Fat-soluble vitamins (A, D, E, and K) occur naturally in foods. However, the natural source of vitamin D in humans is synthesis in the skin. In comparison with the other FSVs, vitamin D functions more like a hormone-it is synthesized in 1 organ and transported to distant organs where it exerts its physiological and metabolic functions. Unlike WSVs, with the exception of vitamin K2, there is no intestinal synthesis of FSVs by intestinal microbiota. Intestinal absorption of the FSVs is strongly dependent on adequate secretion of pancreatic enzymes and hepatic bile acids into the intestinal lumen. In addition, vitamin A and vitamin E esters require hydrolysis prior to intestinal absorption by an intestinal esterase that depends on bile acid. The FSVs are absorbed from the intestine using the same mechanisms as those used for the absorption of other lipids. They are incorporated into mixed micelles with other lipids and bile acids in the small intestinal lumen and enter the enterocyte largely by apical diffusion. Within the enterocyte, they are incorporated into chylomicrons and exported via basal exocytosis into the lymphatic system. Excess FSVs are stored in hepatic and adipose tissues.8
FSVs may be poorly absorbed if any phase of fat digestion, absorption, or transport is interrupted. Therefore, deficiency in people with conditions associated with fat malabsorption, such as cystic fibrosis, celiac disease, and cholestatic liver diseases, is common.8 Deficiency of these vitamins is also associated with inadequate intakes in limited specific clinical situations. Unlike WSVs, FSVs accumulate in body tissues; thus, they account for the majority of the 60,000 cases of vitamin toxicity reported each year in the United States.8 A detailed description of the FSVs is provided in this chapter. Table 20.1 shows a list of FSVs, recommended intake, deficiency symptoms, deficiency risk factors, diagnostic tests, and therapeutic dosages.
The term vitamin A refers to retinol and its derivatives, which have qualitatively similar biologic activities. The principal vitamin A compounds are retinol, retinal (retinaldehyde), retinoic acid, and retinyl esters. The functions of vitamin A include cellular differentiation, epithelial barrier function, immune competency, vision, and reproductive function. It is an immune modulator, being important for helper T cell and B cell development, as well as neutrophil, macrophage, and natural killer cell functioning.9
Vitamin A is present in the diet as retinyl esters derived almost exclusively from animal sources (liver and fish liver oils, dairy products, animal kidney, and eggs) and as provitamin A carotenoids (mainly beta-carotene) that are distributed widely in green, yellow, orange, and red fruits and vegetables. Vitamin A intake is expressed in international units (IU) and recommended intakes vary with age (see Table 20.1).9 Vitamin A activity is expressed as retinol activity equivalents (RAEs; 1 RAE = 3.3 IU of vitamin A activity).
Vitamin A deficiency is rare in the United States, occurring in about 0.3% of the US population in 2013. In high-income countries, vitamin A deficiency is associated with malabsorption, with pancreatic, liver, and intestinal pathology, including as a complication of bariatric surgery. In contrast, vitamin A deficiency in low- and middle-income countries occurs in up to 70% of children younger than 5 years of age, primarily because of inadequate intake.10 Deficiency may lead to xerophthalmia, keratomalacia, and irreversible damage to the cornea, as well as night blindness and pigmentary retinopathy. Xerophthalmia is pathognomonic for vitamin A deficiency. Deficiency may also increase morbidity and mortality from various infections, such as measles. The World Health Organization (WHO) recommends vitamin A supplements for preventing mortality and morbidity in children from 6 months to 5 years of age in low- and middle-income countries. An updated Cochrane Review11 concluded that vitamin A supplements reduce the overall risk of death due to diarrhea by 12%. However, it did not find specific evidence that death was reduced in measles, respiratory infections, or meningitis. However, new occurrences of diarrhea and measles were reduced by supplementation. Vitamin A supplements also reduced the risk of night blindness and Bitot spots in the eye.11 Vitamin A deficiency has also been associated with autism spectrum disorders, particularly in situations associated with limited dietary intake or gastrointestinal comorbidities.12
Vitamin A status is monitored by assessing serum retinol concentration in patients who exhibit signs of vitamin A deficiency. Deficiency is defined as a serum retinol less than 20 mcg/dL, though serum retinol concentration may be normal, even if body stores are low, because of maintenance of circulating retinol levels from hepatic stores. The gold standard for evaluating total body vitamin A is measuring liver retinol concentrations, which is impractical in most clinical situations.13
The AI for infants is 1320 to 1650 IU/day. The recommended dietary allowance (RDA) for older children varies with age and peaks at 3000 IU/day for adolescents (see Table 20.1). Children with conditions associated with fat malabsorption (cystic fibrosis, cholestatic liver disease) may require supplemental oral doses (2000-5000 IU/day) of a water-miscible preparation to prevent deficiency. Treatment of frank vitamin A deficiency depends on the clinical manifestations. When there are clinically significant eye-related findings, such as the presence of Bitot spots, xerophthalmia, or keratomalacia, the child should be treated with 50,000 IU (for children younger than 6 months of age), 100,000 IU (for children 6- to 12 months of age), or 200,000 IU (for children older than 12 months of age) daily for 2 days, followed by an additional oral dose after 2 weeks. For any patient with a severe case of measles, the WHO recommends the aforementioned age-specific dose once daily for 2 days, regardless of whether the patient is known to have vitamin A deficiency or not.13
Vitamin A toxicity can occur from both topical and oral use. The most common adverse effect of topical toxicity is skin irritation with peeling and erythema. Toxicity from oral intake of retinoids can be acute or chronic. Acute intoxication can cause mental status changes, seizures, headache, blurred vision, and increased intracranial pressure. Chronic toxicity can cause alopecia, anorexia, pruritus, dryness of mucous membranes, muscle and bone pain, and hyperlipidemia.14 The most serious adverse event of oral retinoids is teratogenicity. Teenagers who may become pregnant should be informed of the dangers of vitamin A or its derivatives and receive a pregnancy test before oral acne treatment. Teratogenic findings include craniofacial (cleft lip/palate), cardiac (transposition of the great vessels), thymic, and central nervous system abnormalities (microcephaly, hydrocephalus).14 Treatment of vitamin A toxicity includes discontinuing or decreasing the dose. Otherwise, treatment is specific to the symptoms.
Tolerable upper intake levels in children range from 2000 to 10,000 IU, depending on age (see Table 20.2).
Vitamin D (calciferol) refers to 2 secosteroids, vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). Vitamin D2 is derived from plants and fungi, and its use as a food or dietary supplement has largely been replaced by vitamin D3. Vitamin D3 is synthesized in the skin from 7-dehydrocholesterol on exposure to sunlight and is present in nature primarily in the fat of ocean-dwelling fish and egg yolks. Synthetic vitamin D3 used as a food supplement is largely synthesized from sheep wool oil (lanolin). Vitamins D2 and D3 are considered prohormones as they subsequently undergo 25-hydroxylation in the liver to form 25-hydroxyvitamin D (25-OH-D, also known as calcidiol), which is the major circulating form of vitamin D. From the liver, 25-OH-D is transported to the kidney for hydroxylation to form 1,25-dihydroxyvitamin D (1,25-OH2-D, also known as calcitriol). Calcitriol is the biologically active, hormonal form of vitamin D, which stimulates intestinal absorption of calcium and phosphorous, renal reabsorption of filtered calcium, and the mobilization of calcium and phosphorus from bone.15,16 Vitamin D and its many other metabolites are reviewed in detail elsewhere.17 Vitamin D metabolites are transported in the blood by vitamin-D-binding protein (DBP), which carries vitamin D to the cells where it binds with nuclear receptors to initiate its physiological actions.17 This DBP is highly polymorphic, with at least 120 known variants. It is very likely that this polymorphism has clinical implications requiring future research.18
Though vitamin D is essential for bone formation and mineral homeostasis, nuclear receptors for vitamin D are not limited to bone and mucosal cells of the gastrointestinal tract but are found in most tissues of the body.17 This has led to an explosion of clinical research and speculation regarding the potential for nonskeletal actions and other health benefits of vitamin D, such as modulating the risk of heart disease, cancer, multiple sclerosis, obesity, immunity, and diabetes.15,16 However, a report from the National Academy of Medicine (formerly the Institute of Medicine) stated that the evidence was inconclusive and no cause-and-effect relationship of vitamin D could be proven outside of the effects on bone formation and mineral homeostasis.19 More recently, vitamin D may play a possible role in preventing early childhood wheezing and asthma. A combined analysis of 2 randomized controlled clinical trials of maternal vitamin D supplementation during pregnancy showed a significant protective effect of vitamin D supplementation for the prevention of childhood asthma and recurrent wheeze up to age 3 years of age.20 In addition, in a 6-month randomized controlled trial of postnatal vitamin D supplementation in Black preterm infants, there was a 34% decreased risk of recurrent wheezing at 1 year of age among infants who received supplementation.21
Vitamin D is synthesized in the skin by the action of ultraviolet light on a cholesterol precursor. The most effective wavelengths range from 290 to 315 nm.17 The cutaneous synthesis of vitamin D by sunlight is adversely affected by skin pigmentation and environmental factors that limit sunlight exposure.15,16 Thus, the RDA for vitamin D assumes minimal sunshine exposure. The RDA for vitamin D is 400 IU for infants and 600 IU for children 1 to 18 years of age.19 Furthermore, there are concerns for the hazards of ultraviolet radiation exposure as highlighted in the policy statement from the AAP, which recommends sunscreen use to limit the effects of ultraviolet-B light exposure.22 Therefore, exposure to sunlight should not be used as a method to ensure adequate vitamin D status. This necessitates the use of vitamin-D-fortified foods or dietary supplements to maintain vitamin D status in most populations.23
The primary manifestations of vitamin D deficiency are related to the effects on calcium metabolism. Hypocalcemia, hypophosphatemia, tetany, osteomalacia, and rickets are the most common clinical features. Children at higher risk of deficiency include preterm infants, exclusively breastfed infants, children with dark skin pigmentation, and children with dietary fat malabsorption (from cholestatic liver disease, cystic fibrosis, and Crohn disease or as a result of bariatric surgery). More recently, overweight and obese children have also been identified as being at risk of vitamin D deficiency (ie, having low serum 25-OH-D). Adverse effects of obesity include increased inflammation of adipose tissue, with an increased synthesis of proinflammatory cytokines and the development of insulin resistance.24 Data on the treatment of vitamin D insufficiency in obese children and adolescents are contradictory; however, the majority of trials show that an increase in 25-OH-D levels has a positive effect on carbohydrate and lipid metabolism, as well as on the secretion of adipokines.24
AAP Statement on Calcium and Vitamin D Requirements of Enterally Fed Preterm Infants
Preterm infants, especially those <27 weeks of gestation or with birth weight <1000 g with a history of multiple medical problems, are at high risk of rickets.
Routine evaluation of bone mineral status by using biochemical testing is indicated for infants with birth weight <1500 g but not those with birth weight >1500 g. Biochemical testing should usually be started 4 to 5 weeks after birth.
Serum alkaline phosphatase >800 to 1000 IU/L or clinical evidence of fractures should lead to a radiographic evaluation for rickets and management focusing on maximizing calcium and phosphorus intake and minimizing factors leading to bone mineral loss.
A persistent serum phosphorus concentration less than approximately 4.0 mg/dL should be followed, and consideration should be given for phosphorus supplementation.
Routine management of preterm infants, especially those with birth weight <2000 g, should include human milk fortified with minerals or formulas designed for preterm infants.
At the time of discharge from the hospital, very low birth weight infants will often be provided higher intakes of minerals than are provided by human milk or formulas intended for term infants through the use of transitional formulas. If exclusively breastfed, a follow-up serum alkaline phosphatase at 2 to 4 weeks after discharge from the hospital may be considered.
When infants are tolerating full feeds, vitamin D can usually be started at about 400 IU/day up to a maximum of 1000 IU/day.
Preterm infants, especially extremely low birth weight infants (<1000 g), are at high risk for radiographically defined rickets.25 Risk factors, in addition to low birth weight, include gestational age at birth younger than 27 weeks, long-term need for total parenteral nutrition support and an inability to tolerate high-mineral content formulas or human milk fortifiers. A history of necrotizing enterocolitis25 or severe bronchopulmonary dysplasia treated with diuretics, fluid restriction, and long-term steroid exposure are also risk factors for rickets.
Historically, the best indicator of vitamin D status was serum 25-OH-D concentration, which reflects both absorption from the diet and synthesis in the skin. Other potentially useful tests include serum calcium, phosphorous, alkaline phosphatase, and parathyroid hormone concentrations. The AAP, the National Academy of Medicine, and the Pediatric Endocrine Society recommend a target for serum 25-OH-D concentration greater than or equal to 50 nmol/L (20 ng/mL).19,22,26 Deficiency is generally considered to be a concentration less than 30 nmol/L (12 ng/mL) and insufficiency is considered to be a concentration between 30 and 49 nmol/L (13-19 ng/mL). However, distinguishing between the true diagnosis of clinical vitamin D deficiency versus biochemical deficiency is challenging and also complicated by variations in methods of analysis.27 Vitamin D insufficiency (serum 25-OH-D concentration 30-49 nmol/L) is very prevalent across the world but is asymptomatic. In the United States, 46% of Black infants and 10% of white infants have serum 25-OH-D concentration less than 50 nmol/L. About 16% of US children (2-12 years old) and nearly a third of adolescents have vitamin D insufficiency.28 The question of the significance of such widespread prevalence of vitamin D insufficiency has recently come under scrutiny. More than 10 million serum 25-OH-D concentrations are measured in the United States annually. However, no subgroup of subjects defined solely by their "low" baseline 25-OH-D concentration, even below 30 nmol/L, has been shown to benefit from supplements of vitamin D in any clinical trial. Subsequently, it has been argued that there may be no justification for measuring 25-OH-D or treating any targeted serum level in the general population. Though the test may be useful to measure vitamin D status in patients with rickets or hypocalcemia who would be expected to respond to vitamin D therapy, some experts now maintain that the use of the terms vitamin D "sufficiency," "insufficiency," and "deficiency," in the general population should be reconsidered.29
A diagnosis of rickets is made on the basis of a history of inadequate intake and clinical findings (eg, craniotabes, enlargement of the costochondral junctions, beading of the ribs) and is confirmed by biochemical indices and radiographic findings. 25-OH-D concentration would be expected to be low in vitamin-D-deficiency rickets. Parathyroid hormone generally is elevated in rickets associated with vitamin D deficiency.26
In 2011, the National Academy of Medicine increased the recommended intake of vitamin D, establishing an AI of 400 IU/day for infants up to 1 year of age and an RDA of 600 IU/day for children 1 to 18 years of age,19 and this was endorsed by the AAP.23 This new RDA of 600 IU/day for children older than 1 year is higher than the amount provided by food fortification and above typical dietary intakes for most children. The vitamin D content of human milk is low (22 IU/L), and most infant formulas contain 1.5 mcg (62 IU) of vitamin D/100 kcal or 10 mcg/L (400 IU/L), as do fortified cow milk and evaporated milks. Consequently, vitamin D supplementation will be required for many children in addition to exclusively breastfed infants. At the present time, the AAP recommends vitamin D supplementation of 400 IU/day for all exclusively breastfed infants and for all other infants ingesting less than 1000 mL/day of either vitamin-D-fortified formula or milk. All other children may need supplements of vitamin D to meet the RDA of 600 IU/day if not receiving AI from fortified foods or milk.22,23
Patients with diseases associated with fat malabsorption (cholestatic liver disease, cystic fibrosis) may become vitamin D deficient despite an intake of 400 IU/day (see Chapter 39: Nutrition in Children with Liver Disease and Chapter 42: Nutrition in Cystic Fibrosis). Higher-dosage vitamin D supplementation may be necessary to achieve normal vitamin D status in these children. Vitamin D deficiency can be treated with oral vitamin D supplementation (ergocalciferol [Drisdol, oral drops, 800 IU/mL]), at a dose range of 600 to 2000 IU/day. If a vitamin D supplement is prescribed, 25-OH-D concentrations should be measured at 3-month intervals until normal concentrations have been achieved.22
Despite having limited data, in 2013, the AAP developed recommendations for preventing vitamin D deficiency in preterm infants. When able to be enterally fed, 200 to 400 IU of vitamin D is recommended for extremely low birth weight infants (<1000 g).25 Once infants reach approximately 1500 to 2000 g and are taking full enteral feeds, supplementation should be increased to 400 IU as often intake remains less than 1 L of transitional preterm formula.25 Preterm infants with rickets may require higher vitamin D supplementation (up to the established upper tolerable intake level of 1000 IU/day) as well as the addition of calcium and phosphorus supplementation.25
Several approaches have been used for the treatment of nutritional or vitamin-D-deficient rickets, including daily oral administration of 2000 to 5000 IU of ergocalciferol in children with normal gastrointestinal tract function or oral administration of 10,000 to 25,000 IU/day in children with malabsorption for 2 to 4 weeks (see Table 20.1; see also Chapter 39: Nutrition in Children with Liver Disease, and Chapter 36: Nutritional Management of Children with Renal Disease for vitamin D supplementation recommendations for children with liver and renal failure, respectively.)
The principal manifestations of vitamin D intoxication are hypercalcemia, leading to depression of the central nervous system and ectopic calcification, and hypercalciuria, leading to nephrocalcinosis and nephrolithiasis.30 It is caused by excessive vitamin D intake, but not by overexposure to ultraviolet-B light. Laboratory diagnosis can be made by measuring serum calcium (>11 mg/dL indicates excessive vitamin D intake) and serum 1,25-dihydroxyvitamin D, which is also elevated. The treatment is focused on lowering serum calcium by discontinuing any supplements of vitamin D and calcium. In cases of extreme toxicity, both parenteral calcitonin and bisphosphonates have been used.30 The tolerable upper intake level (ie, the highest daily intake that is likely to pose no risk) was revised by the National Academy of Medicine to 1000 IU/day for infants 0 to 6 months of age, 1500 IU/day for infants 6 to 12 months of age, 2500 IU/day for children 1 through 3 years of age, 3000 IU for children 4 through 8 years of age, and 4000 IU/day for children 9 years and older (see Table 20.2).
Vitamin E, or tocopherol, exists in 8 forms, but alpha-tocopherol has the highest biological activity. It is the predominant form in foodstuffs with the exception of soy oil, which contains high levels of gamma-tocopherol. Alpha-tocopherol is also the most abundant form in plasma.31 The major function of vitamin E is its role as an antioxidant, protecting cell membrane polyunsaturated fatty acids, thiol-rich proteins, and nucleic acids from oxidant damage initiated by free-radical reactions. Vitamin E is essential for the maintenance of structure and function of the human nervous system, retina, and skeletal muscle. The common dietary sources of vitamin E are the oil-containing grains and vegetables.31 Vitamin E supplementation prevents severe neuropathy in infants with biliary atresia and other forms of chronic cholestatic liver disease.31,32,33 Little or no basis exists for the claims of the late 20th century that high dietary intakes of vitamin E prolong life, increase sexual potency, prevent cancer, or improve cognitive function in Alzheimer disease. Although it was suggested that vitamin E supplementation may play a role in prevention of cardiovascular disease, large-scale prospective studies have not shown any beneficial effect.34 In contrast, more recent evidence suggests that treatment with vitamin E may benefit patients with obesity-related nonalcoholic fatty liver disease and may improve steatohepatitis in children.35
The wide distribution of vitamin E in vegetable oils and cereal grains makes deficiency in people from industrialized countries unlikely. Vitamin E supplements are necessary for those with malabsorption (eg, pancreatic insufficiency or cystic fibrosis), biliary atresia and other biliary tract disorders, cirrhosis, and lipid transport disorders. Uncorrected vitamin E deficiency during childhood leads to a progressive neurologic disorder, including truncal and limb ataxia, hyporeflexia, depressed vibratory and position sensation, impairment in balance and coordination, peripheral neuropathy, proximal muscle weakness, ophthalmoplegia and retinal dysfunction.31 Ataxia with vitamin E deficiency usually manifests in the preteen to teenage years and clinically manifests with ataxia, dysarthria, decreased proprioception, vibratory sensation, and decreased reflexes due to the neurologic dysfunction linked to vitamin E deficiency, despite normal intake of the vitamin.36
Significant neurodevelopmental and behavioral abnormalities have been associated with vitamin E deficiency, including autism. These may respond to a combination of omega-3 fatty acids and vitamin E therapy, but studies are limited at this time and further clinical trials are needed.37
Vitamin E deficiency has also been linked to hemolytic anemia in preterm infants.38
Vitamin E status is monitored by serum alpha-tocopherol concentrations and in patients with very high total lipid levels, serum alpha-tocopherol-to-total lipid ratios. Levels of alpha-tocopherol less than 0.5 mg/dL are considered a deficiency.32
The AI for alpha-tocopherol is 4 mg/day for infants 0 through 6 months of age and 5 mg/day for infants 7 to 12 months of age. The RDA for alpha-tocopherol is 6 mg/day for children 1 through 3 years of age, 7 mg/day for children 4 through 8 years of age, and 11 to 15 mg/day for children 9 through 18 years of age (see Table 20.1).
For children with conditions associated with fat malabsorption (cholestatic liver disease), supplemental doses of vitamin E are required to prevent deficiency. Maximum doses range from 200 IU daily for ages 1 month to 3 years, to 800 IU daily for ages 14 to 18 years.32
Vitamin E toxicity is rare, and there have been no reports in children.39 Vitamin E is the least toxic FSV. Healthy adults appear to tolerate oral doses of 100 to 800 mg/day without clinical signs or biochemical evidence of toxicity. The National Academy of Medicine has set the tolerable upper intake level for children at 200 to 800 mg/day depending on age, although no limit has been established for the first 12 months after birth (see Table 20.2).
Vitamin K belongs to the family of 2 methyl-1,4 naphthoquinones and exists naturally in 2 forms important to human health.40,41,42 Phylloquinone (vitamin K1) is obtained from leafy green vegetables, soybean oil, fruits, seeds, and cow milk. Menaquinone (vitamin K2), which has 60% of the activity of vitamin K1 is synthesized by intestinal bacteria. Vitamin K is necessary for the posttranslational carboxylation of glutamic acid residues of the vitamin-K-dependent coagulation proteins (factors II, VII, IX, and X, protein C, and protein S). Carboxylation allows these proteins to bind calcium, thus, leading to activation of the clotting factors.40,41,42 Other proteins undergoing this carboxylation of glutamic acid residues include osteocalcin, which is involved in bone mineralization.
Vitamin K deficiency leads to hypoprothrombinemia and hemorrhagic disorders. Newborn infants are especially at risk of newborn vitamin K deficiency bleeding secondary to the inherently poor placental transport of vitamin K and the low concentration of vitamin K in human milk (20 IU/L compared with 60 IU/L in cow milk).42,43,44 Common locations of bleeding include the gastrointestinal tract, the umbilicus, or the circumcision site in the newborn period. Later in infancy, intracranial hemorrhage with devastating results may occur, especially in exclusively breastfed infants who receive no vitamin K prophylaxis at the time of birth. In older children and adults, hypoprothrombinemia associated with vitamin K deficiency is usually secondary to disorders of fat malabsorption or chronic liver disease,45 cystic fibrosis,46 and inflammatory bowel disease.47 Vitamin K deficiency may also be seen in children on highly restricted diets or following bariatric surgery. Several studies have suggested an association between low vitamin K concentrations and abnormal bone mineral density, bone turnover, and osteoporosis in adults.48
Vitamin K status is monitored by prothrombin time, the measurement of vitamin-K-dependent factors (factors II, VII, IX, and X), plasma phylloquinone (vitamin K1), or the analysis of proteins-induced-in-vitamin K absence.42,43
The newborn infant should receive vitamin K soon after birth for prophylaxis against hemorrhagic disease of the newborn. Vitamin K can be administered as a single intramuscular dose of 1 mg for term infants and 0.3 to 0.5 mg/kg for preterm infants with weights less than 1000 g.49 Of note, there have been no randomized controlled trials of vitamin K for prevention of bleeding in preterm infant, so prophylaxis in preterm infants is based on expert consensus.50 If parents decide against intramuscular vitamin K for their infant after consulting with health care providers, then an oral dose of 2 mg should be administered at birth, 1 to 2 weeks of age, and 4 weeks of age.51 As noted later onset vitamin deficiency bleeding with intracranial hemorrhage is largely a disease of exclusively breastfed infants who do not receive intramuscular vitamin K at the time of birth. The human milk content of vitamin K is very low and does not meet the AI. Parents of infants who refuse vitamin K should receive information from care providers about the hazards of vitamin K deficiency in infants, especially exclusively breast fed infants who are in the highest risk group for parental refusal for vitamin K prophylaxis in the newborn infant.49 Following the prophylactic dose of vitamin K at birth, formula fed infants will receive adequate vitamin K from commercially available infant formulas. The AI for infants is 2 mcg/day of phylloquinone or menaquinone for the first 6 months and 2.5 mcg/day for the second 6 months after birth. The AI for older children is 30 mcg/day for children 1 through 3 years of age, 55 mcg/day for children 4 through 8 years of age, and 60 to 75 mcg/day for older children and adolescents (see Table 20.1). Note no RDAs have been established for any age group.
In conditions associated with fat malabsorption and vitamin K deficiency (cystic fibrosis, cholestatic liver disease, inflammatory bowel disease), supplemental doses of 2.5 to 5 mg, 2 to 7 times/week, may be used to prevent deficiency, though the evidence that this is beneficial in preventing bleeding is limited.45,46,47 Hypoprothrombinemia associated with chronic liver disease may be corrected by the administration of 5 to 10 mg of vitamin K given intramuscularly. Failure of the prothrombin time to improve following adequate administration of vitamin K is suggestive of severe liver synthetic dysfunction. Vitamin K does not appear to be an effective treatment for the reversal of excessive anticoagulation secondary to oral anticoagulants.52
AAP Recommendations Concerning the Administration of Vitamin K to Newborn Infants
Vitamin K should be administered to all newborn infants weighing >1500 g as a single intramuscular dose of 1 mg within 6 hours of birth.
Preterm infants weighing ≤1500 g should receive a vitamin K dose of 0.3 mg/kg to 0.5 mg/kg as a single intramuscular dose. A single intravenous dose of vitamin K for preterm infants is not recommended for prophylaxis.
Pediatricians and other health care providers must be aware of the benefits of vitamin K administration as well as the risks of refusal and convey this information to the infant's caregivers.
Vitamin K deficiency bleeding should be considered when evaluating bleeding in the first 6 months after birth, even in infants who received prophylaxis, and especially in exclusively breastfed infants.
Vitamin K toxicity is very rare. In newborn infants, intravenous administration of water-soluble synthetic vitamin K (vitamin K3 or menadione) has been associated with hemolytic anemia, hyperbilirubinemia, and kernicterus.41 However, menadione can no longer be used in humans. No toxicity states have been associated with administration of the natural forms of vitamin K (K1 and K2).41
FSVs occur naturally in foods; with the exception of vitamin K2, menaquinone, they are not synthesized by the intestinal microbiota
All FSVs share the same intestinal absorption process as dietary lipids. Thus, the primary risks for deficiencies of FSVs occur in clinical disorders that affect fat malabsorption.
Supplements of FSVs are not necessary in a healthy population. Exceptions are the need for vitamin K in very early life and supplements of vitamin D in exclusively breastfed infants and other infants and children not receiving the recommended intakes of vitamin D from fortified foods and beverages.
Unlike water-soluble vitamins, FSVs are stored in body tissues and account for the majority of significant reports of vitamin toxicity. Upper tolerable limits for the intake of FSVs have been established with the exception of vitamin K.
Recommended intakes for infants for FSVs are AIs. Recommended intakes for vitamin K for 1 to 18 years of age are AIs. All other intakes for FSVs for 1 to 18 years of age are RDAs.