Pathophysiology

The probable pathogenic sequence is that maternal hyperglycemia causes fetal hyperglycemia, and the fetal pancreatic response leads to fetal hyperinsulinemia; fetal hyperinsulinemia and hyperglycemia then cause increased hepatic glucose uptake and glycogen synthesis, accelerated lipogenesis, and augmented protein synthesis (Fig. 101-1). Related pathologic findings are hypertrophy and hyperplasia of the pancreatic islet β cells, increased weight of the placenta and infant organs except for the brain, myocardial hypertrophy, increased amount of cytoplasm in liver cells, and extramedullary hematopoiesis. Hyperinsulinism and hyperglycemia produce fetal acidosis, which may result in an increased rate of stillbirth. Separation of the placenta at birth suddenly interrupts glucose infusion into the neonate without a proportional effect on the hyperinsulinism, and hypoglycemia and attenuated lipolysis develop during the first hours after birth.

Figure 101-1 The fetal and neonatal events attributable to fetal hyperglycemia (column 1), fetal hyperinsulinemia (column 2), or both in synergy (column 3). Time of risk is denoted in parentheses. RVT, renal vein thrombosis; TTN, transient tachypnea of the newborn.

(From Nold JL, Georgieff MK: Infants of diabetic mothers, Pediatr Clin North Am 51:619–637, 2004.)

Hyperinsulinemia has been documented in infants of mothers with gestational diabetes and in those of mothers with insulin-dependent diabetes (diabetic mothers) without insulin antibodies. The former group also has significantly higher fasting plasma insulin levels than normal newborns do despite similar glucose levels; they also respond to glucose with an abnormally prompt elevation in plasma insulin and assimilate a glucose load more rapidly. After arginine administration, they also have an enhanced insulin response and increased disappearance rates of glucose in comparison with normal infants. In contrast, fasting glucose production and utilization rates are diminished in infants of mothers with gestational diabetes. The lower free fatty acid levels in infants of mothers with insulin-dependent diabetes reflect their hyperinsulinemia. With good prenatal diabetic control, the incidence of macrosomia and hypoglycemia has decreased.

Although hyperinsulinism is probably the main cause of hypoglycemia, the diminished epinephrine and glucagon responses that occur may be contributing factors. Congenital anomalies correlate with poor metabolic control during the periconception and organogenesis periods and may be due to hyperglycemia-induced teratogenesis. Chronic fetal hypoxia, indicated by elevated amniotic fluid erythropoietin values, is associated with increased fetal and neonatal morbidity.

Clinical Manifestations

Infants of mothers with diabetic and those of mothers with gestational diabetes often bear a surprising resemblance to each other (Fig. 101-2). They tend to be large and plump as a result of increased body fat and enlarged viscera, with puffy, plethoric facies resembling that of patients who have been receiving corticosteroids. These infants may also, however, be of normal or low birthweight, particularly if they are delivered before term or if their mothers have associated vascular disease.

Figure 101-2 Large, plump, plethoric infant of a mother with gestational diabetes. The baby was born at 38 wk of gestation but weighed 9 lb, 11 oz (4,408 g). Mild respiratory distress was the only symptom other than appearance.

Hypoglycemia develops in about 25-50% of infants of diabetic mothers and 15-25% of infants of mothers with gestational diabetes, but only a small percentage of these infants become symptomatic. The probability that hypoglycemia will develop in such an infant increases, and glucose levels are likely to be lower with higher cord or maternal fasting blood glucose levels. The nadir in an infant’s blood glucose concentration is usually reached between 1 and 3 hr; spontaneous recovery may begin by 4-6 hr.

The infants tend to be jittery, tremulous, and hyperexcitable during the 1st 3 days of life, although hypotonia, lethargy, and poor sucking may also occur. They may have any of the diverse manifestations of hypoglycemia. Early appearance of these signs is more likely to be related to hypoglycemia, and their later appearance to hypocalcemia; these abnormalities may also occur together. Perinatal asphyxia may produce similar signs. Hypomagnesemia may be associated with the hypocalcemia. These manifestations may also occur in the absence of hypoglycemia, hypocalcemia, and asphyxia.

Tachypnea develops in many infants of diabetic mothers during the 1st 2 days of life and may be a manifestation of hypoglycemia, hypothermia, polycythemia, cardiac failure, transient tachypnea, or cerebral edema from birth trauma or asphyxia. Infants of diabetic mothers have a higher incidence of respiratory distress syndrome than do infants of nondiabetic mothers born at comparable gestational age; the greater incidence is possibly related to an antagonistic effect of insulin on stimulation of surfactant synthesis by cortisol.

Cardiomegaly is common (30%), and heart failure occurs in 5-10% of infants of diabetic mothers. Asymmetric septal hypertrophy may occur and may manifest like transient idiopathic hypertrophic subaortic stenosis. Inotropic agents worsen the obstruction and are contraindicated. Congenital heart disease is more common in infants of diabetic mothers. Birth trauma is also a common sequela of fetal macrosomia.

Neurologic development and ossification centers tend to be immature and to correlate with brain size (which is not increased) and gestational age rather than total body weight. In addition, these infants have an increased incidence of hyperbilirubinemia, polycythemia, and renal vein thrombosis; the last should be suspected in the infant with a flank mass, hematuria, and thrombocytopenia.

The incidence of congenital anomalies is increased threefold in infants of diabetic mothers; cardiac malformations (ventricular or atrial septal defect, transposition of the great vessels, truncus arteriosus, double-outlet right ventricle, tricuspid atresia, coarctation of the aorta) and lumbosacral agenesis are most common. Additional anomalies include neural tube defects, hydronephrosis, renal agenesis and dysplasia, duodenal or anorectal atresia, situs inversus, double ureter, and holoprosencephaly. These infants may also demonstrate abdominal distention caused by a transient delay in development of the left side of the colon, the small left colon syndrome.

Prognosis

The subsequent incidence of diabetes mellitus in infants of diabetic mothers is higher than that in the general population. Physical development is normal, but oversized infants may be predisposed to childhood obesity that may extend into adult life. Disagreement persists about whether these infants have a slightly increased risk of impaired intellectual development unrelated to hypoglycemia; symptomatic hypoglycemia increases the risk, as does maternal ketonuria.

Treatment

Treatment of infants of diabetic mothers should be initiated before birth by means of frequent prenatal evaluation of all pregnant women with overt or gestational diabetes, evaluation of fetal maturity, biophysical profile, Doppler velocimetry, and planning of the delivery of these infants in hospitals where expert obstetric and pediatric care is continuously available. Periconception glucose control reduces the risk of anomalies and other adverse outcomes, and glucose control during labor reduces the incidence of neonatal hypoglycemia. Women with type 1 diabetes who have tight glucose control during pregnancy (average daily glucose levels < 95 mg/dL) deliver infants with birthweights and anthropomorphic features similar to those of infants of nondiabetic mothers. Treatment of gestational diabetes also reduces complications; dietary advice, glucose monitoring, metformin, and insulin therapy as needed decrease the rate of serious perinatal outcomes (death, shoulder dystocia, bone fracture, or nerve palsy). Women with gestational diabetes may also be treated successfully with glyburide, which may not cross the placenta. In these mothers, the incidence of macrosomia and neonatal hypoglycemia is similar to that in mothers with insulin-treated gestational diabetes.

Regardless of size, all infants of diabetic mothers should initially receive intensive observation and care. Asymptomatic infants should undergo blood glucose determination within 1 hr of birth and then every hour for the next 6-8 hr; for an infant found to be clinically well and normoglycemic, oral or gavage feeding with breast milk or formula should be started as soon as possible and continued at 3-hr intervals. If any question arises about an infant’s ability to tolerate oral feeding, peripheral intravenous infusion at a rate of 4-8 mg/kg/min should be given. Hypoglycemia should be treated, even in asymptomatic infants, by frequent feeding and/or intravenous infusion of glucose. Bolus injections of hypertonic glucose should be avoided because they may cause further hyperinsulinemia and potentially produce rebound hypoglycemia.

Managing hypoglycemia in sick or symptomatic infants is discussed in the following section. For treatment of hypocalcemia and hypomagnesemia, see Chapter 100; for respiratory distress syndrome treatment, see Chapter 95.3; for treatment of polycythemia, see Chapter 97.3.