1. Nutrient Needs: Part 2 Vitamin K Vitamin D Calcium and Phosphorus Iron Zinc B-12 Flouride

2. Vitamin K

3. 2 forms: K1 or phylloquinone (plant form) and K2 (synthesized by bacteria) Function: cofactor in metabolic conversion of precursors of Vitamin K dependent proteins to active form ( eg: prothrombins, osteocalcin)

4. Vitamin K Lack of specific information regarding an infant’s requirement Vitamin K concentration of breastmilk is low and for the breastfeeding infant a deficiency state has been described No “gold standard” available

5. Vitamin K deficiency: Haemorrhagic disease of newborn First used in 1894 to describe bleeding in the newborn not due to trauma or haemophilia Current Terminology: – VKDB: vitamin K deficiency bleeding EVKDB: early LVKDB: late

6. Vitamin K Deficiency- definitions – AAP, 2003 TermAge and Incidence Symptoms Early vitamin K deficiency bleeding (VKDB)* First week of life:Unexpected bleeding in previously healthy-appearing neonates Late VKDB2-12 weeks of age unexpected bleeding attributable to severe vitamin K deficiency * Formerly known as classic hemorrhagic disease of the newborn

7. Incidence of VKDB Early: 0.25%–1.7% incidence Late: – No vitamin K prophylaxis: 4.4 to 7.2 per 100,000 births – Single oral vitamin K prophylaxis:1.4 to 6.4 per 100 000 births – IM vitamin K prophylaxis: 0 Oral vitamin K has effect similar to IM in preventing early VKDB, but not in preventing late VKDB

8. Vitamin K DRI for infants 2-2.5 ug/day Formula provides 7-9 ug/kg/d BM contains < 10 ug/L Hemorrhagic disease of the Newborn…Vitamin K deficiency Prophylaxis: 1 mg Vitamin K IM for all newborn infants

9. Controversies Concerning Vitamin K and the Newborn: AAP Policy Statement, 2003

10. Vitamin K Controversy Adequacy of BM Maternal Diet and Vitamin K content of BM ? Significance/prevalence of hemorrhagic disease of newborn IM injections of all newborns

11. Danielson et al Arch Dis Child 2004 89:F546-550 Late onset vitamin K deficient bleeding in infants who did not receive prophylactic vitamin K at birth in Hanoi province – Incidence: 116 per 100,000 births – Higher in rural areas – 9% mortality – 42% impaired neurodevelopmental status at discharge in survivors

12. Incidence Netherlands 2005: 3.2 per 100,000 births Canada 2004: 0.45 per 100,000 births – Conclude low incidence associated with current practice of prophylactic Vitamin K at birth

13. Closing the Loophole:Midwives and the Administration of Vitamin K in the Neonate Adame and Carpenter J Pediatr 2009 154:769-771 Case Report of a previously healthy, exclusively breastfed 6 week old infant delivered by a midwife on the south Texas border. Did not receive Vitamin K at birth. Admitted with severe intracranial hemorrhage, cooagulopathy, and seizures, unresponsive, pupils fixed and dialated

14. Brousson and Klien, Controversies surrounding the administration of vitamin K to newborns; a review. CMAJ. 154(3):307-315, February 1, 1996. Study selection: Six controlled trials met the selection criteria: a minimum 4-week follow-up period, a minimum of 60 subjects and a comparison of oral and intramuscular administration or of regimens of single and multiple doses taken orally. All retrospective case reviews were evaluated. Because of its thoroughness, the authors selected a meta- analysis of almost all cases involving patients more than 7 days old published from 1967 to 1992. Only five studies that concerned safety were found, and all of these were reviewed

15. Brousson and Klien, Controversies surrounding the administration of vitamin K to newborns; a review. CMAJ. 154(3):307-315, February 1, 1996. Data synthesis: Vitamin K (1 mg, administered intramuscularly) is currently the most effective method of preventing HDNB. The previously reported relation between intramuscular administration of vitamin K and childhood cancer has not been substantiated. An oral regimen (three doses of 1 to 2 mg, the first given at the first feeding, the second at 2 to 4 weeks and the third at 8 weeks) may be an acceptable alternative but needs further testing in largeclinical trials.

16. Brousson and Klien, Controversies surrounding the administration of vitamin K to newborns; a review. CMAJ. 154(3):307-315, February 1, 1996 Conclusion: There is no compelling evidence to alter the current practice of administering vitamin K intramuscularly to newborns.

17. Cochran Prophylactic Vitamin K for preventing haemorrhagic disease in newborn infants Vitamin K deficiency can cause bleeding in an infant in the first weeks of life. This is known as Haemorrhagic Disease of the Newborn (HDN) or Vitamin K Deficiency Bleeding (VKDB).

18. Cochran The risk of developing vitamin K deficiency is higher for the breastfed infant because breast milk contains lower amounts of vitamin K than formula milk or cow's milk

19. Cochran In different parts of the world, different methods of vitamin K prophylaxis are practiced.

20. Cochran Oral Doses: The main disadvantages are that the absorption is not certain and can be adversely affected by vomiting or regurgitation. If multiple doses are prescribed the compliance can be a problem

21. Cochran I.M. prophylaxis is more invasive than oral prophylaxis and can cause a muscular haematoma. Since Golding et al reported an increased risk of developing childhood cancer after parenteral vitamin K prophylaxis (Golding 1990 and 1992) this has been a reason for concern.

22. Cochrane Conclusions, 2000 A single dose (1.0 mg) of intramuscular vitamin K after birth is effective in the prevention of classic HDN. Either intramuscular or oral (1.0 mg) vitamin K prophylaxis improves biochemical indices of coagulation status at 1-7 days. Neither intramuscular nor oral vitamin K has been tested in randomized trials with respect to effect on late HDN. Oral vitamin K, either single or multiple dose, has not been tested in randomized trials for its effect on either classic or late HDN.

23. Oral Supplementation with Vitamin K Increase in reports of late VKDB Single oral dose does not provide sustained elevations in serum Vitamin K to prevent late bleeding Multidose regimen (1-2 mg given 3X over first 3 months) has been used in some countries – Some studies report efficacy – Also, reports of treatment failure (eg Germany, Australia, Sweden) – Disadvantages: reliance on compliance, increased cost, unreliable infant intake/feeding – AAP recommends contininuation of IM prophylaxis

24. AAP Recommendations: Pediatrics:Vol112#1 July 2003 1. Vitamin K1 should be given to all newborns as a single, intramuscular dose of 0.5 to 1 mg. 2. Further research on the efficacy, safety, and bioavailability of oral formulations of vitamin K is warranted.

25. AAP Recommendations 3. Health care professionals should promote awareness among families of the risks of late VKDB associated with inadequate vitamin K prophylaxis from current oral dosage regimens, particularly for newborns who are breastfed exclusively 4. Earlier concern regarding a possible causal association between IM vitamin K and childhood cancer has not been substantiated

26. Vitamin D

27. Role Source – Dietary – sunlight Deficiency – Rickets

28. Role Enhances intestinal absorption of Ca Increase tubular resorption of Ph Mediation of recycling of Ca and Ph for bone growth and remodeling Sterol hormone – Deficiency: Rickets

29. Role Extraskeletal effects of Vitamin D – Modulates B and T Lymphocyte fx and deficiency may be associated with autoimmune diseases (diabetes, MS associations) – Regulation of cell growth (assoc with breast, prostrate, and colon cancer)

30. Prevalence Thought to be disease of past (prior to 1960’s) – Disappeared secondary to recognition of role of sunlight, fortification of milk, use of multivitamins, AAPCON recommendation for 400 IU supplementation of infants

31. Prevalence Increased incidence and case reports 1970’2 No national data in US – Georgia 1997-99: 9 per million hospitalized children – National Hospital Discharge Survey: 9 per million – Pediatric Research in Office Setting (AAP):23-32 hospitalized cases reported 1999-2000

32. Prevalence Literature Review – 13 articles published between 1996-2001 – 122 case reports

33. Prevention of Rickets and Vitamin D Deficiency: New Guidelines for Vitamin D Intake PEDIATRICS Vol. 111 No. 4 April 2003, pp. 908-910

34. Vitamin D and Sunlight Vitamin D requirements are dependent on the amount of exposure to sunlight. Dermatologists recommend caution with sun exposure. – Sunscreens markedly decrease vitamin D production in the skin – Decreased sunlight exposure occurs during the winter and other seasons and when sunlight is attenuated by clouds, air pollution, or the environment – AAP recommends against exposing infants < 6 months to direct sun

35. Breastfeeding and Vitamin D Breastmilk has < 25 IU/L Recommended adequate intake can not be met with breastmilk alone Formerly stated that needs could be met with sun exposure, but now, due to cancer concerns recommend against this

36. Vitamin D Recommendations Before 2003 AAP recommended 10  g (400 IU) per day for breastfeed infants 2003: American Academy of Pediatrics recommends supplements of 5  g (200 IU) per day for all infants as recommended in DRIs. 10/14/2008: AAP updates guidelines for vitamin D intake for infants, children, and teens to be published in Nov 5 th ed Pediatrics – 400 IU per day intake of vitamin D beginning in first few days of life

37. Formulas if an infant is ingesting at least 500 mL per day of formula (vitamin D concentration of 400 IU/L), he or she will receive the recommended vitamin D intake of 200 IU per day. If intake is less than 500 ml recommend additional supplement of vitamin D

38. Summary of AAP Recommendations All breastfed infants unless they are weaned to at least 500 mL per day of vitamin D-fortified formula or milk. All nonbreastfed infants who are ingesting less than 500 mL per day of vitamin D-fortified formula or milk. Children and adolescents who do not get regular sunlight exposure, do not ingest at least 500 mL per day of vitamin D-fortified milk, or do not take a daily multivitamin supplement containing at least 200 IU of vitamin D.

39. AAP Recommendations for Vitamin D 2008 – Intake of 400 IU beginning in first few days of life Supplement breastfed, partially breastfed, infants and children consuming less than 1 liter formula or vitamin D fortified whole milk Wagner et al: Prevention of Rickets and Vitamin D Deficiency in Infants, Children, and Adolescents: Pediatrics 2008;122;1142-1152

40. Vitamin D DRI: B-6 months 200 IU, 7-12 months 250 IU UL: 1000 IU

41. Calcium and Phosphorus

42. Basis of recommendations Previous RDA of 400-800 mg/d of Ca was based on formula feeding with 25-30% retention Breastfed infants retain 2/3 of their Ca intake from breastmilk

43. Calcium AgeDRI mg/d Birth-6 months210 7-12 months270 1-3 years500 4-8 years800

44. Hot off the Presses! FNB IOM recommends Calcium intake – B-6 months: 200 mg/d – 7-12 months: 260 mg/d – 1-3 years of age: 700 mg/d – 4-8 years of age: 1000 mg/d

45. Calcium/Phosphorus content of typical Infant feedings: (mg/dl) Breastmilk: – 28/14 Standard Infant Formula – 49/38

46. Iron Function Source – Formula, breast milk, other foods – Bioavailability: Breast milk Soy formula Deficiency – Anemia

47. Anemia Anemia (low Hct, Hgb: not specific for iron deficiency) Causes: – Inadequate iron in diet – Loss – GI bleeding, cows milk proteins, infectious agents – Other Genetics Lead Other nutrients

48. Iron Biological function – Oxygen transport primarily in hemoglobin – Component of other proteins including cytochrome a, b, c, and cytochrome oxidase essential for electron transport and cellular energetics

49. Iron deficiency (ID and IDA) Anemia: Hgb <11 g/dl 12-36 months Iron deficiency Anemia (IDA): anemia due to iron deficiency Iron deficiency: Insufficient iron to maintain normal physiologic functions leading to decrease in iron stores as measured by serum ferritin with or without IDA

50. Association between ID and IDA and neurobehavioral development – Lozoff – McCann and Ames – Cochrane review – Carter – Recent sleep studies

51. Iron Deficiency Anemia Impact on social, neurobehavioral and sleep – Peirano et al: Sleep and Neurofunction Throughout Child development: Lasting Effects of Early Iron Deficiency J Ped Gastroenterology and Nutr 2009 48:S8-S15 – Lozoff et al: Dose-Response Relationships between Iron deficiency with or without anemia and Infant Social-emotional Behavior J Pediatr 2008 152:696-702

52. Peirano Slower neurotransmission in auditory and visual systems Different motor activity patterning sleep- waking and sleep state organization Alterations in behavioral and cognitive function

53. Lozoff N=77 “Infant social-emotional behavior appears to be adversely affected by iron deficiency with or without anemia” – Shyness, orientation engagement, soothability

54. Carter et al: Iron Deficiency Anemia and Cognitive Function in Infancy: Pediatrics 2010 126;2427-e434 N= 87 (28 IDA, 49 no anemia) Methods: at 9 and 12 months series of cognitive, intellegent and behavioral tests administered (Fagan test of infant intellegence (FTII), Emotionality, Activity and Sociability Temperment Survey, and Behavior Rating Scale (BRS))

55. Carter et al: Iron Deficiency Anemia and Cognitive Function in Infancy: Pediatrics 2010 126;2427-e434 Results – Sociodemographic background similar between 2 groups – IDA infants less likely to exhibit object permanence, less novelty preference on the FTII, lower BRS scores, and decrease engagement/orientation, described as “shyer”

56. Iron Deficiency Among children in developing world, iron is the most common single nutrient deficiency No national statistics for prevalence of ID or IDA < 12 months

57. Iron Deficiency in Breastfeeding At 4 to 5 months prevalence of low iron stores in exclusively breastfed infants is 6 - 20%. A higher rate (20%-30%) of iron deficiency has been reported in breastfed infants who were not exclusively breastfed The effect of iron obtained from formula or beikost supplementation on the iron status of the breastfed infant remains largely unknown and needs further study.

58. Iron Deficiency Prevalence at 9 Months

59. Iron Fortification of Formula “The increased use of iron-fortified infant formulas from the early 1970s to the late 1980s has been a major public health policy success. During the early 1970s, formulas were fortified with 10 mg/L to 12 mg/L of iron in contrast with nonfortified formulas that contained less than 2 mg/L of iron. The rate of iron-deficiency anemia dropped dramatically during that time from more than 20% to less than 3%.”

60. ID and IDA 12-35 Months NHANES 2002 PopulationID (%)IDA (%) General US9.22.1 Above poverty8.92.2 Below poverty8.62.3 Enrolled in WIC 10.73.2 Mexican American 13.90.9 Other ethnicity15.24.4

61. Iron Iron absorption from soy formulas is less Greater bioavailabilty of iron in breastmilk

62. Iron Absorption In Infancy

63. Foman on Iron - 1998 Proposes that breastfed infants should have supplemental iron (7 mg elemental) starting at 2 weeks. Rational: – some exclusively breastfed infants will have low iron stores or iron deficiency anemia – Iron content of breastmilk falls over time – animal models indicate that deficits due to Fe deficiency in infants may not be recovered when deficiency is corrected.

64. AAP recommendations for Dx and prevention of ID and IDA:2010 Pediatrics 2010 126 #5 Birth-6 months: 0.27 mg/d – Assuming average content Breastmilk 0.35 mg/L and average intake 0.78 L/day – Noted variability of iron content of breastmilk, high risk populations (IUGR, LGA associate with maternal IDM, maternal anemia, Preterm birth)

65. AAP recommendations for Dx and prevention of ID and IDA:2010 Pediatrics 2010 126 #5 7-12 months: 11 mg/d – Factorial approach: iron loss, iron needed for increased blood volume, tissue mass, and stores – Noted that there isn’t a sudden increase in needs from 6 to 7 months.

66. AAP recommendations for Dx and prevention of ID and IDA:2010 Pediatrics 2010 126 #5 Diagnosis: – Iron status is a continuum with IDA at one end of the spectrum – No single measurement is currently available to characterize iron status – HgB limitations include specificity and sensitivity. Identifies anemia but not necessarily ID or IDA

67. AAP recommendations for Dx and prevention of ID and IDA:2010 Pediatrics 2010 126 #5 Term, healthy infants have sufficient Fe to 4 months. Formula fed: Fe needs met by standard infant formula with 12 mg/dl and introduction of complementary foods after 4-6 months. Whole milk shouldn’t be used < 12 months Breastfed: Exclusively breastfed infants are a increasing risk of ID >4 months and should be supplemented with 1 mg/kg/d oral Fe until appropriate complimentary food are introduced

68. AAP recommendations for Dx and prevention of ID and IDA:2010 Pediatrics 2010 126 #5 6-12 months – 11 mg/d – Use complimentary foods with higher iron content. Liquid supplement may be needed to augment complimentary foods

69. AAP recommendations for Dx and prevention of ID and IDA:2010 Pediatrics 2010 126 #5 Univeral screening should be done at 12 months with Hgb and risk determination Additional screening can be preformed at any time if there is a risk of ID/IDA including inadequate intake

70. Iron: DRI AgeIron mg/d Birth-6 months0.27 7-12 months11 1-3 years7 4-8 years10

71. Food sources of Iron FoodMeasureIron (mg) Iron fortified formula8 oz2.9 Infant Cereal (rice)1TB1.7 Strained meats with vegetable2 Tb0.1 Strained beef2 TB0.2 meats2 TB1.2 egg10.7 Peanut butter1 TB0.3 Bread white1 slice0.2 Enriched macaroni cooked¼ cup0.5 vegetables¼ cup0.2 fruits¼ cup0.1 cheerios½ cup1.2 Rice Chex½ cup1

72. Other Causes of Anemia Jones et al Hidden Threats: Lead Poisoning From Unusual Sources Pediatrics 1999 104(1223-1225) Jones et al Trends in Blood Lead Levels and Blood Lead Testing Among US Children Aged 1-5 years Pediatrics 2009 123 (e376-e385)

73. Iron-Lead Interactions IDA increases intestinal lead absorbtion Epidemiologic association between IDA and increased lead concentrations Primary prevention of IDA may contribute to prevention of lead poisoning IDA also decreases the efficiency of chelation therapy for lead poisoning. Effect of iron supplementation on iron replete children with lead poisoning is not know

74. Zinc Function: metalloenzymes associated with CHO and energy metabolism, protein catabolism and synthesis, nucleic acid synthesis, and heme biosynthesis. Other zinc dependent enzymes include erythrocyte carbonic anhydrase, alkaline phosphatase, DNA and RNA polymerases. Through its role in superoxide dismutase enzyme systems, Zinc acts in stabilzing cell membranes and protecting them from lipid peroxidation. Zinc is also involved in protein and collagen synthesis

75. Zinc Concentration in colostrum is high, but concentration rapidly declines over 1 st year. Reports of subclinical zinc deficiency in growing preterm infant fed human milk – * continued post-discharge

76. Zinc Globally, zinc deficiency is widespread in infants and young children in developing countries, being a major cause of morbidity and mortality, and of impaired growth. – Diarrhea, pneumonia associated morbidities – Due to zinc dependent host defense mechanisms (T and B cell functions)

77. Zinc, Folate, Vitamin E AgeZinc mg/dFolate mcg/dVitamin E mg/d Birth-6 months2654 7-12 months3805 1-3 years31506 4-8 years52007

78. B-12 B-12 concentration in breastmilk may be influenced by maternal diet. Milk from lactating mothers following a strict vegan diet may provide inadequate vitamin B- 12 to their infants. B-12 deficiency has been reported in infants breast-fed by mothers with pernicious anemia.

79. Vitamin B12 No reports of overt toxicity Overt deficiency documented among infants and children who are fed no animal foods & are not supplemented DRI: (mcg.d) – B-6 months: 0.4 – 7-12 months: 0.5 – 1-3 years: 0.9 – 4-8 years: 1.2 15 mo old infant Breastmilk only, 10 x/day Appeared well-nourished Refused solids Demonstrated developmental delay < blood B12, folate, Fe

80. Vitamin B12 Mother, appeared well- nourished taking extra Vit A, 100ug B12, 3-4000mg Vit C/day Reluctant to D/C breastfeeding Worried re: intro of solids, allergies Infant – supplemented folic acid, iron – 1000 ugB12 IM – PolyViFlor

81. Clinical presentation and metabolic consequences in 40 breastfed infants with nutritional Vitamin B-12 deficiency Eur J Paed Neurol Nov 2010 14(16) 488-95 40 Breast fed infants with B-12 deficiency (17 severe, 23 mild Maternal B-12 satus major contributing factor Symptoms: FTT (48%), DD (38%), microcephaly (23%), anemia (63%)

82. Fluoride Fluoride and dental caries – At beginning of 20 th century dental caries was common with extraction only treatment available – Failure to meet minimum standards of 6 opposing teeth was common cause of rejection from military service in WWI and WWII

83. Fluoride 1901 Dr. Frederick S Mckay noted mottled teeth (fluorosis) in practice in Colo Springs Colo that were resistent to decay 1909 Dr. FC Robertson noted same mottling in his area of practice after a new well dug – Believed was due to something in the water

84. Fluoride 1945 study was conducted in 4 city pairs (Michigan, NY, Illinois, Ontario) Followed 13-15 years 50-60% reduction in dental caries

85. Fluoride Proposed mode of action – Promotes remineralization of areas of cariogenic lesions – Increases resistance to acid demineralization – Interferes with formation and function of plaque forming microorganisms – Improves tooth morphology

86. Fluoride Concerns – Excess – Fluorosis – Cancer – other

87. Fluoride Fluoride Recommendations were changed in 1994 due to concern about fluorosis. Breast milk has a very low fluoride content. Fluoride content of commercial formulas has been reduced to about 0.2 to 0.3 mg per liter to reflect concern about fluorosis. Formulas mixed with water will reflect the fluoride content of the water supply. Fluorosis is likely to develop with intakes of 0.1 mg/kg or more.

88. Fluoride, cont. Fluoride adequacy should be assessed when infants are 6 months old. Dietary fluoride supplements are recommended for those infants who have low fluoride intakes.

90. Fluoride To prevent fluorosis, tolerable upper limit (UL) has been set at 0.7 mg/d B-6 months, and 0.9 mg/d 7-12 months AAP – Not recommended < 6 months – 0.25 mg/d after 6 months if water contains < 0.3 ppm) – After tooth eruption: fluoridated water several times/day (BF) or prepare formula with water with fluoridated water (<0.3 mg/L) –

91. Early Childhood Caries AKA Baby Bottle Tooth Decay Rampant infant caries that develop between one and three years of age

92. Early Childhood Caries: Etiology Bacterial fermentation of cho in the mouth produces acids that demineralize tooth structure Infectious and transmissible disease that usually involves mutans streptococci MS is 50% of total flora in dental plaque of infants with caries, 1% in caries free infants

93. Early Childhood Caries: Etiology Sleeping with a bottle enhances colonization and proliferation of MS Mothers are primary source of infection Mothers with high MS usually need extensive dental treatment

94. Early Childhood Caries: Pathogenesis Rapid progression Primary maxillary incisors develop white spot lesions Decalcified lesions advance to frank caries within 6 - 12 months because enamel layer on new teeth is thin May progress to upper primary molars

95. Early Childhood Caries: Prevalence US overall - 5% 53% American Indian/Alaska Native children 30% of Mexican American farmworkers children in Washington State Water fluoridation is protective Associated with sleep problems & later weaning

96. Early Childhood Caries: Cost $1,000 - $3,000 for repair Increased risk of developing new lesions in primary and permanent teeth

97. Early Childhood Caries: Prevention Anticipatory Guidance: – importance of primary teeth – early use of cup – bottles in bed – use of pacifiers and soft toys as sleep aides

98. Early Childhood Caries: Prevention Chemotheraputic agents: fluoride varnishes and supplements, chlorhexidene mouthwashes for mothers with high MS counts Community education: training health providers and the public for early detection