Pregestational diabetes, based on literature, appears to be present in approximately 1% of all pregnancies.¹ Type 1 diabetes mellitus tends to occur early in human life and appears to be associated with an autoimmune disorder that alleviates pancreatic β cells. This generally leads to a requirement for insulin replacement. Type 2 pregestational diabetes mellitus is associated with obesity, insulin deficiency, insulin resistance, and development of certain complications, such as neurologic, renal, and vascular issues. Type 2 diabetes has increased significantly in number due to the obesity epidemic in the United States.² Of diabetic cases in pregnancy, 90% are related to gestational diabetes mellitus. Over 50% of such patients will eventually develop type 2 pregestational diabetes. Obesity, along with diabetes, has many negative consequences during pregnancy, to the mother, to the fetus, to the newborn, or to all.

Type 1 diabetes mellitus accounts for about 5%–7% of diabetes in the United States. This subclass develops as a result of an autoimmune disorder that is usually directed against insulin-producing β cells in the pancreas. Destruction of such cells leads to the requirement for insulin replacement. Usually, onset occurs before age 30 and can affect about 0.5% of all pregnancies in the United States. Prior to insulin therapy, infertility was the most common consequence of diabetes mellitus for reproductive-age women. Mortality rates in neonates could have been as high as 60%.^1,2,3 Advances in insulin therapy and improvements in neonatal care have decreased this mortality rate to 2%. All risks associated with diabetes are increased once obesity is factored in as well.

All of the causes of this disorder are still not clear. Some suggest that there is a general inflammatory state called insulinitis that may lead to this type of diabetes. Macrophages, B lymphocytes, and CD⁺ T lymphocytes may be able to infiltrate the Langerhans islets in the pancreas. A complex cycle generally leads to accumulation of CD⁺ lymphocytes, therefore leading to gradual destruction of insulin-producing β cells.^3,4,5 Ultimately, insulin deficiency that causes hyperglycemia occurs. In general, pregnancy itself is a diabetogenic state in which postprandial glucose levels are already elevated and insulin sensitivities are decreased.⁴ This has been associated with an increase in hormones, including cortisol, progesterone, estrogen, prolactin, and human placental lactogen.⁶ Recently, there have been other molecules that have been associated with this entity as well. The literature has been supportive of the need for an overall increase in insulin requirement during advancing gestational weeks. This increase is even greater if obesity is a factor as well.

This especially has been noted to happen beginning near the second trimester and for the rest of the pregnancy. It is known that those with pregestational diabetes show increasing insulin requirements throughout pregnancy. A Danish prospective study showed an increase in C-peptide during pregnancy in such diabetic moms.⁷ This report showed an association between the variability of insulin requirements throughout the progression of pregnancy, as have several other recent reports.

Hypoglycemia, particularly during the nighttime, is a common complication.³ Hypoglycemia warning signs include tachycardia, sweating, and weakness that can occur due to this effect. If low blood glucose is evident, a glass of milk or juice is the first step in alleviating the symptoms and correcting the blood glucose values.⁸ Hypoglycemia, if untreated, is the leading cause for maternal mortality.

Diabetic ketoacidosis (DKA) may occur due to insulin deficiency that is seen as starvation by the body (Table 23-1).¹⁵ There is a decreased intracellular glucose concentration. Fatty acids are tapped into so energy can be provided for the body. This leads to ketone generation. When this occurs, energy from fatty acids is directed to the brain and heart, which are essential for survival.

Hyperglycemia may actually worsen the insulin-deficiency state by dehydration. As plasma osmolarity increases with glucose increase (Table 23-2),⁸ diuresis occurs that may be at the level of polyuria. This prevents bicarbonate from being reabsorbed. This is turn increases glucose and ketones in the body.

Diabetic ketoacidosis is more commonly seen when compared to hypoglycemic episodes during pregnancy. This issue occurs in about 2% of pregnancies with pregestational diabetes. Decreased levels of bicarbonate may be associated with the physiologic response to increased minute ventilation, which may further decrease the body’s capability of buffering. DKA can develop faster in patients who have urinary tract infections or upper respiratory infections or are on tocolytics or corticosteroids. Intrauterine fetal demise can be seen in about 30% of patients with DKA.⁹ This is increased in obesity, and although the exact numbers and percentages are not known for certain and are debatable, there clearly is an association with more and increased risks.

Diabetes is associated with shoulder dystocia during vaginal delivery, and some reports suggested that the risk can be doubled in such patients.¹⁰ When obesity is involved in those with diabetes, the risks and outcomes in preeclampsia, preterm labor, malformations, urinary tract infections, overdue gestations, labor problems, and cesarean rates all increase, and their outcomes worsen as well. These patients have a higher rate of urinary tract infections and other infections overall. Pyelonephritis, asymptomatic bacteriuria, and preeclampsia could be manifestations of glucose intolerance leading to infections, thus aiding with diagnosing diabetes.

The rate of fetal congenital malformations is approximately 8% in those with pregestational diabetes. The spontaneous abortion rate is approximately 4%. One study showed a direct relationship between hemoglobin A_1C and the rate of fetal malformation.¹¹ When hemoglobin A_1c levels were between 5% and 6%, normal pregnancy outcomes and no major malformations could be expected. Whereas if the levels were above 10%, the malformation rate could be as high as 25%. The risk of macrosomia in a large group of those with diabetes showed a high prevalence.

A recent cohort study¹² that had demonstrated preterm delivery rates as high as 24% in women with pregestational diabetes, there is increased risk for preterm delivery. Spontaneous preterm deliveries were also elevated.

Preeclampsia, characterized by gestational hypertension, systolic and diastolic blood pressures above 140/90 mm Hg, and with onset after 20 weeks of gestation is associated with diabetes mellitus in pregnancy. Pregestational diabetes mellitus is a well-known risk factor for preeclampsia.¹³ The risk is about 15%, compared to about 7% in the general population.³

Diabetic nephropathy affects the interstitial and glomerular compartments of the kidney. Ultimately, end-stage renal disease can occur. Collagen, laminin, and fibronectin can accumulate in such areas and affect clinical and physiologic performance. Due to a heightened risk of preeclampsia in diabetic pregnancies, renal damage can worsen in a shorter amount of time. If patients already have a creatinine level greater than 1.5 mg/dL, end-stage disease progression can occur. Methyldopa can be used for antihypertensive and renoprotective properties. A recent study has shown an improved outcome with such medications.¹⁴

Diabetic retinopathy is the leading cause of blindness in the United States in the reproductive age group.⁸ Glucose permeates into sensitive endothelial cells that line capillaries and blood vessels in the retina. Pericytes are susceptible to high glucose levels and may lead to continuous damage to the endothelial cells, eventually effecting vascular sclerosis and edema. In subsequent response to this environment, retinal tissue secretes proangiogenic growth factors. This neovascularity leads to proliferative diabetic retinopathy. This leads to blindness, retinal detachment, and hemorrhages.¹⁵ New insulin analogues have been associated with increased levels of insulin growth factor, which can negatively affect retinal health. Laser therapy during pregnancy for the treatment of proliferative retinopathy is an appropriate option and actually may cure the pathology that has taken place.

Management of Pregestational Diabetes Mellitus Types 1 and 2

Preconception management can be associated with successful pregnancy outcomes in those with pregestational diabetes even before conception. Strict glycemic control, especially before and throughout pregnancy, has been shown to reduce the rate of perinatal mortality and malformations.¹⁶ It is up to health care providers and physicians to counsel patients and guide them to achieve glycemic control goals as this is the single most important factor associated with a healthy pregnancy outcome. It is also important to uncover any underlying disorder that may be associated with diabetes. For example, vascular damage can be evaluated by a retinal examination, renal function can be evaluated by 24-hour urine protein and creatinine clearance, and cardiac function by electrocardiography.