Which of the following is a common problem in the newborn of a diabetic mother?

Hyperbilirubinemia

IDMs also appear to be at greater risk for hyperbilirubinemia than infants born to nondiabetic mothers. In studies that defined hyperbilirubinemia as a serum bilirubin level greater than 12 mgdL or any bilirubin level requiring phototherapy, the prevalence of hyperbilirubinemia in IDMs was 25% (Cordero et al., 1998); other series report a hyperbilirubinemia prevalence of 10%–13% in IDMs. This increased risk might be attributable to polycythemia (larger source of bilirubin to be conjugated by the liver prior to excretion), ineffective erythropoiesis with an increased red blood cell turnover, as well as to immaturity of hepatic bilirubin conjugation and excretion. Macrosomic IDMs appear to have the greatest risk of hyperbilirubinemia; this probably reflects the role of poor maternal glycemic control during pregnancy as IDMs of these women are most likely to be macrosomic and polycythemic.

Growth Dynamics

IDMs with macrosomia follow a unique pattern of in utero growth compared with fetuses in euglycemic pregnancies. During the first and second trimesters, differences in size between fetuses born to diabetic and nondiabetic mothers are usually undetectable with ultrasound measurements. After 24 weeks, however, the growth velocity of the IDM fetus’ abdominal circumference typically begins to rise above normal (Ogata et al, 1980). Reece et al (1990) demonstrated that the IDM fetus has normal head growth, despite marked degrees of hyperglycemia. Landon et al (1989) have reported that although head growth and femur growth of IDM fetuses were similar to those of normal fetuses, abdominal circumference growth significantly exceeded that of controls beginning at 32 weeks’ gestation (abdominal circumference growth in IDM fetuses is 1.36 cm/week, versus 0.901 cm/week in normal subjects).

Morphometric studies of the IDM newborn indicate that the greater growth of the abdominal circumference is caused by deposits of fat in the abdominal and interscapular areas. This central depositing of fat is a key characteristic of diabetic macrosomia and underlies the pathology associated with vaginal delivery in these pregnancies. Acker et al (1986) showed that although the incidence of shoulder dystocia is 3% among infants weighing more than 4000 g, the incidence in infants from diabetic pregnancies who weigh more than 4000 g is 16%. Finally, despite our emphasis on birthweight, this alone may not be a sensitive measure of fetal growth. Catalano et al (2003) conducted body composition studies on infants born to mothers with diabetes and found that even when appropriate for gestational age, these infants have increased fat mass and percent body fat compared with a normoglycemic control group.

Macrosomia

At the other end of the birth weight spectrum are macrosomic, LGA infants. These infants were exposed to excess nutrient supply in utero, principally of carbohydrates and lipids. Macrosomic newborns have increased specific morbidities primarily associated with metabolic complications of maternal diabetes mellitus during pregnancy and associated birth complications and birth injuries as a result of excessive fetal size.

Macrosomia is defined in a newborn as a birth weight more than two standard deviations above the mean percentile for gestational age or a birth weight greater than 4000 g at term. Neonatal macrosomia has a strong ethnic predisposition affecting up to 50% of Latino and Native American pregnant women versus 19% of African–American pregnant women Macrosomia is characteristic of infants of diabetic mothers (IDMs) who were hyperglycemic during pregnancy. The diabetes can be long standing, but the most common group producing macrosomic infants are women with gestational diabetes mellitus (GDM). The percentage of pregnant women who have some form of GDM has been increasing worldwide and now is well about the historical range of 3 to 5% of all pregnancies. The risk of macrosomia is not consistent across all classes of diabetes; it primarily reflects the degree and duration of maternal hyperglycemia and hypertriglyceridemia and particularly high spikes of these conditions following meals that are more common in gestational diabetes. Maternal hyperglycemia results in fetal hyperglycemia and hyperinsulinemia; maternal and fetal hypertriglyceridemia contribute to the effect of the excess glucose and insulin to produce excess fat deposition in the fetus.

Genes Related to Other Metabolic Pathways and Neural Tube Defects

Pregestational diabetes, maternal obesity, and hypermetabolic status are known epidemiologic risk factors for NTDs. Although, the cellular mechanism of how abnormal glucose homeostasis results in NTDs remains elusive, several candidate genes, particularly those regulating glucose transporter proteins, have been studied. Heilig and colleagues108 developed a glucose transporter 1 (GLUT-1) deficient mouse model and demonstrated that lack of GLUT-1 is associated with a wide range of developmental malformations including NTDs. Subsequent family-based studies have also shown that mutations of the GLUT-1 gene increase NTD susceptibility.109 These studies also demonstrated that other genes involved in glucose metabolism, such as the leptin receptor gene and the hexokinase 1 gene, result in abnormal neural tube closure.109

Stimulated by the identification of candidate genes for the folate-related pathways, genes of pathways related to or over­lapping with folate metabolism such as the methionine cycle, methylation, or transsulfuration have been systematically evaluated. However, the role of these genes with respect to abnormal neurulation and therefore increased risk of NTD formation remains inconclusive, with conflicting results across published reports.96,105,110-113

On the basis of a series of experiments suggesting that periconceptional inositol supplementation can reduce NTDs in the curly tail mouse model,114,115 several pivotal regulatory genes of the inositol metabolic pathway have been explored. Mutations of the inositol 1,3,4-triphosphate 5/6-kinase gene, the phosphatidylinositol-4-phosphate 5-kinase gamma gene, and the inositol polyphosphate-5-phosphatase E gene are associated with an increased risk of NTDs.56,116,117

Maternal diabetes mellitus

Infants of diabetic mothers frequently have polycythemia or the hyperviscosity syndrome, elevated serum erythropoietin concentrations, and decreased serum iron and ferritin concentrations, likely representing a redistribution of fetal iron into erythrocytes to support augmented fetal hemoglobin synthesis. Severely affected infants of diabetic mothers have reduced liver, heart, and brain iron concentrations (Petry et al., 1992). Infants of diabetic mothers with suspected brain iron deficiency (e.g., cord ferritin < 34 μg/L) have impaired neonatal auditory recognition memory and lower developmental motor skills at 1 year of age compared to non-iron-deficient controls (Siddappa et al., 2004). Term infants born to mothers with uteroplacental vascular insufficiency related to severe hypertension, and term and preterm infants with intrauterine growth retardation (IUGR) have a higher prevalence of reduced cord serum ferritin concentrations, which is suggestive of low fetal iron stores (Georgieff et al., 1995). Polycythemia may lead to hyperviscosity syndrome, increasing the risk of ischemia and infarction, particularly of the kidneys and brain (Barnes-Powell, 2007).

Central nervous system malformations are 16 times more likely in infants of diabetic mothers (IDM) than in nondiabetic pregnancies. Malformations include anencephaly, with a rate 13 times that in the general population; spina bifida, at 20 times the risk; and the spectrum of caudal dysplasia syndromes, at 600 times the nondiabetic population. Additionally, CNS injury can occur due to perinatal asphyxia, glucose, and electrolyte abnormalities, polycythemic vascular sludging, and birth trauma, all of which are strongly associated with maternal diabetes. In the neuraxis, the spinal cord is also vulnerable to birth trauma, with most symptoms related to brachial plexus injuries, including Erb's palsy (roots C5–7), Klumpke palsy (roots C7–8), diaphragmatic nerve paralysis (roots C3–5), and recurrent laryngeal nerve damage (roots T1–2). These injuries are more common in IDM with macrosomia, and are related either to the positioning of the large fetus in utero or to stretching of the neck or shoulder during delivery.

Endocrine Disorders

Excessive Intrauterine Exposure to Lipids

Obese and diabetic mothers often give birth to large for gestational age (>4000 g) babies. However, as only 25% of the differences in birth weight can be attributed to maternal hyperglycemia, the majority of large infants are born to normoglycemic mothers. This would suggest that other factors besides glucose may be involved. Indeed maternal prepregancy BMI, maternal fasting triglyceride, and free fatty acid levels have all been implemented in mediating excessive fetal growth. In rodents, fetal exposure to excessive lipid levels leads to lipid accumulation in the adult offspring's liver, predisposing the offspring to nonalcoholic fatty liver disease. Deposition of lipids in liver and muscle can cause mitochondrial dysfunction. Increased fetal lipids may also promote formation of adipocytes over other cell types such as myocytes in early organogenesis. Circulating saturated fatty acids can activate kinases that cause an increase in IRS1 serine phosphorylation, an event that is associated with inhibition of insulin signaling and one of the hallmarks of insulin resistance. Excessive fetal lipid concentrations may also affect hypothalamic regulators of appetite and satiety. For example, consumption of a high-fat diet during pregnancy in the nonhuman primate may compromise the development of the melanocortin system in the fetal hypothalamus. Finally, increased pancreatic beta cell mass and excess insulin secretion, which can lead to islet cell failure and contribute to the development of diabetes, can be found in the models of maternal obesity during pregnancy.

Ventricular Hypertrophy

Beyond structural heart disease, IDM can develop ventricular hypertrophy. A 1944 autopsy study was one of the first to show increased heart weight in IDM [21]. Asymmetric septal hypertrophy was not reported in IDM until 32 years later, when Gutgesell and colleagues showed transient “hypertrophic subaortic stenosis” in three IDM, all of which gradually improved or resolved [22]. Subsequent studies have confirmed the phenomenon and estimated the incidence of asymmetric ventricular hypertrophy (AVH) in IDM between 31% and 43% [10,13,23–26]. AVH in IDM has been further analyzed by diabetic type. Limited data show the highest incidence of AVH in type 1 DM, followed by type 2 DM, then gestational DM [10]. Microscopic evaluation of the septal myocardium has differentiated PVH from HCM, with the former lacking disorganized myocardial fibers and less than 5% cellular disarray [27,28]. The pattern of hypertrophy is not often useful in differentiating between the two disease processes. The interventricular septum is the primary and often solitary site of hypertrophy in AVH, while HCM may be present as either asymmetric septal hypertrophy or concentric LVH [29].

Hypoglycemia

Hypoglycemia is defined as a serum or plasma glucose level less than 40 mg/dL or a whole blood glucose level below 35 mg/dL.

SPECIAL CONDITIONS

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Infants of diabetic mothers tend to be slightly drowsy and hypotonic, have long latency before response during the neurodevelopmental examination and may have only brief periods of alertness. They may take longer to get on track even if their glucose levels are maintained.

Some of these behavioral abnormalities are also seen in infants with hyperbilirubinemia, particularly those undergoing phototherapy.

No systematic studies of polycythemic infant behavior have been performed, but many clinicians have observed that these infants tend to be lethargic, even without demonstration of frank hyperviscosity and with correction of their hematocrit levels.

Infants born to mothers with pregnancy-induced hypertension may be behaviorally disorganized, even if not undergrown. They need more patience in the first days of life to allow for more behavioral recovery. Initiation of breastfeeding is often slower in all these situations, usually because of both maternal and infant factors.

Infants born after long labor with a very distorted head shape may also take longer to get organized.

Babies with fractured clavicles may experience pain with movement and when placed in certain positions. Early splinting, pain relief and avoidance of painful postures will help with adjustment.

Although these conditions are considered routine to most clinicians, many parents will see them as major deviations from their expectations. They may harbor feelings of deep disappointment and worry. This frame of mind sets the stage for “vulnerable child syndrome” (see Chapter 8).