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Update on Perinatal and Pediatric Vitamin D

Update on Perinatal and Pediatric Vitamin D. Michael K. Georgieff M.D., FAAP Professor of Pediatrics University of Minnesota School of Medicine. Vitamin D. Vitamin D is a steroid hormone (not a vitamin) Initial form is Vitamin D3 (cholecalciferol)

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Update on Perinatal and Pediatric Vitamin D

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  1. Update on Perinatal and Pediatric Vitamin D Michael K. Georgieff M.D., FAAP Professor of Pediatrics University of Minnesota School of Medicine

  2. Vitamin D • Vitamin D is a steroid hormone (not a vitamin) • Initial form is Vitamin D3 (cholecalciferol) • Created in dermal cells by UV light exposure (converts cholesterol to D3) • Active form is 1,25 di-hydroxy vitamin D (calcitriol)

  3. Vitamin D • De Novo synthesis of Vitamin D requires • Sun exposure + • Intact liver + • Intact kidney or… • Dietary source of calcitriol

  4. How Vitamin D Works • Enhances intestinal absorption of calcium and phosphorus • Increases tubular reabsorption of phosphorus • Does not work on bone (PTH does) • Important mediator of efficient recycling of calcium and phosphorus so they are available for bone growth and remodeling

  5. Rickets • General term refers to abnormal bone growth and development due to pervasive lack of calcium and phosphorus substrate • Vitamin D deficient rickets results in disorganized cartilage in long bone growth plates • What about subclinical vitamin D deficiency?

  6. Vitamin D Deficient Rickets • Presents between 6 and 18 months • Failure to attain or regression of motor milestones (notably walking or other weight- bearing activities) • Bowed legs, flared wrists, pain on major motor activity, growth failure • History of lack of sun exposure and dietary risk factors

  7. Laboratory Findings • Low serum calcium and phosphorus • Elevated PTH level (parathyroid hormone) • Very low 25-OH vitamin D level (hallmark finding) • <27.5 nmol/L (11 ng/mL) is low in children • <37.5 nmol/L (15 ng/mL) causes increase in PTH level in adults • Unknown at what level PTH rises in children

  8. Radiological Findings In Childhood Rickets • Flared epiphyses • Bowing of long bones • Rib changes • Fractures

  9. What are the Concerns? • Healthy bone growth • In childhood • Bone banking for adulthood • CNS effects • Genes regulated by vitamin D

  10. Who is at Risk for Early Vitamin D Deficiency? • Infants with low intrauterine accretion • Born to vitamin D deficient mothers • IUGR infants • Premature infants • Infants with low vitamin D status • Lack of sun exposure + • Low dietary sources

  11. Pediatric Vitamin D Incidence of D deficiency Populations at Risk Sources of vitamin D Breastfeeding Supplementation (Baby or Mom?)

  12. Prevalence • Rickets thought to be disease of the past • “Disappeared” in early 1960s due to: • Recognition of role of sunlight in vitamin D homeostasis; fortification of milk • Use of multivitamin preps • Higher prevalence of formula use • AAP CON recommended 400 IU/d starting at 2 weeks of age

  13. Prevalence • Increased case reports and series of nutritional rickets since late 1970’s • Exact prevalence remains unknown but prevalence of risk factors increasing • Less sun exposure • Higher prevalence of nursing • Decreased prescription of vitamins for nursing infants

  14. Estimated Incidence from Hospitalized Children • No national data on incidence in US • Georgia (1997-99) • 9 per million hospitalized children • 5/9 due to nutritional rickets (all darkly pigmented children) • All breastfed • National Hospital Discharge Survey (NHDS) • 9 per million hospitalized children in US • 75% darkly pigmented children; 50%<12 months

  15. Estimated Incidence from Office-Seen Children • Pediatric Research in Office Setting (PROS) network of AAP • 23-32 cases per million child office visits between 1/99 and 6/00. • Survey (low response rate=26%) • All darkly pigmented • All breastfed • Maternal Vitamin D status unknown

  16. Estimated Incidence from Literature • 13 articles published between 1996 and 2001 • 122 cases reported • 12 US states • 87% darkly pigmented • Age range from 4 to 58 months at diagnosis

  17. What are the concerns? • Is the scientific evidence solid? • Adverse effect on breastfeeding • Expense of supplementation • Risks of supplementation • Addressing the multiplicity of issues • Increasing the risk of unhealthy sun exposure behaviors

  18. What are the questions? • What level of Vitamin D is adequate? • What do we really know about sunshine, prevention of rickets, and risks of skin cancer • How much does skin pigmentation alter the dose? • If one were to recommend supplementation: • Should the mother, the infant, or both receive supplementation • Should this be universal or targeted? • What would be the correct dose? • What is the right age to start supplements • Are the benefits worth the expense?

  19. Low Sun Exposure: Major Risk Factor for Rickets • Northern climate (but not exclusively) • Seasonal • Dark pigmentation (but not exclusively) • Covered skin • Sunscreen use • Proper sunscreen use decreases vitamin D synthesis by 97%

  20. Effects of Latitude and Season on D Status • Iowa (41 degrees N) (EH Ziegler et al, 2006) • During winter, 78% of breastfed infants were D deficient (25-OH level < 11 ng/ml) • In South Carolina (32 degrees N) (LA Basile et al, 2007) • African-American newborns had mean cord serum 25-OH level of 10.5 ±0.6 ng/ml • Winter decreased cord serum 25-OH levels in A-A by 25% and in Caucasians by 35%

  21. Appropriate Sunlight Exposure Prevents Rickets • Infants born to mother’s with low Vit D • Diaper only: 10-30 minutes/week • Fully clothed, no hat: 2 hours/week • Infants born to mother’s with adequate Vit D • Diaper only: < 10 minutes/week • Fully clothed, no hat: 30 minutes/week • Outside in the shade doesn’t work • 6-fold increased need in darkly pigmented infants

  22. In the Absence of Adequate Sunlight Exposure • Low dietary intake of Vitamin D becomes a major issue • Vitamin D deficient situations in infancy • Exclusive human milk feeding • Infants consuming < 500 ml/d of fortified infant formula • Not receiving vitamin prep containing vitamin D • Vitamin D deficient pregnant or nursing mother

  23. Dietary Content of Vitamin D • Human milk (22 to 100 IU/L) • Varies with maternal diet, pigmentation/sun exposure • Light pigmentation 68 IU/L • Dark pigmentation  35 IU/L • Both fall far short of RDA/DRI (infant does not consume 1L until 14 lbs=5-6 months of age) • Maternal 3000 IU/d supplement-> 100 IU/L

  24. Relative Importance of Fetal Stores, Milk and Sun Sources • Maternal and Infant 25-OH D serum concentrations highly correlated until 8 weeks of age • Combined effects of maternal serum levels on fetal stores (transplacental) and breastmilk content • After 8 weeks, sunlight exposure outweighs effects of mother’s vitamin D status

  25. Dietary Sources of Vitamin D • Unfortified cow milk (24 IU/L) • High variability in measured vitamin D in fortified cow milk (NEJM) • Infant formula (400 IU/L) • Infant must consume 1/2 L per day to receive DRI of 200 IU/day • Term infant consumes that amount; preterm does not • Tri-vitamin (ADC) prep: 400 IU/dose

  26. Daily Dietary Vitamin D Requirement to Prevent Rickets (0-36 months) • Dietary source-USA (IOM, 2001) • 200 IU/day (5 mcg) is the AI • Dietary source-Canada • 400 IU/day in summer • 800 IU/day in winter

  27. Nutritional Strategies to Improve Vitamin D Status • Effective strategies in infants (current recs) • 200 IU vitamin D/day • 1/2 dose tri-vitamin (ADC) prep • 500 ml of fortified infant formula • 5 mcg calcitriol • Recent strategies (experimental) • Supplementing the pregnant mother • Supplementing the nursing mother • Single high dose therapy

  28. Maternal Vitamin D Supplementation During Pregnancy • IOM (2001) determines • AI as 200 IU/day • UL as 2,000 IU/day • NHANES data: 50% of African-American women of reproductive age have low vitamin D level • Infants born to Vitamin D deficient mothers have lower vitamin D stores • Dark skin ± skin coverage during pregnancy: 63% rate of D deficiency in NBs compared to 16% in light skin/no skin coverage (Dijkstra et al, 2007)

  29. Does Supplementation During Pregnancy Work? • Supplementation of pregnant women • Improves neonatal calcium handling • Improves 9 year bone status • Improves maternal vit D levels if she was deficient • Does not alter already sufficient maternal D status • Doses up to 2000 U/day are tolerated, but no trials to determine efficacy on fetal/neonatal stores

  30. Does Maternal Vitamin D Supplementation During Lactation Work? • Human milk vitamin D content is low and reflects maternal vitamin D status • Supplementation of deficient mothers increases milk D levels • The AI during lactation is 200 IU/day (IOM, 2001) • The UL is 2,000 IU/day (IOM, 2001) • 3000 IU/day increases milk levels to 100 IU/L; still too low

  31. High Dose Supplementation of Lactating Mothers (CL Wagner et al, 2006) • Mothers randomized at 1 month to 400 vs 6400 IU/d X 6 months • Control infants received 300 IU; infants of supplemented mothers received 0 IU • Results: anti-rachitic activity of maternal supplemented infants equaled that of infants receiving only postnatal dietary supplementation • No toxicity noted in high dose mothers • Shows feasibility of maternal supplementation only

  32. Cost to prevent • Is universal supplementation of infants cost effective? • Cost of Tri-Vi-Sol ($6.00/month) • Incidence estimate • 5 hospitalized per million children • 25 ambulatory cases per million • Cost per hospitalization averted: $4,800,000 • Cost per case averted: $958,000 • Cost to prevent far outweighs cost to treat

  33. Summary of Pediatric Vitamin D • Vitamin D deficiency is increasingly recognized • Seasonal and Geographical • Mostly in breastfed infants of color • Contributors are lack of sunlight exposure and low levels of D in unsupplemented milk • Effective therapies include supplementation of breastfed infants with 200 IU and supplementation of lactating mothers with >4000 IU/day • Only the former is currently recommended by AAP

  34. Perinatal Vitamin D Populations at Risk Osteopenia of Prematurity Does Postnatal D work? Can Prenatal D prevent?

  35. Osteopenia (Rickets) of Prematurity Staging: 1. Hypodensity of bones 2. Abnormalities of metaphyses Fraying and cupping Dense line (healing) 3. Above findings and fractures 1. 2. 3. Courtesy of Steve Abrams MD

  36. Osteopenia of prematurity: Usually a disease of inadequate calcium and phosphorus intake

  37. Vitamin D in preterm infants Adequate Intake (AI) for vitamin D for full-term infants is 200 IU/day. Upper limit (UL) is 1000 IU/d (US 1997). There is substantial evidence that little Ca absorption is transcellular “active” (Vitamin D-dependent) in first months of life in premature or even in full-term infants. Multiple studies demonstrate that intake of 160-400 IU/day leads to adequate vitamin D levels (Cooke 1990, Pittard 1991, Backstrom 1999, Koo JPGN, 1995). Preterm formula provides, when fed at 120 cal/kg/d to a 1.5 kg infant: SSC:150 IU/100 kcal = 270 IU/day and EPF: 270 IU/100 kcal = 486 IU/day Human milk fortifiers marketed in US provide 150 IU/4 packets.

  38. Higher doses of vitamin D? No evidence for benefits in preterm infants. One study evaluating up to 1000 IU found no short or long-term benefit (up to 11 yrs!) of higher amounts (Backstrom, JPGN, 1999). Some, especially in Europe, recommend providing up to 1000 IU/d routinely for preterm infants- little evidence for or against this.

  39. High dose effects Preterm formula, 2700 IU/L. (1200-1700 IU/L in US) Unanswered question is: What is the target 25-OHD? Nako, Pediatrics International 2004;46:439-443.

  40. When might more vitamin D be helpful? Vitamin D related absorption increases at 6-8 weeks of age – when osteopenia worsens. Provide 400-600 IU/d if alk phos > 800 IU/L. Cholestatic babies cannot form 25-hydroxyvitamin D in their liver. Consider increasing intake for direct bili > 4 to a maximum of 1000 IU/day total vitamin D. If no response or worsening alk phos, consider adding 1,25 dihydroxyvitamin D (calcitriol, Rocaltrol). Obtain 25-OHD level first and treat if < 20-25 ng/mL.

  41. Assessment and Plans

  42. Prenatal Assessment of Maternal Vitamin D Stores SUNLIGHT EXPOSURE FACTORS Sun-seeking Behaviors Never outside Always outside Skin Pigmentation Deep Light Geographic Location ArcticCircle Equator Cultural Dress Mostly covered Mostly uncovered Elevation Seaside Mountains Sunscreen Use Applies to any exposed skin Never Owned Any DIETARY FACTORS Diet No milk, No fish Vit D fortified Milk, Salmon 3 X a week Diseases assoc. with Vit D Deficiency Present Not present 400 IU Vit D per day No supplements Supplements

  43. Questionable sources & stores Good sources & stores Prenatal Counseling Either sun exposure or dietary sources should meet requirements Few or no sources Acknowledge good habits Counsel regarding appropriate diet and sun exposure Counsel regarding appropriate diet and sun exposure and prescribe supplements Counsel regarding appropriate diet and sun exposure and consider supplements

  44. Counseling Options for Mothers • Drink Vitamin D fortified milk • Eat one serving salmon 3 times a week • Expose hands, face, and arms to sunlight for 5-15 minutes 2-3 times a week • Increased time may be necessary for persons with deeper pigmented skin • Take Vitamin D supplement of 200 IU per day

  45. SUNLIGHT EXPOSURE FACTORS Sun-seeking Behaviors Never outside Always outside, frequently in the sun Skin Pigmentation Deep Light Geographic Location ArcticCircle Equator Cultural Dress Mostly covered Diaper only Elevation Seaside Mountains Sunscreen Use Applies to any exposed skin Never Owned Any Weather Long winters Long summers DIETARY FACTORS Diet Exclusively breastfeeding Exclusively formula feeding Diseases assoc. with Vit D Deficiency Present Not present 200 IU Vit D per day No supplements Supplements Infant Vitamin D Status - Assessed at 2 months of age

  46. Counseling Options for Infants • Diaper only: 10-30 minutes/week • Fully clothed, no hat: 2 hours/week • Increased time may be necessary for babies with deeper pigmented skin • Take Vitamin D supplement of 200 IU per day • When weaning, use only infant formula to replace breastfeedings • Vitamin D supplement should be stopped if infant is consuming 500 ml of formula

  47. Summary • “Upsurge” in rickets is real, but the actual incidence is unknown (esp. subclinical) • Upsurge is due to inadequate sunlight exposure, not dietary deficiency • Safe sun exposure can address the problem • Adequate dietary intake will correct the effect of lack of sunlight exposure • Effective dose is 200 IU starting in first two months

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