KEY POINTS
- 1.
Diabetes in pregnant women can be visualized in two distinct subsets: 1% to 2% of women have pregestational disease, whereas 6% to 9% develop diabetes during pregnancy.
- 2.
In mothers with pregestational or early-onset diabetes, placental vasculopathy may cause growth restriction, altered organogenesis, and congenital anomalies.
- 3.
In mothers with gestational diabetes, the fetuses tend to become large for date, show a wide range of metabolic changes, and may be predisposed to short- and long-term complications.
- 4.
The most frequently seen metabolic complications in infants of diabetic mothers (IDMs) are hypoglycemia, hypocalcemia, and hypomagnesemia.
- 5.
Respiratory and cardiovascular complications contribute importantly to neonatal morbidity and mortality, especially in preterm neonates.
- 6.
IDMs have a two- to four-fold increase in the risk of congenital malformations compared with the general population. These malformations are seen most frequently in the cardiovascular, neurologic, renal, gastrointestinal, and skeletal systems.
Infants born to mothers with diabetes mellitus (DM) in pregnancy are predisposed to short- and long-term complications. The extent of these complications depends on the type of diabetes (pregestational or gestational); onset and duration of glucose intolerance; severity of diabetes (degree of glucose intolerance, presence of complications); and therapeutic control. This chapter will review the epidemiology of maternal diabetes, pathophysiology of complications, clinical features, management, and prognosis in affected infants.
Epidemiology
In 2019, an estimated 20 million women experienced hyperglycemia during pregnancy. This accounted for nearly 16% of all live births in the world. Diabetes noted during pregnancy may have already been there as a pregestational disease, referring to type 1 or type 2 DM diagnosed before pregnancy, or it may get diagnosed during pregnancy and then be labeled as gestational diabetes mellitus (GDM). The overall incidence of pregestational diabetes is about 1% to 2%, and that of GDM is about 6% to 9%.
The global incidence of diabetes during pregnancy is rising. In the United States the prevalence of pregestational diabetes increased by 37% and that of GDM by 56% during the period 2000 to 2010. The most important risk factors for maternal diabetes are maternal age ≥35 years, urban residence, and low socioeconomic status. , Prevalence varies by race and ethnicity; Black women have higher rates of pregestational diabetes, whereas Asian women are more susceptible to GDM. Latinas are at higher risk of both pregestational diabetes and GDM. Obesity, family history of diabetes, high parity, and older age at first birth increase the risk of gestational diabetes.
Pathophysiology
Because maternal plasma glucose can cross the placenta by facilitated diffusion, maternal hyperglycemia leads to fetal hyperglycemia. Early-onset placental vasculopathy may cause growth restriction and may alter organogenesis (diabetic embryopathy) with recognizable patterns of congenital anomalies. Poorly controlled GDM and hyperglycemia can cause macrosomia ( Fig. 24.1 ).
The metabolic changes in infants of diabetic mothers (IDMs) are summarized in Fig. 24.2 . In the second trimester, the fetal pancreas responds to the rise in glucose levels by producing insulin, leading to fetal hyperinsulinemia. Fetal hyperglycemia and hyperinsulinemia drive the multisystemic pathology present in IDMs. Elevated fetal insulin levels, upregulated glucose transporters, and increased intracellular glucose concentrations can enhance mitochondrial oxidative phosphorylation. The resulting increase in the production of reactive oxygen species can contribute to diabetic embryopathy. Chronically upregulated fetal metabolic rate and oxygen consumption lead to relative hypoxemia, which in turn elevate proangiogenic factors such as leptin, vascular endothelial growth factor, fibroblast growth factor 2, and matrix metalloproteinases (MMPs) such as MMP14 and MMP15, which lead to altered tissue histoarchitecture and epigenetic changes.
IDMs experience several types of metabolic stress, including in the oxidative, nitrosative, endoplasmic reticulum (unfolded protein response), and hexosamine pathways. Smith et al. demonstrated that insulin impedes the cortisol-induced synthesis of phosphatidylcholine (an essential substrate for surfactant production) by type II alveolar pneumocytes. Hyperinsulinemia has also been shown to suppress the structural maturation of the fetal lung. Together, all these changes predispose IDMs to respiratory distress syndrome even at peri-term gestational ages. IDMs also have an excessive accumulation of liver glycogen, cardiac and skeletal muscles, adipose tissue, and other tissues. Fetal hyperglycemia and hyperinsulinemia accelerate glycogenesis, lipogenesis, and protein synthesis. The cellular effects include hypertrophy and hyperplasia of the pancreatic islets of Langerhans, myocardial hypertrophy, and increased cytoplasm in hepatocytes.
IDMs are at a higher risk of hypoxia and ischemia at peri- and intrapartum stages than are infants of nondiabetic mothers. Fetal hypoxemia raises erythropoietin levels, which can stimulate erythroid progenitor growth that is already activated by hyperinsulinemia. These two phenomena can lead to polycythemia and consequently to neonatal hyperviscosity syndrome. , Many fetal regions have concomitant tissue hypoxia due to increased glycation of hemoglobin and low concentrations of 2,3-diphosphoglycerate, which increase erythropoietin expression and red blood cell (RBC) production. Some premature infants develop polycythemia, and the larger RBC mass and turnover may increase the bilirubin loads to exceed the capacity of the developing liver and cause hyperbilirubinemia.
In the fetal metabolic environment, even small changes can induce epigenetic modifications with altered gene expression and phenotypic changes ( Fig. 24.3 ). , The risk of diabetic embryopathy increases with prolonged fetal exposure to maternal hyperglycemia. , , Insulin binds to the type I insulin-like growth factor receptor to induce intracellular phosphorylation pathways, which activate cellular growth-promoting factors. In IDMs, myocardial hypertrophy leads to cardiomegaly with asymmetric, disproportionate septal hypertrophy. , There is also widespread cellular apoptosis with altered genetics and epigenetic systems, resulting in dysmorphogenesis.
Clinical Features
Fetal Effects
A brief summary of clinical manifestations is provided in Table 24.1 .
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Diabetic mothers experience preterm delivery and unexplained intrauterine demise more often than mothers who do not have diabetes. , The risks are particularly high with pregestational diabetes. In GDM, the odds of congenital anomalies are slightly higher than in the general population (odds ratio, 1.1–1.3) and increase with higher maternal fasting blood glucose or body mass index. ,
Macrosomia with birth weights >4000 g may be seen in up to 25% to 45% of infants born to mothers with pregestational diabetes and 15% to 20% of those born to mothers with GDM. , Many IDMs show greater adiposity compared with infants born to nondiabetic mothers. Macrosomic IDMs frequently show altered growth with higher chest-to-head and shoulder-to-head ratios compared with infants of nondiabetic mothers , and are at increased risk of a birth injury such as shoulder dystocia, brachial plexus injury, clavicular or humeral fractures, cephalohematoma, subdural hemorrhage, and facial palsy.
Epidemiologic data show a recent encouraging downtrend in the proportion of macrosomic IDMs from 9.1% to 7% of the newborn population between 1990 and 2005. However, these figures need cautious evaluation because these changes in birth weights could also originate in prematurity, increased multiple births, or early obstetric intervention with induction of labor and/or cesarean sections. Mothers with type 1 DM and good medical care (HbA 1c ≤7%) still have a 50% increased risk for fetal macrosomia (>90th percentile) and a 33% greater chance of having a very large for gestational age neonate (>97th percentile) compared with the general population. Glycemic control in midpregnancy could be one of the most important determinants of abnormal growth.
About 5% to 10% of IDMs may be small for date with birth weights below the 10th percentile. , These infants may be born to mothers with longstanding diabetes who may have notable placental vascular changes on ultrasound/histopathology. , There is a strong correlation between fetal intrauterine growth restriction and the severity of maternal changes of type 1 DM and preeclampsia. In these pregestational diabetic mothers, microvascular complications such as retinopathy increase the risk of small-for-gestational-age (SGA) birth. Excessive glycemic control may also increase the risk, possibly due to decreased fetal nutrition. Conversely, a few cohort studies have shown that diabetes during pregnancy reduces the risk of SGA. , Coexisting conditions such as preeclampsia, markers of prolonged diabetes such as retinopathy, and the control of diabetes during pregnancy are important for the determination of risk to the fetus. Further studies are also needed to determine the anthropometric measures of adiposity and skeletal growth.
Recent efforts include evaluating 3-dimensional ultrasound to predict fetal weight based on the estimation of subcutaneous tissue in limbs. The amniotic fluid volume also seems to be related to fetal weight. These measurements can be performed with high accuracy. However, further work is needed to assess the impact of these studies on maternal management of diabetes during pregnancy and fetal/neonatal outcomes.
Peripartum Effects
Birth asphyxia occurs more frequently in IDMs due to obstetric complications such as failure to progress, shoulder dystocia, and fetal diabetic cardiomyopathy. , , Mimouni et al. showed that maternal nephropathy, maternal hyperglycemia before delivery, and premature births were associated with the rate of birth asphyxia.
Neonatal Effects
Metabolic
The common metabolic complications in IDMs are hypoglycemia, hypocalcemia, and hypomagnesemia. Neonatal hypoglycemia commonly presents in the first few hours of birth. It occurs due to the cut-off of maternal glucose transfer in a state of persistent hyperinsulinemia. Macrosomic neonates, preterm neonates, and SGA neonates have greater risk of developing hypoglycemia. , Hypocalcemia in IDMs may present as jitteriness, lethargy, apnea, tachypnea, or seizures between 24 and 72 hours of birth.
Cardiorespiratory
Respiratory and cardiovascular complications contribute importantly to neonatal morbidity and mortality, especially in preterm neonates. Respiratory complications including respiratory distress syndrome due to prematurity, relatively immature structure of the developing lung, surfactant deficiency, patent ductus arteriosus, and transient tachypnea of the newborn ( Fig. 24.4 ) predispose the infant to neonatal hypoxia. , , IDMs are vulnerable to transient hypertrophic cardiomyopathy, characterized by left ventricular outflow obstruction due to disproportionate thickening of the interventricular septum and reduced left ventricular size ( Fig. 24.5 ). , Way et al. showed that symptomatic infants recovered within 2 to 4 weeks and echocardiographic findings of septal hypertrophy resolved within 2 to 12 months. Transient hypertrophic cardiomyopathy is usually a benign condition that does not require pharmacologic treatment in most cases. ,
Hematologic
IDMs can have higher hematocrit values owing to the chronic fetal hypoxemia and consequently raised erythropoietin; these changes can set up a feed-forward cycle. Many IDMs develop polycythemia, defined as a central venous hematocrit above 65%. This higher incidence of polycythemia in IDMs has been noted in several studies. , Polycythemia could predispose infants to neonatal hyperviscosity syndrome, which involves ischemia and infarction of major organs due to blood vessel obstruction by sludging. Renal vein thrombosis is a significant complication of hyperviscosity syndrome in IDMs ( Fig. 24.6 ). ,
