Glucose, Calcium, Phosphorus, and Magnesium

Multiple Choice

Of the following, the most likely congenital cardiac defect in an infant of a diabetic mother is:

• Ebstein's Anomaly

• Tetrology of Fallot

• Transposition of the great vessels

• Tricuspid atresia

• Truncus arteriosus

​Effects of maternal diabetes include:

• Congenital heart disease (hypertrophic cardiomyopathy, ventricular septal defect, transposition of the great vessels)

• Renal anomalies

• Caudal regression

• Neural tube defects

• CNS anomalies

• Small left colon. 

The risk of congenital malformations correlates with the degree of uncontrolled maternal diabetes.  If a woman with diabetes achieves glycemic control after conception, the risk of fetal anomalies is 7.8%; however, if glycemic control is attained prior to pregnancy, the risk of fetal anomalies decreases to 2.5%.

Reference: Brodsky D, Martin C.  Neonatology Review.  2nd edition. Lulu. 2010

• Hypertrophic cardiomyopathy is most common, occurring in ~40% of cases (!)

• TGA occurs almost twice as​ often in IDMs as non (per a 2020 article)

• ​Ebstein's anomaly is associated with maternal lithium use but can be associated with DM

Multiple Choice

How does gestational diabetes impact a woman’s health?

• Increases the likelihood of developing metabolic syndrome

• Increases the risk of pregnancy-related hypertension

• Significantly increases the lifetime risk of developing diabetes mellitus

• All of the above

• None of the above

GDM affects ~2% of pregnancies.

Recent evidence has demonstrated long-term effects of gestational diabetes on the mother, notably a significant increase in the risk of diabetes, with some estimates as high as 50% of those affected developing diabetes within 10 years of pregnancy. 

Women with a history of gestational diabetes are also at risk of

• Cardiovascular disease

• Obesity

• Metabolic syndrome

• Pregnancy-induced hypertension

​

References: Brodsky D, Martin C.  Neonatology Review.  2nd edition. Lulu. 2010

Kliegman RM, Behrman RE, Jenson HB, Stanton B (eds). Nelson Textbook of Pediatrics.  18th edition.  Philadelphia: Saunders, 2007

Metzger BE.  Long-term outcomes in mothers diagnosed with gestational diabetes mellitus and their offspring.  Clin Obstet Gynecol. 2007;50:972-979

Multiple Choice

A female infant born at 26 weeks’ gestation is now 10 weeks of age.  Her course was complicated by severe respiratory distress syndrome requiring exogenous surfactant administration and high frequency mechanical ventilation.  She also developed necrotizing enterocolitis requiring an exploratory laparotomy and several weeks of bowel rest.  A chest radiograph to evaluate the percutaneous central line placement reveals bilateral humeral fractures.  The cardiothymic silhouette is noted to be normal. 

The most likely etiology to explain the fractures of the infant in this vignette is:

• Hypoparathyroidism

• Non-accidental trauma

• Osteopenia of prematurity

• Pseudohypoparathyroidism

• Vitamin D-dependent rickets

​The infant in the vignette is at high risk for developing osteopenia of prematurity because of:

• Very premature birth (prevents the placental transfer of calcium and phosphorus during the third trimester)

• Severe illness

• Immobility

• Not maximal enteral nutrition

These factors led to osteopenia, with demineralized bones susceptible to fracture. 

​

Osteopenia of prematurity is best prevented by early establishment of enteral feedings with appropriate calcium and phosphorus supplementation for age, physical therapy, and supplementation with Vitamin D.

• ​Hypoparathyroidism = hypocalcemia with low serum PTH

• Can be attributable to

  • glandular hypoplasia

  • neonatal glandular suppression as a result of maternal hyperparathyroidism

  • autoimmune parathyroiditis

  • mutations in the calcium receptor

​Vitamin D-dependent rickets causes pathologic fractures, rachitic rosary, and moth-eaten metaphases on radiograph. 

It is caused by decreased calcium absorption mediated by Vitamin D.

Management Approach for an Enterally Fed Preterm Infant with Radiologic Evidence of Rickets

1. Maximize nutrient intake. Consider increasing HMF or volume of milk.

2. If you can't increase feeds, add elemental calcium and phosphorous as tolerated, starting at 20 mg/kg/d of calcium and 10-20 mg/kg/d of phosphorous, increasing to a max of 70-80 of Ca and 40-50 of Phos.

3. Evaluate for cholestasis and Vit D deficiency.

4. Follow serum phos and serum alk phos weekly.

5. Recheck for X-ray evidence of rickets every 5-6 weeks, until resolved

6. Remind caregivers to cautiously handle infant.

7. Limit use of steroids and lasix.

   Adapted from Abrams SA. "Calcium and Vitamin D Requirements of Enterally Fed Preterm Infants" Pediatrics 2013.​

​Pseudohypoparathyroidism is caused by defects in peripheral PTH receptors, leading to hypocalemia in the setting of elevated PTH. 

​

Non-accidental trauma is unlikely to occur in a hospitalized preterm infant, though infants with complex medical problems are at high-risk of non-accidental traumatic fractures once they are discharged from the hospital.

Multiple Choice

Which of the following statements is TRUE about the physiologic effects of parathyroid hormone?

• Decreases renal calcium reabsorption

• Increases hydroxylation of vitamin D in the kidney, indirectly increasing intestinal absorption of calcium and phosphorus

• Increases renal phosphorus reabsorption

• Inhibits renal calcitriol production

• Inhibits the release of calcium and phosphorus from bone

​Parathyroid hormone (PTH) is produced by the parathyroid gland and is secreted in response to low serum calcium concentrations.  It stimulates the activity of renal 1-alpha-hydroxylase, increasing the active form of vitamin D and indirectly increasing intestinal calcium and phosphorus absorption. 

PTH increases renal calcium absorption and decreases renal phosphorus absorption.  PTH also acts directly on bone, mobilizing calcium and phosphorus.  This hormone also increases renal calcitriol production.

Multiple Choice

A female infant of a diabetic mother is admitted to the Neonatal Intensive Care Unit with irritability, tremulousness, and concern for seizure activity.  Physical examination reveals a jittery full-term infant with laryngospasm and episodes of rhythmic left lower extremity jerking.  Her chest radiograph reveals a normal cardiothymic silhouette.  Her electrocardiogram reveals a prolonged QT interval.  Her blood glucose is 80 mg/dL. 

Serum electrolyte evaluation of this infant would most likely reveal:

• Hypercalcemia

• Hyperkalemia

• Hypermagnesemia

• Hypocalcemia

• Hypomagnesemia

​Maternal diabetes can lead to neonatal hypocalcemia, hypoglycemia and hypomagnesemia. 

​

Although jitteriness most commonly reflects hypoglycemia in an infant of a diabetic mother, the infant in this vignette has a normal glucose concentration, heightening suspicion for another electrolyte problem. 

​

Although infants with hypocalcemia and hypomagnesemia may be asymptomatic, both can induce jitteriness.  Hypocalcemia and hypomagnesemia are both treated with careful monitoring and replacement of the deficient electrolyte.

Hypocalcemia​

• Chvostek sign (twitching of facial muscles when tapping the facial nerve)

• Trousseau sign (involuntary contraction of wrist muscles with BP cuff)

• Irritability

• Laryngospasm

• Tetany

• Seizures

• Prolonged QT interval

• Muscle weakness

• Increased deep tendon reflexes

• Irritability

• Jitteriness

• Seizures

• Prolonged QT interval. 

​Hypomagnesemia

Multiple Choice

A neonatologist is evaluating an infant of a diabetic mother who was born at term weighing 4.6 kg.  The infant appears plethoric and is admitted to the NICU for management of hypoglycemia. The family asks the neonatologist to discuss neonatal complications of maternal diabetes.

Which of the following findings in the newborn is NOT associated with maternal diabetes?

• Hypoglycemia

• Hypercalcemia

• Thickening of the intracardiac septum

• Surfactant Deficiency

• Polycythemia

Multiple Choice

Which of the following statements is TRUE about infants of diabetic mothers?

• Fetal hyperinsulinemic state restricts substrate availability for surfactant biosynthesis

• Fetalal hyperinsulinism decreases erythropoeisis

• IDMs with a small left colon have recurrent intestinal obstructions

• IDMs with cardiomyopathy frequently have clinical signs of heart failure

​Infants of diabetic mothers have a 4- to 6-fold increase in surfactant deficiency as a result of decreased surfactant production.

​

Fetal hyperinsulinism is associated with increased erythropoeisis, resulting in polycythemia and indirect hyperbilirubinemia.

​

Thickening of the interventricular septum and left or right ventricular wall that occurs in cardiomyopathy of infants of diabetic mothers is usually asymptomatic and regresses in the first postnatal year. 

​

A small left colon that can occur in infants of diabetic mothers is a transient anomaly.

​

Reference: Ogata ES.  Problems of the infant of the diabetic mother.  NeoReviews.  2010;11:e627-e631

Multiple Choice

The metabolic abnormalities in infants of diabetic mothers resolve in the neonatal period.

• True

• False

​The metabolic effects that occur in infants of diabetic mothers, such as transient hypoglycemia, hypocalcemia and hypomagnesemia, do resolve.

​

However, offspring of mothers with diabetes mellitus have higher rates of obesity, impaired glucose tolerance, and hypertension in childhood and adulthood.

Multiple Choice

Which hormone contributes to the development of macrosomia among infants of diabetic mothers?

• Adiponectin

• Cortisol

• Growth hormone

• Insulin-like growth factor

• Leptin

​There are two main types of insulin-like growth factor present in intra-uterine life: 

1. insulin-like growth factor binding protein-3

2. insulin growth factor-1. 

​

These are both increased in the fetuses of diabetic women, leading to macrosomia.  

Multiple Choice

Which of the following is NOT a risk factor for HYPERglycemia in the preterm neonate?

• Early and high rates of IV lipid infusions

• Insufficient pancreatic insulin secretion

• IUGR

• Lack of enteral feedings --> increased incretin action/secretion, thereby limiting insulin

• IUGR status can lead to both hyper and hypoglycemia in neonates

• Hyperglycemia is also commonly seen in preterm and IUGR neonates, secondary to insufficient secretion of insulin from the pancreas

• Use of IV lipid infusions --> high circulating concentrations of circulating free fatty acids. This promotes gluconeogenesis, leading to hyperglycemia.

​

Lack of enteral feedings actually leads to diminished secretion of incretin. This promotes insulin secretion, resulting in HYPOglycemia rather than hyperglycemia.

Multiple Choice

A 2-month old male infant born at term presents to his pediatrician for a routine follow-up appointment.  He was born by emergent Cesarean section because of a concern for placental abruption.  He had perinatal depression at the time of delivery with an Apgar score of 1 at 1 minute, 3 at 5 minutes, and 5 at 10 minutes.  He required mechanical ventilation for the first 48 hours of life and received therapeutic hypothermia.  He did well through the remainder of his NICU course and was discharged home on day of life 12. 

At this visit, his examination is remarkable for palpable, non-tender, non-erythematous, subcutaneous nodules on his arms, thighs, and buttocks. The mother reports that these lesions have been there for several weeks. 

The most appropriate next step in the management of this infant is:

• Administer an IV fluid bolus and furosemide

• Obtain a CBC and blood culture 

• Obtain total and ionized calcium levels

• Routine Care

• Use a fine needle to aspirate the lesions

This patient with a history of perinatal depression presenting with ​firm nodules and plaques on the back, buttocks, thighs, forearms, and cheeks has subcutaneous fat necrosis.

​

• Subcutaneous fat necrosis is uncommon and usually occurs in the first few weeks of life

• Characterized by firm nodules and plaques on the back, buttocks, thighs, forearms, and cheeks, which can b eerythematous, flesh colored, or blue in color. 

• A CBC and blood culture are not required unless there is a high suspicion for infection. 

• Fine needle aspiration of classic lesions is rarely required. ​

​

​Pathophysiology

• Not completely known

• Potential etiologies include

  • primary defect in subcutaneous fat

  • birth hypoxia associated with skin ischemia, hypothermia, local trauma, or maternal factors

• A granulomatous reaction is noted on histologic examination of skin biopsy specimens. 

• Hypercalcemia is a potential complication of these lesions- most likely results from increased production of 1,25-dihydroxyvitamin D by the granulomatous lesions that subsequently stimulates intestinal uptake of calcium.

​Differential diagnosis of hypercalcemia in an infant

• Primary hyperparathyroidism

• Tertiary hyperparathyroidism

• Hyperthyroidism

• Familial hypocalciuric hypercalcemia

• Williams syndome

• Increased intake of calcium or vitamin D. 

​Infants with hypercalcemia can present with

• failure to thrive

• anorexia

• constipation

• polyuria

• hypotonia

• vomiting

• dehydration

• irritability.

• Potentially life-threatening complications include seizures, cardiac arrest, and renal failure.  

​Hypercalcemia requires immediate treatment

• Measurement of the total and ionized calcium levels

• Dietary intake of supplemental calcium should be stopped and a diet low in calcium and vitamin D should be started

• Intravenous fluid hydration

• Furosemide (can be given to increase calciuresis)

• If hypercalcemia persists, alternative therapies include corticosteroids, calcitonin, and/or bisphosphonates.  

Multiple Choice

A male infant is born at 26 weeks’ gestation.  At 12 hours of age, his blood culture that had been sent on admission is positive for Candida albicans. After discussing the case with the Infectious Diseases consultation service, the team orders liposomal amphotericin B.  At 3 days of age, the infant has a spontaneous intestinal perforation.  A penrose drain is placed to manage the perforation and two days later, the infant has a seizure.  His serum potassium, glucose and calcium concentrations are all within the normal range.

Of the following, the electrolyte or mineral that is most likely responsible for this infant’s seizure is:

• Magnesium

• Chloride

• Zinc

• Phosphorus

• Sodium

​Amphotericin B administration is known to lead to hypomagnesemia. 

​

Other etiologies of hypomagnesemia include the following:

• Maternal illness such as diabetes or preeclampsia

• IUGR

• Prematurity

• Malabsorption

• Chronic diarrhea

• Liver disease

• Perinatal depression

Multiple Choice

An infant is delivered at 38 weeks’ gestation by vaginal delivery.  He has a micropenis (phallic length < 2.5 cm) but has palpable testes.  The infant also has a cleft palate and a narrow nasal bridge. 

Which of the following would be unexpected in this infant’s clinical course?

• Hypernatremia

• Hyperglycemia

• Hypotension

• Polyuria

• Prolonged Jaundice

​The infant in this vignette has hypoplastic genitalia and midline facial abnormalities, which is consistent with hypopituitarism.  Hypoglycemia is a classic finding in an infant with hypopituitarism; affected infants do not have hyperglycemia. 

This hypoglycemia can result from impaired adrenocorticotropic hormone (ACTH) secretion or growth hormone (GH) deficiency.  Additionally, an infant with hypopituitarism can have hypotension, as a result of ACTH deficiency. 

​

Hypothermia, lethargy, poor feeding, prolonged jaundice, and constipation are common nonspecific findings in infants with hypopituitarism.  Impaired prolactin and gonadotropin secretion do not cause acute illness but an infant with a microphallus may have ACTH or GH deficiency.  Polyuria and hypernatremia may indicate antidiuretic hormone (ADH) deficiency.

Multiple Choice

An infant is delivered prematurely at 28 weeks’ gestation.  At a few hours of age, the infant has hypotension and the neonatology fellow orders a calcium level.  The infant’s calcium level is 5.7 mg/dL.  The fellow postulates that the infant’s hypocalcemia results from low mineral levels because peak intrauterine transfer of calcium occurs late in pregnancy. 

Which of the following is most useful in the management of hypocalcemia in an infant?

• Bisphosphonate

• Calcitonin

• Calcitriol

• Corticosteroids

• Furosemide

​Vitamin D (in the form of calcitriol) supplementation can help to treat hypocalcemia in an infant, specifically if it is caused by hypoparathyroidism. 

• Ergocalciferol can also be used if the infant’s parathyroid function is normal.

• Oral intake of a low phosphate formula will also help to increase calcium absorption. 

​The other options listed are helpful in the management of an infant with hypercalcemia.

• Corticosteroids can be used to inhibit reabsorption of calcium. 

• Bisphosphonates

  • inhibit osteoclasts leading to a decrease in bone turnover

  • increase calciuresis. 

• Calcitonin has been shown to inhibit intestinal reabsorption of calcium

• Furosemide can increase calciuresis

​Question 38 (4-part question)

A 4-month old male infant born at 24 weeks’ gestation had a clinical course complicated by necrotizing enterocolitis requiring an ileostomy and prolonged parenteral nutrition.

​

A radiograph demonstrates a fracture of the left humerus. 

​

The neonatologist recalls the distinction between osteopenia and osteomalacia.

Multiple Choice

Of the following, the description that is most consistent with osteomalacia is:

• Decreased osteoid production, normal mineralization

• Increased matrix resorption, normal mineralization

• Increased osteoid production, decreased mineralization

• Increased matrix resorption, normal mineralization

• Normal osteoid production, decreased mineralization

Multiple Choice

38b. Which of the following positively influences mineral accretion in the fetus?

• Fetal parathyroid hormone

• IUGR

• Maternal Estrogen

• Maternal Vitamin D deficiency

• Preeclampsia

​Estrogen has an anabolic effect on bone growth and positively influences mineral accretion in the fetus. 

• The placenta transfers calcium from the mother to fetus throughout pregnancy with the greatest amount of transfer occurring during the 3rd trimester. 

• The high fetal serum calcium levels lead to increased fetal calcitonin and suppressed fetal parathyroid function. High fetal calcitonin concentrations inhibit bone resorption. 

• A fetus who is growth restricted or born to a woman with Vitamin D deficiency or preeclampsia may have decreased mineral accretion.

Multiple Choice

38c. Which of the following is NOT a risk factor in the development of osteopenia of prematurity?

• Aluminum contamination of parenteral nutrition

• Arthrogryposis

• Corticosteroids

• Early Enteral Feeds

• Lasix

​Delayed enteral feedings and feeding restriction increases the risk for metabolic bone disease of prematurity. 

Circumstances of limited movements increase an infant’s risk of developing osteopenia of prematurity. 

• Sedation

• Paralysis

• Spina bifida

• Arthrogryposis

• Osteogenesis imperfecta

Aluminum toxicity and medications such as furosemide and corticosteroids, are also risk factors for developing osteopenia of prematurity.

Multiple Choice

38d. Which of the following is elevated in an infant with osteomalacia?

• 25 (OH) Vitamin D

• Alkaline Phosphatase

• Calcitonin

• Serum Calcium

• Serum Phosphate

Key Point: Infants with osteomalacia often have elevated alkaline phosphatase levels because of increased osteoblast activity to produce bone matrix.  

Elevated alkaline phosphatase values can also be found in infants with:

• Normal growth

• Healing after a fracture

• Copper deficiency

​

Affected infants with osteomalacia have decreased supply of both calcium and phosphate but serum levels may be normal if infants have appropriate increases in PTH and adequate phosphate supplementation, respectively. Infants with osteomalacia may have normal or low (OH) Vitamin D levels.  Calcitonin levels are usually normal.

Multiple Choice

Soon after birth, a full-term male newborn is noted to have hypospadias.  

Which of the following statements about hypospadias is FALSE?

• Advanced maternal age, pre-existing maternal diabetes mellitus, and maternal smoking have been associated with hypospadias 

• Delayed circumcision is recommended in case the foreskin may be required for repair

• Hypospadias is estimated to occur in approximately 1 in 500 births  

• If associated with bilateral undescended testes, congenital adrenal hyperplasia must be considered

• The majority of cases of hypospadias are in a sub-coronal location

​Hypospadias is the result of incomplete folding or partial closure of the urethra in males and is estimated to occur in approximately 1 in 500 births.  The final position of the urethral opening is determined by the extent of incomplete folding or closure. 

The following are associated with hypospadias:

• Advanced maternal age

• Pre-existing maternal diabetes mellitus

• GA < 37 weeks

• History of paternal hypospadias

• Maternal smoking

• Pesticide exposure

Delayed circumcision is recommended in case the foreskin may be required for repair.  If hypospadias is noted with bilateral undescended testes, congenital adrenal hyperplasia must be ruled out.   

​The location of the displaced urethral occurs

• glans or corona in 50% of cases

• sub-coronal or penile shaft in 30% of cases

• scrotum or perineum in 20% of cases

• In a rare variant, the foreskin may appear normal and the urethral abnormality is only noted after circumcision when the glans of the penis becomes visible

Multiple Choice

Of the following, the most likely change in neonatal carbohydrate physiology soon after birth is a DECREASE in:

• Catecholamine secretion

• Glucagon levels

• Glycogenolysis

• Insulin Production

• Ketogenesis

​At birth, the maternal glucose supply is acutely interrupted and the neonate accommodates by:

• increasing glucagon levels (3- to 5-fold) within minutes to hours after birth

• decreasing insulin production

• rapidly increases catecholamine secretion

All of these changes lead to an increase in glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis.

​

Glucose concentration is lowest 30 to 90 minutes after birth in a full term-infant.

Multiple Choice

All of the following are true about calcium and phosphate homeostasis in the neonate, EXCEPT:

• Calcitonin increases immediately after birth

• Calcitriol levels increase during the first day of life

• Calcium levels increase in the first six hours after delivery

• Phosphate is high in the first few days of life

• Parathyroid hormone levels increase during the first day of life

​Fetal skeletal growth and cell growth is dependent upon maternal calcium and phosphorous supply.

​

Calcium

• increases throughout gestation

• greatest increase during the third trimester

• Levels decrease rapidly in the first six hours after delivery

• Lowest levels at ~24 hours of age

​

PTH

• Following the initial decrease in calcium, PTH increases during the first day of life

• Peaks at ~48 hours of life

​Calcitriol [1,25(OH)2 vitamin D3]

• Levels also increase initially

​

Phosphate

• High in the first few days of life

• Slowly declines

​

Calcitonin

• Secretion varies with acute changes in serum calcium concentration.

• Calcitonin increases immediately after birth and then slowly decreases.​

Multiple Choice

You are called to the bedside of a 2-week old female infant who had been born at 33 weeks’ gestation.  The infant is currently being treated with Amphotericin B for a fungal infection.  The nurse has witnessed seizure activity.  Upon your arrival, the seizure has stopped but you observe that the infant is very irritable with tremors and hyperreflexia. She also has a weak respiratory effort. You ask the nurse to send blood for specific laboratory tests.

Of the following, the most likely abnormality in this infant is: 

• Hypercalcemia

• Hyperkalemia

• Hypernatremia

• Hypo-magnesemia

• Hypo-phosphatemia

​Hypomagnesemia occurs when serum magnesium concentrations fall below 1.6 mg/dL, although clinical signs often do not develop until they fall below 1.2 mg/dL.

​

The signs of hypomagnesemia are the same as those of hypocalcemia:

• irritability

• tremors

• seizures

• hyperreflexia

• muscle weakness (especially of the respiratory muscles)

• prolonged QT interval.

​The causes of hypomagnesemia in a neonate include the following

• Maternal magnesium deficiency (including diabetes)

• Malabsorption

• Chronic diarrhea

• Drug-induced (of which Amphotericin is a cause)

• Hypoparathyroidism

• Perinatal depression