1. Steven A. Abrams, MD Professor of Pediatrics Baylor College of Medicine sabrams@bcm.edu Calcium and Vitamin D Needs During Pregnancy, Lactation and In Neonates

2. Disclosures  “I have the following financial relationships with the manufacturers(s) of any commercial products(s) and/or provider of commercial services discussed in this CME activity:”  Research Support from: Mead-Johnson Nutrition, Evansville, Indiana  No off-label medication use will be discussed in this talk.

3. Learning Objectives  Recognize the causes and treatment of hypo- and hypercalcemia in newborns  Identify the principal causes of osteopenia and rickets in premature infants  Choose nutritional strategies for managing infants with evidence of osteopenia or rickets  Describe vitamin D metabolism and dietary sources of vitamin D in infants

4. Hypocalcemia: Definition  No absolute definitions. Usual values are:  Babies ≥ 1500 g  Total calcium (Ca) < 8.0 mg/100 mL (2mM) – don’t measure total Ca in first week of life.  Ionized calcium (iCa) < 4.4 mg/dl = 1.1 mM  Usually no symptoms unless < 1.0 mM  VLBW infants (< 1500 g)  Total Ca < 7.0 mg/100 mL (1.75 mM)  iCa < 4 mg/100 mL (1.0 mM)  Usually no symptoms unless < 0.8 mM

5. Early hypocalcemia (first 3-4 days of life)  Prematurity  Impaired PTH function, etiology unknown  Infants of diabetic mothers: 10-20% or more  Excess calcitonin and inadequate PTH function  Cardio-respiratory depression at birth  Increased phosphate load from tissue catabolism  We are seeing with fluid restriction in cooled infants  Intrauterine growth retardation (IUGR)  Decreased transplacental Ca and phosphorus transfer  Maternal long-term magnesium sulfate therapy (rare)  Severe maternal vitamin D deficiency (rare in US)  Hyperventilation, exchange transfusion

6. Interventions  Prevention via early TPN in high-risk populations  Early TPN. No benefit to separate infusion.  Symptomatic  10% Ca gluconate: 60-100 mg/kg (0.6-1.0 mL/kg) IV  Repeat in 10-15 minutes if clinically indicated.  Or: Ca chloride 20 mg/kg (0.2 mL/kg)  Then begin Ca via continuous infusion. No boluses without infusions.  Hypomagnesemia (≤ 1.5 mg/100 mL): Suppresses PTH  Magnesium sulfate 25 mg/kg/dose (0.2 mEq/kg/dose) q12 hours IV over 2 hours. Usually 2 doses.

7. Hypocalcemia Case: Seizures  You are called from the emergency center about a 5 day old baby they would like to admit due to seizures.  ER History: Full-term infant, first child, male, weight 3.2 kg. Routine vaginal delivery, Apgars 9/9. Has been feeding both breast and bottle. On the 3 rd day of life infant was noted by mom to be a bit jittery.  This worsened and on 4 th DOL was taken to pediatrician who ordered a blood glucose that mother says was normal and reassured her that this was typical for babies.  Overnight, episodes worsened and decreased appetite. This AM mom noted stiffening of arms and legs and brought baby to the ER.

8. Differential at presentation?  Infection: including Herpes simplex virus, other viral, bacterial sepsis/meningitis.  Hypoglycemia  Inborn errors of metabolism or brain malformation  Non-accidental injury or other trauma  Benign “5 th day fits”  Hyponatremia  Hypocalcemia  Genetic entities such as DiGeorge’s Syndrome

9. Ideas!  If iCa is < 1.0, then single most likely diagnosis is “late hypocalcemic tetany.”  A poorly defined condition with seizures in healthy infants typically beginning on 4 th -6 th days of life.  Associated with very low total and ionized calcium (Ca), and very high serum phosphorus (P).  Not generally a vitamin D deficiency condition.  Often accompanied by very low serum magnesium.  Classically occurred with whole cow milk consumption.  Currently occurs uncommonly in infants fed infant formulas from birth. True incidence is unknown.  Rarely if ever, seen in exclusively breast-fed infants.

10. Mineral content (mg/100 mL) Milk/formula Ca P Human milk2814 Cow milk12095 Goat milk136112 Cow milk formulas 42-5224-35 Preterm formulas132-14666-81 Transitional formulas78-9046-49 *A medical, not a routine formula

11. Late Hypocalcemia and other hypocalcemic entities  Always obtain: Ionized calcium, total P, total magnesium (Mg).  Can measure intact PTH and total 25-hydroxyvitamin D (25- OHD) but results do not impact initial management.  Do not measure serum 1,25 dihydroxyvitamin D (1,25-OH 2 D)  Therapy with low P formula and Ca supplement. Prognosis very good.

12. Does vitamin D deficiency cause symptomatic hypocalcemia?  Maternal vitamin D deficiency can cause symptomatic neonatal hypocalcemia.  Probably rare in US but limited data.  Recent case series of 19 babies in Qatar*.  Symptomatic hypocalcemia (13 seizures, 5 jittery, 1 stridor), mean age about 9 days.  Serum 25-OHD mean of 9 ng/mL (range 3 to 18 ng/mL), in mothers was 6 ng/mL (range 4 to 12 ng/mL). *Teaema FH, Al Ansari K. Nineteen cases of symptomatic neonatal hypocalcemia secondary to vitamin D deficiency: a 2-year study. J Trop Pediatr. 2010 Apr;56(2):108-10.

13. Case: Itsy bitsy baby with hypercalcemia  Asked to see infant at 72 hours of age due to ionized calcium of 1.84 mmol/L (mM).  History:  Born at 580 g and 24 3/7 weeks gestation.  Started on TPN at 2 hours of age providing 1.2 mmol/dL Ca, no P. IV rate = 100 mL/kg/d.  At 60 hours of age, 1.2 mmol/dL phosphorus (P) added  Serum P = 3.1 mg/dL, serum Mg = 1.8 mg/dL.  Infant is asymptomatic, remains on ventilator.

14. Etiology/symptoms  Probably a combination of low usage of Ca for bone formation, limited renal calcium excretion.  May also have high P utilization.  Not usually primarily related to vitamin D or PTH.  Most commonly seen in ELBW infants. Very common < 750 g birthweight.  Extremely high iCa seen on DOL 3-5: iCa may exceed 2.0 mmol/L – values that are life-threatening in older children.

15. Etiology/Symptoms (cont.)  Relatively common to have mild hypercalcemia (total Ca 11- 12 mg/dL or iCa 1.45-1.6 mM). Probably a non-disease.  Hypercalcemic neonates do not have symptoms, but serious concern for peripheral or CNS calcification.  Also seen in cardiac babies given calcium infusions.  Can occur if KPhos and KCl are stopped for > 48 hours due to concern of K excess in any infant.

16. Hypercalcemia: Therapy  Start P within 24 hours of life in most cases in VLBW infants to prevent hypercalcemia. Usually 1:1 mmol:mmol with Ca.*  Mild-moderate hypercalcemia (iCa 1.4-1.7 mM) – decrease TPN Ca infusion to < 1 mmol/dL  Some infants only tolerate 0.3-0.5 mmol/dL Ca in TPN with increase of 0.1-0.2 mmol/dL daily.  If severe (iCa > 1.7-1.8 mM), stop all TPN calcium and recheck in 12-24 hours.  Can persist in smallest infants for several weeks. *Ca is 40 mg = 1 mmol and P is 31 mg = 1 mmol

17. Case: Rickets in ELBW infant  Asked to see an infant due to an incidental finding on a chest X-ray of two rib fractures with subsequent measurement of serum alk phos of 1480 IU/L.  History: Former 25 2/7 week, 760 g male with history of BPD, sepsis, medical NEC not requiring surgery.  Now 53 days old and weight 1560 g. Tolerating feeds of 120 mL/kg/day of a specialized formula with high MCT. TPN stopped DOL #51.  Continues on mechanical ventilation. Medications include low-dose IV hydrocortisone and furosemide.

18. Factors contributing to rickets  Major:  ELBW (< 1000 g birth weight)  Long-term TPN  Although full TPN has enough Ca and P to avoid rickets, often have fluid restriction or mineral intake limitation in long-term TPN.  Steroids  Often a major etiology. Steroids block Ca absorption, increase renal losses and demineralize bone directly.

19. Other factors  Use of non-preterm formula  Low Ca and P content relative to needs.  May have inhibitors of Ca absorption (e.g. soy protein)  Fluid restriction  Critical unrecognized factor.  Nutrient malabsorption secondary to bowel injury?

20. Less likely to be involved  Immobility  Loop diuretics  Usually use furosemide which causes approximate doubling of urinary Ca. Smaller factor in rickets than intake decreases.  Vitamin D deficiency  Rarely principal factor in VLBW infants.

21. X-ray findings in infants with rickets Abnormalities of metaphyses Fraying and cupping Dense line (healing) Findings similar to older infants with rickets

22. More information  Further lab evaluation to include:  Serum P, conjugated bilirubin/other liver function tests.  Serum 25-OHD (not 1,25-OH 2 D), PTH, fractionated (bone-specific) alkaline phosphatase activity may be considered, but difficult to identify normal values.  Needs X-rays of at least one wrist or knee.

23. Osteopenia of prematurity/rickets Primarily inadequate Ca and P intake Ca intake (mg/kg/d) Ca retention (%) Ca retention (mg/kg/d) In UteroN/A 100-130 Human milk4060-7025-30 Routine cow milk- based formula 80-9040-5035-45 Total parenteral nutrition Up to 80>9560-80 P follows similar pattern, at about half the intake (mg:mg) and total amounts retained. In TPN usually target about 1:1 Ca:P on mmol/mmol basis. (Ca is 40 mg = 1 mmol and P is 31 mg = 1 mmol)

24. AAP guidelines for preterm infants High-Risk Criteria for Rickets in Preterm Infants  Born at less than 27 weeks’ gestation  Birth weight less than 1000 g  Long-term parenteral nutrition (e.g., more than 4 to 5 weeks)  Severe bronchopulmonary dysplasia with use of loop diuretics (e.g., furosemide) and fluid restriction  Long-term steroid use  History of necrotizing enterocolitis  Failure to tolerate formulas or human milk fortifiers with high mineral content Abrams SA and Committee on Nutrition, AAP, Pediatrics 2013

25. Recommendations Abrams SA and Committee on Nutrition, AAP, Pediatrics, 2013

26. Some details of AAP recommendations for preterm infants  When infants reach a body weight >1500 g and tolerate full enteral feeds, vitamin D intake should generally be approximately 400 IU/day, up to a maximum of 1000 IU/day.  Serum APA >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 P concentration < about 4.0 mg/dL should be followed, and consideration should be given for P supplementation. Abrams SA and Committee on Nutrition, AAP, Pediatrics, May 2013

27. Diuretics/nephrocalcinosis  Moderate hypercalciuria is common in preterms.  Loop diuretics (furosemide) increase urinary Ca (and Na, K, Cl). Effects of intermittent dosing regimens not well documented.  Thiazide diuretics decrease urinary Ca (but not Na, K, Cl). Combined use with furosemide not well evaluated.  High Ca containing formulas and fortificants (with P) do not cause hypercalciuria or nephrocalcinosis.  Citrate supplementation may decrease risk of nephrocalcinosis. More data are needed.

28. Vitamin D in high risk infants  Dietary requirements have on-going research and controversy.  Routine assessment of vitamin D status in all preterms is not part of IOM/AAP recommendations. We do not recommend it.  Also not recommended in all older children (AAP Oct. 2014)  Screening may be considered with rickets, bowel or liver disease, poor nutritional status or some chronic illnesses such as renal failure.  Target 25-OHD ≥ 20 ng/mL

29. When to use more vitamin D?  Vitamin D related absorption may increase at 6-8 weeks of age. Consider 400-600 IU/d vitamin D supplement if alk phos > 800 IU/L or radiological rickets.  Cholestatic babies may not fully produce 25-OHD in liver.  If clinical concern, obtain serum 25-OHD (not 1,25-(OH) 2 D) and increase vitamin D intake if < 20 ng/mL.  Consider increasing vitamin D intake to 1000 IU/day total.  If no response or worsening alk phos, consider adding 1,25- dihydroxyvitamin D (calcitriol) and continuing vitamin D.  Risks of vitamin D toxicity include hypercalcemia and less likely hypercalciuria.

30. Vitamin D: fullterm babies  Pediatric Endocrine Society and 2011 Institute of Medicine (IOM) recommend 400 IU/day for all infants. AAP has signed on to IOM guidelines (2013).  Provide 400 IU daily as a single dropper. Do not use high concentration drops (AAP and FDA 2010).  Can give from first week of life as D alone, multivitamins (tri or poly), or as multivitamins and iron (use for < 2500 g or < 37 weeks gestation at birth).  Change to multivitamins with Fe at 4 months (AAP 2010).  Give to partially breast-fed until fully weaned.

31. Dietary recommendations for calcium and vitamin D:IOM  IOM 1997: Adequate intakes of 1000 mg/day calcium and 200 IU/day vitamin D.  IOM 2011: RDA of 1000 mg for calcium (1300 mg if < 18 yrs)  IOM 2011: RDA of 600 IU for vitamin D  IOM 2011:Tolerable Upper Intake Level: 4000 IU/day vitamin D  IOM 2011: No recommendation for routine testing.  25(OH)D should be > 20 ng/mL in all populations over 1 year of age.

32. Dietary recommendations for calcium and vitamin D: Pregnancy  Endocrine Society: Pregnant women are at high risk for vitamin D deficiency, which increases the risk of preeclampsia and cesarean section.  Their daily regimen should at least include a prenatal vitamin containing 400 IU vitamin D with a supplement that contains at least 1000 IU vitamin D.  Thus, at a minimum, lactating women may need to take 1400– 1500 IU/d, and to satisfy their infant’s requirement, they may need 4000–6000 IU/d if they choose not to give the infant a vitamin D supplement. Holick et al: J Clin Endo Metab 2011

33. ACOG throws its hat in the ring

34. ACOG 2011  Basically say that you shouldn’t screen but that if you do they have no opinion on what is normal, no opinion on what you should do, but are pretty sure that vitamin D doses of 1000- 2000 IU/day are safe.  They await randomized controlled trials that they say are ongoing. Actually, not much is going on in this regard in the US.  Conclude “At this time, there is insufficient evidence to recommend vitamin D supplementation for the prevention of preterm birth or preeclampsia. (ACOG 2011)

35. Canadian Pediatric Society  Consideration should be given to administering 2000 IU of vitamin D daily to pregnant and lactating women, especially during the winter months, to maintain vitamin D sufficiency. The effectiveness of this regimen and possible side effects should be checked with periodic assays for 25(OH)D and calcium (recommendation grade A). First Nations, Inuit and Métis Health Committee, Canadian Paediatric Society (CPS) Paediatr Child Health 2007;12(7):583-9. Reaffirmed October 2010.

36. Controlled trial of vitamin D during pregnancy Hollis BW et al. Journal of Bone and Mineral Research 2011:26;2341–2357.

37. Outcome findings Hollis BW et al. Journal of Bone and Mineral Research 2011, 26:2341–2357.

39. Limitations of the study: safety  Too small for a safety study. An effect in up to 0.5% of individuals could not be identified. This might mean 20,000 or more pregnancies/year in US.  Supplementation started second trimester  Those with high baseline 25-OHD were not randomized to higher doses and those with high 25-OHD were dropped  Extremely high drop-out/lost to follow-up rate  No long-term toxicity were done (e.g. long-term risks of kidney stones)

40. Confounding  Individuals who have higher vitamin D intakes or 25-D levels are also more likely to:  Not be obese  Exercise and spend more time outdoors  Consume dairy products and other vitamins  Have other indicators of healthier lifestyle  Have higher socioeconomic status  Associational studies of vitamin D may really be comparing healthier to less healthy individuals  Many associational studies which suggested cardiovascular and mortality benefits of estrogen replacement and anti-oxidant use  The benefits were not found in the subsequent clinical trials

41. Not recommended by WHO

42. That’s the End…. sabrams@bcm.edu