Infant of Diabetic Mother

Overview

Infants of diabetic mothers (IDMs) have experienced a nearly 30-fold decrease in morbidity and mortality rates since the development of specialized maternal, fetal, and neonatal care for women with diabetes and their offspring. Before then, fetal and neonatal mortality rates were as high as 65%.

Today, 3-10% of pregnancies are affected by abnormal glucose regulation and control. Of these cases, 80-88% are related to abnormal glucose control of pregnancy or gestational diabetes mellitus. Of mothers with preexisting diabetes, 35% have been found to have type 1 diabetes mellitus, and 65% have been found to have type 2 diabetes mellitus.

Infants born to mothers with glucose intolerance are at an increased risk of morbidity and mortality related to the following:

Respiratory distress
Growth abnormalities (large for gestational age [LGA], small for gestational age [SGA])
Hyperviscosity secondary to polycythemia
Hypoglycemia
Congenital malformations
Hypocalcemia, hypomagnesemia, and iron abnormalities

These infants are likely to be born by cesarean delivery for many reasons, among which are such complications as shoulder dystocia with potential brachial plexus injury related to the infant's large size. These mothers must be closely monitored throughout pregnancy. If optimal care is provided, the perinatal mortality rate, excluding congenital malformations, is nearly equivalent to that observed in normal pregnancies.

References

Complications

Communication between members of the perinatal team is of crucial importance to identify infants who are at the highest risk for complications from maternal diabetes.

Fetal congenital malformations are most common when maternal glucose control has been poor during the first trimester of pregnancy. As such, the need for preconceptional glycemic control in women with diabetes cannot be overstated. Maternal hyperglycemia during late gestation is more likely to lead to fetal macrosomia, hypoxia, polycythemia, and cardiomegaly with outflow tract obstruction.^{[1, 2]}

Fetal macrosomia

Fetal macrosomia (>90th percentile for gestational age or >4000 g in the term infant) occurs in 15-45% of diabetic pregnancies. It is most commonly observed as a consequence of maternal hyperglycemia. When macrosomia is present, the infant appears puffy, fat, ruddy, and often hypotonic.^{[3, 4, 5, 6]}

Fetal growth is assessed by plotting birth weight against gestational age on standard growth curves. Infants whose weight exceeds the 90th percentile for gestational age are classified as large for gestational age (LGA). Maternal hyperglycemia during late pregnancy is commonly followed by excessive fetal growth.

LGA infants should be routinely screened for hypoglycemia. This is particularly important if the mother has received glucose-containing fluids during her labor.

Impaired fetal growth

Infants whose birthweight is below the 10th percentile, when plotted against gestational age on a standard growth curve, are considered small for gestational age (SGA).

Impaired fetal growth may occur in as many as 20% of diabetic pregnancies, compared with a 10% incidence (by definition) for infants born to mothers without diabetes. Maternal renovascular disease is the common cause of impaired fetal growth in pregnancies complicated by maternal diabetes.

Perinatal asphyxia, more common in infants with impaired fetal growth, may be anticipated by prenatal history; this demonstrates the importance of communication between the obstetrician and the pediatrician.

Pulmonary disease

These infants are at an increased risk of respiratory distress syndrome and may present within the first few hours after birth with tachypnea, nasal flaring, intercostal retractions, and hypoxia. Operative delivery due to macrosomia also increases the risk for transient tachypnea of the newborn, whereas polycythemia predisposes the infant to persistent pulmonary hypertension of the newborn.

Initially, the differential diagnosis includes transient tachypnea of the newborn, respiratory distress syndrome, pneumonia, and persistent pulmonary hypertension.

Metabolic and electrolyte abnormalities

Hypoglycemia may present within the first few hours of life. Although the infant is generally asymptomatic, symptoms may include jitteriness, irritability, apathy, poor feeding, high-pitched or weak cry, hypotonia, or frank seizure activity. Hypoglycemia that requires intervention may persist for as long as 1 week.

Hypoglycemia is caused by hyperinsulinemia due to hyperplasia of fetal pancreatic beta cells consequent to maternal-fetal hyperglycemia. Because the continuous supply of glucose is stopped after birth, the neonate develops hypoglycemia because of insufficient substrate. Stimulation of fetal insulin release by maternal hyperglycemia during labor significantly increases the risk of early hypoglycemia in these infants. Perinatal stress may have an additive effect on hypoglycemia due to catecholamine release and glycogen depletion. The overall risk of hypoglycemia is anywhere from 25-40%, with LGA and preterm infants at highest risk.

Hypocalcemia or hypomagnesemia may also be apparent in the first few hours after birth. Symptoms may include jitteriness or seizure activity. Hypocalcemia (levels < 7 mg/dL) is believed to be associated with a delay in parathyroid hormone synthesis after birth.

Sixty-five percent of all infants of diabetic mothers (IDMs) demonstrate abnormalities of iron metabolism at birth. Iron deficiency increases the infant's risk for neurodevelopmental abnormalities. Iron is redistributed to the iron-deficient tissues after birth, as the red blood cell (RBC) mass is postnatally broken down.

Hematologic problems

Polycythemia, caused by increased erythropoiesis triggered by chronic fetal hypoxia, may present as a clinically "ruddy" appearance, sluggish capillary refill, or respiratory distress. Hyperviscosity due to polycythemia increases the IDM’s risk for stroke, seizure, necrotizing enterocolitis, and renal vein thrombosis.

Thrombocytopenia

Thrombopoiesis may be inhibited because of an excess of RBC precursors within the bone marrow as a result of chronic in utero hypoxia and increased erythropoietin concentration.

Hyperbilirubinemia

This is common, especially in association with polycythemia. The increased red cell mass results in increased number of RBCs that are taken out of circulation each day and increase the bilirubin burden presented to the liver.

Cardiovascular anomalies

Cardiomyopathy with ventricular hypertrophy and outflow tract obstruction may occur in as many as 30% of IDMs.^[7]The cardiomyopathy may be associated with congestive failure with a weakly functioning myocardium or may be related to a hypertrophic myocardium with significant septal hypertrophy and outflow tract obstruction. When cardiomegaly or poor perfusion and hypotension are present, performing echocardiography to differentiate between these processes is important.

These infants are also at an increased risk of congenital heart defects, including (most commonly) ventricular septal defect (VSD) and transposition of the great arteries (TGA).

Congenital malformations

Central nervous system (CNS) malformations are 16 times more likely in IDMs. In particular, the risk of anencephaly is 13 times higher, whereas the risk of spina bifida is 20 times higher. The risk of caudal dysplasia is up to 600 times higher in these infants.^[8]

Neurologic immaturity, demonstrated by immature sucking patterns, has been found in infants born to insulin-managed mothers with diabetes.^[9]Studies in fetal sheep indicate that this may be a reflection of the abnormal brain metabolism and electroencephalogram (EEG) findings as a result of the fetal hyperglycemia.^[10]

Renal (eg, hydronephrosis, renal agenesis, ureteral duplication), ear, gastrointestinal (eg, duodenal or anorectal atresia, small left colon syndrome), and, as mentioned earlier, cardiovascular (eg, single umbilical artery, VSDs, atrial septal defects, TGA, coarctation of the aorta, cardiomegaly) anomalies are more frequent in these infants.

References

Workup

CBC count

Polycythemia, commonly defined as a central hematocrit level higher than 65%, is a potential concern. Maternal-fetal hyperglycemia and fetal hypoxia is a strong stimulus for fetal erythropoietin production and subsequent increase in fetal hemoglobin concentration. Thrombocytopenia may occur because of impaired thrombopoiesis due to "crowding-out" of thrombocytes by the excess of erythroid precursors in the bone marrow.

Glucose concentration (serum or whole-blood)

Seizures, coma, and long-term brain damage may occur if neonatal hypoglycemia is unrecognized and untreated. Most centers recognize levels lower than 20-40 mg/dL within the first 24 hours after birth as abnormal, but the precise level remains controversial.^[11]

A policy to screen infants of diabetic mothers (IDMs) for hypoglycemia should be in place in every hospital. Operational thresholds were proposed by Cornblath et al.^[12]They suggested that an infant with compromised metabolic adaptation (ie, IDM) undergo blood glucose measurements (1) as soon as possible after birth, (2) within 2-3 hours after birth and before feeding, and (3) at any time abnormal clinical signs are observed.

Magnesium concentration (serum)

Hypomagnesemia is related to younger maternal age, severity of maternal diabetes, and prematurity. Neonatal magnesium levels are also related to maternal serum magnesium, neonatal calcium and phosphorus levels, and neonatal parathyroid function. The clinical significance of low magnesium levels in these infants remains controversial and uncertain.

Calcium concentration (serum, ionized or total levels)

Low serum calcium levels in IDMs are common. They are speculated to be caused by a functional hypoparathyroidism; however, their clinical relevance remains uncertain and controversial.

Bilirubin level (serum, total and unconjugated)

Hyperbilirubinemia (see bilirubin) is notably more common in IDMs than in the general population of neonates. Causative factors include prematurity, hepatic enzyme immaturity, polycythemia, and reduced RBC half-life.

Arterial blood gas

Assessing oxygenation and ventilation is essential in infants with clinical evidence of respiratory distress. Although noninvasive methods (eg, transcutaneous oxygen and carbon dioxide electrodes, oximeters) have gained wide acceptance at many centers, comparison of results with those from arterial blood is intermittently required.

Chest radiography

Clinical evidence of cardiopulmonary distress requires a detailed evaluation, which should always include a chest radiograph. The image should be evaluated for adequacy of lung expansion, evidence of focal or diffuse atelectasis, presence of interstitial fluid, signs of free air in pleural or interstitial spaces, and findings of respiratory distress syndrome or pneumonia. The possibility of pulmonary malformations should also be considered.

Cardiac size, shape, and great vessel/outflow tract should be carefully examined. In the infant with macrosomia who has a history of shoulder dystocia, the clavicles should be evaluated on the film as well on physical examination.

Abdominal, pelvic, or lower extremity radiography

When caudal dysplasia is present, other orthopedic anomalies should be investigated, including fusion of the legs, hypoplastic femur, defects of the tibia and the fibula, flexion contractures of the knee and hip, or clubfoot. Caudal dysplasia or sacral agenesis is the most common orthopedic anomaly in the IDM.

Lower extremity congenital malformations require radiographic evaluation to determine the exact skeletal defect or defects present.

Cardiac echocardiography

A thickened myocardium and significant septal hypertrophy may be present in as many as 1 in 3 IDMs. Evidence of a hypercontractile, thickened myocardium, often with septal hypertrophy disproportionate to the size of the ventricular free walls, may be noted on examination. Myocardial contractility should also be evaluated, because the myocardium is overstretched and poorly contractile with congenital cardiomyopathies.

Evidence of anatomical malformation must be searched for carefully because cardiac malformations, including VSDs and TGAs, are significantly more common in IDMs.

Barium enema

Infants with feeding intolerance, abdominal distention, nonbilious emesis, or poor passage of meconium may require a barium enema. Congenital anomalies of the gastrointestinal tract are more common in IDMs. These infants may have small left colon syndrome, also known as "lazy colon."

Clinical features of the small left colon syndrome may mimic those of Hirschsprung disease, and distal tapering of the colon is a radiologic feature of both disorders. The 2 disorders can be distinguished using a biopsy because normal ganglionic cells are present in lazy colon and absent in Hirschsprung disease.

Indwelling vascular lines (peripheral, umbilical, or central)

Noninvasive blood gas monitoring using transcutaneous electrodes (PaO₂ and PaCO₂) and oximeters (O₂% saturation) has greatly reduced the need for invasive, indwelling catheters. However, indwelling lines are often needed early in the course of cardiorespiratory disease. In some instances, the need for continuous arterial blood pressure monitoring may warrant placement of a peripheral or umbilical arterial line.

Placement of an umbilical venous or a central venous catheter is often used when the infant requires high concentrations of intravenous (IV) dextrose or when peripheral access is limited or exhausted.

Histologic findings

The pancreas has larger and more numerous islets (see image below). Sections from neonatal myocardium show cellular hyperplasia and hypertrophy.

View Image

An increase in the number and size of the islets is commonly seen in the pancreas of infants born to diabetic mothers.

References

Hypoglycemic Management

Improved maternal glucose control during the pregnancy and labor improves postnatal glucose adaptation and a decreases the need for IV glucose treatment in the infant. A screening policy for hypoglycemia during the hours after birth is necessary to detect hypoglycemia.

Serum or whole blood glucose levels of less than 20-40 mg/dL within the first 24 hours after birth are generally agreed to be abnormal and to require intervention. Cornblath et al recommended critical values of glucose that require intervention.^[12]Determination of plasma or whole blood glucose should be made at the following points:

As soon as possible after birth
Repeat determinations at 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, and 12 hours after birth
At any time abnormal clinical signs are observed

Guidelines for maintaining euglycemia

If the plasma value is less than 36 mg/dL (2 mmol/L), intervention is needed (1) if plasma glucose remains below this level, (2) if it does not increase after a feeding, or (3) if the infant develops symptoms of hypoglycemia.

If the plasma value is less than 20-25 mg/dL (1.1-1.4 mmol/L), IV glucose should be administered, with the target glucose level being more than 45 mg/dL (2.5 mmol/L). This goal of 45 mg/dL is accentuated as a margin of safety. This should include a bolus of dextrose followed by a constant infusion of dextrose. Profound hypoglycemia may require therapy with hydrocortisone.

Determining which infants require the highest dextrose administration to maintain euglycemia is difficult. The following suggestions represent a guideline for glucose administration to an infant with hypoglycemia.

Immediate IV therapy with 2-mL/kg infusion of dextrose 10% is required in any symptomatic infant with hypoglycemia; dextrose 10% (D10) provides 100 mg/mL of dextrose, and the starting dose is 200 mg/kg of dextrose. Administration over 5-10 minutes is usually recommended because of the high osmolarity. This is especially true for immature infants younger than 32 weeks' gestational age who are at some risk for intracranial hemorrhage. This procedure originally was described as a 2-minute infusion and accomplishes a filling of the glucose space analogous to the volume of distribution of glucose.

Maintenance of a continuous infusion of dextrose at an infusion rate of 6-8 mg/kg/min of dextrose is necessary once bolus therapy is complete. Failure to do so may result in rebound hypoglycemia as a result of heightened pancreatic insulin release triggered by the glucose infusion.

Frequent serum or whole blood glucose analyses are important to properly titrate the dextrose infusion. Should follow-up glucose levels remain less than 40 mg/dL, the dextrose infusion may be increased by 2 mg/kg/min until euglycemia is achieved.

If the infant requires a dextrose concentration of more than D12.5 through a peripheral vein at 80-100 mL/kg/day, placement of a central venous catheter may be considered to avoid venous sclerosis. Continued enteral feedings hasten improvement in glucose control because of the presence of protein and fat in the formula. Hydrocortisone therapy may be required for ongoing hypoglycemia.

Once the infant's glucose levels have been stable for 12 hours, IV glucose may be tapered by 1-2 mg/kg/min, depending on maintenance of preprandial glucose levels higher than 40 mg/dL.

Electrolyte management

Hypocalcemia and hypomagnesemia may complicate the clinical course. Because low serum calcium levels cannot be corrected in the presence of hypomagnesemia, correction of low magnesium levels is an initial step in the treatment of hypocalcemia.

In infants of diabetic mothers (IDMs), calcium and magnesium levels are commonly measured within the first hours after birth. Ideally, ionized levels of these electrolytes should be obtained and used to properly manage these electrolyte disturbances.

True symptomatic hypocalcemia is extremely rare in these infants. In most cases, symptoms interpreted to be caused by low calcium or magnesium levels are due to low glucose levels associated with perinatal asphyxia or associated with various CNS problems.

Low levels may be treated by adding calcium gluconate to the IV solution to deliver 600-800 mg/kg/day of calcium gluconate. Bolus therapy should be avoided unless cardiac arrhythmia is present. Bolus therapy may result in bradycardia.

Respiratory management

Pulmonary management is tailored to the individual infant's signs and symptoms. Increased ambient oxygen concentrations may be required to maintain oxygen saturations higher than 90%, transcutaneous oxygen tensions at 40-70 mm Hg, or arterial oxygen tensions at 50-90 mm Hg.

When an inspired oxygen concentration (FiO₂) higher than 40% is required, the most important task is to determine a precise diagnosis of the cause for the hypoxemia and to administer therapy appropriate for the underlying pathophysiology.

Assisted ventilation

Nasal continuous positive airway pressure (NCPAP) or endotracheal intubation with intermittent mandatory ventilation (IMV) or synchronized positive pressure ventilation (SIMV) may be used for the management of severe respiratory distress.

Common criteria for such interventions include inspired oxygen requirements (FiO₂) of 60-100% to maintain arterial PO₂ of 50-80mm Hg, arterial PCO₂ levels higher than 60 mm Hg or rising 10 mm Hg, and apnea. The specific criteria for using these modes of assisted ventilation may vary depending on the underlying respiratory pathology and clinical condition of the infant.

Cardiac management

If signs of congestive heart failure or cardiomyopathy with cardiomegaly, hypotension, or significant cardiac murmur are observed, echocardiographic evaluation is essential to distinguish among cardiac anomalies, septal hypertrophy, and/or cardiomyopathy.

Once a precise diagnosis is available, management of the cardiac disorder is no different for the IDM than for any other newborn with a similar cardiac condition. Extreme care in the use of cardiotonic agents is important in the presence of any hypertrophic cardiomyopathy or significant septal hypertrophy. These infants are at risk for actual decreased left ventricular output resulting from this form of therapy. Beta blockers, such as propranolol, may be used to relieve the outflow obstruction that is seen with septal hypertrophy.

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Transfer, Consultations, and Follow-Up

Infants of diabetic mothers (IDMs) having congenital anomalies, heart disease, or significant respiratory illness may require transfer to a tertiary care neonatal intensive care unit (NICU) for continued care and access to subspecialists. Because of the frequency with which cardiac problems occur in IDMs, early consultation with a pediatric cardiologist often is necessary. Other consultations depend on which other congenital malformations or complications are present.

Basic outpatient care should consist of routine well-baby care provided by the infant's general pediatrician. Additional follow-up by consultant subspecialists depends on the neonatal clinical problems and their resolution.

References

Author

Charles F Potter, MD, Consulting Neonatologist, Newborn Care Physicians of Southeastern Wisconsin