Hemorrhagic disease of the fetus and newborn: clinical guidelines

List of Abbreviations

aPTT – activated partial thromboplastin time

HDN – hemorrhagic disease of the newborn

GI – gastrointestinal tract

INR – international normalized ratio

PT – prothrombin time

PT – prothrombin index

РКИ – randomized controlled trial

FFP – fresh frozen plasma

Terms and Definitions

Hemorrhagic disease of the newborn (HDN) or vitamin K deficiency bleeding is an acquired condition characterized by increased bleeding in newborns and infants during the first months of life due to a deficiency of vitamin K-dependent clotting factors (II, VII, IX, X).

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Hemorrhagic disease of the newborn (HDN) or vitamin K deficiency bleeding is an acquired condition characterized by increased bleeding in newborns and infants during the first months of life due to a deficiency of vitamin K-dependent clotting factors (II, VII, IX, X) [1–8].

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

The biological role of vitamin K is to activate the gamma-carboxylation of glutamic acid residues in prothrombin (factor II), proconvertin (factor VII), antihemophilic globulin B (factor IX), and Stuart-Prower factor (factor X), as well as plasma antiproteases C and S, which play a major role in the anticoagulant system [9–12]. Vitamin K deficiency leads to the hepatic synthesis of inactive factors II, VII, IX, and X, which are unable to bind calcium ions and fully participate in blood coagulation [13].

Several types of vitamin K occur in nature. Vitamin K1, or phylloquinone, is widely found in food products (green vegetables, vegetable oils, dairy products). Vitamin K2, or menaquinone, is synthesized by the intestinal microflora and absorbed in extremely small quantities. One of the pathways for converting vitamins K1 and K2 into a stored form is their metabolism in the intestine into menadione (vitamin K3) [14]. The stored form, menaquinone-4, is subsequently synthesized in extrahepatic tissues from circulating blood menadione.

Menadione sodium bisulfite (ATC code B02BA02) is a synthetic water-soluble analogue of vitamin K, sometimes referred to as vitamin K3, which is currently not used for HDN prophylaxis in developed countries [15,16]. Menadione does not act directly, but via metabolites after being converted in the liver into phylloquinone (K1) and menaquinone (K2), therefore its therapeutic effect develops slowly after administration [17].

Transplacental transfer of vitamin K is limited; consequently, its hepatic reserves in newborns and its concentration in umbilical cord blood are very low [18–20]. The vitamin K level in the cord blood of healthy newborns is often below the detection limit of 0.02 ng/mL [20]. In addition, vitamin K is a fat-soluble vitamin, so its intestinal absorption requires the presence of bile salts. The body's capacity to store vitamin K is low, and the half-life of vitamin K-dependent clotting factors is short. Thus, vitamin K deficiency develops very rapidly when intake is insufficient.

In healthy newborns, the plasma levels of vitamin K-dependent clotting factors are 50% of adult levels [21]. Their concentration increases gradually, reaching adult levels by 6 months of age [22]. Virtually all healthy term newborns exhibit a combined decrease in procoagulants, physiological anticoagulants, and plasminogen during the first five days of life [23,24].

The only source of vitamin K for a newborn is exogenous intake: via breast milk, infant formula, or as a medicinal product. The amount of vitamin K a child receives depends on the type of feeding. Vitamin K1 levels in breast milk are significantly lower than in infant formula (averaging 2.5 mcg/L vs. 24–175 mcg/L, respectively) [25,26], and there are significant individual variations [27].

Thus, due to the physiological characteristics of the coagulation system and vitamin K metabolism, newborns are predisposed to developing vitamin K deficiency bleeding. Significant risk factors contributing to the development of HDN include exclusive breastfeeding and the failure to administer prophylactic vitamin K immediately after birth [2,3].

1.3 Epidemiology of the Disease or Condition

Without prophylaxis, the incidence of early and classical HDN ranges from 0.25% to 1.70%, while late HDN ranges from 4.4 to 72 (up to 80) per 100,000 newborns according to various authors [18,28,29]. Routine vitamin K prophylaxis at birth reduces the incidence of late HDN to 1.1 or less per 100,000 live births [30,31].

1.4 Features of Coding the Disease or Condition

P53 – Haemorrhagic disease of fetus and newborn

When bleeding caused by the late form of hemorrhagic disease develops in the postneonatal (infant) period, the code D68.8 – Other specified coagulation defects is used.

1.5 Classification of the disease or condition

1. Early form – symptoms appear within 24 hours after birth. The early form is often associated with the mother taking medications that interfere with vitamin K metabolism. This form of the disease cannot be prevented by administering vitamin K to the infant after birth. Characteristic manifestations include hematemesis, pulmonary hemorrhage, melena, and hemorrhage into the abdominal organs and adrenal glands [1,3,7,18,32,33].

2. Classical form presents with bleeding on days 2–7 of life. In most cases, it develops in newborns with inadequate milk intake and the absence of prophylactic vitamin K administration immediately after birth. Characteristic manifestations include gastrointestinal bleeding, cutaneous hemorrhages, bleeding from the umbilical stump, injection sites, mucous membranes, etc. Intracranial hemorrhages are less typical for the classical form of HDN [1,3,7,18,32,33].

3. Delayed or late form is characterized by the onset of symptoms between the 8th day and the 6th month of life [6,34]; however, manifestation typically occurs at 2–12 weeks of age [1,3,6,35]. In most cases, late HDN develops against the background of conditions and disorders in the infant that impair vitamin K synthesis and absorption (cholestasis, malabsorption syndrome) [36–38]. The disease occurs in exclusively breastfed infants who did not receive vitamin K prophylaxis after birth. Intracranial hemorrhages are most frequently recorded in this form (50–75%): subdural hematomas (40%), parenchymal (40%), intraventricular (10%), and subarachnoid (10%) hemorrhages [18,32,35,39,40]. Hemorrhages and bleeding in other locations may also be observed. In more than 1/3 of infants, ecchymoses or so-called minor "warning" hemorrhages may appear prior to brain hemorrhage (from a day to several weeks beforehand) (epistaxis; umbilical stump bleeding; petechiae and ecchymoses on the skin or mucous membranes; intermuscular hematomas or bleeding from invasive procedures (injections, vaccinations, blood collection sites, circumcision, surgery)) [35,41–44]. The mortality rate for late HDN is 30% [45].

1.6 Clinical presentation of the disease or condition

The clinical presentation of HDN is characterized by the appearance of spontaneous bleeding of any localization:

- Gastrointestinal bleeding (melena, hematemesis);

- Umbilical stump bleeding (including upon detachment of the umbilical cord remnant);

- Cutaneous hemorrhages (ecchymoses, petechiae);

- Mucosal hemorrhages;

- Bleeding from injection and surgical sites;

- Pulmonary and nasal bleeding;

- Hematuria;

- Clinical signs of hemorrhage into abdominal organs (abdominal distension, abdominal tenderness on palpation);

- Expansion of hematomas at the site of trauma (cephalhematoma, ecchymoses);

- Neurological symptoms depending on the localization of intracranial hemorrhage (poor sucking, lethargy, coma, convulsions, bulging and tense anterior fontanelle, focal and general cerebral neurological symptoms);

- Skin pallor in the event of anemia;

- Hypovolemic shock in massive bleeding;

- Fever [42,44];

- Tachypnea, grunting respiration, bradypnea, apnea.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The diagnosis of hemorrhagic disease of the newborn is established based on [5,16,46]:

1) physical or instrumental examination: spontaneous bleeding of any localization;

2) laboratory studies: prolongation of prothrombin time (PT) ≥ 4 times, marked decrease in prothrombin index (PTI) and increase in international normalized ratio (INR) ≥ 4, prolongation of activated partial thromboplastin time (aPTT), with normal fibrinogen levels and platelet counts.

The diagnosis is confirmed by the normalization of PT following the administration of vitamin K preparations.

If PT and aPTT are prolonged above the normal ranges for the patient's age, but do not reach the values presented in criterion 2, hemorrhagic disease cannot be ruled out in an infant with bleeding, and the case should be classified as suspected hemorrhagic disease of the newborn.

2.1 Complaints and Anamnesis

When taking the medical history of a patient with suspected HDN, attention should be paid to risk factors and a positive family history of bleeding disorders. HDN is typically characterized by the absence of a burdened family history.

Risk factors depend on the form of hemorrhagic disease of the newborn (HDN). Early-onset HDN is characterized by: maternal intake of medications during pregnancy, including vitamin K antagonists (ATC code B01AA) such as warfarin**, antiepileptic drugs (ATC code N03A), high doses of systemic antibacterial drugs (ATC code J01) (especially other beta-lactam antibacterials [ATC code J01D]), antituberculosis drugs (ATC code J04A), intake of other analgesics and antipyretics (ATC code N02B), non-steroidal anti-inflammatory and antirheumatic drugs (ATC code M01A) immediately before delivery; preeclampsia; maternal disorders (liver and intestinal diseases). Classic HDN is characterized by: low transplacental transfer of vitamin K, low vitamin K concentration in breast milk, intrauterine growth restriction, prematurity, underdeveloped intestinal flora of the newborn during this period, and failure to administer prophylactic vitamin K (ATC code B02BA) immediately after birth. Late-onset HDN is characterized by: exclusively breastfeeding, lack of HDN prophylaxis, hepatobiliary system disorders (including cholestasis), malabsorption, short bowel syndrome, and prolonged antibiotic therapy in the infant [47,48]

2.2 Physical Examination

Comments: The visual therapeutic examination includes: inspection of the skin and mucous membranes (presence of hemorrhagic manifestations: petechiae, ecchymoses, bleeding from injection sites), inspection of the umbilical stump (bleeding), assessment of stool and urine (color, presence of blood impurities), assessment of gastric contents if gastrointestinal (GI) bleeding is suspected, presence of respiratory disorders, assessment of sputum (color, amount) if pulmonary hemorrhage is suspected, and neurological status assessment. A characteristic clinical sign of HDN in an infant is the presence of bleeding of various localizations.

2.3 Laboratory Diagnostics

Comment: In a complete blood count (CBC), the platelet count should be assessed first, which in HDN falls within age-related normal ranges. Red blood cell parameters (total hemoglobin level, hematocrit) must be evaluated to rule out anemia, which may develop secondary to bleeding.

Comments: The most significant changes in children with HDN involve prothrombin complex parameters: prolongation of PT, often by 4 times or more, a marked decrease in PTI, and an increase in INR ≥ 4; prolongation of APTT is also characteristic. The fibrinogen level in a child with HDN is within age-related normative values. The diagnosis of HDN is confirmed by the cessation of bleeding and normalization of PT, PTI, and INR values following the administration of vitamin K (ATC code B02BA).

2.4 Instrumental Diagnostics

Comments: Continuous monitoring of oxygen saturation, heart rate, respiratory rate, blood pressure, and body temperature allows for the timely diagnosis of developing anemia and hemodynamic disorders resulting from blood loss due to bleeding.

2.5 Other Procedures

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative Treatment

Comments: According to the prescribing information for phytomenadione (ATC code B02BA01) the 1% emulsion is administered to newborns (with a gestational age of at least 36 weeks) at a dose of 1 mg via intramuscular injection at birth or immediately after birth; to premature infants (gestational age less than 36 weeks, body weight at least 2.5 kg) and newborns at high risk of bleeding (immaturity, birth asphyxia, stagnation jaundice, swallowing disorders, maternal intake of vitamin K antagonists [ATC code B01AA] or antiepileptic drugs [ATC code N03A]) as a single dose of 1 mg at birth or immediately after birth, administered intramuscularly or intravenously; the number of subsequent doses and dosing frequency depend on the blood coagulation status; to premature infants (gestational age less than 36 weeks, body weight less than 2.5 kg) at a dose of 0.4 mg/kg (equivalent to 0.04 ml/kg) via intramuscular or intravenous injection at birth or immediately thereafter, with the number of subsequent doses and dosing frequency depending on the blood coagulation status. Contraindications: hypersensitivity to phytomenadione (ATC code B02BA01) and other components of the drug.

In the absence of phytomenadione (ATC code B02BA01) 1% emulsion, menadione sodium bisulfite** (ATC code B02BA02) 1% solution may be administered. It should be taken into account that its effect begins 8–24 hours after administration. Menadione sodium bisulfite** (ATC code B02BA02) 1% solution is administered via intramuscular injection. The daily dose of the drug is: for newborns—1–1.5 mg/kg/day (0.1–0.15 ml/kg/day) [4], but not more than 4 mg/day; for children under 1 year of age—2–5 mg/day. Frequency of administration—1 to 2–3 times a day. Duration of the treatment course—from 2–3 days [1] to 3–4 days. If necessary, the course of treatment can be repeated after a 4-day washout period. Contraindications: hypercoagulation, thromboembolism, hemolytic disease of the newborn. Use with caution in glucose-6-phosphate dehydrogenase deficiency.

Comments: The standard FFP dose is 10-20 mL/kg, administered intravenously over at least 60 minutes, but not more than 4 hours. At this dose, the increase in circulating blood coagulation factor levels is approximately 20%, i.e., greater than 10%, which is usually required to correct hemostasis [70]. Fresh frozen plasma transfusion must be initiated within 1 hour after thawing.

Comments: The dose of #coagulation factors II, VII, IX, X in combination [prothrombin complex]** (ATC code B02BD), according to published clinical case reports, is 50 IU/kg [71].

Comments: The hemoglobin level requiring correction via blood transfusion depends on postnatal age. Indications for blood transfusion are provided in the Clinical Guidelines "Fetal Anemia Due to Blood Loss" and "Early Anemia of Prematurity."

3.2 Surgical Treatment

Surgical treatment in children with VKDB depends on the bleeding site, volume of blood loss, and the development of a life-threatening condition. Cases of massive intracranial hemorrhage requiring neurosurgical intervention have been described [36,53,63,64,72].

3.3 Other Treatment

Feeding of children with any form of VKDB is carried out either with breast milk or with an adapted infant formula for feeding from birth (or a special infant formula for premature and low-birth-weight infants, depending on gestational age) if breastfeeding is not possible.

4. Medical Rehabilitation and Sanatorium-Resort Treatment

Medical rehabilitation depends on the extent of central nervous system hemorrhagic damage resulting from intracranial hemorrhage caused by VKDB, and associated neurological complications.

5. Prevention and Dispensary Observation

Comments: According to the drug prescribing information, 1% phytomenadione emulsion (ATC code B02BA01) is administered to newborns (with a gestational age of at least 36 weeks) at a dose of 1 mg intramuscularly, at birth or immediately after birth; to premature infants (gestational age under 36 weeks, birth weight at least 2.5 kg) and newborns at high risk of bleeding (immaturity, birth asphyxia, congestive jaundice, swallowing disorders, maternal use of vitamin K antagonists (ATC code B01AA) or antiepileptic drugs (ATC code N03A)) as a single dose of 1 mg at birth or immediately after birth, administered intramuscularly or intravenously; the number of subsequent doses and dosing frequency depend on the blood coagulation status; to premature infants (gestational age under 36 weeks, birth weight under 2.5 kg) at a dose of 0.4 mg/kg (equivalent to 0.04 mL/kg) administered intramuscularly or intravenously at birth or immediately thereafter; the number of subsequent doses and dosing frequency depend on the coagulation status. Table 1 shows the recommended doses for premature infants for whom phytomenadione (ATC code B02BA01) is indicated for the prevention of bleeding caused by vitamin K deficiency (at birth or immediately after birth). Contraindications: hypersensitivity to phytomenadione (ATC code B02BA01) and other components of the drug.

Table 1. Recommended doses of phytomenadione (ATC code B02BA01) for premature infants.

When administering the medicinal product intravenously, the emulsion must be diluted 1:5 prior to injection (using solvents and diluents, including irrigation solutions (ATC code V07AB) – water for injections** or other irrigation solutions (ATC code B05CX) – 5% dextrose** solution). The diluted emulsion should be injected slowly, in a volume of approximately 1 mL over 20 seconds.

Due to the increasing frequency of parental refusals of any interventions for the newborn (VKDB prevention, vaccination, etc.) [74–77], parents may be offered an alternative method of VKDB prevention: oral administration of vitamin K (ATC code B02BA) – #phytomenadione (ATC code B02BA01) 1% emulsion [32,78]. Dosing regimen: three doses of 2 mg orally after birth, at 4-6 days of life, and at 4-6 weeks of life [78]. In case of vomiting or regurgitation within an hour after oral administration of #phytomenadione (ATC code B02BA01), it is advisable to repeat the oral administration of #phytomenadione (ATC code B02BA01) at the same dose [78].

If phytomenadione (ATC code B02BA01) 1% emulsion is unavailable, menadione sodium bisulfite^** (ATC code B02BA02) 1% solution may be administered [13,79,80]. It should be noted that its onset of action is 8-24 hours after administration. Menadione sodium bisulfite** (ATC code B02BA02) is administered intramuscularly. The daily dose of the drug is: for newborns – 1-1.5 mg/kg/day (0.1-0.15 mL/kg/day), but not more than 4 mg/day; for children under 1 year – 2-5 mg/day. Frequency of administration – 1 to 2-3 times a day. Contraindications: hypercoagulation, thromboembolism, hemolytic disease of the newborn. Use with caution in glucose-6-phosphate dehydrogenase deficiency.

Comments: The vitamin K1 content in retinol + ergocalciferol + phytomenadione + alpha-tocopherol (ATC code A11BA) is 20 mcg per 1 mL. For total parenteral nutrition, the standard dose is 4 mL/kg/day for newborns with a birth weight under 2.5 kg and 10 mL/day for other children. As enteral nutrition is introduced, the dose is reduced accordingly.

Comments. Children with cholestasis and malabsorption syndrome develop vitamin K deficiency regardless of the feeding substrate due to impaired absorption of fat-soluble vitamins [36–38,72,91]. The absorption rate of fat-soluble vitamins in liver and intestinal pathologies varies and requires monitoring of coagulation profile parameters such as INR (and/or PT, PTI). The prophylactic dosing regimen ranges from 1 mg/kg once a week in children weighing under 5 kg to 2.5-5.0 mg 1 to 3 times a week, or 10 mg once every 2 weeks in children weighing over 5 kg. The dose and frequency of prophylaxis are selected individually depending on the coagulation results and, in severe cases, may reach daily administration. In the presence of cholestasis or malabsorption syndrome, parenteral administration of vitamin K (ATC code B02BA) is advisable [84–90].

Comments. A maternal daily intake of 5.0 mg (800% of the recommended daily allowance) of phylloquinone increases the vitamin K concentration in the newborn's serum to almost the same level as that in formula-fed infants [94]. Appendix B provides information on the vitamin K1 content in food products (mcg/100 g) [92].

6. Organization of Medical Care

Indications for hospital admission to a medical organization:

1) Presence of spontaneous bleeding at any site.

Indications for discharging a patient from a medical organization:

1) Satisfactory condition;

2) Stabilization of the child's condition is achieved, no bleeding is present;

3) Normalization of coagulogram parameters (exploratory hemostasis test);

4) Absence of other contraindications for discharge.

7. Additional Information

The prognosis of the disease in the absence of pulmonary hemorrhage and intracranial hemorrhage is generally favorable. In the presence of intracranial hemorrhage, the prognosis is determined by the location and severity of the hemorrhage. Mortality in late VKDB in cases of intracranial hemorrhage is 15–20% [95], and adverse long-term outcomes (motor and intellectual deficit) are observed in 20–50% [6,18,39,40].

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Balashova Ekaterina Nikolaevna – Candidate of Medical Sciences, Leading Researcher at the Prof. A.G. Antonov ICU, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Associate Professor at the Department of Neonatology, Member of the Council of the Russian Society of Neonatologists

2. Volodin Nikolay Nikolaevich – Academician of the Russian Academy of Sciences, Professor, Doctor of Medical Sciences; President of the Association of Specialists in Perinatal Medicine, Healthcare Provision for Pregnant Women, Fetuses, Newborns, and Children under 3 Years of Age (ASPM+)

3. Degtyarev Dmitry Nikolaevich – Doctor of Medical Sciences, Professor, Deputy Director for Research at the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Head of the Department of Neonatology at the N.F. Filatov Clinical Institute of Child Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Member of the Council of the Russian Society of Neonatologists

4. Anna V. Degtyareva – Doctor of Medical Sciences, Professor, Head of the Pediatrics Department, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Professor at the Department of Neonatology, N.F. Filatov Clinical Institute of Child Health, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of Russia (Sechenov University), Member of the Council of the Russian Society of Neonatologists

5. Zharkov Pavel Aleksandrovich – Doctor of Medical Sciences, Hematologist, Head of the Department of Hemostasis Pathology, Associate Professor at the Department of Hematology and Cellular Technologies, National Medical Research Center of Pediatric Hematology, Oncology and Immunology named after Dmitry Rogachev of the Russian Ministry of Health, Member of the National Society of Pediatric Hematologists and Oncologists

6. Karpova Anna Lvovna – Candidate of Medical Sciences, Head of the Neonatal Inpatient Unit, City Clinical Hospital No. 67 named after L.A. Vorokhobov of the Moscow Healthcare Department, Associate Professor at the Prof. V.V. Gavryushov Department of Neonatology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Assistant at the Department of Outpatient Therapy, Clinical Laboratory Diagnostics and Medical Biochemistry, Institute of Professional Education, Yaroslavl State Medical University of the Russian Ministry of Health, Member of the Council of the Russian Society of Neonatologists.

7. Makieva Mziya Ilyinichna – Candidate of Medical Sciences, Head of the Newborn Department, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Associate Professor at the Department of Neonatology, Member of the Russian Society of Neonatologists

8. Mebelova Inessa Isaakovna – Deputy Chief Physician for Neonatology, Republican Perinatal Center named after K.A. Gutkin, Chief Freelance Specialist in Neonatology of the Ministry of Health of the Republic of Karelia, Member of the Council of the Russian Society of Neonatologists

9. Mostovoy Aleksey Valerievich – Candidate of Medical Sciences, Head of the Resuscitation and Intensive Care Unit, City Clinical Hospital No. 67 named after L.A. Vorokhobov of the Moscow Healthcare Department, Associate Professor at the Prof. V.V. Gavryushov Department of Neonatology, Russian Medical Academy of Continuous Professional Education of the Russian Ministry of Health, Assistant at the Department of Outpatient Therapy, Clinical Laboratory Diagnostics and Medical Biochemistry, Institute of Professional Education, Yaroslavl State Medical University of the Russian Ministry of Health, Chief Freelance Neonatologist of the Russian Ministry of Health in the North Caucasian Federal District, Member of the Council of the Russian Society of Neonatologists, Member of the European Society for Paediatric Research (ESPR)

10. Narogan Marina Viktorovna – Doctor of Medical Sciences, Leading Researcher at the Department of Pathology of Newborns and Premature Infants, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Professor at the Department of Neonatology, N.F. Filatov Clinical Institute of Child Health, I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Member of the Council of the Russian Society of Neonatologists

11. Sapun Olga Ilyinichna – Head of the Neonatal Resuscitation and Intensive Care Unit No. 2, Children's Regional Clinical Hospital, Krasnodar, Chief Freelance Neonatologist of the Ministry of Health of Krasnodar Krai, Assistant at the Department of Pediatrics with a Course in Neonatology, Faculty of Advanced Training and Professional Retraining, Kuban State Medical University

12. Timofeeva Leila Akakievna – Candidate of Medical Sciences, Head of the Newborn Department, Institute of Neonatology and Pediatrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov of the Russian Ministry of Health, Associate Professor at the Department of Neonatology, Member of the Russian Society of Neonatologists

No conflict of interest.

Appendix A2. Methodology for Developing Clinical Guidelines

Methods used for collecting/selecting evidence: electronic database search.

Description of methods used for evidence collection/selection: the evidence base for the guidelines included publications from the Cochrane Library, PubMed, EMBASE, MEDLINE, Scopus, Web of Science, eLIBRARY, clinicaltrials.gov, electronic libraries, and clinical guidelines published by the National Institute for Health and Care Excellence, the European Association of Perinatal Medicine, the European Society for Pediatric Research, the European Foundation for the Care of Newborn Infants, and the European Society for Neonatology. The search depth was 59 years.

Methods used for assessing the quality and strength of evidence:

expert consensus;

assessment of significance in accordance with the rating scheme.

Grading scales for evidence levels (Tables 1, 2) for diagnostic, preventive, therapeutic, and rehabilitation methods (interventions) with definitions, and the grading scale for recommendation strength levels (Table 3) for preventive, diagnostic, therapeutic, and rehabilitation methods (interventions).

Methods used for analyzing evidence:

reviews of published meta-analyses;

systematic reviews with evidence tables.

Description of methods used for analysis of evidence.

When selecting publications as potential sources of evidence, the methodology used in each study was reviewed to ensure its validity. Methodological evaluation was based on questions focused on study design features that significantly affect the validity of the results and conclusions.

To minimize potential subjective errors, each study was evaluated independently by at least two members of the working group. Any discrepancies in assessments were discussed by the full working group. If consensus could not be reached, an independent expert was involved.

Economic analysis:

Cost analysis was not performed, and pharmacoeconomic publications were not evaluated.

Method of guidelines validation:

external expert review;

internal expert review.

Description of the guidelines validation method:

The preliminary version of these guidelines was reviewed by independent experts who were asked to comment primarily on whether the interpretation of the evidence underlying the recommendations was accessible and understandable.

Comments were received from primary care physicians and district pediatricians regarding the clarity of the presentation of the guidelines and their assessment of the importance of the guidelines as a working tool in daily practice.

The draft version was also sent to a non-medically trained reviewer to obtain comments from a patient perspective.

Comments received from experts were carefully systematized and discussed by the chair and members of the working group. Each point was discussed, and resulting modifications to the guidelines were recorded. If no changes were made, the reasons for declining the changes were recorded.

Consultation and peer review:

The latest amendments to these guidelines are presented for discussion as a draft version. The updated version for broad discussion was posted on the websites of the Russian Society of Neonatologists (RSN) www.neonatology.pro and the Russian Association of Perinatal Medicine (RAPM) www.raspm.ru to allow all interested parties to participate in the discussion and improvement of the guidelines.

The draft guidelines were reviewed by independent experts who were asked to comment primarily on the clarity and accuracy of the interpretation of the evidence base underlying the recommendations.

For the final revision and quality control, the recommendations were re-evaluated by the members of the working group, who concluded that all comments and feedback from the experts had been taken into account and the risk of bias in the development of the recommendations was minimized.

Target audience for these clinical guidelines:

1. Neonatologists

2. Anesthesiologists-intensivists

3. Pediatricians

4. Obstetricians-gynecologists

Table 1. Levels of Evidence (LoE) grading scale for diagnostic methods (diagnostic interventions)

Table 2. Levels of Evidence (LoE) grading scale for prevention, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions)

Table 3. Scale for assessing the grades of recommendation (GR) for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (preventive, diagnostic, therapeutic, and rehabilitative interventions)

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

1. Federal Law No. 323-FZ "On the Fundamentals of Protecting the Health of Citizens in the Russian Federation" dated November 21, 2011.

2. Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019, "On Approval of the List of Vital and Essential Medicines for 2020" as amended by Order No. 3073-r dated November 23, 2020.

3. Procedure for the Provision of Medical Care in the Profile "Obstetrics and Gynecology (Excluding the Use of Assisted Reproductive Technologies)" (Order of the Ministry of Health of the Russian Federation No. 1130n dated October 20, 2020)

4. Rules for the provision of medical care in the specialty "Neonatology" (Order of the Ministry of Health of the Russian Federation No. 921n dated November 15, 2012).

5. Order of the Ministry of Health of the Russian Federation No. 203n dated May 10, 2017, "On Approval of Criteria for Assessing the Quality of Medical Care."

6. Order of the Ministry of Health of the Russian Federation No. 804n dated October 13, 2017, on Approval of the Nomenclature of Medical Services (as amended on September 24, 2020).

7. Methodological letter edited by Prof. E.N. Baybarina, "Resuscitation and Stabilization of Newborn Infants in the Delivery Room" dated March 4, 2020.

8. International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) (World Health Organization) 1994.

9. State Register of Medicines: https://grls.rosminzdrav.ru

Appendix B. Physician Action Algorithms

Diagram. Algorithm of physician actions in case of suspected VKDB in a newborn

Appendix C. Patient Information

All newborns have a relative vitamin K deficiency. Several types of vitamin K occur in nature. Vitamin K1, or phylloquinone, is widely present in foods (green vegetables, vegetable oils, dairy products). Vitamin K2, or menaquinone, is synthesized by the intestinal microflora and absorbed in extremely small amounts. Vitamin K deficiency in newborns is due to the fact that its placental transfer is extremely limited, so the concentration of vitamin K in the fetal blood and its stores by birth are extremely small.

Vitamin K deficiency can cause bleeding in infants during the first months of life. This condition is known as "hemorrhagic disease of the fetus and newborn" or "vitamin K deficiency bleeding." Vitamin K deficiency leads to impaired blood clotting, resulting in bleeding.

Hemorrhagic disease of the newborn is divided into three forms: early, classic, and late. The early form is characterized by the development of bleeding within 24 hours after birth. This form cannot be prevented by administering vitamin K (ATC code B02BA) to the infant after birth. The classic form occurs after the first 7 days of life. The late form occurs mainly between the 2nd and 12th weeks of life. Conditions accompanied by symptoms of diarrhea and cholestatic jaundice increase the risk of developing the late form of hemorrhagic disease, as they impair the intestinal absorption of vitamin K.

For a newborn, the only source of vitamin K is its intake from external sources: breast milk, infant formula, or as a medicinal product. The level of vitamin K in breast milk (an average of 2.5 mcg/L) is significantly lower than in infant formula (24-175 mcg/L).

Due to their physiological characteristics, infants in the first months of life are predisposed to developing "hemorrhagic disease of the newborn." Given the high risk of life-threatening bleeding, all newborns should receive prophylaxis for "hemorrhagic disease of the newborn." For prophylactic purposes, vitamin K (ATC code B02BA) is administered to infants during the first hours of life. In our country, a medicinal product from the vitamin K group (ATC code B02BA)—phytomenadione (vitamin K1) (ATC code B02BA01)—is approved as an emulsion for intravenous and intramuscular administration at 10 mg/mL. For most infants, a single administration immediately after birth is sufficient for prophylaxis. Additional doses of the drug are prescribed by a physician if there are medical indications. In our country, intramuscular administration of a medicinal product from the vitamin K group (ATC code B02BA)—menadione sodium bisulfite** (ATC code B02BA) (vitamin K3) as a 1% solution for intramuscular injection—is also used.

If the disease has already developed, vitamin K (ATC code B02BA) is used for treatment, and fresh frozen plasma may be administered to stop bleeding.

To increase the concentration of vitamin K in breast milk, a nursing mother is advised to consume foods rich in vitamin K and to take multivitamins.

Vitamin K1 content in foods (mcg/100 g)

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Not applicable.