Obstetric Neuropathy in Diabetic Patients: The "Double Hit Hypothesis"

Abstract

The two-hit model has been proposed to explain the effects of diabetes on mothers who are already in a putative subclinical damaged state and then undergo neuronal damage during the delivery process. However, the anatomical and pathophysiological mechanisms are not well understood. Our overarching hypothesis in this review paper is that pregnant women who are diabetic have a damaged peripheral nervous system, constituting the "first hit" hypothesis. The delivery process itself-the "second hit"-can produce neurological damage to the mother. Women with diabetes mellitus (DM) are at risk for neurological damage during both hits, but the cumulative effects of both "hits" pose a greater risk of neurological damage and pathophysiological changes during delivery. In our analysis, we introduce the different steps of our concept paper. Subsequently, we describe each of the topics. First, we outline the mechanisms by which diabetes acts as a detrimental variable in neuropathy by focusing on the most common form of diabetic neuropathy, diabetic distal symmetrical polyneuropathy, also known as distal sensorimotor neuropathy. The possible role of macrosomia in causing diabetic neuropathy and obstetric neurological injury is discussed. Second, we describe how vaginal delivery can cause various obstetrical neurological syndromes and pathophysiological changes. Third, we highlight the risk of obstetric neuropathy and discuss anatomical sites at which lesions may occur, including lesions during delivery. Fourth, we characterize the pathophysiological pathways involved in the causation of diabetic neuropathy. Finally, we highlight diabetic damage to sensory vs. motor nerves, including how hyperglycemia causes different types of damage depending on the location of nerve cell bodies.

Keywords: diabetic neuropathy; neurological damage during delivery.

Figure 1

Pathways Involved in diabetic neuropathy: hyperglycemia causes diabetic neuropathy through several pathways. Elevated blood glucose leads to an increased conversion of glucose to sorbitol. Sorbitol can cause osmotic swelling, causing compression neuropathy, and can inhibit axonal repair mechanisms. Hyperglycemia can also cause direct damage to nerve cells through the stimulation of the PTEN (phosphatase and tensin homolog) pathway. Hyperglycemia causes Schwann cell toxicity, thereby producing advanced glycation end products (AGEs) and leading to axonal demyelination. Macrophages are important for nerve repair and regeneration, but can be inhibited by hyperglycemia. Hyperglycemia also leads to dyslipidemia and the formation of foam cells from macrophages. These foam cells contribute to the formation of atherosclerotic plaques, leading to vascular and endoneurial microvascular damage to produce reactive oxygen species (ROS). ROS use the NF-κB pathways to cause leukocyte recruitment and apoptosis, leading to inflammation, ischemia, and cellular nerve damage [16].

Figure 2

Diabetic damage to sensory vs. motor nerves: hyperglycemia causes different types of damage, depending on the location of nerve cell bodies. Sensory nerve cell bodies are located in the dorsal root ganglia, which are supplied by spinal segmental arteries. Hyperglycemia in this blood supply causes axonal damage and cell body damage, leading to a loss of sensory input and perikaryal dropout. Motor nerve cell bodies are located in the anterior horns of the spinal cord. The blood–spinal cord barrier, similar to the blood–brain barrier, protects these cell bodies from the damaging effects of hyperglycemia. However, the axons of motor nerves and their motor units can still be damaged, leading to the loss of motor function.

Figure 3

Two-hit hypothesis of diabetic neuropathy in pregnancy: The first hit is believed to be caused by the pathways previously discussed, leading to cell body toxicity and nerve damage. This damage may lead to subacute neuropathy with few symptoms. Diabetes is a common cause of macrosomia, which increases the risk of compression neuropathies during vaginal birth. This compression damage, combined with impaired nerve repair pathways, leads to the second hit, causing the more frequent or severe radiculopathies and neuropathies seen in vaginal births with diabetic mothers.