Background

Diabetes has long been associated with maternal and perinatal morbidity and mortality. Before the discovery of insulin in 1921, women with diabetes rarely reached reproductive age or survived pregnancy.

Fetal and neonatal mortality rates were as high as 65% before the development of specialized maternal, fetal, and neonatal care. Since then, infants of diabetic mothers (IDMs) have experienced a nearly 30-fold decrease in morbidity and mortality rates. 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% had type 1 diabetes mellitus, and 65% had 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.

Pathophysiology

Understanding the physiology of fetal glucose control is necessary to appreciate the causes of the associated complications. Increased levels of both estrogen and progesterone affect glucose homeostasis as counter-regulatory hormones in the mother early in pregnancy. As a result, beta-cell hyperplasia occurs in the pancreas, stimulating an increased release of insulin.

Increased insulin levels stimulate glycogen deposition and decrease hepatic glucose production. A decreased need for insulin in women with diabetes is not unusual in early pregnancy. Furthermore, amino acids decrease, and fatty acid triglycerides and ketones both increase with increased fatty acid deposition. As a result, increased protein catabolism and accelerated renal gluconeogenesis occurs.

As pregnancy progresses, human placental lactogen is released by the syncytiotrophoblast, leading to lipolysis in the mother. The subsequent release of glycerol and fatty acids reduces maternal use of glucose and amino acid, thus preserving these substrates for the fetus.

The release of increasing amounts of contrainsulin factors as placental growth continues causes up to a 30% increase in maternal insulin needs as pregnancy progresses. Mothers with previous borderline glucose control, obesity, or frank diabetes may require initiation of or increase in their insulin requirements to maintain glucose homeostasis.

Glucose and amino acids traverse the placental membrane. On the other hand, insulin is unable to cross from maternal to fetal circulations. Using a carrier-mediated facilitated diffusion mechanism, fetal glucose levels are maintained at a level that is 20-30 mg/dL lower than those of the mother.

The fetus is subjected to high levels of glucose during times of maternal hyperglycemia. Before 20 weeks’ gestation, fetal islet cells are incapable of responding, subjecting the fetus to unchecked hyperglycemia and decreased fetal growth. Poor growth is especially noted in mothers with diabetic vascular disease. After 20 weeks’ gestation, the fetus responds to hyperglycemia with pancreatic beta-cell hyperplasia and increased insulin levels.

Proinsulin (insulinlike growth factor-1 [IGF-1], insulinlike growth factor–binding protein-3 [IGFBP-3]) also acts as a growth factor that, in the presence of increased fetal amino acids, results in fetal macrosomia. Fetal growth acceleration can be noted on ultrasonography by 24 weeks’ gestation, especially with fluctuating maternal glucose levels. The combination of hyperglycemia and insulin increases fetal fat and glycogen stores, resulting in weight increases marked by hepatosplenomegaly and cardiomegaly without abnormal growth of the brain or head circumference.

Chronic fetal hyperglycemia and hyperinsulinemia increase the fetal basal metabolic rate and oxygen consumption, leading to a relative hypoxic state. The fetus responds by increasing oxygen-carrying capacity through increased erythropoietin production, potentially leading to polycythemia. The fetus redistributes iron from developing organs, including the heart and brain, to support this expanded blood mass, leaving these organs iron deficient and with possible long-term functional consequences.

Prior to birth, elevated insulin levels may inhibit the maturational effect of cortisol on the lung, including the production of surfactant from type 2 pneumocytes. This puts the fetus at risk for developing respiratory distress syndrome after birth at a gestational age normal lung function is expected.

Clinical History

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.

Fetal macrosomia

Fetal growth is assessed by plotting birthweight 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.

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

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 infant of diabetic mother’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 erythopoietin 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 these infants. The cardiomyopathy may be associated with congestive failure with a weakly functioning myocardium or 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 malformations are 16 times more likely in these infants. 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. Neurologic immaturity, demonstrated by immature sucking patterns, has been found in infants born to insulin managed mothers with diabetes. Based on studies in fetal sheep, this may be a reflection of the abnormal brain metabolism and EEG findings as a result of the fetal hyperglycemia.

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

Causes

Glycated hemoglobin (HbA1C) levels

  • Complications caused by maternal hyperglycemia during pregnancy are reflected by elevated HbA1C levels, particularly during the first trimester of pregnancy.
  • Because HbA1C is a direct measure of glucose control in the mother, higher levels are predictive of increased risks for congenital complications. Thus, the incidence of complications has been reported as 3.4% with HbA1C levels lower than 8.5% and 22.4% with levels higher than 8.5%.
  • Birth defects in infants of diabetic mothers may be related to reduced arachidonic acid and myoinositol levels and elevated sorbitol and trace metal levels in the fetus.
  • Others speculate about the role of excess oxygen radicals and hydroperoxides in the mitochondria of susceptible fetal tissues because these prostacyclin inhibitors may cause disruption in the vascularization of developing tissues.
  • A past history of LGA infants, diabetes, stillbirth, hypertension, gestational diabetes, obesity, or glycosuria, or a current history of excessive weight gain in the present pregnancy or low socioeconomic class place the mother at an increased risk of poor glucose control during pregnancy and increase her risk of delivering an infant with subsequent complications.

Fetal macrosomia

  • Infants of diabetic mothers experience higher levels of glucose during gestation, resulting in pancreatic beta-cell hyperplasia, with increased secretion of insulin and proinsulin factors (insulinlike growth factor [IGF]-1, insulinlike growth factor-binding protein [IGFBP]-3). Amino acid availability is also increased. All of these factors are involved in the excessive growth observed in the infants of diabetic mothers.
  • All organ systems, aside from the kidney and brain, are sensitive to the increased glucose and amino acid pools. Increased insulin levels result in an increase in cell number and cell size.

Impaired fetal growth

  • The major cause of impaired fetal growth is maternal diabetic nephropathy. Maternal vascular disease compromises uteroplacental blood flow and impairs fetal nutrient supply.
  • Infants of diabetic mothers are at increased risk of preterm labor, stillbirth, neonatal death, birth injury, and perinatal asphyxia.

Pulmonary disease

  • These infants are at increased risk for respiratory distress syndrome, transient tachypnea of the newborn, and persistent pulmonary hypertension.
  • Insulin restricts substrate availability for surfactant biosynthesis and interferes with the normal timing of glucocorticoid-induced biosynthesis.
  • Insulin also blocks cortisol action at the fibroblast level by reducing production of fibroblast-pneumocyte factor, which normally would stimulate type II cells to produce surfactant.
  • Several studies suggest that the risk of respiratory distress syndrome in well-managed diabetic women delivered at term is no higher than in the general population. Measurement of phosphatidylglycerol levels or the lecithin/sphingomyelin ratio prior to elective delivery helps ensure lung maturity at birth.

Metabolic abnormalities

  • These infants are at high risk for hypoglycemia, especially within the early hours after birth.
  • High levels of fetal insulin with cessation of continued maternal glucose supply take place after birth. The neonatal shift to gluconeogenesis with fatty acid use may provide an insufficient supply of substrate, and, thus, the infant may experience hypoglycemia (
  • Hypocalcemia, with or without hypomagnesemia, may also be present and is believed to be secondary to parathyroid hormone suppression.
  • Postnatal parathormone response of infants of diabetic mothers is decreased compared to their gestationally matched controls. The associated hypomagnesemia has been speculated to be secondary to increased urinary losses associated with a more severe diabetic state. This maternal hypomagnesemia is also reflected in the fetus.

Cardiovascular anomalies

  • Cardiac hypertrophy may be observed in as many as 30% of infants of diabetic mothers.
  • Fetal growth is regulated by insulin binding to cell receptors. Compared with adults, fetuses have an increased number of receptors. Because the fetal heart is particularly rich in receptors, this may lead to increased myocardial protein, glycogen, and fat synthesis with hyperplasia and hypertrophy of myocardial cells.

Congenital malformations

  • Some speculate that many of the congenital anomalies in infants of diabetic mothers may arise from an insult to the developing somite mesoderm and cephalic neural crest cells.
  • Metabolic disturbances, such as hyperglycemia, hypoglycemia, hyperketonemia, and hypoxia, may also be involved.
  • Glucose-induced free radicals of oxygen have also been implicated.

Frequency in the United States

The 1988 National Maternal and Infant Health Survey reported that diabetes complicated 4% of pregnancies resulting in live births. Of these, 88% were the result of gestational diabetes mellitus, 8% were the result of non–insulin-dependent diabetes, and 4% were from insulin-dependent diabetes mellitus. Given estimates of 0.2-0.3% of pregnancies complicated by preexisting diabetes and a further 1-5% complicated by gestational diabetes mellitus, approximately 50,000-150,000 infants are born to diabetic mothers every year.

Birth defects in infants of diabetic mothers have risen from 1-2% to 8-15% as a consequence of increased perinatal survival. Major congenital malformations are found in 5-9% of affected infants and account for 30-50% of perinatal deaths of infants of mothers with gestational diabetes. Guidelines for detection and diagnosis of gestational diabetes have been established by the American Diabetes Association. Most teratogenic complications occur in infants born to mothers with pregestational diabetes that is poorly controlled. These complications can be reduced with strict glycemic control prior to and during pregnancy.

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