Newborn

Register      Login

VOLUME 1 , ISSUE 1 ( January-March, 2022 ) > List of Articles

REVIEW ARTICLE

Approach to Neonatal Hypocalcemia

Sabitha S Pillai, Christy A Foster, Ambika P Ashraf

Keywords : Calcium, Hypocalcemia, Neonate

Citation Information : Pillai SS, Foster CA, Ashraf AP. Approach to Neonatal Hypocalcemia. 2022; 1 (1):190-196.

DOI: 10.5005/jp-journals-11002-0017

License: CC BY-NC 4.0

Published Online: 31-03-2022

Copyright Statement:  Copyright © 2022; The Author(s).


Abstract

Hypocalcemia in neonates is defined as total serum calcium concentration less than 7.5–8 mg/dL and/or ionized calcium less than 4.4 mg/dL in neonates (>1500 g) and total serum calcium concentration less than 7 mg/dL or ionized calcium less than 3.6 mg/dL in low-birth-weight neonates (<1500 g). About 80% of the calcium transfer across the placenta occurs in the last trimester. Parathyroid hormone-related peptide (PTHrP) regulates the positive calcium balance in the placenta. Postpartum serum calcium level in neonates depends on an intricate relationship between PTH and renal and skeletal factors. Based on the timing of the presentation, hypocalcemia can be early onset (develops in the first 72 hours of life) and late onset (occurs after 72 hours of life). Causes of early-onset hypocalcemia include prematurity, SGA, IUGR, birth asphyxia, diabetes mellitus, or toxemia in the mother. Late-onset neonatal hypocalcemia may be caused by increased dietary phosphate content, neonatal vitamin D deficiency, hypomagnesemia, hypoparathyroidism, or parathyroid hormone resistance. We present a neonate with hypocalcemia due to transient hypoparathyroidism secondary to maternal adenoma. A thorough history and physical examination are essential to identify at-risk asymptomatic infants who need screening for hypocalcemia. Neonatal hypocalcemia can be a serious event and can cause serious morbidity and mortality. Majority of the early as well as transient late neonatal hypocalcemia resolves completely, while lifelong treatment may be required in some cases depending on the etiology.


HTML PDF Share
  1. Root AW, Levine MA. Disorders of mineral metabolism. II. Abnormalities of mineral homeostasis in the newborn, infant, child and adolescent. In: Sperling pediatric endocrinology. Elsevier Philadelphia; 2021. p. 705–721.
  2. Gertner JM. Disorders of calcium and phosphorus homeostasis. Pediatr Clin North Am 1990;37(6):1441–1465. DOI: 10.1016/s0031-3955(16)37019-5.
  3. Abrams SA, Tiosano D. Disorders of calcium, phosphorus, and magnesium metabolism in the neonate. In: Martin RJ, Fanaroff AA, Walsh MC, editors. Fanaroff & Martin's neonatal-perinatal medicine: diseases of the fetus and infant. Philadelphia, PA: Elsevier Saunders; 2015. p. 1460–1489.
  4. Marshall RW, Nordin BEC, Speed R. Calcium, phosphate and magnesium metabolism. London: Churchill Livingstone; 1976. p. 162.
  5. Hsu SC, Levine MA. Perinatal calcium metabolism: physiology and pathophysiology. Semin Neonatol 2004;9(1):23–36. DOI: 10.1016/j.siny.2003.10.002.
  6. Steichen JJ, Tsang RC, Gratton TL, et al. Vitamin D homeostasis in the perinatal period: 1,25-dihydroxyvitamin D in maternal, cord, and neonatal blood. N Engl J Med 1980;302(6):315–319. DOI: 10.1056/NEJM198002073020603.
  7. Taylor-Miller T, Allgrove J. Endocrine diseases of newborn: epidemiology, pathogenesis, therapeutic options, and outcome “current insights into disorders of calcium and phosphate in the newborn”. Front Pediatr 2021;9:600490. DOI: 10.3389/fped.2021.600490.
  8. Venkataraman PS, Tsang RC, Greer FR, et al. Late infantile tetany and secondary hyperparathyroidism in infants fed humanized cow milk formula. Longitudinal follow-up. Am J Dis Child 1985;139(7):664–668. DOI: 10.1001/archpedi.1985.02140090026018.
  9. Vuralli D. Clinical approach to hypocalcemia in newborn period and infancy: who should be treated? Int J Pediatr 2019;2019:4318075. DOI: 10.1155/2019/4318075.
  10. Chincholikar SP, Ambiger S. Association of hypomagnesemia with hypocalcemia after thyroidectomy. Indian J Endocrinol Metab 2018;22(5):656–660. DOI: 10.4103/ijem.IJEM_599_17.
  11. Yamamoto M, Yamaguchi T, Yamauchi M, et al. Acute-onset hypomagnesemia-induced hypocalcemia caused by the refractoriness of bones and renal tubules to parathyroid hormone. J Bone Miner Metab 2011;29(6):752–755. DOI: 10.1007/s00774-011-0275-7.
  12. Huynh T, Wilgen U. An unusual cause of metabolic alkalosis and hypocalcemia in childhood. Clin Chem 2019;65(4):514–517. DOI: 10.1373/clinchem.2018.287136.
  13. Kakajiwala A, Barton KT, Rampolla E, et al. Acute hypocalcemia and metabolic alkalosis in children on cation-exchange resin therapy. Case Rep Nephrol 2017;2017:6582613. DOI: 10.1155/2017/6582613.
  14. Besarab A, Caro JF. Increased absolute calcium binding to albumin in hypoalbuminaemia. J Clin Pathol 1981;34(12):1368–1374. DOI: 10.1136/jcp.34.12.1368.
  15. Besarab A, DeGuzman A, Swanson JW. Effect of albumin and free calcium concentrations on calcium binding in vitro. J Clin Pathol 1981;34(12):1361–1367. DOI: 10.1136/jcp.34.12.1361.
  16. Thomas TC, Smith JM, White PC, et al. Transient neonatal hypocalcemia: presentation and outcomes. Pediatrics 2012;129(6):e1461–e1467. DOI: 10.1542/peds.2011-2659.
  17. Tsang RC, Light IJ, Sutherland JM, et al. Possible pathogenetic factors in neonatal hypocalcemia of prematurity. The role of gestation, hyperphosphatemia, hypomagnesemia, urinary calcium loss, and parathormone responsiveness. J Pediatr 1973;82(3):423–429. DOI: 10.1016/s0022-3476(73)80115-5.
  18. Venkataraman PS, Tsang RC, Chen IW, et al. Pathogenesis of early neonatal hypocalcemia: studies of serum calcitonin, gastrin, and plasma glucagon. J Pediatr 1987;110(4):599–603. DOI: 10.1016/s0022-3476(87)80560-7.
  19. Tsang RC, Chen I, Hayes W, et al. Neonatal hypocalcemia in infants with birth asphyxia. J Pediatr 1974;84(3):428–433. DOI: 10.1016/s0022-3476(74)80733-x.
  20. Tsang RC, Kleinman LI, Sutherland JM, et al. Hypocalcemia in infants of diabetic mothers. Studies in calcium, phosphorus, and magnesium metabolism and parathormone responsiveness. J Pediatr 1972;80(3):384–395. DOI: 10.1016/s0022-3476(72)80494-3.
  21. Tsang RC, Kleinman LI, Sutherland JM, et al. Hypocalcemia in infants of diabetic mothers. Studies in calcium, phosphorus, and magnesium metabolism and parathormone responsiveness. J Pediatr 1972;80(3):384–395. DOI: 10.1016/s0022-3476(72)80494-3.
  22. Specker BL, Tsang RC, Ho ML, et al. Low serum calcium and high parathyroid hormone levels in neonates fed ‘humanized’ cow's milk-based formula. Am J Dis Child 1991;145(8):941–945. DOI: 10.1001/archpedi.1991.02160080119033.
  23. Yilmaz B, Aygun C, Cetinoglu E. Vitamin D levels in newborns and association with neonatal hypocalcemia. J Matern Fetal Neonatal Med 2018;31(14):1889–1893. DOI: 10.1080/14767058.2017.1331430.
  24. Thomas SD, Fudge AN, Whiting M, et al. The correlation between third-trimester maternal and newborn-serum 25-hydroxy-vitamin D in a selected South Australian group of newborn samples. BMJ Open 2011;1(2):e000236. DOI: 10.1136/bmjopen-2011-000236.
  25. Mehta Y, Shitole C, Setia MS. Factors associated with changes in magnesium levels in asymptomatic neonates: a longitudinal analysis. Iran J Pediatr 2016;26(1):e2662. DOI: 10.5812/ijp.2662.
  26. Tsang RC, Strub R, Brown DR, et al. Hypomagnesemia in infants of diabetic mothers: perinatal studies. J Pediatr 1976;89(1):115–119. DOI: 10.1016/s0022-3476(76)80944-4.
  27. Saha D, Ali MA, Haque MA, et al. Association of hypoglycemia, hypocalcemia and hypomagnesemia in neonates with perinatal asphyxia. Mymensingh Med J 2015;24(2):244–250. PMID: 26007249.
  28. Nesibe A, Sinasi O. Primary familial hypomagnesemia syndrome: a new approach in treatment. J Pediatr Endocrinol Metab 2012;25(5–6): 599–602. PMID: 22876566.
  29. Guran T, Akcay T, Bereket A, et al. Clinical and molecular characterization of Turkish patients with familial hypomagnesaemia: novel mutations in TRPM6 and CLDN16 genes. Nephrol Dial Transplant 2012;27(2):667–673. DOI: 10.1093/ndt/gfr300.
  30. Godron A, Harambat J, Boccio V, et al. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: phenotype-genotype correlation and outcome in 32 patients with CLDN16 or CLDN19 mutations. Clin J Am Soc Nephrol 2012;7(5):801–809. DOI: 10.2215/CJN.12841211.
  31. Tseng UF, Shu SG, Chen CH, et al. Transient neonatal hypoparathyroidism: report of four cases. Acta Paediatr Taiwan 2001;42(6):359–362. PMID: 11811226.
  32. Korkmaz HA, Ozkan B, Terek D, et al., Neonatal seizure as a manifestation of unrecognized maternal hyperparathyroidism. J Clin Res Pediatr Endocrinol 2013;5(3):206–208. DOI: 10.4274/Jcrpe.1037.
  33. Hendy GN, Cole DEC. Familial isolated hypoparathyroidism. In: Brandi ML, Brown E, editors. Hypoparathyroidism. Milano: Springer; 2015. p. 167–175.
  34. Shoback DM, Bilezikian JP, Costa AG, et al. Presentation of hypoparathyroidism: etiologies and clinical features. J Clin Endocrinol Metab 2016;101(6):2300–2312. DOI: 10.1210/jc.2015-3909.
  35. Pearce SH, Williamson C, Kifor O, et al. A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor. N Engl J Med 1996;335(15):1115–1122. DOI: 10.1056/NEJM199610103351505.
  36. Bai M, Quinn S, Trivedi S, et al., Expression and characterization of inactivating and activating mutations in the human Ca2+o-sensing receptor. J Biol Chem 1996;271(32):19537–19545. DOI: 10.1074/jbc.271.32.19537.
  37. Naiki M, Ochi N, Kato YS, et al. Mutations in HADHB, which encodes the beta-subunit of mitochondrial trifunctional protein, cause infantile onset hypoparathyroidism and peripheral polyneuropathy. Am J Med Genet A 2014;164A(5):1180–1187. DOI: 10.1002/ajmg.a.36434.
  38. Taylor SC, Morris G, Wilson D, et al. Hypoparathyroidism and 22q11 deletion syndrome. Arch Dis Child 2003;88(6):520–522. DOI: 10.1136/adc.88.6.520.
  39. Hieronimus S, Bec-Roche M, Pedeutour F, et al. The spectrum of parathyroid gland dysfunction associated with the microdeletion 22q11. Eur J Endocrinol 2006;155(1):47–52. DOI: 10.1530/eje.1.02180.
  40. Minagawa M, Yasuda T, Kobayashi Y, et al. Transient pseudohypoparathyroidism of the neonate. Eur J Endocrinol 1995;133(2):151–155. DOI: 10.1530/eje.0.1330151.
  41. Dixit A, Chandler KE, Lever M, et al. Pseudohypoparathyroidism type 1b due to paternal uniparental disomy of chromosome 20q. J Clin Endocrinol Metab 2013;98(1):E103–E108. DOI: 10.1210/jc.2012-2639.
  42. Elli FM, Bordogna P, Arosio M, et al. Mosaicism for GNAS methylation defects associated with pseudohypoparathyroidism type 1B arose in early post-zygotic phases. Clin Epigenet 2018;10:16. DOI: 10.1186/s13148-018-0449-4.
  43. Mantovani G, Bastepe M, Monk D, et al. Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement. Nat Rev Endocrinol 2018;14(8):476–500. DOI: 10.1038/s41574-018-0042-0.
  44. Hooman N, Honarpisheh A. The effect of phototherapy on urinary calcium excretion in newborns. Pediatr Nephrol 2005;20(9):1363–1364. DOI: 10.1007/s00467-005-1951-4.
  45. Hakanson DO, Bergstrom WH. Phototherapy-induced hypocalcemia in newborn rats: prevention by melatonin. Science 1981;214(4522): 807–809. DOI: 10.1126/science.6895262.
  46. Cakir U, Alan S, Erdeve O, et al. Late neonatal hypocalcemic tetany as a manifestation of unrecognized maternal primary hyperparathyroidism. Turk J Pediatr 2013;55(4):438–440. PMID: 24292040.
  47. Jain A, Agarwal R, Sankar MJ, et al. Hypocalcemia in the newborn. Indian J Pediatr 2010;77(10):1123–1128. DOI: 10.1007/s12098-010-0176-0.
  48. Tseng MH, Chu SM, Lo FS, et al. A neonate with recurrent tetany: questions and answers. Pediatr Nephrol 2016;31(5):753, 755–757. DOI: 10.1007/s00467-015-3107-5.
  49. Rustico SE, Kelly A, Monk HM, et al. Calcitriol treatment in metabolic bone disease of prematurity with elevated parathyroid hormone: a preliminary study. J Clin Transl Endocrinol 2015;2(1):14–20. DOI: 10.1016/j.jcte.2014.12.001.
  50. McDonald-McGinn DM, Hain HS, Emanuel BS, et al. 22q11.2 deletion syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews((R)). Seattle (WA); 1993.
  51. Zhou P, Markowitz M. Hypocalcemia in infants and children. Pediatr Rev 2009;30(5):190–192. DOI: 10.1542/pir.30-5-190.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.