema, proprioceptive deficits) or Korsakoff syndrome (eg, anterograde amnesia, confabulation)
• Iron deficiency
  • Common in pregnant patients and females of reproductive age ¹⁰
  • Can mask the most obvious feature of megaloblastic anemia, namely macrocytosis ^27 28
  • Anemia caused by iron or folate deficiency can exacerbate one another; early recognition of each deficiency and supplementation of each micronutrient is vital ²⁷

Special populations

• Females of reproductive age
  • Daily folate supplementation is recommended for all females of reproductive age ²⁹
• Pregnant patients ¹
  • Physiological demands for folate increase during pregnancy, and pregnant patients are particularly at risk for folate deficiency
  • Folate deficiency during pregnancy can be associated with adverse maternal anemia or peripheral neuropathy and fetal congenital abnormalities, particularly neural tube defects ²⁴
  • Risk factors for fetal neural tube defects or low-folate status in pregnancy ²⁴
    • Personal or family history of neural tube defects
    • Maternal medical or surgical conditions
      • Medications: antiepileptic or other folate-inhibiting medications
      • Gastrointestinal conditions: malabsorption, inflammatory bowel disease, active celiac disease, gastric bypass surgery, or advanced liver disease
      • Diabetes type 1 or 2
      • Maternal obesity: BMI 30 kg/m² or higher, or prepregnancy weight 80 kg or more
      • Kidney dialysis
    • Sociocultural maternal factors
      • Low socioeconomic status
      • Limited access to health care, and language or knowledge barriers
      • Poor adherence to oral medication (such as multivitamins during previous pregnancy)
      • Smoking
      • Alcohol use disorder
      • Nonprescription drug use
      • Poor or restricted diet
  • Screening for neural tube defect is routinely done in all females during second-trimester anatomical ultrasonography (at 18-22 weeks of gestation) ³⁰³¹
    • First-trimester sonographic neural tube defect screening and diagnostic techniques are recommended for females with moderate- or high-risk factors for neural tube defects, including those who may be folate deficient
    • First- or second-trimester maternal serum α-fetoprotein assay has a limited role
  • Folic acid supplementation is recommended during pregnancy to prevent fetal neural tube defects; all females require a diet of folate-rich foods with additional supplementation individualized according to risk ³²³³
    • Low risk for neural tube defects: females (and male partner) with no personal or family history of any folic acid–sensitive anomalies
    • Moderate risk for neural tube defects: females with a family history of neural tube defect in first- or second-degree relative, personal or family history of other folic acid–sensitive anomalies, diabetes, use of teratogenic medications, or gastrointestinal malabsorption conditions, or with a male partner with either a family history of neural tube defect in first- or second-degree relative or a personal or family history of other folic acid–sensitive anomalies ³⁰
    • High risk for neural tube defects: females with a previous pregnancy affected by a neural tube defect or a neural tube defect themselves or with a male partner with a neural tube defect that affected himself or his children ^24 30

Monitoring

• Patients treated for folate deficiency are reevaluated for evidence of response to therapy ¹
  • Obtain reticulocyte count 7 to 10 days from start of vitamin therapy, because reticulocytosis should be present at that time. If reticulocytosis is not present, reconsider the diagnosis and seek an alternative coexisting cause of anemia (eg, iron deficiency)

Complications

• Neuropsychiatric complications, particularly in geriatric patients ¹³
  • Depression
  • Dementia
• Severe anemia
  • Urgent transfusion is required to achieve a hemoglobin level above 8 g/dL for patient with severe anemia, particularly when cardiovascular disease is present and patient is symptomatic (eg, dyspnea, orthostatic hypotension, chest pain) ⁴
  • Consider transfusion in patients whose megaloblastic anemia presents in a severe stage (ie, hemoglobin level of 7-8 g/dL; 8 g/dL in patients with preexisting cardiovascular disease) ^4 34
• Neural tube defects
  • Risk occurs in infants of folate-deficient mothers ³³
    • Risk is elevated even if maternal folate deficiency is subclinical with no megaloblastic anemia ³
  • Average incidence of neural tube defect is 1 in 1000 births but varies geographically ³⁵
    • More than 1 to 11 in 1000 births in Latin America, Africa, Middle East, Asia, and Far East ³⁵
    • Incidence has been dropping in developed countries as a result of the following:
      • Food fortified with folic acid
      • Periconceptional folic acid supplementation
        • Has decreased neural tube defect prevalence by 50% to 70% ³⁵
  • Spina bifida is the most common neural tube defect (approximately 50% of neural tube defects) ³⁰³⁶
    • Acrania, exencephaly, and anencephaly make up approximately 40% of cases: encephalocele accounts for 8.5% of defects ³⁰
• Other folic acid–related congenital anomalies ³⁰
  • Cardiac, urinary tract, or limb-reduction defects
  • Oral-facial clefting

Prognosis

• For children with cerebral folate deficiency, the younger the age at treatment initiation, the better the outcome ²
  • Earlier diagnosis and treatment (before age 6 months) is associated with significant neurologic recovery and cessation of seizures
  • Later diagnosis shows a delayed response to therapy and incomplete neurologic recovery, especially persistence of mental deficits
• In prenatal folate deficiency, folate supplementation decreases incidence of neural tube defects
  • Data predict incidence of neural tube defects will be reduced by 36% with 400 mcg of daily folic acid and 82% with 4 mg of daily folic acid ²⁹
• In systemic folate deficiency
  • Folate supplementation is effective in reversing deficiency
    • CBC results will show a rise in hemoglobin levels and a fall in mean corpuscular volume within 10 to 14 days of therapy ²²
    • Full hematologic response seen in 8 weeks ²²

Screening and Prevention

Prevention

• Increased intake of folate-fortified foods ²⁰
  • Includes cereals and grains, which have shown success in reducing rates of neural tube defects across multiple populations
  • Folate-fortified corn masa is advocated particularly to address neural tube defects in Latino populations
• Folate supplementation ³²
• Use of folate-fortified oral contraceptives ³⁷
• Avoidance of overcooking vegetables, because folates are vulnerable to degradation by cooking processes ¹
• Recognition and treatment of excessive ethanol use

References

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