Diabetic Embryopathy

Etiology

The etiology of diabetes mellitus and its impact on fetal development are complex. Maternal diabetes adversely affects embryogenesis and fetal growth, leading to multiple congenital anomalies and medical complications collectively known as "diabetic embryopathy."

Notably, it has been elucidated that maternal hyperglycemia, as observed in poorly controlled diabetic pregnancies, leads to an increase in glucose transport into the embryo via glucose transporter 2 (GLUT2). GLUT2 facilitates the diffusion of glucose, transporting it bidirectionally across cell membranes in response to concentration gradients. Excess maternal glucose levels lead to increased glucose transport across the membrane to the embryo. This, in turn, can lead to oxidative stress, altered gene expression, and increased apoptosis in developing neural tissues, which ultimately contributes to NTDs.[1]

Epidemiology

Racial and ethnic disparities have been documented among women with pregestational diabetes, with a study reporting higher prevalence rates among Black, Native American, and Hispanic populations.[2] Additional evidence concurs that the risk of diabetic embryopathy may vary by race and ethnicity, with Black families experiencing a higher incidence of congenital anomalies compared to White families.[3]

Additionally, the prevalence of congenital malformations is higher in pregnancies complicated by type 1 diabetes compared to type 2 diabetes. Elevated maternal HbA1c levels during the periconceptional period and early gestation are strongly associated with an increased risk of major congenital anomalies, highlighting the critical importance of achieving optimal glycemic control in early pregnancy.

Pathophysiology

Elevated fetal glucose levels are teratogenic and represent the primary driver of diabetic embryopathy. Hyperglycemia disrupts normal physiology and organ development through multiple contributing factors. 

Oxidative Stress 

Oxidative stress is a central mechanism in the pathogenesis of diabetic embryopathy, significantly contributing to the development of NTDs and congenital heart anomalies. Maternal hyperglycemia promotes excessive production of reactive oxygen species (ROS), which interfere with normal embryonic development by inducing widespread cellular damage. ROS can impair critical cellular components, including membranes, DNA, RNA, proteins, and lipids, through mechanisms such as lipid peroxidation and oxidative modification.[4] This oxidative damage compromises cellular integrity and function, particularly during the process of organogenesis. Furthermore, oxidative stress has been shown to dysregulate the expression of key developmental genes essential for neural tube closure, thereby increasing the risk of NTDs and heart defects. The interplay between metabolic disturbance and oxidative injury underscores the importance of maintaining strict glycemic control to mitigate teratogenic risk in diabetic pregnancies.

Ketone Bodies 

Ketone bodies, primarily β-hydroxybutyrate and acetoacetate, contribute to the pathogenesis of diabetic embryopathy through multiple mechanisms. These metabolites have been shown to enhance the production of ROS, which leads to oxidative stress, cellular damage, and apoptosis. Additionally, ketone bodies can disrupt intracellular calcium homeostasis, a critical regulatory mechanism during embryogenesis, further promoting apoptosis and increasing the risk of NTDs.[5]

Hypoxic Stress 

Maternal hyperglycemia exacerbates embryonic hypoxic stress by primarily increasing the metabolic rate and oxygen consumption of the developing embryo. During the early stages of organogenesis, the embryo exists in a physiologically hypoxic state due to the absence of a fully developed vascular system. Hyperglycemia-induced elevation in oxygen consumption further intensifies this hypoxic environment, potentially disrupting normal embryonic development and contributing to the formation of congenital anomalies.

Other Glucose By-Products

Hyperglycemia disrupts the uptake of inositol by embryonic tissues. Depletion of myo-inositol, especially during critical stages of embryogenesis, has been associated with the development of congenital malformations associated with diabetic embryopathy. Recent experimental studies suggest that myo-inositol supplementation may help mitigate some of these adverse effects, although it is not yet included in standard clinical recommendations.[6] 

Placental Alterations 

Maternal hyperglycemia is associated with various structural and functional changes in the placenta. These include increased placental weight and size, along with histopathological features such as enhanced syncytial knot formation, fibrinoid necrosis, and villous immaturity.[7] Although hyperglycemia is traditionally linked to fetal macrosomia, it can also impair placental development through mechanisms such as abnormal angiogenesis, inadequate spiral artery remodeling, and placental hypervascularization. These alterations may lead to placental insufficiency and increase the risk of fetal growth restriction, despite the potential for increased fetal size.[8]

Histopathology

Diabetic pregnancy is associated with significant alterations in uterine contractility. The diabetic myometrium shows reduced contraction amplitude and shortened contraction duration, even in response to oxytocin, due to impaired intracellular calcium signaling and downregulated expression of voltage-dependent calcium channels. This functional impairment contributes to higher rates of emergency cesarean delivery in patients with diabetes.[9]

Over time, chronic hyperglycemia also induces structural remodeling of the myometrium, including thinning of muscle layers, decreased myocyte proliferation, and disorganization of the contractile apparatus, further compromising uterine function during pregnancy.[10]

History and Physical

A comprehensive maternal history and physical examination are essential components of prenatal care for women with diabetes. The history should carefully document the age of diabetes onset, the presence of diabetes-related complications, including diabetic ketoacidosis, hypoglycemia, gastroparesis, nephropathy, neuropathy, retinopathy, hypertension, and coronary artery disease, as well as any previous adverse pregnancy outcomes and abnormal glucose tolerance test results.[11]

A detailed physical examination should include assessment of peripheral perfusion and sensory function, along with a focused foot evaluation to identify signs of neuropathy or vascular compromise. Additionally, a retinal examination is essential to screen for diabetic retinopathy, which may progress during pregnancy.

Recommended first-trimester prenatal laboratory investigations include measurement of HbA1c, thyroid-stimulating hormone (TSH), a 24-hour urine collection (if baseline renal function is unavailable), and an electrocardiogram (ECG). HbA1c testing is crucial for detecting undiagnosed pregestational diabetes and establishing a baseline for glycemic control. The 24-hour urine collection assesses renal function, whereas the ECG screens for subclinical cardiovascular disease, which is more prevalent in pregnant women with diabetes. Thyroid function testing is imperative, given that up to 40% of young women with type 1 diabetes concurrently exhibit thyroid dysfunction.

Evaluation

Screening and monitoring of women for diabetes during pregnancy are critical components of prenatal care. Women with preexisting diabetes should have HbA1c levels assessed at their initial prenatal visit. All other pregnant individuals should undergo gestational diabetes screening between 24 and 28 weeks of gestation. Although earlier screening based on risk factors is sometimes considered, current evidence does not support improved outcomes with early testing.[12]

Monitoring of Glucose Levels 

The 1-hour glucose challenge test, typically performed between 24 and 28 weeks of gestation, is used to screen for gestational diabetes. A serum glucose level exceeding 140 mg/dL 1 hour after oral glucose intake is considered abnormal. Women who screen positive should undergo a diagnostic 3-hour glucose tolerance test. Additionally, measuring HbA1c before conception is valuable for identifying individuals at high risk, as pregestational diabetes is the primary contributor to diabetic embryopathy. Elevated HbA1c levels in early pregnancy are also associated with an increased risk of developing gestational diabetes later in pregnancy.

Maintaining strict glycemic control throughout pregnancy is essential to minimize the risk of fetal complications. In diabetic pregnancies, the American Diabetes Association (ADA) recommends monitoring blood glucose levels at least 4 times daily, including fasting, preprandial, and postprandial measurements, to ensure optimal glucose management.[13]

Ultrasound and Fetal Echocardiograms 

Ultrasound imaging is used to monitor fetal growth and development, as well as fetal anatomy. This includes a detailed fetal anatomy scan performed around 18 to 20 weeks and serial growth ultrasounds in the third trimester to assess for macrosomia and other growth abnormalities. A fetal echocardiogram is recommended, particularly in the second trimester, for patients with poorly controlled pregestational diabetes, due to the higher incidence of congenital heart defects in these pregnancies.[11][14] Given the increased risk of stillbirth, enhanced antenatal surveillance with either nonstress tests or biophysical profiles is recommended for pregnancies complicated by pregestational diabetes and for gestational diabetes that requires medications to control hyperglycemia. This monitoring typically begins at 32 weeks, but may start earlier if fetal growth restriction is detected before this time. 

Hemoglobin A1C Levels and Risk

HbA1c levels directly correlate with the risk of congenital anomalies in pregnancies complicated by diabetes. A study found that women with pregestational diabetes and higher HbA1c levels had a significantly higher risk of fetal anomalies, reporting a 10% anomaly rate at an HbA1c of 10% and a 20% rate at an HbA1c of 13%.[15] Another study demonstrated that the prevalence of major congenital malformations increased progressively with rising HbA1c levels in both type 1 and type 2 diabetes, with no clearly defined safe threshold. Women with HbA1c levels of 9.5% or higher had significantly higher odds of major congenital malformations.[16]

Treatment / Management

Preconception surveillance is the best way to prevent diabetic embryopathy. This is essential to counsel patients on the importance of achieving tight glycemic control, making dietary changes, and considering the addition of supplements. The ADA recommends an HbA1c level of less than 6.5% before pregnancy.[13] This recommendation is supported by observational studies showing a direct correlation between elevated HbA1c levels during early pregnancy and an increased risk of diabetic embryopathy. 

Nutritional interventions are a key component of care and are typically the first recommendation for pregnant women with diabetes. Dietary interventions should be individualized to help achieve glycemic targets and support appropriate gestational weight gain. The recommended carbohydrate intake during pregnancy is 175 g/d. Emphasizing high-quality carbohydrates can lead to improved fasting and postprandial glucose control.[13] In addition, the American Association of Clinical Endocrinology (AACE) recommends small, frequent meals, including a bedtime snack, to help prevent overnight hypoglycemia and ketosis.

Supplementation can have a supportive role in reducing the risk of diabetic embryopathy. Dietary interventions using oils rich in oleic and linoleic acids, such as olive and safflower oils, have been shown to normalize prostaglandin levels and reduce the incidence of malformations in pregnancies affected by diabetes. The antioxidant, vitamin E, may help counteract oxidative stress and its harmful effects on embryonic development. Additionally, folic acid supplementation is strongly recommended to reduce the risk of NTDs.

Drug therapies may be necessary to manage diabetes during pregnancy. Insulin administration is recommended when nutritional interventions alone fail to achieve adequate glycemic control.

Differential Diagnosis

The structural anomalies associated with diabetic embryopathy can phenotypically overlap with those seen in various congenital syndromes, making accurate differential diagnosis essential during both prenatal and postnatal evaluation.

Neural Tube Defects

NTDs are congenital malformations resulting from the incomplete closure of the neural tube during early embryogenesis. Although maternal diabetes is a recognized risk factor, folic acid deficiency remains the most common cause. Additional contributing factors include vitamin B12 deficiency and various genetic syndromes.

DiGeorge Syndrome

The clinical features of DiGeorge syndrome can closely resemble those of diabetic embryopathy. Overlapping manifestations include conotruncal cardiac anomalies, craniofacial dysmorphisms, and cognitive impairments, all of which may mimic complications associated with diabetic embryopathy.[17]

VACTERL Association

VACTERL association is a nonrandom association of congenital anomalies that affect multiple anatomical structures, including vertebral anomalies, anal atresia, cardiac defects, tracheoesophageal fistula, renal abnormalities, and/or limb abnormalities. A detailed maternal prenatal history of diabetes can help differentiate VACTERL association from diabetic embryopathy.[18]

CHARGE Syndrome

CHARGE syndrome affects multiple organ systems and is characterized by coloboma, heart defects, atresia choanae (also known as choanal atresia), growth retardation, genital abnormalities, and ear abnormalities.[19] Although some features overlap with diabetic embryopathy, CHARGE syndrome is generally distinguished by its wider range of organ involvement and its underlying genetic etiology.

Prognosis

Pregnancy outcomes are significantly influenced by maternal diet during pregnancy. Preconceptional assessment of maternal risk factors and blood glucose levels is essential for accurate prognostication. Maintaining strict glycemic control remains the most effective strategy for preventing or reducing the incidence of congenital anomalies.[20]

The perinatal mortality rate in diabetic pregnancies is approximately 2.5 to 9 times higher than in the general population. Several studies have shown that type 2 diabetes is associated with a higher rate of perinatal deaths than type 1 diabetes, mainly due to additional risk factors such as hypertension, advanced maternal age, obesity, and multiparity. However, data from French studies indicate that stillbirths are more frequently observed in patients with type 1 diabetes.

Complications

Maternal diabetes is strongly associated with an increased risk of NTDs, such as anencephaly and spina bifida. These congenital malformations are primarily attributed to hyperglycemia-induced oxidative stress and apoptosis in the developing neuroepithelium.[21] In addition to structural anomalies, maternal diabetes can affect neurodevelopment, increasing the risk of behavioral and cognitive disorders. Children born to mothers with diabetes have a higher incidence of conditions such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder, likely due to fetal programming and the adverse effects of maternal hyperglycemia on brain development.[22] 

Diabetic embryopathy is also associated with significant cardiovascular abnormalities. Affected children are at increased risk for congenital heart defects such as ventricular septal defects, transposition of the great arteries, truncus arteriosus, and tricuspid atresia. In addition, cardiac hypertrophy is common and may lead to diastolic dysfunction, left ventricular outflow tract obstruction, and reduced cardiac output. 

Diabetic embryopathy can affect multiple organ systems in neonates. One such condition is the oculoauriculovertebral spectrum, a rare craniofacial disorder resulting from defective organogenesis and often associated with vertebral column abnormalities. Sacral agenesis—defined as the complete or partial absence of the sacrum—is also more common in these pregnancies. The most frequent manifestations include ear malformations and hearing loss, followed by hemifacial microsomia, ocular anomalies, and vertebral column anomalies. Additional findings may include femoral hypoplasia, renal agenesis, growth restriction, and macrosomia at birth. 

Children born to mothers with diabetes are at increased risk of developing metabolic syndrome, insulin resistance, and diabetes later in life. They may also experience polycythemia secondary to fetal hypoxia, which increases erythropoietin and red blood cell production. These changes can lead to hyperbilirubinemia.

Respiratory distress due to decreased surfactant levels in preterm infants and hypoglycemia resulting from fetal hyperinsulinemia have been reported in infants of diabetic mothers. Macrosomic infants are at increased risk of shoulder dystocia during delivery. Additionally, these pregnancies are associated with a higher incidence of perinatal mortality, including an increased risk of stillbirth and delivery-related complications. 

Certain differences have been observed between type 1 and type 2 diabetes in pregnant women.[23] Type 1 diabetes has been associated with younger mothers at the time of pregnancy. There is also a higher rate of reported preterm deliveries and large-for-gestational-age births. In contrast, type 2 diabetes is typically associated with older maternal age, a higher maternal body mass index (BMI), and a greater burden of comorbidities at the time of pregnancy. In addition, type 2 diabetes is also associated with an increased risk of neonatal death compared to type 1 diabetes.