Pediatric Hypocalcemia

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Hypocalcemia is a laboratory and clinical abnormality that is observed with relative frequency, especially in neonatal pediatric patients. Laboratory hypocalcemia is often asymptomatic, and its treatment in neonates is controversial. However, children with hypocalcemia in pediatric intensive care units (PICUs) have mortality rates higher than those of children with normal calcium levels. (See Prognosis, Clinical, Workup, and Treatment.)

The definition of hypocalcemia is based on both gestational and postnatal age in neonates and is different for children. Calcium data are presented as both mg/dL and mmol/L (1 mg/dL = 0.25 mmol/L)

In children, hypocalcemia is defined as a total serum calcium concentration less than 2.1 mmol/L (8.5 mg/dL).

In term infants, hypocalcemia is defined as total serum calcium concentration less than 2 mmol/L (8 mg/dL) or ionized fraction of less than 1.1 mmol/L (4.4 mg/dL)

In preterm infants, hypocalcemia is defined as total serum calcium concentration less than 1.75 mmol/L (7 mg/dL) is defined as hypocalcemia in infants weighing less than 1500 g birthweight. Symptomatology often manifests when the ionized calcium level falls below 0.8-0.9 mmol/L.

Calcium metabolism and function

Calcium is the most abundant mineral in the body. Of the body’s total calcium, 99% is stored in bone, and serum levels constitute less than 1%. [1] Various factors regulate the homeostasis of calcium and maintain serum calcium within a narrow range. These include parathormone (PTH), vitamin D, hepatic and renal function (for conversion of vitamin D to active metabolites), and serum phosphate and magnesium levels. (See Etiology and Workup)

Serum calcium is present in two forms: the free (ionized) and the bound form. Only about 50% of circulating calcium is present in the physiologically free form. The rest is either bound to proteins (40%) or complexed (10%) with bicarbonate, citrate, and phosphate. The ionized calcium level varies based on the level of serum albumin, blood pH, serum phosphate, magnesium, and bicarbonate levels, the administration of transfused blood containing citrate and free fatty acid content in total parenteral nutrition. The normal range for ionized calcium is 1-1.25 mmol/L (4-5 mg/dL).

The concentration of calcium in the serum is critical to many important biologic functions, including the following:

Calcium messenger system by which extracellular messengers regulate cell function

Activation of several cellular enzyme cascades

Smooth muscle and myocardial contraction

Nerve impulse conduction

Secretory activity of exocrine glands

Calcium physiology during pregnancy and Lactation

The fetus requires approximately 30gm calcium to mineralize its skeleton and to maintain normal physiologic processes. The newborn requires more than this amount during the first few months of life from breastmilk. The unique adaptations of the mother’s body allow her to meet the baby’s calcium demands without adverse long-term consequences to the maternal skeleton. The bulk of the calcium transmitted to the fetus during the third trimester is derived from the maternal intestinal absorption. Intestinal absorption of calcium doubles in pregnancy. Serum calcitriol level doubles or triples and stays elevated in pregnancy despite falling PTH level. It is instead increased, as 1-hydroxylase is upregulated by PTH-related Protein (PTHrP), prolactin and placental lactogen. The rise in PTHrP allows for the rise in calcium while protecting the maternal skeleton.

There is an average daily loss of 210 mg of calcium during lactation. Unlike during pregnancy, elevated PTHrP and low estradiol result in temporary demineralization of maternal skeleton to meet the calcium needs of the breastfeeding infant. These bone density losses are significantly reversed within twelve months of weaning. [2]

Hypocalcemia manifests as central nervous system (CNS) irritability and poor muscular contractility. Low calcium levels decrease the threshold of excitation of neurons, causing them to have repetitive responses to a single stimulus. Because neuronal excitability occurs in sensory and motor nerves, hypocalcemia produces a wide range of peripheral and CNS effects, including paresthesias, tetany (i.e., contraction of hands, arms, feet, larynx, bronchioles), seizures, and even psychiatric changes in children.

Tetany is not caused by increased excitability of the muscles. Muscle excitability is depressed because hypocalcemia impedes acetylcholine release at neuromuscular junctions and, therefore, inhibits muscle contraction. However, the increase in neuronal excitability overrides the inhibition of muscle contraction. Cardiac function may also be impaired because of poor muscle contractility.

Overall, one of the most common causes of hypocalcemia in children is renal failure, which results in hypocalcemia because of inadequate 1-hydroxylation of 25-hydroxyvitamin D and hyperphosphatemia due to diminished glomerular filtration.

Although hypocalcemia is most commonly observed among neonates, it is frequently symptomatic and reported in older children and adolescents, especially in PICU settings. The causes of hypocalcemia can be classified by the child’s age at presentation.

Early neonatal hypocalcemia, which occurs within 48-72 hours of birth, is most commonly seen in preterm and very low birth weight infants, infants asphyxiated or depressed at birth, infants of diabetic mothers, and the intrauterine growth restricted infants. The mechanisms underlying hypocalcemia caused by these conditions are as follows:

Prematurity: Possible mechanisms include inadequate nutritional intake, decreased responsiveness of parathyroid hormone to vitamin D, increased calcitonin level, increased urinary losses, and hypoalbuminemia leading to a decreased total (but normal ionized) calcium level. [3]

Birth asphyxia: Delayed introduction of feeds, increased calcitonin production, increased endogenous phosphate load due to tissue catabolism, renal failure, metabolic acidosis, and its treatment with alkali therapy all may contribute to hypocalcemia. [4, 5]

Infants of a diabetic mother: The degree of hypocalcemia is associated with the severity of diabetes in the mother. Magnesium depletion in mothers with diabetes mellitus causes a hypomagnesemic state in the fetus, which induces functional hypoparathyroidism and hypocalcemia in the infant. In addition, infants of diabetic mothers have higher serum calcium in utero and this may also suppress the parathyroid gland. A high incidence of birth complications due to macrosomia and difficult delivery and, in some cases, higher incidence of preterm birth in infants of diabetic mothers are contributing factors for hypocalcemia.

Intrauterine growth restriction: Infants with intrauterine growth restriction may develop hypocalcemia because of decreased transplacental passage of calcium. In addition, decreased accretion is present if they are delivered preterm or have experienced perinatal asphyxia as a result of placental insufficiency.

This occurs 3-7 days after birth, although occasionally it is seen as late as age 6 weeks. The following are some important causes of late neonatal hypocalcemia:

Exogenous phosphate load: This is most commonly seen in developing countries. The problem results when the neonate is fed with phosphate-rich formula or cow’s milk. Whole cow’s milk has 7 times the phosphate load of breast milk (956 vs 140 mg/L in breast milk). This may cause symptomatic hypocalcemia in neonates. [6]

Vitamin D deficiency: In a review of the medical records of 78 term neonates with hypocalcemia, moderate-to-severe late-onset neonatal hypocalcemia developed more often in male infants and Hispanic infants. It was often a sign of coexistent vitamin D insufficiency or deficiency and hypomagnesemia. The newborns respond well to one or more of the following: calcium supplements, calcitriol, low phosphorus formula (PM 60/40), and magnesium supplements for a limited period of time. [7]

Primary immunodeficiency disorder: DiGeorge Syndrome is the most important immunodeficiency disorder to be aware of that is associated with hypocalcemia. DiGeorge Syndrome is a primary immunodeficiency, often but not always, characterized by cellular (T-cell) deficiency, characteristic facies, congenital heart disease and hypocalcemia. Hypoparathyroidism causes hypocalcemia; 90% of infants with the features of DiGeorge syndrome have a 22q11 chromosomal deletion.

Data suggest an association between late-onset neonatal hypocalcemia and gentamicin therapy, especially with the newer dosing schedule of every 24 hours. [8]

Other causes of late-onset neonatal hypocalcemia include the following:

Magnesium deficiency (usually transient)

Transient hypoparathyroidism of newborn

Hypoparathyroidism due to other causes

Maternal hyperparathyroidism

Blood transfusion or sodium bicarbonate (alkali) infusions

Phototherapy for hyperbilirubinemia [9]

Hypoparathyroidism, abnormal vitamin D production or action, and hyperphosphatemia are among the causes of hypocalcemia in infants and children.

Hypoparathyroidism can result from the following:

Aplasia or hypoplasia of parathyroid gland –DiGeorge syndrome also known as velocardiofacial (Shprintzen) syndrome or 22q11 deletion syndrome; fetal exposure to retinoic acid; complex of vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, and radial and renal abnormalities (VATER/VACTERL); and association of coloboma, heart defects, choanal atresia, renal abnormalities, growth retardation, male genital anomalies, and ear abnormalities (CHARGE) (Details of DiGeorge syndrome are discussed in the late-onset hypocalcemia section above.)

Parathormone (PTH) receptor defects – Pseudohypoparathyroidism

Autoimmune parathyroiditis

Infiltrative lesions –Hemosiderosis, Wilson disease, thalassemia

Activating mutations of the calcium-sensing receptor leading to inappropriately suppressed PTH secretion (e.g. GNA11 mutation) [10]

Idiopathic causes

Abnormal vitamin D production or action can be caused by the following:

Vitamin D deficiency: Dietary insufficiency and maternal use of anticonvulsants have been reported.

Acquired or inherited disorders of vitamin D metabolism

Resistance to actions of vitamin D

Liver disease: Liver disease can affect 25-hydroxylation of vitamin D; certain drugs (eg, phenytoin, carbamazepine, phenobarbital, isoniazid, and rifampin) can increase the activity of P-450 enzymes, which can increase the 25-hydroxylation and also the catabolism of vitamin D.

Hyperphosphatemia can result from the following:

Excessive phosphate intake from feeding cow milk or infant formula with improper (low) calcium to phosphate ratio

Excessive phosphate intake caused by inappropriate use of phosphate-containing enemas

Excessive phosphate or inappropriate Ca:P ratio in total parenteral nutrition

Increased endogenous phosphate load caused by anoxia, chemotherapy, or rhabdomyolysis

Renal failure

Other causes of hypocalcemia in infants and children include the following:

Malabsorption syndromes

Alkalosis: Respiratory alkalosis is caused by hyperventilation; metabolic alkalosis occurs with the administration of bicarbonate, diuretics, or chelating agents, such as the high doses of citrates taken in during massive blood transfusions.

Pancreatitis

Pseudohypocalcemia (ie, hypoalbuminemia): Serum calcium concentration decreases by 0.8 mg/dL for every 1 g/dL fall in concentration of plasma albumin.

“Hungry bones syndrome:” Rapid skeletal mineral deposition is seen in infants with rickets or hypoparathyroidism after starting vitamin D therapy.

The incidence of neonatal hypocalcemia varies in different studies. Data on the incidence and prevalence rates in the neonatal period are limited. Hypocalcemia occurs frequently in very low birth weight infants (< 1500 g). In a small study of 19 infants, the reported incidence of early onset hypocalcemia was 37% by 12 hours, 83% by 24 hours, and 89% by 36 hours in very preterm infants less than 32 weeks’ gestation. [11] Among very preterm infants, the onset of hypocalcemia is earlier than in more mature at-risk neonates.

The risk of developing early onset neonatal hypocalcemia is also greater among infants of diabetic mothers (7% [gestational DM], 32% [pregestational]) and infants experiencing perinatal asphyxia. The overall prevalence of moderate-to-severe, late-onset neonatal hypocalcemia (onset 5-10 d after birth) is low and appears to be more common among Hispanic and male infants; the severity of hypocalcemia is greater among infants who also exhibit hyperphosphatemia, hypomagnesemia, and vitamin D deficiency or insufficiency. [12]

No variation is reported across national boundaries. However, late-onset hypocalcemia is more common in infants in developing countries where babies are fed cow’s milk or formulas containing high amounts of phosphate than in countries where infants are fed human milk or formulas containing low amounts of phosphate.

Most pediatric patients with hypocalcemia are newborns. In older children, hypocalcemia is usually associated with critical illness, acquired hypoparathyroidism, activating mutations of the calcium-sensing receptor, or defects in vitamin D supply or metabolism.

Most cases of early-onset neonatal hypocalcemia resolve within 48-72 hours without any clinically significant sequelae.

Late-onset neonatal hypocalcemia secondary to exogenous phosphate load and magnesium deficiency responds well to phosphate restriction and magnesium repletion. A renewed emphasis on exclusive breastfeeding and use of contemporary infant formulas with more appropriate Ca:P ratios for mothers choosing not to breastfeed reduce this risk. Early supplementation with vitamin D in breastfeeding infants is another important prevention strategy.

When caused by hypoparathyroidism, hypocalcemia requires continued therapy with vitamin D metabolites and calcium salts. The period of therapy depends on the nature of the hypoparathyroidism, which can be transient, last several weeks to months, or be permanent.

Higher mortality rates have been reported in children with hypocalcemia than in normocalcemic children in PICU settings. [13]

Gertner JM. Disorders of calcium and phosphorus homeostasis. Pediatr Clin North Am. 1990 Dec. 37(6):1441-65. [Medline].

Kovacs CS. Calcium Metabolism in Pregnancy and Lactation. www.endotext.org. Available at https://www.ncbi.nlm.nih.gov/books/NBK279173/. 2015 Mar 10;

Rubin LP. Disorders of calcium and phosphorus metabolism. Avery’s diseases of the Newborn. 9th edition. Philadelphia: WB Saunders; 1998.

Tsang RC, Chen I, Hayes W, Atkinson W, Atherton H, Edwards N. Neonatal hypocalcemia in infants with birth asphyxia. J Pediatr. 1974 Mar. 84(3):428-33. [Medline].

Venkataraman PS, Tsang RC, Chen IW, Sperling MA. Pathogenesis of early neonatal hypocalcemia: studies of serum calcitonin, gastrin, and plasma glucagon. J Pediatr. 1987 Apr. 110(4):599-603. [Medline].

Venkataraman PS, Tsang RC, Greer FR, Noguchi A, Laskarzewski P, Steichen JJ. Late infantile tetany and secondary hyperparathyroidism in infants fed humanized cow milk formula. Longitudinal follow-up. Am J Dis Child. 1985 Jul. 139(7):664-8. [Medline].

Thomas TC, Smith JM, White PC, Adhikari S. Transient neonatal hypocalcemia: presentation and outcomes. Pediatrics. 2012 Jun. 129(6):e1461-7. [Medline].

Jackson GL, Sendelbach DM, Stehel EK, et al. Association of hypocalcemia with a change in gentamicin administration in neonates. Pediatr Nephrol. 2003 Jul. 18(7):653-6. [Medline].

Alizadeh-Taheri P, Sajjadian N, Eivazzadeh B. Prevalence of phototherapy induced hypocalcemia in term neonate. Iran J Pediatr. 2013 Dec. 23(6):710-1. [Medline]. [Full Text].

Tenhola S, Voutilainen R, Reyes M, Toiviainen-Salo S, Jüppner H, Mäkitie O. Impaired growth and intracranial calcifications in autosomal dominant hypocalcemia caused by a GNA11 mutation. Eur J Endocrinol. 2016 Jun 22. 211-218. [Medline]. [Full Text].

Venkataraman PS, Tsang RC, Steichen JJ, Grey I, Neylan M, Fleischman AR. Early neonatal hypocalcemia in extremely preterm infants. High incidence, early onset, and refractoriness to supraphysiologic doses of calcitriol. Am J Dis Child. 1986 Oct. 140(10):1004-8. [Medline].

Thomas TC, Smith JM, White PC, Adhikari S. Transient neonatal hypocalcemia: presentation and outcomes. Pediatrics. 2012 Jun. 129(6):e1461-7. [Medline].

Broner CW, Stidham GL, Westenkirchner DF, Tolley EA. Hypermagnesemia and hypocalcemia as predictors of high mortality in critically ill pediatric patients. Crit Care Med. 1990 Sep. 18(9):921-8. [Medline].

Shaw NJ. A Practical Approach to Hypocalcaemia in Children. Allgrove J, Shaw NJ. Calcium and Bone Disorders in Children and Adolescents. 2nd. Kraeger; 2015 Jun 12. 84-100. [Full Text].

Bilezikian JP, Brandi ML, Cusano NE, Mannstadt M, Rejnmark L, Rizzoli R, et al. Management of Hypoparathyroidism: Present and Future. J Clin Endocrinol Metab. 2016 Mar 03. 2313-2324. [Medline]. [Full Text].

[Guideline] Wagner CL, Greer FR. Prevention of rickets and vitamin d deficiency in infants, children, and adolescents. Pediatrics. 2008 Nov. 122(5):1142-52. [Medline].

Newfield RS. Recombinant PTH for initial management of neonatal hypocalcemia. N Engl J Med. 2007 Apr 19. 356(16):1687-8. [Medline].

Mulligan ML, Felton SK, Riek AE, Bernal-Mizrachi C. Implications of vitamin D deficiency in pregnancy and lactation. Am J Obstet Gynecol. 2009 Oct 19. [Medline].

Yogangi Malhotra, MD Assistant Professor, Department of Pediatrics, Division of Neonatology, Albert Einstein College of Medicine; Attending Neonatologist, Montefiore New Rochelle Hospital

Yogangi Malhotra, MD is a member of the following medical societies: American Academy of Pediatrics, American Pediatric Society, New York State Perinatal Association

Disclosure: Nothing to disclose.

Deborah E Campbell, MD, FAAP Professor of Pediatrics, Albert Einstein College of Medicine; Chief, Division of Neonatology, Children’s Hospital at Montefiore

Deborah E Campbell, MD, FAAP is a member of the following medical societies: Academic Pediatric Association, American Academy of Pediatrics, American Medical Association, American Pediatric Society, National Perinatal Association, New York Academy of Medicine

Disclosure: Nothing to disclose.

Sasigarn A Bowden, MD Associate Professor of Pediatrics, Section of Pediatric Endocrinology, Metabolism and Diabetes, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Associate Fellowship Program Director, Division of Endocrinology, Nationwide Children’s Hospital; Affiliate Faculty/Principal Investigator, Center for Clinical Translational Research, Research Institute at Nationwide Children’s Hospital

Sasigarn A Bowden, MD is a member of the following medical societies: American Society for Bone and Mineral Research, Central Ohio Pediatric Society, Endocrine Society, International Society for Pediatric and Adolescent Diabetes, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children’s Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Endocrinology, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Robert J Ferry Jr, MD Le Bonheur Chair of Excellence in Endocrinology, Professor and Chief, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, University of Tennessee Health Science Center

Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics, American Diabetes Association, American Medical Association, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Disclosure: Eli Lilly & Co Grant/research funds Investigator; MacroGenics, Inc Grant/research funds Investigator; Ipsen, SA (formerly Tercica, Inc) Grant/research funds Investigator; NovoNordisk SA Grant/research funds Investigator; Diamyd Grant/research funds Investigator; Bristol-Myers-Squibb Grant/research funds Other; Amylin Other; Pfizer Grant/research funds Other; Takeda Grant/research funds Other

Abhay Singhal, MD Assistant Professor of Clinical Pediatrics, Department of Pediatrics, Division of Neonatology, Indiana University School of Medicine

Abhay Singhal, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

Sunil Sinha, MD Assistant Professor, Division of Pediatric Endocrinology and Metabolism, Department of Pediatrics, University of Tennessee Health Science Center

Sunil Sinha, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, Endocrine Society, and Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Thomas A Wilson, MD Professor of Clinical Pediatrics, Chief and Program Director, Division of Pediatric Endocrinology, Department of Pediatrics, The School of Medicine at Stony Brook University Medical Center

Thomas A Wilson, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Pediatric Hypocalcemia

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