List of Abbreviations
INR – international normalized ratio
CT – computed tomography
MCV – mean corpuscular volume
MCH – mean corpuscular hemoglobin
MCHC – mean corpuscular hemoglobin concentration
MTHFR – methylenetetrahydrofolate reductase
FDA – folate-deficiency anemia
US – ultrasound examination
EGD – esophagogastroduodenoscopy
ECG – electrocardiography
Terms and Definitions
Folate-deficiency anemia is a macrocytic anemia caused by folate deficiency in the body.
Folates are derivatives of folic acid.
Tetrahydrofolic acid is the active coenzyme form of folates.
Reticulocyte crisis – an increase in reticulocyte count by more than 20–25% from baseline.
1. Brief information on the disease or condition
1.1 Definition of the disease or condition
Folate-deficiency anemia (FDA) is an anemia developing as a result of folic acid deficiency. The main characteristics of FDA are megaloblastic erythropoiesis in the bone marrow and macrocytic hyperchromic anemia, often accompanied by thrombocytopenia and neutropenia.
1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)
The body's folate content ranges from 7 to 22 mg. Unlike vitamin B12 deficiency, the depletion of folate stores occurs rapidly, within a few weeks or months after the onset of the causative factor. Folates are found in many plant (tomatoes, avocados, onions, mushrooms) and animal (liver, meat) products. However, unlike vitamin B12, folates are rapidly destroyed during heat treatment. With a sufficient amount of fresh vegetables and fruits in the diet, 400–600 mcg of folates are ingested daily with food, but the requirement increases significantly during pregnancy, rapid child growth, heavy physical exertion, and sharp activation of erythropoiesis. Folic acid is absorbed in the jejunum in combination with a glutamic acid molecule. Once inside the body, folic acid is converted into its active metabolite, tetrahydrofolic acid. Tetrahydrofolic acid is the active coenzyme form of folates. Folates participate in the synthesis of purines and pyrimidines, thymidine monophosphate from uridine, and the formation of methionine from homocysteine (methylation process). Folic acid deficiency leads to impaired cell division and the accumulation of toxic metabolites such as homocysteine [1–4].
Main causes of folic acid deficiency:
dietary deficiency (a common cause in elderly individuals; insufficient intake of raw vegetables; in newborns – feeding with goat's milk);
intestinal malabsorption (jejunal resection, celiac disease, chronic enteritis, amyloidosis, scleroderma, lymphatic and other tumors of the jejunum, chronic alcoholism);
use of medications – folic acid antagonists, antiepileptic drugs, barbiturates and their derivatives, antineoplastic agents, medications for diabetes mellitus;
increased demand for folates (pregnancy, hereditary hemolytic anemias, prematurity, low birth weight);
increased intestinal consumption of folates (helminthic infestation, blind loop syndrome);
increased excretion (hemodialysis).
Factors provoking the development of folate deficiency are frequently combined [5, 6].
1.3 Epidemiology of the Disease or Condition
Data on the prevalence of folic acid deficiency and FDA in Russia are lacking. An association has been established with low socioeconomic status, alcohol abuse, and the prevalence of hereditary hemolytic anemias. The worldwide prevalence of folate deficiency has decreased significantly as a result of mandatory food fortification with folic acid in many countries [6].
1.4 Features of Coding the Disease or Condition
D52 Folate-deficiency anemia
D52.0 Dietary folate-deficiency anemia
D52.1 Drug-induced folate-deficiency anemia
D52.8 Other folate-deficiency anemias
D52.9 Folate-deficiency anemia, unspecified
1.5 Classification of the disease or condition
There is no classification, as folate deficiency is generally secondary in nature. Hereditary disorders of folic acid absorption are extremely rare, and their molecular mechanism has not been studied [7–9].
1.6 Clinical presentation of the disease or condition
The clinical presentation consists of symptoms typical of all anemia syndromes: weakness, dizziness, shortness of breath, palpitations upon exertion, increased fatigue, poor appetite, lethargy, or increased irritability. In addition, angular stomatitis, glossitis, and dyspeptic disorders (nausea, vomiting, abdominal pain, diarrhea) may be observed. Mild scleral and skin icterus is possible, caused by ineffective erythropoiesis in the bone marrow and, consequently, increased destruction of hemoglobin-containing cells, leading to elevated blood levels of indirect bilirubin. In severe forms of FDA, mild splenomegaly (reactive hyperplasia) may be observed. Thus, there is some similarity in the symptoms of folate-deficiency anemia and hemolytic anemia.
The manifestations of FDA resemble the symptoms of vitamin B12 deficiency anemia, but are usually less pronounced. Unlike vitamin B12 deficiency, neurological damage is not characteristic of FDA (except for patients with alcoholism and epilepsy who have neurological symptoms due to another cause) [1–3, 10].
The clinical course of FDA depends on the underlying cause, the success of treatment of the "primary" disease, and is rarely severe unless combined with other severe "deficiency" or hemolytic anemias [11, 12].
2. Diagnostics, medical indications and contraindications for diagnostic methods
The diagnosis of FDA is based on the characteristic clinical and hematological presentation of the disease and laboratory evidence of folic acid deficiency: macrocytic, hyperchromic anemia with an increased mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH), combined with a picture of megaloblastic hematopoiesis in the bone marrow and low serum folate levels [1–3,10].
Differential diagnosis of FDA is performed with other diseases presenting with a hemolytic component and pancytopenia [11, 13]:
Vitamin B12 deficiency anemia;
various forms of hemolytic anemias;
myelodysplastic syndromes (refractory anemias, including refractory sideroblastic anemia, refractory anemia with excess blasts);
acute erythromyelosis;
macrocytosis associated with cytostatic therapy (cytarabine**, hydroxycarbamide**, methotrexate**);
liver diseases with hypersplenism;
primary amyloidosis;
hypothyroidism.
2.1 Complaints and Anamnesis
A thorough history taking can be a crucial link for targeted diagnostic investigation, since FDA is generally secondary in nature (see the "Clinical Presentation" section).
2.2 Physical Examination
Clinical manifestations of the anemia syndrome are nonspecific, and characteristic signs of folate deficiency do not allow for differential diagnosis with vitamin B12 deficiency anemia. Accordingly, laboratory tests are of decisive importance in the diagnosis of FDA (see the "Clinical Presentation" section).
2.3 Laboratory Diagnostics
It is recommended that all patients with macrocytic anemia undergo the following laboratory tests for the diagnosis of FDA [1, 3, 11, 12, 14–16].
complete blood count (CBC), hematocrit evaluation, red blood cell count, reticulocyte count, determination of mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration, determination of red blood cell size;
determination of vitamin B12 (cyanocobalamin) level in the blood, assessment of serum folic acid level;
investigation of serum iron metabolism parameters: serum ferritin level, serum transferrin level, total iron-binding capacity (TIBC), serum iron level, and transferrin saturation (TSAT) to exclude concomitant iron deficiency;
general clinical biochemical blood test (assessment of total protein in the blood, blood albumin level, total bilirubin level, free and conjugated bilirubin levels, aspartate aminotransferase activity in the blood, alanine aminotransferase activity in the blood, blood creatinine level, blood urea level, alkaline phosphatase activity in the blood, gamma-glutamyltransferase activity in the blood);
determination of blood homocysteine level;
direct antiglobulin test (direct Coombs test) to rule out autoimmune hemolytic anemia.
GCR CLEL 5Grade of Recommendation C (Level of Evidence – 5)
Comments: the results of the listed baseline tests can guide further diagnostic workup. Patients with malabsorption syndrome may present with combined folate and iron deficiency. In such cases, the typical laboratory picture of folate-deficiency anemia may be masked, preventing timely diagnosis and delaying pathogenetic therapy.
FA is characterized by macrocytic, hyperchromic anemia with an increased mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and a negative direct Coombs test. Typical morphological findings on a blood smear include basophilic stippling, Howell-Jolly bodies, Cabot rings, and occasional normoblasts. The reticulocyte count is usually decreased, but may be normal. Hypersegmentation of neutrophil nuclei, granulocytopenia, and thrombocytopenia without hemorrhagic manifestations are early signs of FA.
It is recommended that all patients with moderate-to-severe macrocytic anemia, as well as those developing bi- or pancytopenia, undergo bone marrow aspiration and cytologic examination (myelogram) to detect hematopoiesis abnormalities characteristic of folate deficiency and to rule out other hematologic disorders [2, 3, 12–14].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: FA is typically characterized by a sharp increase in bone marrow cellularity and the presence of megaloblasts (>10%).
Bone marrow examination must be performed prior to initiating therapy with folic acid**, since the characteristic signs of megaloblastic hematopoiesis in the bone marrow disappear within a few hours after folic acid** intake.
Bone marrow morphological analysis is the primary evidence of megaloblastic erythropoiesis characteristic of FA. However, in recent years, reduced serum folate levels have been considered sufficient for diagnosing FA in many countries. Diagnosis is confirmed by decreased serum folate levels (less than 4 mg/L, normal range 5-9 ng/mL) combined with a normal or elevated vitamin B12 concentration and a negative direct Coombs test. Characteristic, though nonspecific, laboratory signs of FA include hyperbilirubinemia (at the expense of the unconjugated fraction), elevated serum LDH and homocysteine levels. Sometimes a borderline folate level (4-8 mg/L) is associated with high serum homocysteine, which should be interpreted as folate deficiency. Conversely, borderline folic acid levels combined with a normal serum homocysteine level do not prove folate deficiency [10]. Hyperhomocysteinemia is a hallmark of FA, especially if the patient carries common population mutations in folate cycle genes (encoding methylenetetrahydrofolate reductase [MTHFR], methionine synthase [MTR], or methionine synthase reductase [MTRR]).
2.4 Instrumental Diagnostics
No
2.5 Other Procedures
No
3. Treatment, including drug and non-drug therapies, diet therapy, and pain management
3.1. Conservative management
Timely diagnosis and treatment of FA, as well as elimination of its underlying cause, generally lead to rapid correction of folate deficiency and recovery of hematological parameters within 4-6 weeks.
It is recommended that all patients over 18 years of age and children over 3 years of age with a confirmed diagnosis of FA be prescribed folic acid** at a dose of 1-5 mg daily (in children, the dose of folic acid** may be less than 1 mg daily, in accordance with the product labeling) [14, 17–19].
Level of Evidence CGrade of Recommendation 5Level of Clinical Effectiveness C (level of evidence – 5)
It is recommended that patients over 18 years of age with a confirmed diagnosis of FA in the presence of malabsorption syndrome be prescribed folic acid** at a dose of 5-15 mg/day [17, 19].
Level of Evidence CGrade of Recommendation 5Level of Clinical Effectiveness C (level of evidence – 5)
It is recommended that patients aged 1 month to 3 years with a confirmed diagnosis of FA be prescribed #folic acid** at a dose not exceeding 1 mg daily (calculated starting dose 15 mcg/kg daily, therapeutic dose 30-45 mcg/kg daily) [19].
Level of Evidence CGrade of Recommendation 5Level of Clinical Effectiveness C (level of evidence – 5)
3.2 Surgical Treatment
Not applicable.
3.3 Diagnosis at the treatment stage
It is recommended that patients with FA receiving folic acid** treatment undergo monitoring of treatment efficacy by performing a complete blood count (CBC) and blood reticulocyte count on days 7–10 of treatment initiation, then weekly for a month (or less frequently if hemoglobin > 100 g/L), and once every 2 months for half a year after achieving remission, followed by once every 6–12 months [1, 3].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: the presence of a reticulocyte crisis on days 7–10 of treatment with folic acid** medications is an important criterion for FA treatment efficacy. However, this phenomenon is much less pronounced than in the treatment of vitamin B12-deficiency anemia.
Signs of patient improvement and reduction in "anemic" symptoms appear after the first week of therapy, and hemoglobin levels begin to rise after 10–12 days. Normalization of hemoglobin is typically observed 4–6 weeks after treatment initiation and serves as definitive confirmation of the correct diagnosis.
Treatment efficacy can also be assessed by the normalization of serum folate, LDH, unconjugated and conjugated bilirubin, and homocysteine levels. The dynamics of serum iron metabolism parameters (decrease or normalization of ferritin and iron levels) can provide additional information on treatment efficacy.
The duration of FA therapy is determined by its underlying cause. A 4-month course of treatment is usually sufficient to achieve remission. However, if the primary cause of folate deficiency is not eliminated, long-term or continuous administration of folic acid** (2-4 mg daily) is required, for example, in hereditary hemolytic anemias or congenital hyperhomocysteinemia caused by a homozygous MTHFR gene mutation.
When folic acid deficiency is combined with vitamin B12 deficiency, treatment should be initiated with vitamin B12 medications, followed (after correcting the vitamin B12 deficiency) by the addition of folic acid** preparations.
3.4 Other treatment
Pain management and dietary therapy are not used.
3.5 Therapeutic nutrition (diet therapy)
Therapeutic medical nutrition for patients with folate-deficiency anemia during inpatient treatment in medical organizations is organized in accordance with current orders of the Russian Ministry of Health, taking into account the patient's somatic status, comorbidity, and the presence and severity of cytopenia.
4. Medical Rehabilitation and Sanatorium-Resort Treatment
There are no specific rehabilitation measures for patients with folic acid deficiency anemia.
5. Prevention and Dispensary Observation
Dispanserisation (clinical follow-up) of patients is carried out taking into account the causes of folic acid deficiency (the underlying disease, dietary habits).
It is recommended to prescribe prophylactic therapy with folic acid** (in accordance with the instructions for use) for patients at risk of folate deficiency; the "at-risk" category includes patients [17, 19]:
with hereditary hemolytic anemias [20];
with hyperhomocysteinemia associated with mutations in the folate cycle genes (encoding methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR)) [21];
receiving treatment with antimetabolites (folic acid antagonist drugs) [22];
pregnant women [23];
with malabsorption syndrome (celiac disease, chronic inflammatory bowel diseases) [14];
undergoing regular maintenance hemodialysis [24, 25].
GDR CLE 5Grade of recommendation C (level of evidence – 5)
Comments: in patients over 18 years of age, the prophylactic dose of folic acid** ranges from 150 mcg/day to 1 mg/day. The prophylactic dose of #folic acid** for children under 3 years of age is 25–50 mcg/day, the dose of folic acid** for children aged 4–6 years is 75 mcg/day, and for children 7 years and older it is 100 mcg/day. [3] The duration of prophylaxis is determined individually. Administered orally.
6. Organization of Medical Care
Indications for emergency hospitalization to a medical organization:
1) severe anemia with pronounced hypoxic manifestations and lack of adaptation to a low hemoglobin level (decompensation of anemia).
Indications for planned hospitalization in a medical organization:
1) dispensary follow-up examinations, including upon initial diagnosis of moderate or severe FDA.
Indications for patient discharge from a medical organization:
1) regression of anemia decompensation symptoms, completion of the workup to identify the cause of folate deficiency.
7. Additional Information
The prognosis for folic acid deficiency anemia is favorable. The detection of FDA serves as a sort of "warning" regarding a potential deterioration in the patient's general health and necessitates an analysis of the patient's working and living conditions, diagnosis of latent underlying diseases, and/or hereditary metabolic defects responsible for the established folate deficiency. It is necessary to take into account the presence of acquired (smoking, ineffective erythropoiesis, chronic kidney disease, etc.) and congenital (homozygous MTHFR gene mutation) risk factors for hyperhomocysteinemia. In such cases, folate deficiency can dramatically increase the risk of thrombotic and pregnancy-related complications, which determines the need for long-term prophylactic administration [17, 19, 21, 22].
Criteria for Evaluating the Quality of Medical Care
№ | Quality criteria | Performance evaluation |
|---|---|---|
1. | A complete blood count (CBC) was performed, including hematocrit evaluation, red blood cell count, reticulocyte count, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), and red blood cell sizing. | Yes/No |
2. | Vitamin B12 (cyanocobalamin) blood level determination and serum folic acid level testing were performed. | Yes/No |
3. | Serum iron metabolism parameters were assessed: serum ferritin, serum transferrin, total iron-binding capacity (TIBC), serum iron, and transferrin saturation (TSAT). | Yes/No |
4. | A general medical biochemical blood analysis was performed (total protein, albumin, total bilirubin, direct and indirect bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine, urea, alkaline phosphatase, gamma-glutamyl transferase). | Yes/No |
5. | Folic acid** therapy was prescribed at a dose of 1–5 mg/day (in children, the dose of folic acid** may be less than 1 mg/day, in accordance with the drug's instructions) for all patients over 18 years of age and children over 3 years of age with a confirmed diagnosis of FDA. | Yes/No |
6. | Folic acid** therapy was prescribed at a dose of 5–15 mg/day for patients over 18 years of age with a confirmed diagnosis of FDA in the presence of malabsorption syndrome. | Yes/No |
7. | Folic acid** therapy was prescribed at a dose of no more than 1 mg per day (calculated initial dose – 15 mcg/kg/day, therapeutic dose – 30–45 mcg/kg/day) for patients aged 1 month to 3 years with a confirmed diagnosis of FDA. | Yes/No |
8. | Folic acid** was prescribed (in accordance with the instructions for use) prophylactically to patients at risk of folate deficiency; the "at-risk" category includes patients: a. with hereditary hemolytic anemias; b. with hyperhomocysteinemia associated with mutations in folate cycle genes (encoding methylenetetrahydrofolate reductase (MTHFR), methionine synthase (MTR), methionine synthase reductase (MTRR)); c. receiving treatment with antimetabolites (folic acid antagonist drugs); d. pregnant women; e. with malabsorption syndrome (celiac disease, chronic inflammatory bowel diseases); f. undergoing regular maintenance hemodialysis. | Yes/No |
References
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Vorobiev A.I. Hematology Guide: in 3 volumes. Moscow: Niudiamed; 2005.
Vorobyov A.I. Rational Pharmacotherapy of Blood System Diseases / Vorobyov A.I., Al-Radi L.S., Andreyeva N.E. et al.; Edited by A.I. Vorobyov - Moscow: Litterra 2009. - 688 p.
Pediatric Hematology. Clinical Guidelines / Rumyantsev A.G., Maschan A.A., Zhukovskaya E.V. Moscow: GEOTAR-Media, 2015. 656 p.
Naderi N., House J.D. Recent Developments in Folate Nutrition // Advances in Food and Nutrition Research. 2018. Vol. 83.
Ortiz Z. et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis ( Review ) // Cochrane Database Systemic Review. 2009. № 1.
Allen L.H. Causes of vitamin B12 and folate deficiency // Food and Nutrition Bulletin. 2008. Vol. 29, № 2 SUPPL.
Babior B.M. The megaloblastic anemias // Williams Hematology, 6th ed. / ed. Butler E., Lichtman M.A., Coller B.S. 2001. P. 425–445.
Zittoun J. 8 Congenital errors of folate metabolism // Baillieres Clin Haematol. Baillieres Clin Haematol, 1995. Vol. 8, № 3. P. 603–616.
Michael Whitehead V. Acquired and inherited disorders of cobalamin and folate in children // British Journal of Haematology. Br J Haematol, 2006. Vol. 134, № 2. P. 125–136.
Green R., Datta Mitra A. Megaloblastic Anemias: Nutritional and Other Causes // Medical Clinics of North America. 2017. Vol. 101, № 2.
Green R., Dwyre D.M. Evaluation of Macrocytic Anemias // Seminars in Hematology. 2015. Vol. 52, № 4.
Nagao T., Hirokawa M. Diagnosis and treatment of macrocytic anemias in adults // Journal of General and Family Medicine. 2017. Vol. 18, № 5.
De Bruyn E., Gulbis B., Cotton F. Serum and red blood cell folate testing for folate deficiency: New features? // Eur J Haematol. 2014. Vol. 92, № 4.
Khan K.M., Jialal I. Folic Acid (Folate) Deficiency // StatPearls. 2018.
Egorova M.O., Tsvetayeva N.V., Sukhacheva E.A., Komolova E.N. Practical guidelines for screening laboratory diagnostics of anemia // Hematology and Transfusiology. 2011. Vol. 56, № 5. P. 24–36.
FORSHAW J., HARWOOD L. THE DIRECT ANTIGLOBULIN (COOMBS) TEST IN MEGALOBLASTIC ANAEMIA. // J Clin Pathol. 1965. Vol. 18.
Devalia V., Hamilton M.S., Molloy A.M. Guidelines for the diagnosis and treatment of cobalamin and folate disorders // Br J Haematol. 2014.
Socha D.S. et al. Severe megaloblastic anemia: Vitamin deficiency and other causes // Cleve Clin J Med. 2020. Vol. 87, № 3.
Merrell B.J., McMurry J.P. Folid Acid // STATPEARLS. 2021.
Bolton-Maggs P.H.B. et al. Guidelines for the diagnosis and management of hereditary spherocytosis // British Journal of Haematology. John Wiley & Sons, Ltd, 2004. Vol. 126, № 4. P. 455–474.
Maron B.A., Loscalzo J. The treatment of hyperhomocysteinemia // Annual Review of Medicine. 2009. Vol. 60.
Hagner N., Joerger M. Cancer chemotherapy: Targeting folic acid synthesis // Cancer Manag Res. 2010. Vol. 2, № 1.
Greenberg J.A. et al. Folic Acid supplementation and pregnancy: more than just neural tube defect prevention. // Rev Obstet Gynecol. MedReviews, LLC, 2011. Vol. 4, № 2. P. 52–59.
Harshman L.A., Lee-Son K., Jetton J.G. Vitamin and trace element deficiencies in the pediatric dialysis patient // Pediatric Nephrology. 2018. Vol. 33, № 7.
Manns B. et al. Oral vitamin B12 and high-dose folic acid in hemodialysis patients with hyper-homocyst(e)inemia // Kidney Int. 2001. Vol. 59, № 3.
Appendix A1. Working Group Composition
Members of the Association for the Promotion of Hematology and Bone Marrow Transplantation "National Hematological Society":
Lukina E.A., MD, Professor, Head of the Department of Orphan Diseases, National Medical Research Center for Hematology of the Russian Ministry of Health
Tsvetayeva N.V., PhD, Senior Researcher at the Sector for the Study of Non-Neoplastic Blood System Diseases, National Medical Research Center for Hematology of the Russian Ministry of Health
Sysoyeva E.P., PhD, Leading Researcher at the Sector for the Study of Non-Neoplastic Blood System Diseases, National Medical Research Center for Hematology of the Russian Ministry of Health
Ponomarev R.V., PhD, Head of the Sector for the Study of Non-Neoplastic Blood System Diseases, National Medical Research Center for Hematology of the Russian Ministry of Health
Latyshev V.D., Head of the Day Hospital for Patients with Hereditary Metabolic Diseases, National Medical Research Center for Hematology of the Russian Ministry of Health
Dvirnyk V.N., PhD, Head of the Centralized Clinical Diagnostic Laboratory, National Medical Research Center for Hematology of the Russian Ministry of Health
Members of the Russian Scientific Medical Society of Internal Medicine (RSMSIM):
Martynov A.I., Academician of the RAS, MD, Professor at the Department of Hospital Therapy, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health
Malyavin A.G., MD, Professor at the Department of Phthisiology and Pulmonology, A.I. Evdokimov Moscow State University of Medicine and Dentistry of the Russian Ministry of Health
Members of the Russian Society of Pediatric Hematologists and Oncologists:
Rumyantsev A.G., MD, Professor, Academician of the RAS, President of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health.
Maschan A.A., MD, Deputy General Director of the Dmitry Rogachev NMRC PHOI, Professor at the Department of Hematology, Oncology and Radiation Therapy of the Pediatric Faculty at the Pirogov Russian National Research Medical University, President of the National Society of Pediatric Hematologists and Oncologists, Member of the European Hematology Association.
Demikhov V.G., MD, Professor, Director of the Scientific and Clinical Center of Hematology, Oncology and Immunology at the Ryazan State Medical University named after Academician I.P. Pavlov of the Russian Ministry of Health, Member of the European Hematology Association (EHA).
Skobin V.B., PhD, Hematologist at the Scientific and Clinical Center of Hematology, Oncology and Immunology at the Ryazan State Medical University named after Academician I.P. Pavlov of the Russian Ministry of Health.
Zhurina O.N., PhD, Head of the Laboratory at the Scientific and Clinical Center of Hematology, Oncology and Immunology at the Ryazan State Medical University named after Academician I.P. Pavlov of the Russian Ministry of Health.
Stefanov D.N., Researcher at the Scientific and Organizational Department, Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of the Russian Ministry of Health
Conflict of interest: the authors declare no conflict of interest
Appendix A2. Methodology for Developing Clinical Guidelines
Target audience for these clinical guidelines:
general practitioners
pediatricians
obstetricians and gynecologists;
gastroenterologists
hematologists
Methodology for evidence collection
Methods used for the collection/selection of evidence:
Search for publications in specialized peer-reviewed periodicals;
Search in electronic databases.
Databases used for the collection/selection of evidence:
The evidence base for the guidelines includes publications indexed in the Cochrane Library, PUBMED, and MEDLINE databases. The search depth was 30 years.
Methods used for evidence analysis:
Reviews of published meta-analyses;
Systematic reviews with evidence tables.
Methods used for assessing the quality and strength of evidence:
Expert consensus;
The evaluation of evidence significance was carried out in accordance with the grading of levels of evidence (LoE) for diagnostic methods (Table 1) and for prevention, treatment, and rehabilitation methods (Table 2).
Table 1. Level of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)
LoE | Definition |
1 | Systematic reviews of studies with reference standard control or systematic reviews of randomized controlled trials with meta-analysis |
2 | Individual reference-controlled studies, individual randomized clinical trials, and systematic reviews of studies of any design other than randomized clinical trials with meta-analysis |
3 | Studies without consecutive reference standard control or studies with a reference standard that is not independent of the evaluated method, or non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports |
5 | Rationale based solely on mechanism of action or expert opinion |
Table 2. Level of Evidence (LoE) grading scale for prevention, treatment, and rehabilitation methods (preventive, therapeutic, and rehabilitative interventions)
LoE | Clarification |
1 | Systematic review of RCTs with meta-analysis |
2 | Individual RCTs and systematic reviews of studies of any design, excluding RCTs, with meta-analysis |
3 | Non-randomized comparative studies, including cohort studies |
4 | Non-comparative studies, case reports or case series, case-control studies |
5 | There is only a justification of the mechanism of action of the intervention (preclinical studies) or expert opinion. |
Description of the methodology for evidence analysis and recommendation development:
When selecting publications as potential sources of evidence, the methodology used in each study was examined to ensure its compliance with evidence-based medicine principles. The result of this examination influenced the level of evidence assigned to the publication, which in turn affects the strength of the resulting recommendations.
Methodological analysis focused on the study design features that had a significant impact on the quality of results and conclusions.
To eliminate the influence of subjective factors, each study was evaluated independently by at least two independent members of the authoring team. Discrepancies in evaluation were discussed at meetings of the working group of the authoring team for these guidelines.
Based on the evidence analysis, the sections of the clinical guidelines were consistently developed with strength assessment in accordance with the recommendation grading scheme (Table 3).
Methods used to formulate the recommendations:
Expert consensus;
Evaluation of the significance of recommendations according to the rating scheme (Table 3).
Table 3. Grade of Recommendation (GoR) scale for prevention, diagnostic, treatment, and rehabilitation methods (preventive, diagnostic, therapeutic, and rehabilitative interventions)
GoR | Definition |
A | Strong recommendation (all considered criteria of effectiveness (outcomes) are important, all studies have high or satisfactory methodological quality, and their conclusions on the outcomes of interest are consistent) |
B | Conditional recommendation (not all considered criteria of effectiveness (outcomes) are important, not all studies have high or satisfactory methodological quality and/or their conclusions on the outcomes of interest are not consistent) |
C | Weak recommendation (lack of evidence of proper quality (all considered criteria of effectiveness (outcomes) are unimportant, all studies have low methodological quality, and their conclusions on the outcomes of interest are not consistent) |
Final version
For the final version and quality control, the guidelines were re-analyzed by the members of the authoring team, who concluded that all significant comments and feedback from experts had been taken into account, and the risk of bias during development was minimized.
Procedure for updating clinical guidelines.
The mechanism for updating clinical guidelines provides for their systematic revision at least once every three years, as well as upon the emergence of new evidence-based medicine data on the diagnosis, treatment, prevention, and rehabilitation of specific diseases, or in the presence of justified additions/comments to previously approved clinical guidelines, but no more frequently than once every 6 months.
Appendix A3. Reference Materials
No
Appendix B. Physician Action Algorithms
Folic acid**
Appendix C. Patient Information
The folate content in the human body is 7–22 mg. Depletion of their reserves occurs rapidly, within just a few weeks or months from the onset of the causal factor. Folates are found in many plant-based (tomatoes, avocados, onions, mushrooms) and animal-based (liver, meat) products, but are rapidly destroyed during thermal processing. With a sufficient amount of fresh vegetables and fruits in the diet, 400–600 mcg of folate is ingested daily with food; however, the requirement increases significantly during pregnancy, rapid child growth, and high physical exertion. The main causes of folic acid deficiency include inadequate dietary intake (a frequent cause in elderly people, low consumption of raw vegetables, and in newborns—feeding with goat milk), impaired intestinal absorption (jejunal resection, celiac disease, chronic enteritis, amyloidosis, scleroderma, jejunal tumors, chronic alcohol intoxication), the use of medications that impede folic acid assimilation (antiepileptic drugs, phenobarbital**, methotrexate**, co-trimoxazole [sulfamethoxazole+trimethoprim]**, metformin**), increased demand for folates (pregnancy, hereditary hemolytic anemias, prematurity, low birth weight), and increased folate excretion (hemodialysis).
Factors provoking folate deficiency are often combined with each other.
Folic acid deficiency leads to impaired red blood cell formation and a decrease in blood hemoglobin levels—folic acid deficiency anemia.
After starting treatment with folic acid**, signs of patient improvement and a reduction in "anemic" complaints appear after the first week of administration, and normalization of hemoglobin levels occurs 4–6 weeks after the start of treatment.
Prophylactic administration of folic acid** is indicated for children at risk (premature, born with low weight), pregnant women, patients with intestinal malabsorption syndrome, hereditary hemolytic anemias, and patients on hemodialysis.
Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools
No.