Infant of a Diabetic Mother
Heather Morein French and Rebecca A. Simmons
Abnormal maternal glucose metabolism occurs in 3% to 10% of pregnancies in the United States.1 While 90% of cases encountered during pregnancy are caused by gestational diabetes mellitus, the incidence of pregestational diabetes mellitus is rapidly increasing, in large part because of the increased incidence of obesity-related type 2 diabetes.2
The infant of the diabetic mother (IDM) is at increased risk for periconceptional, fetal, neonatal, and long-term morbidities. All of the complications faced by this fragile group of infants are the direct result of maternal glycemic control both before and during pregnancy. Before the availability of insulin to the pregnant mother, perinatal mortality rates were as high as 75%. With the addition of insulin therapy and good prenatal care, perinatal mortality rates now approach those seen in the nondiabetic population.3
Even with strict glycemic control, fetal and infant complications persist. Congenital anomalies are more frequent in the diabetic versus nondiabetic pregnancies. Macrosomia and the resulting birth injuries occur 10 times more frequently in diabetic pregnancies. Electrolyte abnormalities and the hyperviscosity syndrome can make management in the neonatal period challenging for pediatricians. Commonly encountered complications in the perinatal and neonatal period include intrauterine fetal demise, macrosomia or intrauterine growth restriction, birth trauma, perinatal depression, congenital anomalies, respiratory distress syndrome, hypoglycemia, electrolyte abnormalities such as hypocalcemia and hypomagnesemia, polycythemia and hyperviscosity syndrome, hyperbilirubinemia, and cardiomyopathy. No single pathogenic mechanism has been identified that can explain the diversity of problems encountered in the IDM. Nevertheless, most researchers agree that many of the effects can be attributed to maternal metabolic control. In 1977, the hypothesis of “hyperinsulinism” in the IDM was proposed and recognized that maternal hyperglycemia causes fetal hyperglycemia that results in fetal islet cell hypertrophy and beta cell hyperplasia due to chronic fetal pancreas stimulation.4 Insulin, an anabolic hormone, and the hyperinsulinemic state lead to visceromegaly and macrosomia. At delivery, with the sudden loss of maternal glucose supplies, hypoglycemia quickly ensues. However, this hypothesis does not tell the whole story because birth weight is not always correlated with mean maternal plasma glucose concentration.5 It is likely that control of fetal growth and fetal glucose homeostasis are multifactorial.
CONGENITAL ANOMALIES
Major congenital anomalies are the leading cause of perinatal mortality in pregnancies complicated by pregestational diabetes, occurring in 6% to 12% of IDMs.6 The incidence of major congenital anomalies is reported to range between 6% and 9%, compared to a 2% to 3% incidence in the general population.7 Most studies support that the risk of major malformations is related to the degree of maternal glycemic control during organogenesis in the first trimester. Unfortunately, the critical window for glycemic control may occur before the pregnancy is even recognized. Glycosylated hemoglobin (Hb AIc) levels correlate directly with the frequency of anomalies. An Hb AIc of 7% to 8.5% is associated with a 5% to 6% risk of congenital anomaly. However, an Hb AIc greater than 10% is associated with an anomaly rate of 20% to 25%.8
It is currently unknown what precisely leads to congenital malformations in IDMs. Attempts to definitively answer this question in animal models and human studies have been unsuccessful. Hypoglycemia, hyperglycemia, insulin, ketone bodies, tumor necrosis factor-α, free oxygen radicals, and disordered metabolism of arachidonic acid and prostaglandin have all been proposed as candidate teratogens, but each lacks solid scientific support to be declared the solo responsible teratogen.9-12
Congenital heart defects are a commonly reported anomaly in IDMs. Ventral septal defects are the most prevalent congenital heart defect, but more severe defects, such as atrial septal defects, transposition of the great arteries, and left-sided obstructive lesions, are also reported. Neural tube defects, including myelomeningocele, encephalocele, anencephaly, and hydro-cephalus, have an increased incidence in IDMs compared to the general population. Gastrointestinal atresia, gastroschisis, intestinal malrotation, renal and urinary tract malformations, and skeletal malformations are also reported.13 Spinal agenesis associated with caudal regression syndrome is a congenital anomaly found exclusively in IDMs. Additionally, small left colon syndrome is a rare but well-described anomaly associated with IDM. Presenting symptoms of gastrointestinal obstruction are caused by a transient but decreased diameter of the descending and sigmoid colon and rectum. This syndrome mimics Hirschsprung disease, but colonic innervation and, ultimately, function are normal.
BODY SIZE
Insulin is the major anabolic hormone and glucose is the major anabolic fuel for fetal growth. In the setting of excess glucose and cellular uptake, glycogen and fat synthesis increase, especially during the third trimester after 32 weeks. Macrosomia, which is defined as a birth weight above the 90th percentile for gestational age, or greater than 4000 grams, is the result of excess fuel deposition, causing increased body fat, muscle mass, and organomegaly, especially of the heart and liver. Skeletal growth is largely unaffected. Therefore, IDMs have higher weight than length and head circumference percentiles. Macrosomia occurs in 15% to 45% of cases, which is 3 times higher than the general population.
The majority of the excess fat in IDMs is deposited centrally in the abdomen and intrascapular areas, placing the infant at risk for shoulder dystocia and delivery by cesarean section. While linear relationships between insulin levels and birth weight have been shown,14 other metabolic fuels may contribute to macrosomia in the IDM as well. Positive correlations have been demonstrated between maternal triglyceride levels, amino acids, and free fatty acids with birth weight.15-17 Thus, macrosomia is likely multifactorial in nature.
The rate of delivery by cesarean section in diabetic women is 3 times higher than that of the general population, but the difference is not entirely attributable to macrosomia. Given the concerns over shoulder dystocia and perinatal depression, caregivers are more prone to perform cesarean deliveries because of the concerns for a poor outcome and the imperfect clinical ability to predict which infants are at the highest risk.18,19 Macrosomia can lead to a difficult vaginal delivery due to shoulder dystocia, with resultant birth injury or perinatal depression. Birth injuries, which include cephalohematoma, subdural or ocular hemorrhage, facial palsy, brachial plexus injuries, clavicular fractures, and abdominal organ injury, are 2 to 4 times more common among IDMs, with macrosomic infants at the highest risk.
Not all IDMs are macrosomic. Mothers with advanced pregestational diabetes are at risk for giving birth to a small-for-gestationalage infant. Advanced maternal vascular disease, seen in pregnant women with diabetes-associated retinal or renal vasculopathies and/or chronic hypertension, leading to placental insufficiency, can result in fetal growth restriction and a deficiency of nutrients and oxygen.
HYPOGLYCEMIA
At delivery, the maternal supply of glucose is abruptly terminated, and hypoglycemia, defined as a blood glucose less than 40 mg/dL, can occur in all infants. This is particularly likely to occur in IDMs, especially if macrosomic, for several reasons. Most IDMs have elevated C-peptide or insulin levels at baseline that quickly leads to clearance of available serum glucose. Hypoglycemia normally leads to catecholamine and glucagon release, resulting in glycogen breakdown and gluconeogenesis. In the IDM, this response to hypoglycemia may be blunted. Additionally, if perinatal stress was experienced, catecholamine release and glycogen depletion may have occurred. Therefore, the IDM has increased glucose clearance from serum as well as decreased glucose production.
Hypoglycemia usually develops within the first 24 hours of life. Infants can be asymptomatic or present with nonspecific symptoms such as jitteriness, irritability, tachypnea, apnea, lethargy, hypotonia, poor feeding, or frank seizure activity. Hypoglycemia, even if asymptomatic, can cause brain injury and lead to long-term neurodevelopmental complications. Therefore, it is recommended that blood glucose concentrations be maintained above 50 mg/dL (see Chapter 51).
HYPOCALCEMIA AND HYPOMAGNESEMIA
Hypocalcemia occurs in 20% to 50% of IDMs during the neonatal period. Unlike hypoglycemia, hypocalcemia usually arises between 48 and 72 hours of life. Serum calcium levels lower than 7 mg/dL are frequently observed. Clinical signs of hypocalcemia include tremors, twitching, sweating, irritability, arrhythmia, and seizures. A prolonged QT interval is associated with hypocalcemia but is not often observed in IDMs.
During fetal life, calcium is transferred by active transport across the placenta. The fetus, especially during the third trimester, has low parathyroid hormone (PTH) due to the relatively high serum calcium levels. At birth, with the abrupt end of maternal calcium transfer, infant parathyroid hormone levels rise to compensate for decreasing serum calcium. In the IDM, parathyroid hormone levels and end-organ sensitivity to PTH are lower than age-matched controls during the first 4 days after birth. Additionally, PTH secretion may be hampered by hypomagnesemia, even in the setting of hypocalcemia. Hypocalcemia can be magnified if the IDM is born prematurely or suffers from perinatal depression. Persistently high levels of calcitonin and alterations in vitamin D metabolism may also play a role.
Hypomagnesemia occurs in up to one third of IDMs. Neonatal magnesium levels correspond to the mother’s levels as well as to maternal insulin requirements.20 Mothers with advanced diabetes and renal insufficiency may have significant renal losses of magnesium, which contribute to low placental transfer of this electrolyte.
Total and ionized serum calcium should be measured at least daily during the first 72 to 96 hours of life. Daily calcium requirements are 100 to 200 mg/kg, and IDMs may require up to 3 times that amount. Symptomatic infants should be treated with 10% calcium gluconate given intravenously under careful monitoring because of the risk of arrhythmias and intravenous infiltrates. Daily maintenance therapy can be considered on the basis of feeding status and laboratory value trends. It should be noted that if a hypocalcemic infant is also hypomagnesemic, calcium therapy is futile unless magnesium levels are replete.
HYPERBILIRUBINEMIA AND POLYCYTHEMIA
Hyperbilirubinemia occurs more frequently in the IDM than in the general population. The pathogenesis remains uncertain because red blood cell life span, osmotic fragility, and deformability are not different between the 2 groups. Some research points to increased hemoglobin turnover.21 However, other information points to delayed clearance of bilirubin by the liver.22 Other risk factors for hyperbilirubinemia are macrosomia, which increases the risk for birth trauma, bruising and cephalohematoma, and polycythemia. Because of an increased hemoglobin load, bilirubin levels rise more rapidly and peak later in IDMs than in neonates of nondiabetic women.
Chronic fetal hyperglycemia and hyperinsulinemia increase the fetal metabolic rate and increase oxygen consumption. Given that the fetus develops in a relatively hypoxic environment and oxygen extraction from maternal blood is at a maximal rate, the fetus increases its oxygen-carrying capacity by increasing erythropoiesis. Increased red cell production puts the infant at risk for polycythemia (hematocrit > 65). Up to 20% of IDMs have polycythemia. The associated hyperviscosity and vascular sludging that can occur puts this group of infants at risk for stroke, seizures, necrotizing enterocolitis, renal vein or sinus venous thrombosis, and persistent pulmonary hypertension of the newborn. Symptomatic polycythemic infants should be treated with a partial exchange transfusion (see Chapter 53).
RESPIRATORY DISTRESS
Respiratory distress syndrome requiring admission to a neonatal intensive care unit occurs almost 6 times as frequently in IDMs as in infants of nondiabetic mothers.23 IDMs are at increased risk for respiratory distress syndrome for several reasons. Surfactant deficiency due to a delayed maturation of type II alveolar cells has been observed, but it is unclear whether the cause is hyperglycemia, hyperinsulinemia, or both.24
Glycogen levels in the lung normally decline with increasing gestational age. This decrease corresponds with increased surfactant production. Insulin inhibits glycogen breakdown, decreasing available substrate for the synthesis of phosphatidylglycerol (PG), an important component of surfactant. The presence of PG in the amniotic fluid is an indicator of lung maturity. There are several reports of delayed appearance of PG in diabetic pregnancies.25,26 Even using amniotic fluid analysis to document maturation of the surfactant production system, there is still a 10% incidence of respiratory distress syndrome in IDMs. Other causes of respiratory distress in the IDM include increased rates of premature birth, congenital heart disease, and diaphragmatic paralysis from a brachial plexus injury.
CARDIOMYOPATHY
Reversible cardiomyopathy with intraventricular hypertrophy and outflow tract obstruction can occur in up to 30% of IDMs. Cardiomyopathy may be caused by congestive failure due to a poorly functioning myocardium or hypertrophy of the intraventricular septum and one or both ventricular walls. Occasionally, the outflow tract obstruction becomes so profound as to require extracorporeal membrane oxygenation while awaiting regression of the obstruction.
The mechanism by which hypertrophic cardiomyopathy occurs is not completely understood. The human heart is rich in insulin receptors. It is postulated that the fetus of the diabetic mother in whom hyperinsulinism develops will have increased myocardial receptor sites and increased affinity for insulin. This could lead to increased protein, glycogen, and fat synthesis in the myocardium and subsequent hyperplasia and hypertrophy of the myocardium. Postnatally, as serum insulin levels and the number of insulin receptors decrease, the septal hypertrophy should decrease as well. Although this hypothesis is consistent with the natural history of this disease process, other yet unidentified factors may be important as well. Fetuses of diabetic mothers who were thought to be in good glycemic control, as compared with normal controls, had evidence of cardiac hypertrophy at the level of the intraventricular septum and at the right and left ventricular free wall by late gestation.27 More sensitive markers of maternal metabolic control may be needed to define better the in utero environment that promotes this type of cardiac growth.
OUTCOMES
Complications of the IDM occurring in the neonatal period are of great concern to the pediatrician. However, equal concern should be given to the long-term outcomes on growth and development, psychosocial intellectual capabilities, and the subsequent risk of developing diabetes and obesity later in life. The IDM is more vulnerable to intellectual impairment independent of hypoglycemia.28,29 Several studies have shown problems with memory formation, verbal conceptualization ability, acquired knowledge, spatial ability, and sequencing ability in IDMs.30,31 It is unknown how much of this intellectual impairment is due to birth trauma, perinatal depression, hypoglycemia in the neonatal period, or other neonatal morbidities. Vigilant obstetric care of the mother to maintain euglycemia during pregnancy and medical care of the infant to manage associated symptoms can greatly reduce the risk of complications in the neonatal period and childhood.
Even if the infant does not suffer from any early complications of maternal disease, the risk of developing obesity and diabetes later in life is increased. Macrosomic infants of diabetic or obese mothers are at significant risk of developing metabolic syndrome (obesity, hypertension, dyslipidemia, glucose intolerance) in childhood.32 Given the relationship of obesity and gestational diabetes, it is likely that gestational diabetes will continue to increase in future generations.
REFERENCES
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