Neonatal Hypocalcemia

Hypocalcemia is a common metabolic condition seen among neonates . Because calcium plays a vital role in multiple biochemical processes, severely low calcium levels can lead to life-threatening situations. Hypocalcemia is defined based on low levels of total serum calcium or its ionized fraction.

Serum calcium represents a small proportion of total body calcium since most of total body calcium remains sequestered in developing bones. (1) Ionized calcium (iCal) is the physiologically active component of total calcium (tCal) and is responsible for the symptoms of hypocalcemia. (2)

At a physiological steady state, iCal is typically the largest fraction of tCal. The remaining serum calcium is biologically inert and includes the protein-bound and anion-complexed fractions. (23)

Total serum calcium does not always correlate well with iCal since tCal can be affected by several factors such as acid-base status and plasma albumin concentration. (4) The iCal is the preferred measure; however, if not available, tCal can be corrected to assess whether low tCal is a result of low albumin status. A commonly used correction formula is:

Corrected total calcium (in milligrams per deciliter) = Measured total calcium (in milligrams per milliliter) + (0.8 × [4.0 – measured serum albumin, grams per deciliter]) in which albumin is assumed to have a value normal 4.0 g/dL (40 g/L). (5)

The threshold to define hypocalcemia is determined by birth weight and gestational age.

In full-term and preterm infants with birth weights greater than 1500 g, hypocalcemia is defined as tCal less than 8 mg/dL (2 mmol/L) or iCal less than 4.4 mg/dL (1.1 mmol/L). ). (6)

In premature newborns with birth weight less than 1500g, hypocalcemia is defined as tCal less than 7 mg/dL (1.75 mmol/L) or iCal less than 4 mg/dL (1 mmol/L). (6) Each cutoff reflects values ​​2 standard deviations below the mean nadir in each age-adjusted group. (23)

A notable limitation is that values ​​at or near these thresholds generally do not correlate with the onset of symptoms. Observational studies have noted that very low birth weight babies are often asymptomatic until iCal values ​​fall below 3.2 mg/dL (0.8 mmol/L) or lower. (3)(7)

Determining the etiology of hypocalcemia requires an understanding of the uniqueness of calcium metabolism among neonates. Calcium homeostasis involves a delicate balance between the parathyroid gland, bones and kidneys. The mature parathyroid gland is the main modulator of calcium homeostasis.

Parathyroid hormone (PTH) is released when calcium levels fall below a threshold recognized by calcium-sensitive receptors in parathyroid tissue. PTH communicates with the bones to release calcium and phosphorus from the matrix into the serum. In this way it acts on the kidneys to increase calcium retention at the expense of phosphorus lost in the urine.

PTH also increases the 1α-hydroxylation of calcidiol (25-hydroxyvitamin D) in the kidneys to synthesize calcitriol. Calcitriol (1,25-dihydroxyvitamin D) is the biologically active metabolite of vitamin D that increases intestinal calcium absorption by increasing the presence of calcium transport proteins throughout the lumen of the small intestine.

Absorption through these calcium channels is the only mechanism to increase total body calcium stores, making the intestines the most important site of calcium acquisition.

Before the intestines become the main organ of calcium absorption, the placenta serves as the critical regulator of mineral homeostasis in fetal life. (8)(9) This transition from maternal-fetal to postnatal mineral regulation matures in the neonatal period and allows for unique causes of hypocalcemia when disrupted.

Fetal calcium metabolism is marked by dependence on active calcium transport across the placenta. The kidneys and intestines are not important fetal mineral sources, although the cycle of ingestion-absorption-excretion of calcium through a renal-amniotic-intestinal loop may contribute to maintaining a positive calcium balance. (10)(11)

The 2 main goals of fetal calcium homeostasis are the successful mineralization of the developing skeleton and the accumulation of calcium against the electrochemical gradient to maintain a relatively high serum calcium level. (12)

During the third trimester, approximately 150 mg/kg of calcium is actively transported across the placenta to the fetus. (9) Fetal serum calcium levels remain approximately 1.2 to 2 mg/dL (0.3–0.5 mmol/L) higher than those of the pregnant person in the second half of pregnancy. (10)(12) This state of relative hypercalcemia in fetal life also appears to be protective against a precipitous drop in calcium levels after birth due to separation from the constant maternal supply. (13)

Increased maternal intestinal absorption and fetal bone resorption of calcium facilitates fetal supply while maintaining adequate maternal levels throughout pregnancy. Maternal PTH levels start out low but increase throughout pregnancy until the third trimester, augmented by maternal intake of vitamin D and calcium. (14)

Maternal PTH does not cross the placenta, but affects calcium delivery to the fetus through maintenance of maternal serum calcium levels. (10) Calcium transport across the placenta increases exponentially during the third trimester.

Approximately 80% of calcium transport occurs after the 24th week of pregnancy as fetal accumulation increases 6-fold. (15) (16)

Studies have shown that total body calcium accumulation is exponentially related to gestational age and linearly related to weight in preterm infants with appropriate weight for gestational age and in full-term neonates. (17) (18) (19) At term gestation, the fetus should have accumulated approximately 30g of calcium or about 1% of its body weight. (13) (15)

The developing calcium-PTH-vitamin D axis appears to play an increasing role in regulating fetal serum calcium levels. The fetal parathyroid glands are functionally active from 12 weeks of gestation and respond to the state of fetal hypercalcemia by suppressing PTH production. (10) (12) (16)

Low PTH suppresses fetal renal 1α-hydroxyl activity, effectively decreasing fetal calcitriol production despite passive transport of maternal calcidiol derivatives across the placenta. Fetal levels of the PTH antagonist calcitonin also increase, complementing an appropriate hormonal environment for bone mineral deposition upon resorption. (twenty)

Human cord bioassays show that, despite low concentrations of intact PTH, there is high PTH-like activity in fetal life. (21) PTH-related protein (PTHrP), which is synthesized by maternal and fetal tissues including the fetal parathyroid gland and placenta, plays a similar role to PTH in the regulation of fetal iCal. (10)(22)

The upregulation of fetal PTHrp in the absence of a hypocalcemic stimulus suggests that, unlike PTH, PTHrp is secreted autonomously. (22) It is likely that the 2 hormones work together with the net effect of facilitating placental mineral transfer, bone differentiation and mineralization, and maintenance of elevated fetal serum mineral levels. (10)(12)(22)

Neonatal hypocalcemia is defined as early onset before 72 hours of age. Early onset hypocalcemia ( EITH) can be generalized as an inappropriate physiological response to a calcium nadir. This altered response may be due to suboptimal fetal calcium accumulation and calcium reserve, a decreased ability to increase calcium absorption in response to the physiological nadir, or an insufficient supply of exogenous calcium.  

> Common causes of HIT

Premature babies are at higher risk for HIT as they have lower levels of calcium buildup compared to their full-term counterparts. Furthermore, they experience a faster and more significant drop in postnatal calcium since the magnitude of the nadir is inversely related to gestational age. (13)

Elevated fetal calcitonin levels facilitate bone mineralization in utero and are typically more than double that in a full-term newborn.

This elevation may persist after delivery, contributing to HIT. (13) (20) Furthermore, the immature parathyroid glands in premature neonates cannot release enough PTH, while the immature renal tubules do not respond adequately to PTH. (12)

When present, concomitant hypomagnesemia further diminishes the hypocalcemic response. The combination of these factors is often called early hypocalcemia of prematurity. Despite having a low tCal, premature babies are usually asymptomatic due to preserved iCal levels. Although the exact mechanism of preservation of iCal levels is unknown, the relative acidosis and hypoproteinemia associated with prematurity likely contribute. (3)

Similarly, growth-restricted infants are at increased risk of developing HIT. Decreased transfer of calcium and other minerals in the uterus may be a consequence of placental pathology, particularly when associated with ischemia. (23)

Chronic fetal hypoxia and prolonged suboptimal nutritional supply lead to ineffective metabolic adaptations that impair adequate intestinal absorption and bone resorption, leading to hypocalcemia. (20) (23) The severity of growth restriction is directly correlated with the severity of hypocalcemia. (2) (24)

In children of diabetic mothers (HMD), HIT can occur as frequently as in 50% of births. (25) These infants experience an exaggerated postnatal calcium nadir that correlates with the severity of poor maternal glycemic control. (3)

Glycosuria in diabetic mothers is associated with increased urinary magnesium loss, leading to maternal problems and fetal hypomagnesemia. Magnesium is essential for the proper synthesis and release of PTH. (10)

Functional hypoparathyroidism secondary to hypomagnesemia is the suspected mechanism of hypocalcemia in HMD. (2) Concomitant hyperphosphatemia may be present and aligns with features of hypoparathyroidism.

The underlying mechanism is probably multifactorial since magnesium supplementation did not demonstrate a decrease in the incidence of hypocalcemia among these neonates. (26) The increased risk of perinatal asphyxia, prematurity, and increased calcium demand in macrosomic infants have been suggested as contributing factors to HIT among HMD. (25)

> Rare causes of HIT

Severe cardiorespiratory depression at birth may be associated with severe early-onset hypocalcemia (ITH).

Hypocalcemia in this scenario is multifactorial. Slow and impaired PTH secretion and increased phosphate load secondary to decreased filtration rate are suggested factors. (2)(3) Perinatal asphyxia is also associated with elevated calcitonin levels, blunting the calcium nadir response. (3)

It is unclear whether the severity of early-onset hypocalcemia (ITH) correlates with the severity of hypoxic-ischemic encephalopathy. Decreased calcium intake with late initiation of enteral feeding also contributes. With correction of metabolic acidosis, the iCal level will fall as more calcium binds to serum albumin.

Chronic maternal serum calcium disorder may increase the risk of an infant developing HIT. Although the feto-placental unit can adapt to brief fluctuations in calcium levels, prolonged exposure to maternal hypercalcemia or hypocalcemia can result in neonatal hypocalcemia. Two rare causes of maternal hypercalcemia leading to HIT are untreated maternal hyperparathyroidism and excessive maternal calcium intake.

Maternal hyperparathyroidism with hypercalcemia can affect the newborn and causes symptoms in approximately 50% of those babies. (10) (27) Although maternal PTH cannot cross the placenta, maternal calcium does flow to the fetus.

Prolonged exposure to maternal hypercalcemia suppresses fetal parathyroid glands. This suppression persists after birth and may present as HIT or late-onset hypocalcemia (Late HIT). (10) Severe neonatal hypocalcemia may be the presenting feature of undiagnosed maternal parathyroid disease.

Maternal hypercalcemia due to excessive nutritional calcium intake has been reported to contribute to early-onset hypocalcemia (EIT). Excessive ingestion of calcium carbonate contained in antacids may cause fetal hypoparathyroidism due to maternal hypercalcemia. (28) (29) (30)

At the opposite end of the spectrum, maternal hypocalcemia can also lead to HIT. Long-term exposure to decreased maternal calcium levels can increase fetal PTH levels, leading to increased bone resorption resulting in HIT.

> Rare causes of early-onset hypocalcemia (HIT)

Osteopetrosis is a rare congenital disorder that can often be fatal without a hematopoietic stem cell transplant.

Dysregulated osteoclastic activity results in abnormal bone remodeling, which is prone to fracture and can narrow the cranial nerve foramen, causing compression of the nerve.

The typical presentation of osteopetrosis is fractures, visual impairment due to compression of the optic nerve, and bone marrow failure. (3) Dysregulated osteoclasts cannot mobilize calcium from trabecular bone, resulting in hypocalcemia with elevated PTH levels. (31)

Acute respiratory alkalosis is associated with a 0.16 mg/dL (0.04 mmol/L) decrease in iCal with each 0.1 increase in pH. (2) Correction of alkalosis can also cause a rapid decrease in iCal levels by increasing the protein-bound fraction.

It was observed that newborns with severe hyperbilirubinemia have lower iCal levels. (32) Infusion of citrated blood products used in exchange transfusion treatments reduces iCal levels by increasing the fraction of calcium complexed with anions despite the calcium present in blood transfusions. (32)

Medications such as aminoglycosides have been observed to cause hypocalcemia through increased renal calcium excretion. (33) Although renal tubular injury from exposure to aminoglycosides is unlikely to lead to hypocalcemia, it is unclear whether this mechanism of action is due to hyperphosphatemia or phosphate accumulation secondary to renal injury. (3. 4)  

Late-onset hypocalcemia (Late HIT) is defined as low calcium levels that occur after 72 hours of age. Most cases of Late HIT occur before the end of the first postnatal week.

Compared with HIT, Late HIT has a greater association with severe iCal disorders, with patients more likely to be symptomatic. Fortunately, late HIT is less common than HIT, with many causes that are rarely encountered in clinical practice.  

> Common causes of Late HIT

One of the most common causes of Late HIT is hyperphosphatemia due to a diet consisting of cow’s milk formula. It is suggested that increased serum phosphorus results in poorly soluble calcium salts, which limits its intestinal absorption. (8) (35) A higher phosphate load also leads to increased bone calcium deposition, resulting in hypocalcemia.

Neonatal vitamin D deficiency may present as late HIT, hypophosphatemia, elevated alkaline phosphatase, and secondary hyperparathyroidism. This deficiency may result from low maternal levels of vitamin D or poor neonatal absorption.

If maternal vitamin D stores are low, the newborn is at increased risk of also having vitamin D deficiency. Several reports have noted a high incidence of mothers with vitamin D deficiency among infants presenting with hypocalcemic tetany. (36) (37) (38)

Malabsorption, hepatobiliary disease, and renal failure are common causes of vitamin D deficiency. (2) Vitamin D absorption is chylomicron dependent. Any condition of fat malabsorption increases the newborn’s risk of developing vitamin D deficiency. (39)

Transient neonatal hypomagnesemia can often present with hypocalcemia. Magnesium deficiency inhibits PTH secretion and reduces its responsiveness. Transient hypomagnesemia may also occur secondary to renal magnesium wasting due to urinary tract obstruction, acute renal failure, and certain medications such as aminoglycosides and loop diuretics. (3)

Primary hypomagnesemia is a rare autosomal recessive disease that leads to defects in intestinal magnesium transport. In affected infants, hypocalcemia is refractory to treatment until the magnesium concentration is corrected.

> Uncommon causes of  Late Onset Hypocalcemia (Late HIT)

Parathyroid dysfunction causing late HIT in newborns is classified into 3 categories:

1. primary hypoparathyroidism
2. secondary hypoparathyroidism
3. pseudohypoparathyroidism

Primary hypoparathyroidism is a rare cause of Late HIT and will be discussed in the next section.

Secondary hypoparathyroidism may be due to untreated maternal hyperparathyroidism, intrauterine growth restriction, maternal magnesium deficiency, disorders of neonatal intestinal transport, and disorders of neonatal renal magnesium excretion.

> Rare causes of Late HIT

Primary hypoparathyroidism is generally rare in the neonatal population. Microdeletion of chromosome 22q11, observed in the spectrum of DiGeorge syndrome, is an important cause of hypoplasia or aplasia of the parathyroid glands. The 22q11 microdeletion occurs in approximately 1 in 4,000 live births. Hypocalcemia has been reported in up to 70% of infants with the DiGeorge phenotype. (40)

The clinical features of this syndrome include abnormal facies, cleft palate, thymic aplasia, and congenital heart disease with conotruncal defects. Other causes of congenital hypoparathyroidism are extremely rare. Few cases of isolated or idiopathic primary hypoparathyroidism have been reported. (23)

Autosomal dominant inheritance of activating calcium sensor receptor mutations can cause hypocalcemia with inappropriate calciuria, nephrocalcinosis, and late HIT. (41) Kenny Caffey syndrome is a rare disorder characterized by skeletal, optic, otic, and renal anomalies with autosomal recessive and dominant forms that present impaired PTH production. (42)

Infants are usually small for gestational age and may experience recurrent episodes of late-onset hypocalcemia in the neonatal period. (2)

Pseudohypoparathyroidism is a rare, heterogeneous group of disorders characterized by hypocalcemia and hyperphosphatemia despite elevated PTH levels. This pattern reflects the resistance of target organs to PTH.

In neonates, this etiology is suspected when these abnormalities persist despite adequate calcium and vitamin D supplementation. Reported neonatal cases are transient, and immaturity of PTH1R signaling has been postulated to be the cause. (43)

Hypocalcemia can be life-threatening. Although HIT is usually clinically silent, late HIT tends to be symptomatic. Newborns may present acutely with neuromuscular irritability.

Premature neonates may present with subtle manifestations such as nervousness, exaggerated startle reflex, myoclonic jerks, or generalized/focal seizures. (32)(44)

Electroencephalographic findings associated with hypocalcemia include the presence of rapid rhythms and generalized spike-and-wave discharges. (Four. Five)

The electrocardiogram may show prolonged QTc due to lengthening of the ST interval. While cardiac changes correlate with the degree of hypocalcemia, other nonspecific symptoms such as apnea, tachypnea, cyanosis, and laryngospasm are not related to the severity of hypocalcemia. (46)

Patients with Late HIT may experience seizures. Unlike seizures in older children, newborns tend to have multifocal seizures because their neurological system is less able to sustain any organized and generalized epileptiform activity. (28)

Before initiating treatment of neonatal hypocalcemia, appropriate laboratory investigations should be performed. Recommended studies should include blood samples for iCal, phosphate, magnesium, alkaline phosphatase, albumin, intact PTH, creatinine, and 25-hydroxyvitamin D, and urine for calcium-creatinine ratio. (31) Pseudohypocalcemia can occur in a state with low albumin and low total calcium, supporting the use of iCal over tCal levels.

There is debate about whether asymptomatic hypocalcemia should be treated. For asymptomatic patients, starting with oral supplementation is an option. A common practice for patients not receiving complete enteral nutrition is to increase the amount of calcium administered through their intravenous fluids. If treatment of asymptomatic hypocalcemia is with an intermittent dose of intravenous calcium gluconate, it should be infused slowly over one hour.

When considering correction for symptomatic patients, treatment will depend on their severity as well as the cause of the underlying disease. Acute symptomatic treatment may be administered more rapidly over 10 to 20 minutes with consideration for a second dose if there is no clinical response within 10 to 20 minutes. For continuous infusions and maintenance therapy, it is important to calculate the dose based on the elemental calcium content rather than the calcium salt contained. (31)

Calcium gluconate should preferably be administered through a central line. If administered peripherally, extravasation of calcium gluconate may cause subcutaneous necrosis. Therefore, frequent skin checks around the peripheral IV line are recommended. (47) When starting the infusion, close cardiovascular monitoring is necessary, as arrhythmias may occur with rapid calcium infusions. (32) Serum calcium levels should be assessed regularly as additional doses may be necessary.

Once an adequate calcium level has been achieved, daily supplements may be required to maintain this range. Maintenance therapy can be gradually withdrawn as long as the newborn’s serum calcium level remains normal.

• Hypocalcemia is a relatively common condition observed in the neonatal period.
   
• It is essential to understand calcium homeostasis in terms of the regulation of both maternal and fetal calcium-PTH-vitamin D hormonal, renal and intestinal axis.
   
• While this review presents common, uncommon, and rare causes of HIT and Late HIT, there is a certain degree of overlap between these categories.
   
• Understanding the mechanisms of HIT and Late HIT is important for the management of neonatal hypocalcemia.