How do you recognize and treat diabetic ketoacidosis (DKA)?
How do you manage newly diagnosed or uncontrolled diabetic patients who are admitted for glycemic control during the antepartum period?
How do you recognize, manage, and prevent labor complications in patients with diabetes?
How do you manage and counsel postpartum patients with gestational diabetes mellitis (GDM) and pregestational diabetes?
An 18-year-old G1P0 at 29 0/7 weeks by stated last menstrual period presents to the obstetrical triage unit with the chief complaint of nausea, dysuria, and “not feeling well.” Her pregnancy is complicated by absent prenatal care.
She reports that she has been having dysuria for the past four days, and starting today, she had had nausea and vomiting. She has noted decreased energy for months, but she has really been feeling fatigued this week. She did not find out that she was pregnant until two weeks ago, but she has not yet had her first prenatal appointment.
Her vital signs reveal a temperature of 38.9°C, a heart rate of 112, a respiratory rate of 20, and a blood pressure of 125/70. Physical exam is significant for a slight fruity odor to the patient's breath, mild suprapubic tenderness, and left-sided flank pain. A bedside ultrasound is used to perform fetal biometry and confirms her gestational age by dates. A spot urinalysis first returns displaying abnormal findings, including 1+ protein, 3+ glucose, 3+ ketones, moderate leukocyte esterase, positive nitrites, and positive white blood cells. Serum labs then return with a complete metabolic panel revealing mild hyponatremia, mild hypokalemia, and a blood glucose level of 387 mg/dL. Her blood urea nitrogen, creatinine, and liver function tests are within normal limits. A CBC shows an elevated WBC count of 21, mild microcytic anemia, and normal platelets.
According to the Centers for Disease Control and Prevention (CBC) in 2016, there are 29 million Americans living with diabetes and another 86 million with insulin resistance or prediabetes.1 The rapid increase in patients with this disease spectrum is especially relevant in our patient population, given pregnancy's inherent insulin resistance and the role that this can play in maternal and fetal morbidity and mortality. More than 6% to 7% of deliveries are now occurring in patients with either pregestational diabetes or gestational diabetes mellitus (GDM).2 To care for these patients safely, the OB/GYN providers must be familiar with the common complications of diabetes during pregnancy as well as the antepartum, intrapartum, and postpartum management of patients with all classifications of diabetes (Fig. 24-1).
Diabetic classifications. Data from American Diabetes Association: 2. Classification and Diagnosis of Diabetes, Diabetes Care. 2016 Jan;39 Suppl 1:S13-S22.
MATERNAL COMPLICATIONS OF DIABETES
Apart from the associated complications surrounding delivery, as elaborated upon in the section entitled “Intrapartum Considerations,” later in this chapter, pregnant patients with diabetes are at higher risk of developing multiple pregnancy-related complications, including infection (e.g. pyelonephritis, influenza), preeclampsia, venous thromboembolism (VTE), cardiovascular disease (CVD), and diabetic ketoacidosis (DKA). They are also at higher risk of exacerbating diabetes-related complications like retinopathy and nephropathy.
Ideally, gravid diabetic patients will have been started on low-dose aspirin after 12 weeks of gestation to decrease the risk of developing preeclampsia;4–6 however, they will still have up to a fourfold higher risk of developing this morbid disease.7 Furthermore, this risk is closely correlated to their level of glycemic control.8 Thus practitioners should have a high level of suspicion for preeclampsia if patients present with headache, visual changes, right-upper-quadrant pain, epigastric pain, or worsening peripheral edema. Complicating the diagnosis of preeclampsia is the fact that diabetics have varying levels of baseline proteinuria prior to pregnancy. Evaluating for an acute elevation in proteinuria in comparison to baseline levels obtained early in pregnancy may be beneficial.9 The risk of preeclampsia is even higher in the setting of concomitant diabetes and chronic hypertension. Optimization of chronic hypertension using modalities other than angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers is imperative.10
Pregnancy and diabetes are both independent risk factors for deep venous thrombosis (DVT) and pulmonary embolism.11,12 Thus for patients presenting with concerning symptoms for VTE such as asymmetric lower-extremity edema, new-onset dyspnea, or pleuritic chest pain, practitioners should have a lower threshold for initiating a diagnostic workup.
Diabetes is a strong risk factor for CVD, and this is especially relevant given that that is now the leading cause of pregnancy-related mortality.13 Physiologic changes during pregnancy lead to volume overload, increased cardiac output, and increased heart rate, all of which may reveal or overwhelm a previously well compensated defect caused by diabetes-related vascular disease.14 Practitioners should have a higher level of suspicion for peripartum cardiomyopathy and myocardial infarction if diabetic pregnant patients present with concerning cardiac symptoms. Further, if patients were taking a statin prior to pregnancy, this should have been discontinued as soon as pregnancy is confirmed.
FETAL COMPLICATIONS OF DIABETES
Maternal hyperglycemia is associated with up to a threefold increase in the rate of spontaneous abortion,15,16 a fivefold increase in preterm delivery, and a fourfold increase in intrauterine fetal demise.17,18 The overall fetal death rate is further increased when fetal birth weight is >4250 g.19 Diabetes during pregnancy is also associated with a threefold-to-eightfold increase in fetal malformations, with neural tube defects and congenital heart diseases being the most common.17,20 Importantly, the severity of hyperglycemia—especially during the first trimester—is correlated with an increased incidence of these complications, and therefore expedited normalization of sugars may reduce morbidity (Fig. 24-2).
The frequency of major congenital malformations in newborns of women with pregestational diabetes stratified by hemoglobin A1c levels at the first prenatal visit. (Data from Galindo A1, Burguillo AG, Azriel S, et al: Outcome of fetuses in women with pregestational diabetes mellitus, J Perinat Med. 2006;34(4):323-331.)
Furthermore, as excess glucose in the maternal bloodstream crosses the placenta, fetal hyperinsulinemia acts as a growth hormone and can lead to macrosomia through increased fetal adipose deposition, which is associated with an increased risk for shoulder dystocia and birth trauma.21 This may include fractures of the clavicle and humerus as well as nerve palsies.15,22
Polyhydramnios is 30 times more common in patients with diabetes and can occur in 3% to 32% of pregnancies. It is thought to occur secondary to fetal polyuria from an increased fetal glycemic load, decreased fetal swallowing, or fetal gastrointestinal obstructions. In gestational diabetics, polyhydramnios has been correlated with a fivefold higher risk of stillbirth, in addition to higher proportions of large-for-gestational age infants, macrosomia, neonatal respiratory distress, and neonatal jaundice.23 In pregestational diabetics, polyhydramnios has been associated with increased risks of preterm delivery and cesarean section (C-section).24
While fetal macrosomia is more common, intrauterine growth restriction (IUGR) also occurs with significant frequency. It is more common in type 1 and long-standing type 2 diabetic mothers, and is thought to arise from placental insufficiency in the setting of maternal vasculopathy. Antepartum fetal monitoring, as well as umbilical and uterine artery Doppler studies, can guide the surveillance and timing of delivery in these pregnancies.25
Following delivery, neonates born to diabetic mothers have increased risk of hypoglycemia, hypocalcemia, hyperbilirubinemia, polycythemia, respiratory distress syndrome, and need for neonatal intensive care.26,27 However, the complications do not end in the neonatal period. Children born to diabetic mothers are also predisposed to metabolic syndrome and glucose intolerance later in life,28,29 and 15-year follow-up studies have found a negative influence on intellectual and psychomotor development.30
Treatment of GDM has been associated with a significant reduction in the rate of composite perinatal outcomes (perinatal death, shoulder dystocia, and birth trauma). It has also been associated with a decreased frequency of large-for-gestational age infants from 22% to 13%, and decreased risk of preeclampsia from 18% to 12%.31
Classics signs and symptoms of pregestational diabetes include polydipsia, polyuria, and unexplained weight loss. Patients that present with any of these symptoms and a random plasma glucose level of >200 mg/dL meet the diagnosis of diabetes.3 However, frequently the clinician's suspicion may be elevated in the circumstance of an incidental finding of glucosuria or an elevated serum glucose level. These diagnostic criteria are based on criteria from the American Diabetes Association (ADA)3, shown in Figure 24-3.
ADA diagnostic criteria for diabetes.
For the diagnosis of GDM, all pregnant women should be routinely screened between 24 and 28 weeks of gestation, and possibly sooner in the first trimester if they have risk factors (see Fig. 24-4). While historically, a 2-hour oral glucose tolerance test (OGTT) was performed, it is now recommended that testing first begin with a 1-hour OGTT. During a 1-hour OGTT, a 50-g load of glucose is given to a nonfasting patient. If the patient screens positive, a diagnostic 3-hour OGTT will be performed. Choosing a screening threshold serum glucose level ≥140 mg/dL will identify 80% of patients with GDM, while a threshold of ≥130 mg/dL will be more sensitive and identify 90% of patients with GDM, but that also will have a higher false positive rate.32 Notably, if the glucose level is ≥200, a diagnosis of GDM can be made without having to proceed with a 3-hour OGTT. Criteria for the diagnosis of GDM via 3-hour OGTT can be found in Figure 24-5. Classically, two out of the four values had to be abnormal for diagnosis; however, given the risks for adverse perinatal outcomes, diagnosis may be considered if even one level is abnormal.33 Finally, if an OGTT is performed while someone is an inpatient, be sure that it is delayed at least 7 days following betamethasone (BMZ) administration.
Criteria for early screening of GDM in pregnancy.144 Data from American Diabetes Association: 2. Classification and Diagnosis of Diabetes, Diabetes Care. 2016 Jan;39 Suppl 1:S13-S22.
Diagnostic criteria for GDM with a 3-hour OGTT.144–146 Criteria for the diagnosis of gestational diabetes from a 3-hour oral glucose tolerance test. If one or more of the values are abnormal, a diagnosis of gestational diabetes may be considered.
Admission to the hospital for glycemic control during pregnancy often occurs in order to expedite the normalization of plasma glucose levels and establish an appropriate insulin regimen. Not only is this important for reducing long-term fetal and maternal morbidity but it may be critical in preventing mortality.
Diabetic ketoacidosis (DKA) is one of the most dangerous complications of diabetes during pregnancy, and it warrants immediate hospital admission to avoid maternal and fetal mortality. With improved treatment strategies and patient education, maternal mortality has continued to decrease to approximately 1%; however, fetal mortality over the last decade has ranged from 9% to 35%.2,34–37 While DKA is well known to occur in type I diabetics, it can still occur in type 2 diabetics and gestational diabetics. An important consideration in patients who present in DKA is latent autoimmune diabetes in adults (LADA), a slow-progressing form of autoimmune diabetes which may include about 25% of women under 35 years old who were presumed to have type II diabetes.38 Finally, practitioners should have a high level of suspicion for DKA in pregnancy, given that up to 30% of cases occurred in patients not previously known to have any diagnosis of diabetes.35 Notably, DKA is more likely to occur during the second and third trimesters.39,40
DKA is caused by relative or absolute insulin deficiency that leads to severe hyperglycemia and glucosuria, which causes osmotic diuresis. This diuresis leads to dehydration and urinary electrolyte loss. The insulin deficiency also leads to lipolysis and hepatic oxidation of fatty acids, which leads to ketosis and metabolic acidosis. Interestingly, while DKA is typically characterized by grossly abnormal glucose levels (>300 mg/dL), during pregnancy, DKA can occur with only mildly elevated glucose levels, or even normal glucose levels.41,42
Thus if one cannot rely on glucose levels to raise suspicion, the clinician should be on alert for the following signs and symptoms: nausea, vomiting, poor oral intake or dehydration, weakness, polyuria, fever, hyperventilation (often accompanied by a fruity odor on the patient's breath), blurry vision, altered mental status, or maternal tachycardia.43 In fact, one of the most common precipitating events for DKA is emesis itself. Other precipitating factors for DKA include infection, diabetic gastroparesis, poor compliance with therapy or insulin pump failure, use of β-sympathomimetic agents (for tocolysis) or corticosteroids, or physician management error.44
Laboratory findings of hyperglycemia, acidosis, and ketonemia are typically present. Acidosis is confirmed when the pH on an arterial blood gas (ABG) is <7.3. In addition, the ABG will often reveal an elevated base deficit and anion gap >12 mEq/L secondary to an abnormal elevation of the unmeasured anions, such as ketoacids and lactic acid. Ketonemia is confirmed by evaluating for urine and/or serum ketones (3-β-hydroxybutyrate). Finally, serum bicarbonate levels are often decreased to <15 mEq/L; sodium, potassium, and phosphate levels may be abnormal; and the blood urea nitrogen and creatinine may be elevated in the setting of dehydration or renal failure.43 Laboratory assessment should be repeated every 1 to 2 hours as needed in severe cases.45
Initial management is hallmarked by volume replacement as well as correction of hyperglyclemia and electrolyte abnormalities. The primary insult leading to DKA should be established and treated if necessary (e.g. sepsis), and a multidisciplinary team including a maternal fetal medicine (MFM) specialist, anesthesiologist, general internist or endocrinologist, and often intensive care team members should be mobilized. Importantly, recommendations for early management are almost identical to that of nonpregnant patients.
Immediate resuscitation with intravenous (IV) 0.9% sodium chloride is started at a rate of 1000 mL/hour for the first 1 to 2 hours, and a Foley catheter should be placed to strictly monitor urine output (goal > 0.5 mL/kg/hour).43 A simple way of estimating a patient's fluid deficit is by calculating 100 mL/kg of body weight. This is often between 4 and 10 L.46 After the first 1 to 2 hours, the rate can be decreased to 250 to 500 mL/hour with the goal of correcting 75% of the fluid deficit over a 24-hour period. If hypernatremia occurs, 0.45% normal saline can be used instead of isotonic saline. Once the serum glucose levels are <250 mg/dL (14 mmol/L), isotonic saline should be switched to 5% dextrose. Once the glucose levels normalize, continue fluid repletion until the fluid deficit is met as calculated previously. Note that in patients whom DKA was provoked by sepsis (especially pyelonephritis), the risk of acute respiratory distress syndrome is elevated.47 Thus practitioners should maintain a high level of suspicion for the development of pulmonary edema or acute respiratory distress syndrome (ARDS), and fluid status should be managed vigilantly.
During repletion, if the patient is becoming hyperchloremic, switching to a more physiologic fluid like PlasmaLyte can help to prevent hyperchloremic acidosis.48 Note that even with normal serum potassium levels, often the total body potassium is low, and upon administration of insulin, potassium will be driven intracellularly. Thus in this acute setting, consider evaluation and repletion of electrolytes frequently, with the goal of maintaining a potassium level between 4 and 5 mEq/L, and a phosphate level >1 mg/dL (although normal is 2.8–4.6 mg/dL). Repletion of calcium and magnesium is debatable, and repletion with bicarbonate to correct acidosis is also controversial. One may consider adding one ampule (44 mEq) of bicarbonate to 1 L of 0.45% normal saline in settings when the pH is <7.1 or in patients complicated by cardiac dysfunction, sepsis, or shock.43,45
A regular insulin drip can be initiated starting with a 0.1-U/kg bolus, and followed by a 0.1-U/kg/hour rate. If glucose levels do not fall by 50 to 75 mg/dL over the first hour, consider doubling the hourly infusion rate. Even upon normalizing the serum glucose levels, continue the insulin drip at a rate of 1 to 2 U/hour until the ketosis and acidosis resolves, because it is the intracellular hypoglycemia that drives the counterregulatory hormone activity, and thus the ketoacidosis.
Euglycemia is defined as consistent fasting blood sugar levels of 60 to 90 mg/dL (3.3–5.0 mmol/L), preprandial levels of 60 to 105 mg/dL (3.3–5.8 mmol/L), 1-hour postprandial levels less than 140 mg/dL (7.8 mmol/L), 2-hour postprandial levels less than 120 mg/dL (6.7 mmol/L), and levels between 2 and 4 am glucose <60 mg/dL (3.3 mmol/L).49,50 Thus after the hyperglycemia acidosis resolve, a subcutaneous insulin regimen will need to be either titrated or established. Deciding upon a proper insulin regimen should be individualized and factors including body weight, body fat, physical activity, insulin sensitivity, blood glucose levels, and target blood glucose should be taken into account.51 Insulin dosage is usually determined based on body weight (insulin U/kg), and is discussed in more detail later in this chapter. Once the appropriate regimen has been established and the first subcutaneous dose of insulin is administered, the insulin drip can be discontinued.42
During DKA, continuous fetal heart rate (FHR) monitoring should be initiated for gestational ages >24 weeks gestation. However, FHR abnormalities are common while both the mother and fetus are in an acidotic state. When considering delivery for a nonreassuring FHR tracing, the risks and benefits must be carefully weighed, in that the patient may be unstable and operative intervention can result in increased risk of maternal death. Furthermore, neonatal morbidity is higher when delivering a preterm infant and when the infant is in a severely acidotic state. If the metabolic abnormalities are corrected, both the maternal and fetal status will likely improve over the next 4 to 8 hours.2,52 However, if the fetal status is not improving or maternal condition continues to deteriorate, delivery is warranted.
HYPEROSMOLAR HYPERGLYCEMIC STATE
Hyperosmolar hyperglycemic state (HHS) can have a similar presentation; however, it is characterized by extreme hyperglycemia (≥1000 mg/dL) and hyperosmolality (≥320 mOsm/kg) without development of ketoacidosis. A total of 25% to 50% of patients also have neurologic findings, and other common laboratory findings include an elevated blood urea nitrogen (BUN)–to-creatinine ratio and bicarbonate >15 mEq/L. There can be low-level ketonemia/ketonuria. Infection is the leading precipitating factor of HHS (about 60% of cases). Inadequate fluid intake during the acute illness combined with the ensuing stress response can decrease the effectiveness of circulating insulin and lead to significant hypertonic osmotic diuresis and dehydration. The management is very similar to DKA and the mainstays should include treating the underlying cause, providing aggressive IV hydration, insulin therapy, and electrolyte replacement.53,54
Similar to the euglycemic levels discussed previously, actual glycemic targets for pregestational diabetics include fasting, premeal, and bedtime levels between 60 and 99 mg/dL (3.3–5.4 mmol/L), peak postprandial levels of 100 to 129 mg/dL (5.4–7.2 mmol/L), and hemoglobin A1c levels <6.0. For gestational diabetics, targets include preprandial levels <95 mg/dL (5.3 mmol/L), 1-hour postprandial levels <140 mg/dL (7.8 mmol/L), and 2-hour postprandial levels <120 mg/dL (6.7 mmol/L).30,55 ACOG's recommendations for pregestational diabetic targets are less stringent and reflect those of the gestational diabetic targets given previously.45
ADMISSION FOR GLYCEMIC CONTROL
For less severe levels of hyperglycemia, there is no expert consensus or clear evidence to support recommendations regarding what glucose levels warrant admission to the hospital for glycemic control. The decision must be individualized and take into account the severity of abnormal glucose levels, the gestational age, comorbidities, access to care, and predicted compliance. However, OB providers face this scenario often, and so they must understand how to initiate and titrate insulin therapy in the hope of decreasing maternal and fetal morbidity and mortality.
While occasionally an insulin drip is started and titrated to calculate the insulin requirements during a 24-hour period, it is common to start a weight-based, subcutaneous insulin regimen. While basal-bolus regimens are the most commonly used, many types of insulin regimens can be employed.51,56 However, before these regimens can be understood, one must have a thorough understanding of the types of insulin.50,51,57
The initial dosing decision and the titration of insulin are primarily based on gestational age and current weight. However, individualized considerations also should take into account the patient's response to interventions such as diet or exercise. During pregnancy, progressive insulin resistance, increased weight gain, and decreasing physical activity will cause insulin requirements to grow progressively. In fact, insulin requirements may double or triple during the course of pregnancy.30 It is also notable that obese women may require higher insulin dosages to start, that no more than 50 units of insulin should be administered in one site because it has decreased or delayed absorption, and that the preferred site for injection is the subcutaneous layer of the abdomen to maximize absorption.58
Figure 24-8 features the steps recommended by the American Diabetes Association (ADA) in calculating insulin dosing for women with GDM if more than one-third of her fasting values are >90 and <120 mg/dL or more than one-third of postmeal values are >130 and <180 mg/dL.59 If a patient's GDM is poorly controlled, or the patient has type 1 or 2 diabetes, proper steps in calculating insulin dosing can be found in Figure 24-9.30 Notably, these recommendations by Jovanovic, Kitzmiller, and Coustan are held by the ADA and the California Diabetes and Pregnancy Program (CDAPP) Sweet Success Program (Fig. 24-9);60,61 however, many institutions are familiar with Gabbe's more simplified recommendations (Fig. 24-10).62 Ultimately, regardless of the initial regimen that is chosen, insulin levels will often need to be adjusted and individualized. Once a starting total insulin dose has been determined, the total daily doses should not be adjusted by more than 10% at a time. Postmeal insulin sliding scales are never recommended because they lead to overtreatment without avoiding fetal exposure to hyperglycemia.63
ADA suggested total daily insulin dosing for GDM.59
ADA's suggested total daily insulin dosing for type 1, type 2 diabetes, or poorly-controlled GDM.30,61
Gabbe's suggested total daily insulin dosing.62
While discussing every consideration for choosing an insulin regimen is beyond the scope of this chapter, a few other notes are important to make here. Normal pressure hydrocephalus (NPH) is still the recommended standard for basal insulin.30,56 In comparison to NPH, some practitioners are starting to favor glargine, given it has been associated with less pregnancy hypertension, microalbuminuria and macroalbuminuria, hypoglycemic episodes, neonatal intensive care unit (NICU) admissions, fetal death, jaundice, and fetal malformations in one study.64,65 However, in a meta-analysis, there were no differences in outcomes between long-acting insulin and intermediate-acting insulin.66 In the most recent research, Negrato and colleagues again reviewed 17 studies in 2012, looking at more than 1000 pregnant patients that had been treated with the long-acting analogs, and did not find any increase in maternal or neonatal morbidity. Ultimately, they encourage the use of long-acting agents but desire more conclusive safety profiling before recommending them over the gold standard treatment during pregnancy.50 Finally, the use of nonimmunogenic insulins is preferred.50,67,68
Often, oral hypoglycemic agents (OHAs) will not be initiated by an OB hospitalist, given the circumstances in which their use is typically recommended. However, an understanding of these medications and their adverse effects is imperative. The appeal of these agents stem from their pharmacology, route, cost, and decreased risk of hypoglycemia; however, these benefits must be balanced with their risk of maternal hyperglycemia, maternal side effects, transplacental passage with potential for teratogenicity, and postpartum implications, including breastfeeding.69–71
The two most common classes of oral agents used in pregnancy include insulin secretagogues (e.g. glyburide), and insulin sensitizers (e.g. metformin). There are some smaller studies where α-glucosidase inhibitors have been evaluated; however, all other classes of OHAs either have no evidence to support their use, or else evidence recommending against their use. Figure 24-11 highlights the pharmacology, effectiveness, safety, and dosing of such medications.69,70,72–75 Notably, insulin remains the preferred agent for treating diabetes in pregnancy, and patients with type 1 or long-standing type 2 diabetes are not candidates for oral therapies, given residual pancreatic β-cell function is required.
Oral hypoglycemic agents. *Note: Large-scale and long-term safety data are limited.69,70,72–75
In reliable and motivated patients, insulin pumps are more convenient and may improve glycemic control. This is especially true in patients with recurrent hypoglycemia or a prominent dawn phenomenon, given that they can be programmed to infuse varying levels of both basal and bolus insulin and can be titrated based off carbohydrate counting.30 However, in comparison to basal-bolus regimens as described previously, the evidence has found no difference in macrosomia, operative births, C-section rates, DKA, or perinatal outcomes.76,77 Usually, 50% to 60% of the total daily dose is administered at a continuous basal rate, with 40% to 50% administered as boluses before meals and snacks.78 Importantly, patients and practitioners should be vigilant for pump-tubing occlusion or infusion set leakage, especially as their body changes to accommodate the growing fetus.
Unfortunately, insulin pumps can become a conundrum when patients are admitted to the hospital. To rely on the glucose readings from patients’ monitors and allow patients to administer their own insulin creates liability and quality assurance issues; thus the use of insulin pumps may be either discouraged or not allowed. If a patient using continuous subcutaneous insulin infusion (CSII) is admitted, check with your hospital's policy regarding its use. If CSII is allowed, as with all basal-bolus regimens, the patient and staff must be educated in carbohydrate counting with hospital meals to decrease hypoglycemia or hyperglycemia. If there is a need to convert to a basal-bolus regimen in the hospital, interrogate the patient's pump to find the average doses that have been given recently, and individualize the treatment based on the patient's condition and hospital diet. Further information regarding their use during labor is discussed later in this chapter.
SELF-MONITORING BLOOD GLUCOSE
It is recommended that finger-stick capillary glucose levels are evaluated frequently, depending upon whether our patients are using insulin and what the route is. Postprandial levels have been found to be superior to preprandial levels in predicting macrosomia and morbidity during pregnancy.79 For diet-controlled gestational diabetic patients, fasting blood glucose (FBG) and 1-hour postprandial glucose levels should be tested. For gestational or pregestational diabetic patients using OHAs or insulin, the monitoring should remain the same unless 2 to 3 a.m. glucose levels are needed to evaluate for the Somogyi effect (also known as the dawn phenomenon). For patients using an insulin pump, preprandial and postprandial glucose levels are typically monitored. Patients should also understand how to perform ketone measurements (using blood ketone testing strips) at times of illness, or when the blood glucose levels are >200 mg/dL. Home tests for β-hydroxybutyric acid are commercially available, but they have not been evaluated in pregnancy.30,56
Multiple conditions can increase glucose levels, including preterm labor, preeclampsia, surgery, infections, and medications like beta-mimetics or steroids. Corticosteroid therapy is often administered during pregnancy when concern for preterm delivery arises, in the hope of increasing pulmonary lung maturity and decreasing the risk of intraventricular hemorrhage. Corticosteroids should not be withheld from women who have diabetes out of fear of DKA or exacerbating uncontrolled diabetes in patients <34 weeks gestational age. The use of corticosteroids in the late preterm setting (34–36 5/7 weeks gestation) in diabetics is more controversial. Instead, one must plan accordingly. Corticosteroids will result in acute elevations in serum glucose values within 6 hours after the initial dose and can last up to 3 days after the last dose.80 Pregnant diabetic patients receiving steroids should be hospitalized for frequent serum glucose checks, titration of insulin dosing, or even consideration of an insulin drip to control blood glucose levels.2,43 Treatment must be individualized to patient response; however, Figure 24-12 presents one recommended algorithm.
Insulin adjustments with BMZ use. Note: These recommendations remain consistent with betamethasone or dexamethasone.30,80
As a patient's insulin requirements and clinical status changes during pregnancy, another concerning complication may be hypoglycemia. Hypoglycemia is defined as <60 mg/dL (3.3 mmol/L) during pregnancy,30 and this most commonly occurs at 8 to 9 weeks and 15 to 16 weeks gestation.81,82 While this most often occurs after inappropriate dosing of insulin or glyburide, it also may occur with inadequate nutritional intake or in patients with an infection. Common neurogenic signs and symptoms of hypoglycemia include sweating, shaking, tachycardia, or tingling in the hands, feet, lips, or tongue. In this setting, the patient should ingest 15 g of fast-acting carbohydrates (4 glucose tabs with water, 8 ounces of nonfat milk, or 4 ounces of juice) and then recheck her blood sugar with a standard capillary blood glucose meter. If her blood glucose has not risen above 70 mg/dL after 15 minutes following treatment, or if she still feels low, then she should treat again. This is known as the “Rule of 15.”83 When levels have returned to normal, the patient should consume a snack or meal to prevent recurrence.
More severe neuroglycopenic signs include mood changes, confusion, irritability, seizure, or coma. If the patient is unable to swallow or is found unconscious, the patient's partner, family member, or close companion should inject 1 mg of glucagon subcutaneously and call an emergency service for help.30
FASTING CONSIDERATIONS IN DIABETES
Another special consideration is while patients are nil per os (NPO). While the OB hospitalist will frequently experience this scenario while patients are in labor (discussed later in this chapter), there are a variety of other situations when a patient may be NPO. For example, patients are typically made NPO at midnight the day of their scheduled C-section. They should be encouraged to take their bedtime basal insulin dose the night before and hold their morning doses of insulin. Upon arrival, their blood glucose should be checked. If the patient's blood glucose is between 50 and 70 mg/dL, infuse IV D5 solution at 200 mL/hour, and check blood glucose every 15 minutes until it is >70 mg/dL twice. When the blood glucose is >70 mg/dL, reduce D5 to 100 mL/hour. If the NPO patient was previously on an insulin drip, the drip can be restarted at a lower rate once the glucose level is stable over 70 mg/dL. If the blood glucose is ever <50 mg/dL, it is recommended to infuse D10 instead of D5 at 200 mL/hour, and consider giving 10 mL of D50 IV push if the blood glucose is continuing to fall, or does not rise above 70 mg/dL within 30 minutes.84,85 As an inpatient, avoid glucagon unless the patient is losing consciousness or IV access is lost given it can cause nausea and vomiting and will block insulin for hours.86
ANTEPARTUM EVALUATION OF FETAL WELL-BEING
For pregestational diabetics, a first-trimester ultrasound should be performed not only for proper dating but also to perform a nuchal translucency to evaluate for neural tube defects. For both pregestational and newly diagnosed gestational diabetics, at approximately 18 to 20 weeks, a specialized (Level 2) anatomy scan and fetal echocardiogram should be performed. These evaluations can be considered while your patient is admitted to the hospital if there is concern for delaying these tests.
In the second trimester, the patient should be taught how to perform fetal kick counts. Low-risk, diet-controlled gestational diabetic patients do not require nonstress testing unless indicated for other reasons; however, ACOG PB 190 recommends considering testing according to local practice. For medication-controlled gestational and pregestational diabetics without vasculopathy, begin twice weekly antepartum FHR testing at 32 to 34 weeks. For diabetic women with vasculopathy, hypertension, uncontrolled diabetes, or history of ketoacidosis during the current pregnancy, initiate testing twice weekly at 28 weeks.45,87,88 These recommendations remain unchanged while an inpatient unless there is another reason to perform FHR testing more frequently. Serial growth ultrasounds and umbilical artery Doppler studies are indicated for fetal growth restriction.87
SPECIAL ANTEPARTUM CONSIDERATIONS
If a diabetic patient has preexisting retinopathy, it is even more imperative that she or he has follow-up with ophthalmology, given it is the leading cause of blindness in individuals 24 to 64 years of age.45 Retinopathy is known to progress during pregnancy, and rapid improvement in glycemic control is associated with worsening preexisting retinopathy.89,90 Pregnancy is also known to worsen any underlying nephropathy in diabetic patients. Outpatient monitoring of glomerular filtration rate (GFR), creatinine, and random urine protein and urine creatinine should be obtained. Consideration of nephrology referral is recommended if any of these exams are abnormal.56,91 Given the increased likelihood of preeclampsia during pregnancy, baseline preeclampsia labs should be considered and 81 mg of aspirin should be initiated. Thyroid disease is a common comorbidity, and thyroid function tests should also be considered. Women with diabetic gastroparesis are at a higher risk for maternal and fetal morbidity, and standard medications for hyperemesis and nutritional support should be provided. For all patients with poorly controlled diabetes, a fasting triglyceride level can be considered during the antepartum period, given their increased risk of hypertriglyceridemia-induced pancreatitis. Finally, all patients should be educated about foot care and should be screened for symmetric distal polyneuropathy and autonomic neuropathy at least annually.30
When arranging outpatient antepartum follow-up for diabetic patients after their glucose levels are under relative control, it is recommended that the patient understands how to appropriately treat themselves at home, how to recognize dangerous symptoms, and how to chart their glucose levels. Ideally, they should be seen within 1 week for evaluation and possible further titration of their regimen. Patients may need to be evaluated every 1 to 2 weeks during the first and second trimester and weekly after 28 to 30 weeks of gestation.45 Follow-up of their weight gain, nutritional intake, and medical comorbidities are also of importance.
DKA is one of the most dangerous complications of diabetes during pregnancy and warrants immediate hospital admission to avoid maternal and fetal mortality.
Titrating or establishing an insulin regimen while inpatient is a common antepartum practice. Familiarizing oneself with the types of insulin and their risks and benefits will allow you to individualize a regimen that a patient can compliantly administer.
Upon discharge, a patient should understand how to recognize the symptoms of hypo- and hyperglycemia and be set up to follow up with specialists to help manage their comorbidities.
In addition to the many of the abovementioned antepartum complications of pregestational diabetes and GDM, including premature rupture of membranes and stillbirth, there is also a higher incidence of induction of labor (IOL), operative delivery, C-section, and birth trauma due to macrosomia.17,27,92
The risk of severe birth injury complicates up to 4% of pregnancies in infants born of diabetic mothers, and the risk is even higher among macrosomic infants.31,93–95 The most common birth injuries include brachial plexus injury, facial nerve injury, humerus or clavicle fracture, and cephalohematoma. In diabetic mothers, the risk of these injuries is 5 times greater than normal when the patient experiences a shoulder dystocia. The risk of these injuries is also 2 times greater than normal when there is an operative vaginal delivery.62,96,97 Unfortunately, about 50% of these dystocias occur in infants of normal birth weight and are difficult to predict, so the delivery team should always anticipate this potential complication.
Given the incidence and severity of morbidity during delivery, extensive analysis of complications has been done in an attempt to provide insight into the timing and route of delivery in gestational and pregestational diabetic patients.98–100 However, the interpretation of such data is still ambiguous, and our major governing organizations share a difference of opinion.
For well-controlled gestational diabetics, ACOG PB 190 maintains there is not current evidence to recommend altering the timing of delivery.101 The National Institute for Health and Care Excellence (NICE) in the United Kingdom recommends delivery before 40 6/7 weeks.
Currently, for pregestational diabetic patients, the ADA recommends delivery between 38 and 39 weeks gestation in the absence of other indications for earlier delivery,102 and ACOG recommends delivery between 39 and 40 weeks unless the patient is poorly controlled or has evidence of vasculopathy, nephropathy, or prior stillbirth.103 NICE recommends delivery between 37 and 38 6/7 weeks. Viteri and colleagues recently revisited the available evidence and reported that while delivery between 38 and 39 weeks appears to lead to more favorable outcomes and less morbidity, that there is still no concrete evidence to ignore ACOG's recommendations.100
For most diabetic patients who have not gone into labor spontaneously prior to their indicated delivery time period as referenced previously, IOL is recommended. In a recent review by Melamed and colleagues, they found that IOL at both 38 and 39 weeks in gestational diabetic patients was associated with a lower risk for C-section, while not carrying any significant increase in operative delivery, sphincter injury, or composite neonatal morbidity.104 Nonetheless, as stated earlier, ACOG does not recommend IOL prior to 39 weeks in gestational diabetic mothers unless otherwise indicated, and OB hospitalists should feel comfortable with IOL according to ACOG's guidelines. Furthermore, diabetes alone should not be considered a contraindication to TOLAC.56
DIABETES AND FETAL MACROSOMIA
In the setting of diabetes and suspected fetal macrosomia, ACOG's recommendations on the timing of delivery do not change.105 Although it has been shown that induction between 38 and 39 weeks can decrease the risk of shoulder dystocia compared to that of expectant management,106 a recent Cochrane review did not find a significant decrease in shoulder dystocia with earlier induction.107 However, ACOG does endorse counseling diabetic mothers regarding the option of outright cesarean delivery if the estimated fetal weight is >4500 g.105 They further note that fetal macrosomia is not a contraindication for a trial of labor after cesarean (TOLAC). Nonetheless, the patient must be counseled that the success rate of a Vaginal Birth after Cesarean (VBAC) decreases if the estimated fetal weight is >4000 g.105,108
It is notable that estimation of fetal weight by ultrasound, clinical palpation maneuvers, or prediction by parous women of their expected fetus's weight have not proven to be significantly different from one another. Another consideration when assessing risk is disproportionality between the fetal head and abdomen. One such sonographic modality includes subtracting the biparietal diameter from the abdominal diameter (AD‒BPD). Miller et al (2007) found that with an AD–BPD of 2.6 cm or greater, the risk rates of SD were 25% for unselected control group of patients and 38.5% for diabetics.109 It is noteworthy that the smallest infant for which shoulder dystocia occurred in this study was 3800 g.
INTRAPARTUM GLYCEMIC MANAGEMENT
Maintenance of metabolic homeostasis during labor optimizes postnatal infant transition by reducing neonatal hyperinsulinemia and risk of hypoglycemia. Tight control of both insulin and glucose infusions during labor is achieved through maintaining maternal blood sugars between 80 and 110 mg/dL (see Figs. 24-12 and 24-13). Volume resuscitation is typically done with lactated ringers or 5% dextrose at 50 to 100 mL/hour, and the regular insulin drip (continuous insulin infusion; CII) rate is most commonly between 0.5 and 1.0 U/hour. Blood glucose levels are routinely monitored every hour while in active labor, and every 15 to 30 minutes when adjusting the rate. For patients with diet-controlled GDM or well-controlled type 2 diabetes, avoiding dextrose in IV fluids throughout labor normally maintains excellent blood glucose control. Importantly, upon delivery of the placenta, the insulin drip rate should be cut in half and blood glucose levels monitored hourly until the drip can be discontinued.84,85,110,111
Intrapartum glycemic management recommendations.84,85,110,111
While it is rare, if a patient is using CSII during labor, it is recommended that (1) the basal insulin rate be decreased by 30% of the prelabor setting when in early labor or using clear, noncaloric fluids, (2) the basal insulin rate be decreased by 50% of the prelabor setting when in active labor, (3) blood glucose levels be checked every 30 minutes if not between 80 and 110 mg/dL, and (4) if correction bolus insulin is needed for levels over 110 md/dL, that they are 50% of the dose typically given.112,113 Following delivery, reset all pump parameters to one-third of the pregnancy dose when glucose levels stabilize at <140 mg/dL.
It is recommended to offer an anesthesia consult to diabetic patients with comorbidities such as obesity, heart disease, or autonomic neuropathy during the third trimester or upon admission to the hospital. If general anesthesia is used during a C-section, blood glucose levels should be monitored every 30 minutes until the baby is born and the mother has awoken.56
Diabetic patients should be advised to deliver in hospitals where advanced neonatal resuscitation skills are available 24 hours a day. Although full newborn management is beyond the scope of this chapter, a few points are notable. Breastfeeding is recommended within 30 minutes and at frequent intervals (every 2–3 hours). Newborns should have blood glucose testing within 1 hour of birth, given that infants of diabetic mothers have a 25% to 40% chance of experiencing neonatal hypoglycemia. Newborns should also be monitored for polycythemia, hyperbilirubinemia, hypocalcemia, and hypomagnesemia. They should not be discharged until they are >24 hours old, have stable glucose levels, and are feeding well.56
The recommended timing of delivery for well-controlled gestational diabetic patients is 41 0/7 weeks, and the recommended timing of delivery for diabetic patients without vasculopathy is 390/7 weeks.
Gestational or pregestational diabetes are not contraindications to IOL or TOLAC.
Fetal macrosomia <4500 g is not a contraindication for labor, but for fetuses suspected of weighing >4500 g, patients should be offered an outright C-section.
OB hospitalists should have a high clinical suspicion of shoulder dystocia with all diabetic patients in labor.
Patients should take their evening basal insulin the night before any scheduled induction or C-section and hold their morning doses to be checked upon arrival.
Most gestational diabetic patients will not require an insulin drip; however, all diabetic patients will require an insulin drip during labor.
Immediately following delivery, insulin dose needs will need to be cut by 50% and the drip can slowly be titrated off.
Not only do insulin requirements decrease significantly immediately postpartum but they typically remain low for approximately 1 to 2 weeks following delivery and then begin to return to normal. The postpartum period offers another opportune time to establish an appropriate treatment regimen and to discuss the short- and long-term sequelae and management of diabetes.
POSTPARTUM MANAGEMENT OF GESTATIONAL DIABETES
For gestational diabetics, they can resume a normal healthy diet using the same caloric allotment as pregnancy if they are breastfeeding. If they are NPO (e.g. awaiting a postpartum tubal ligation), IV fluids with 5% dextrose is recommended at 100 mL/hour. However, if blood glucose levels are consistently >130 mg/dL, fluids can be switched to lactated ringers or normal saline. Diet-controlled gestational diabetic patients should get at least one fasting and one postprandial blood glucose level prior to discharge, and medication-controlled gestational diabetic patients should have fasting and 24 hours of postprandial levels taken. The goal glucose levels are fasting levels of <100 mg/dL and 1-hour postprandial levels of <140 mg/dL. If the blood glucose levels remain elevated, consider whether the patient has type 2 diabetes.114,115 In this scenario, also consider initiating metformin while the patient is breastfeeding.116,117
POSTPARTUM MANAGEMENT OF PREGESTATIONAL DIABETES
For pregestational diabetics, the insulin drip should be slowly titrated off following delivery. When the blood glucose levels are consistently <140 mg/dL, the insulin drip can be completely discontinued. Continue to monitor glucose levels closely during recovery and on admission to the postpartum unit. Patients with type 2 diabetes may use metformin, glyburide, or both at their prepregnancy dosing. If they are taking insulin, they can revert to prepregnancy insulin dosing levels or decrease their insulin to 50% of the dosing regimen that they were using prior to labor. Type 1 diabetics will initially need lower insulin doses than even before pregnancy and may not need any insulin for 24 to 48 hours following delivery. The general recommendation is to decrease their insulin dosing to 33% of the dosing regimen that they were using prior to labor. While adjusting the treatment regimen between delivery and discharge, it is recommended to check fasting, preprandial, 2-hour postprandial, bedtime, and 3 a.m. glucose levels as needed. It is further recommended to consider checking glucose levels before and after breastfeeding immediately postpartum. Goal levels include FBG levels <110 mg/dL and 2-hour postprandial levels <160 mg/dL.115,118,119
While diabetic patients are at continued risk of hypoglycemia, hyperglycemia, infection, preeclampsia, DVT, and other complications, these risks are exacerbated following a C-section. Specifically, the risk of wound complications in pregestational diabetic patients is 2.5 times higher than in nondiabetics. Thus appropriate antibiotics should be administered during a C-section, with consideration of the patient's weight during dosing.120
Postpartum diabetic patients are at greater risk of venous thromboembolism. Diabetes in itself is associated with a twofold increased risk of DVT, and postpartum infection may further increase this risk by fourfold, cesarean delivery by twofold to fivefold, and obesity by fourfold. GDM in itself has not been found to increase postpartum DVT risk; however, there was a fourfold increase in antepartum DVT.121,122 Taken together, at the very least, venous compression devices should be worn,123 and weight-based enoxaparin dosing should be considered following a C-section in obese patients.124–126
BREASTFEEDING AND DIABETES
Another postpartum complication of diabetes in pregnancy is delayed or encumbered onset of lactation following delivery, especially in those with poor glucose control.127 The benefits of breastfeeding for both mother and baby are numerous, and successfully initiating and supporting breastfeeding while in the hospital are of paramount importance. Studies have shown that both gestational and pregestational diabetics, especially insulin-dependent patients, have a higher incidence of either not initiating or rapidly discontinuing breastfeeding.128,129 Furthermore, poor blood glucose control can affect prolactin levels and ultimately breast milk production.127,130 Breastfeeding also has long-term benefits of decreasing the risk of developing type 2 diabetes in both the mother and the infant.131 Breastfeeding should be initiated within 30 minutes of life with a target of 10 to 12 feedings per 24 hours, and it is recommended for at least 6 months, and preferably for 12 months.
DISCHARGE RECOMMENDATIONS FOR GESTATIONAL DIABETES
Upon discharge, women with GDM should be screened for type 2 diabetes with a 75 g, 2-hour oral glucose tolerance test at 6 to 12 weeks postpartum. A hemoglobin A1c can also be considered after 12 weeks postpartum. If these results are normal, the recommendation is to repeat testing for 1 year following delivery, and then every 3 years thereafter. Given the conversion rates to type 2 diabetes are approximately 50% to 70%,132–135 healthy eating and 30 to 60 minutes of exercise daily are recommended. Women should be alerted to the signs and symptoms of diabetes including increased thirst, increased urinary frequency, and a higher incidence of vaginal yeast infections.
DISCHARGE RECOMMENDATIONS FOR PREGESTATIONAL DIABETES
Upon discharge, pregestational diabetic patients have different goal ranges depending upon if they are breastfeeding or not. For patients who are breastfeeding, optimal fasting and premeal targets are <110 mg/dL, and the 2-hour postmeal target is 150 to 170 mg/dL. If they are not breastfeeding, the optimal fasting and premeal targets are <120 mg/dL, and the 2-hour postmeal target is <180 mg/dL.
It is recommended that pregestational diabetics have one or more follow-up appointments with their primary care provider, dietician, or both between 2 and 6 weeks postpartum to monitor their glucose levels, titrate their regimen, and reinforce appropriate meal planning that is catered to the patient based on their breastfeeding and weight goals. Moderate exercise for 30 to 60 minutes daily is recommended. The patient's metabolic status should also be monitored by a primary care provider at 6 months postpartum with a hemoglobin A1c, lipid panel, and thyroid testing.30,114,136–138
FAMILY PLANNING CONSIDERATIONS
Pregestational and gestational diabetic patients should attempt to space future pregnancies by at least 18 to 24 months and optimize their metabolic status prior to their next pregnancy.139 Because of this goal, contraceptive management should be tailored to each individual's lifestyle and preferences, and consideration of long-acting modalities should be offered.
If patients are breastfeeding and do not desire long-acting modalities, consideration of combined hormonal contraceptives using the lowest doses can be started 6 to 8 weeks after delivery, so long as there are no contraindications to estrogen. Notably, in the Latina population of breastfeeding women, the use of progestin-only oral contraceptives and injectable depo-medroxyprogesterone acetate has been associated with a twofold to threefold increase in risk of progression to type 2 diabetes in gestational diabetic patients. Thus progestin-only agents should be used with caution during breastfeeding.45,140–143
Diet-controlled gestational diabetic patients should get at least one fasting and one postprandial blood glucose level prior to discharge, and medication-controlled gestational diabetic patients should have fasting and 24 hours of postprandial levels taken.
Type 1 diabetics will initially need lower insulin doses than even before pregnancy and may not need any insulin for 24–48 hours following delivery.
Breastfeeding should be encouraged for 6–12 months for both maternal and fetal benefits.
Gestational diabetics should be screened for type 2 diabetes at 6–12 weeks postpartum. Even if this screening test is negative, the recommendation is for repeat testing 1 year following delivery and every 3 years thereafter, given that the conversion rates to type 2 diabetes are approximately 50% to 70%.
Pregestational and gestational diabetic patients should attempt to space future pregnancies by at least 18 to 24 months; thus contraceptive counseling is an important aspect of postpartum planning.
CASE 24-1 FOLLOW-UP
The patient is diagnosed with both DKA and pyelonephritis, which likely provoked this severe disease state. Readings of ABG and serum ketones are taken. The ABG reveals a pH of 7.21 with an anion gap of 16 mEq/L, and the 3-β-hydroxybutyrate is elevated. The patient is admitted for glycemic management, fluid rehydration, electrolyte repletion, and treatment of her pyelonephritis with IV antibiotics.
Sibai BM, Viteri OA. Diabetic ketoacidosis in pregnancy. Obstet Gynecol
Bujold E, Roberge S, Lacasse Y,
et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin
started in early pregnancy: a meta-analysis. Obstet Gynecol
. 2010;116(2, Part 1):402–414.
Roberge S, Giguère Y, Villa P,
et al. Early administration of low-dose aspirin
for the prevention of severe and mild preeclampsia: a systematic review and meta-analysis. Obstet Gynecol Surv
Schisterman EF, Silver
RM, Lesher LL,
et al. Preconception low-dose aspirin
and pregnancy outcomes: results from the EAGeR randomised trial. Lancet
Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies. BMJ
, Young IS, Patterson CC,
et al. Diabetes and Pre-eclampsia Intervention Trial Study Group. Optimal glycemic control, preeclampsia, and gestational hypertension in women with type 1 diabetes in the diabetes and pre-eclampsia intervention trial. Diabet Care
Powe CE, Thadhani R. Diabetes and the kidney in pregnancy. Semin Nephrol. 2011 Jan;31(1):59–69. doi:10.1016/j.semnephrol.2010.10.006.
Simpson LL. Maternal medical disease: risk of antepartum fetal death. Semin Perinatol
Ghaji N, Boulet SL, Tepper N, Hooper WC. Trends in venous thromboembolism among pregnancy-related hospitalizations, United States, 1994–2009. Am J Obstet Gynecol. 2013;209(5):433 e1–e8.
Marik PE, Plante LA. Venous thromboembolic disease and pregnancy. N Engl J Med
Hameed AB, Lawton ES, McCain CL,
et al. Pregnancy-related cardiovascular deaths in California: Beyond peripartum cardiomyopathy. Am J Obstet Gynecol. 2015; pii: S0002-9378(15)00457-3.
Simpson LL. Maternal cardiac disease: Update for the clinician. Obstet Gynecol
Galindo A, Burguillo AG, Azriel S, Fuente Pde L. Outcome of fetuses in women with pregestational diabetes mellitus. J Perinat Med
Jovanovic L, Liang Y, Weng W,
et al. Trends in the incidence of diabetes, its clinical sequelae, and associated costs in pregnancy. Diabet Metab Res Rev. 2015; 31:707–716.
Macintosh MC, Fleming KM, Bailey JA,
et al. Perinatal mortality and congenital anomalies in babies of women with type 1 or type 2 diabetes in England, Wales, and Northern Ireland: population based study. BMJ. 2006;333(7560):177.
Allnut KJ, Allan CA, Brown J. Early pregnancy screening for identification of undiagnosed pre-existing diabetes to improve maternal and infant health (Protocol). Cochrane Database Syst Rev. 2015, 4. Art. No.: CD011601. doi:10.1002/14651858.CD011601.
Mondestin MAJ, Ananth CV, Smulian JC, Vintzileos AM. Birth weight and fetal death in the United States: the effect of maternal diabetes during pregnancy. Am J Obstet Gynecol
Reece EA, Sivan E, Francis G,
et al. Pregnancy outcomes among women with and without diabetic microvascular disease (White's classes B to FR) versus non-diabetic controls. Am J Perinatol
Modanlou HD, Komatsu G, Dorchester W,
et al. Large-for-gestational-age neonates: anthropometric reasons for shoulder dystocia. Obstet Gynecol
Wahabi HA, Esmaeil SA, Fayed A,
et al. Pre-existing diabetes mellitus and adverse pregnancy outcomes. BMC Research Notes
Lee V, Burwick R, Pilloid R,
et al. 882: Outcomes of term pregnancies complicated by gestational diabetes mellitus and polyhydramnios. Am J Obstet Gynecol. 2015;212(1):S420.
Idris N, Wong SF, Thomae M,
et al. Influence of polyhydramnios on perinatal outcome in pregestational diabetic pregnancies. Ultrasound Obstet Gynecol. 2010 Sep;36(3):338–343. doi:10.1002/uog.7676.
Gutaj P, Wender-Ozegowska E. Diagnosis and management of IUGR in pregnancy complicated by type 1 diabetes mellitus. Curr Diab Rep
Weintrob N, Karp M, Hod M. Short- and long-range complications in offspring of diabetic mothers. J Diabet Comp. 1996;10:294–301.
Yang J, Cummings EA, O’Connell C, Jangaard K. Fetal and neonatal outcomes of diabetic pregnancies. Obst Gynecol. 2006;108(3 Pt 1):644–650.
Dabelea D, Knowler WC, Pettitt DJ. Effect of diabetes in pregnancy on offspring: follow-up research in the Pima Indians. J Maternal-Fetal Med. 2000;9:83–88.
Patel S, Fraser A, Davey Smith G,
et al. Associations of gestational diabetes, existing diabetes, and glycosuria with offspring obesity and cardiometabolic outcomes. Diabet Care. 2012;35(1):63–71.
Kitzmiller JL, Block JM, Brown FM,
et al. Management of preexisting diabetes and pregnancy. Diabet Care. 2008 May;31(5):1060–1079. doi:10.2337/dc08-9020.
Crowther CA, Hiller JE, Moss JR,
et al. Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med. 2005 Jun 16;352(24):2477–2486.
Vandorsten JP, Dodson WC, Espeland MA,
et al. NIH consensus development conference: diagnosing gestational diabetes mellitus. NIH Consens State Sci State. 2013;29:1–31.
Roeckner JT, Sanchez-Ramos L, Jijon-Knupp R, Kaunitz AM. Single abnormal value on 3-hour oral glucose tolerance test during pregnancy is associated with adverse maternal and neonatal outcomes: a systematic review and metaanalysis. Am J Obstet Gynecol
Cullen MT, Reece EA, Homko CJ,
et al. The changing presentations of diabetic ketoacidosis during pregnancy. Am J Perinatol
Montoro MN, Myers VP, Mestman JH,
et al. Outcome of pregnancy in diabetic ketoacidosis. Am J Perinatol
Schneider M, Umpierrez G, Ramsey R,
et al. Pregnancy complicated by diabetic ketoacidosis: maternal and fetal outcomes. Diabet Care. 2003;26:958–959.
Drury MI, Greene AT, Stronge JM. Pregnancy complicated by clinical diabetes mellitus: a study of 600 pregnancies. Obstet Gynecol
Stenstrom G, Gottsater A, Bakhtadze E,
et al. Latent autoimmune diabetes in adults: definition, prevalence, B-cell function, and treatment. Diabetes. 2005; 54(Suppl 2):568–572.
Marcinkevage JA, Narayan KM. Gestational diabetes mellitus: taking it to heart. Primary Care Diabet. 2011;5(2):81–88.
Setji T, Brown A, Geinglos M. Gestational diabetes. Clin Diabet. 2005;23:17–24.
Guo RX, Yang LZ, Li LX, Zhao XP. Diabetic ketoacidosis in pregnancy tends to occur at lower blood glucose levels: case-control study and a case report of euglycemic diabetic ketoacidosis in pregnancy. J Obstet Gynaecol Res
Whiteman V, Homko CJ, Reece EA. Management of hypoglycemia and diabetic ketoacidosis in pregnancy. Obstet Gynecol Clin N Am. 1996;23:87–107.
Parker JA, Conwar DL. Diabetic ketoacidosis in pregnancy. Obstet Gynecol Clin N Am. 2007;34:533–543.
Rodgers BD, Rodgers DE. Clinical variables associated with diabetic ketoacidosis during pregnancy. J Reprod Med
American College of Obstetricians and Gynecologists (ACOG). ACOG Practice Bulletin No. 60: pregestational diabetes mellitus. Obstet Gynecol. 2005 Mar;105(3):675–685.
Carroll M, Yeomans ER. Diabetic ketoacidosis in pregnancy. Crit Care Med
Wing DA, Fassett MJ, Getahun D. Acute pyelonephritis in pregnancy: an 18-year retrospective analysis. Am J Obstet Gynecol
Mahler SA, Conrad SA, Wang H, Arnold TC
. Resuscitation with balanced electrolyte solution prevent hyperchloremic metabolic acidosis in patients with diabetic ketoacidosis. Am J Emerg Med
Weisz B, Shrim A, Homko CJ,
et al. One hour versus two hours postprandial glucose measurement in gestional diabetes: a prospective study. J Perinatol. 2005 Apr;25(4):241–244.
Negrato CA, Montenegro RM Jr, Von Kostrisch LM,
et al. Insulin
analogues in the treatment of diabetes in pregnancy. Arq Brasil Endocrinol Metabol
. 2012 Oct;56(7):405–414.
O’Neill SM, Kenny LC, Khashan AS,
et al. Different insulin
types and regimens for pregnant women with pre-existing diabetes (Protocol). Cochrane Database Syst Rev
. 2015, 9, CD011880. doi:10.1002/14651858.CD011880.
Hagay ZJ, Weissman A, Laurie S, Insler V. Reversal of fetal distress following intensive treatment of maternal diabetic ketoacidosis. Am J Perinatol
Nugent BW. Hyperosmolar hyperglycemic state. Emerg Med Clin N Am. 2005;23(3):629–648.
Nayak S, Lippes HA, Lee RV. Hyperglycemic hyperosmolar syndrome (HHS) during pregnancy. J Obstet Gynaecol
American Diabetes Association (ADA). (12) Management of diabetes in pregnancy. Diabet Care. 2015 Jan;38(Suppl):S77–S79. doi:10.2337/dc15-S015.
National Institute for Clinical Excellence (NICE). Diabetes in pregnancy: management of diabetes and its complications from preconception to the postnatal period. Available at https://www.nice.org.uk/guidance/ng3
. Last updated August 2015.
Mooradian AD, Bernbaum M, Albert SG. Narrative review: a rational approach to starting insulin
therapy. Ann Int Med
ter Braak EW, Woodworth JR, Bianchi R,
et al. Injection site effects on the pharmacokinetics and glucodynamics of insulin
lispro and regular insulin
. Diabet Care
Region 1 California Diabetes and Pregnancy Program Insulin
Guidelines, adapted from the American Diabetes Association. In: Jovanovic L, ed-in-chief, Medical management of pregnancy complicated by diabetes
, 3rd ed. Alexandria VA
Medical Management of Pregnancy Complicated by Diabetes by Coustan and the ADA. State of California guidelines book.
Gabbe SG, Graves CR. Management of diabetes mellitus complicating pregnancy. Obstet Gynecol. 2003 Oct;102(4):857–868.
Moghissi E. Hospital management of diabetes: beyond the sliding scale. Cleve Clin J Med. 2004 Oct;71(10):801–808.
Negrato C, Rafacho A, Negrato G,
et al. Glargine versus NPH insulin
therapy in pregnancies complicated by diabetes: an observational cohort study. Diabet Res Clin Pract
Mathiesen ER, Damm P, Jovanovic L,
et al. Basal insulin
analogues in diabetic pregnancy: a literature review and baseline results of a randomised, controlled trial in type 1 diabetes. Diabet Metab Res Rev
Pollex E, Moretti EM, Koren G, Feig DS. Safety of insulin
glargine use in pregnancy: a systematic review and meta-analysis. Ann Pharmacother
Balsells M, Corcoy R, Mauricio D,
et al. Insulin
antibody response to a short course of human insulin
therapy in women with gestational diabetes. Diabet Care
Lindsay R, Ziegler A, Hamilton B,
et al. Type 1 diabetes-related antibodies in the fetal circulation: prevalence and influence on cord insulin
and birth weight in offspring of mothers with type 1 diabetes. J Clin Endocrinol
. 2004; 89:3436–3439.
Berggren EK, Boggess KA. Oral agents for the management of gestational diabetics. Clin Obstet Gynecol. 2013 Dec;56(4):827–836. doi:10.1097/GRF.0b013e3182a8e0a5.
Jacqueminet S, Jannot-Lamotte MF. Therapeutic management of gestational diabetes. J Gynecol Obstet Biol Reprod (Paris). 2010 Dec;39(8 Suppl 2):S251–S263. doi:10.1016/S0368-2315(10)70051-X.
Coustan DR. Pharmacological management of gestational diabetes: an overview. Diabet Care. 2007;30(Suppl 2):S206–S208.
Langer O, Conway DL, Berkus MD,
et al. A comparison of glyburide
in women with gestational diabetes mellitus. N Engl J Med
. 2000 Oct 19;343(16):1134–1138.
Feig DS, Briggs GG, Koren G. Oral antidiabetic agents in pregnancy and lactation: a paradigm shift? Ann Pharmacol. 1993;24(6);1299–1309.
Hebert MF, Ma X, Naraharisetti SB,
et al. Are we optimizing gestational diabetes treatment with glyburide
? The pharmacologic basis for better clinical practice. Clinc Pharmacol Ther
Moore LE, Clokey D, Rappaport VJ, Curet LB. Metformin
compared with glyburide
in gestational diabetes: a randomized controlled trial. Obstet Gynecol
Castorino K, Paband R, Zisser H, Jovanovic L. Insulin
pumps in pregnancy: using technology to achieve normoglycemia in women with diabetes. Curr Diab Rep
. 2012;12(1):53–59. doi:10.1007/s11892-011-0242-7.
Farrar D, Tuffnell DJ, West J. Continuous subcutaneous insulin
infusion versus multiple daily injections of insulin
for pregnant women with diabetes. Cochrane Database Syst Rev
. 2007 Jul 18;(3):CD005542.
Gabbe SG, Holing E, Temple P, Brown ZA. Benefits, risks, costs, and patient satisfaction associated with insulin
pump therapy for the pregnancy complicated by type 1 diabetes mellitus. Am J Obstet Gynecol
de Veciana M, Major CA, Morgan MA,
et al. Postprandial versus preprandial blood glucose monitoring in women with gestational diabetes mellitus requiring insulin
therapy. N Engl J Med
Mathiesen ER, Christensen AB, Hellmuth E,
et al. Insulin
dose during glucocorticoid treatment for fetal lung maturation in diabetic pregnancy: test of an algorithm [correction of an algorithm]. Acta Obstet Gynecol Scand
Garcia-Patterson A, Gich I, Amini SB,
et al. Insulin
requirements throughout pregnancy in women with type 1 diabetes mellitus: three changes of direction. Diabetologia
Jovanovic L, Knopp RH, Brown Z,
et al. Declining insulin
requirement in the late first trimester of diabetic pregnancy. Diabet Care
Cryer PE, Davis SN, Shamoon H. Hypoglycemia in diabetes. Diabet Care. 2003 Jun;26(6):1902–1912.
Jovanovic L. Glucose and insulin
requirements during labor and delivery: the case for normoglycemia in pregnancies complicated by diabetes. Endocr Pract
. 2004 Mar–Apr;10(Suppl 2):40–45.
Palmer GD, Inturrisi M. Insulin
infusion therapy in the intrapartum period. J Perinat Neonatal Nurs
. 1992 Jun;6(1):25–36.
Rayburn W, Piehl E, Sanfield J, Compton A. Reversing severe hypoglycemia during pregnancy with glucagon
therapy. Am J Perinatol
. 1987 Jul;4(3):259–261.
Graves CR. Antepartum fetal surveillance and timing of delivery in the pregnancy complicated by diabetes mellitus. Clin Obstet Gynecol
Siddiqui F, James D. Fetal monitoring in type 1 diabetic pregnancies. Early Hum Dev
Klein BEK, Moss SE, Klein R. Effect of pregnancy on progression of diabetic retinopathy. Diabet Care. 1990;13(1):34–40.
Rasmussen LK, Laugesen CS, Ringholm L,
et al. Progression of diabetic retinopathy during pregnancy in women with type 2 diabetes. Diabetologia. 2010;53(6):1076–1083. doi:10.1007/s00125-010-1697-9.
Nevis IF, Reitsma A, Dominic A,
et al. Pregnancy outcomes in women with chronic kidney disease: a systematic review. Clin J Am Soc Nephrol
Walkinshaw SA. Pregnancy in women with pre-existing diabetes: management issues. Semin Fetal Neonat Med. 2005;10:307–315.
Leary J, Pettitt DJ, Jovanovic L. Gestational diabetes guidelines in HAPO world. Best Pract Res Clin Endocrinol Metab. 2010 Aug;24(4):673–685. doi:10.1016/j.beem.2010.05.009.
HAPO Study Cooperative Research Group, Metzger BE, Lowe LP,
et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008 May 8;358(19):1991–2002. doi:10.1056/NEJMoa0707943.
Gilbert WM, Nesbitt TS, Danielsen B. Associated factors in 1611 cases of brachial plexus injury. Obstet Gynecol
Palatnik A, Grobman WA, Hellendag MG,
et al. Predictors of shoulder dystocia at the time of operative vaginal delivery. Am J Obstet Gynecol. 2016 Nov;215(5):624.e1–e5. doi:10.1016/j.ajog.2016.06.001.
Nesbitt TS, Gilbert WM, Herrchen B. Shoulder dystocia and associated risk factors with macrosomic infants born in California. Am J Obstet Gynecol
Boulvain M, Stan CM, Irion O. Elective delivery in diabetic pregnant women. Cochrane Database Syst Rev. 2001;2:CD001997. doi:10.1002/14651858.CD001997.
Rosenstein MG, Cheng YW, Snowden JM,
et al. The risk of stillbirth and infant death stratified by gestational age in women with gestational diabetes. Am J Obstet Gynecol. 2012;206:309.e1–e7.
Viteri OA, Dinis J, Roman T, Sibai BM. Timing of medically indicated delivery in diabetic pregnancies: a perspective on current evidence-based recommendations. Am J Perinatol
Witkop CT, Neale D, Wilson LM,
et al. Active compared with expectant delivery management in women with gestational diabetes: a systematic review [published erratum appears in Obstet Gynecol.
2010; 115:387]. Obstet Gynecol
American Diabetes Association (ADA). Gestational diabetes mellitus. Diabet Care. 2004 Jan;27(Suppl 1):S88–S90.
American College of Obstetricians and Gynecologists (ACOG). ACOG Committee Opinion No. 560: medically indicated late-preterm and early-term deliveries. Obstet Gynecol. 2013;121(4):908–910.
Melamed N, Ray JG, Geary M,
et al. Induction of labor before 40 weeks is associated with lower rate of cesarean delivery in women with gestational diabetes mellitus. Am J Obstet Gynecol. 2016 Mar;214(3):364.e1–e8. doi:10.1016/j.ajog.2015.12.021.
American College of Obstetricians and Gynecologists (ACOG). ACOG Practice Bulletin No. 173: fetal macrosomia. Obstet Gynecol. 2016 Nov;128(5):e195–e209.
Lurie S, Insler V, Hagay ZJ. Induction of labor at 38 to 39 weeks of gestation reduces the incidence of shoulder dystocia in gestational diabetic patients class A2. Am J Perinatol
Boulvain M, Irion O, Dowswell T, Thornton JG. Induction of labour at or near term for suspected fetal macrosomia. Cochrane Database Syst Rev. 2016;5:CD000938. doi:10.1002/14651858.CD000938.pub2.
Elkousy MA, Sammei M, Stevens E,
et al. The effect of birth weight on vaginal birth after cesarean delivery success rates. Am J Obstet Gynecol
Miller RS, Devine PC, Johnson EB. Sonographic fetal asymmetry predicts shoulder dystocia. J Ultrasound Med
. 2007; 26:1523–1528.
Balsells M, Corcoy R, Adelantado JM,
et al. Gestational diabetes mellitus: metabolic control during labour. Diabet Nutr Metab. 2000 Oct;13(5):257–262.
Grylack LJ, Chu SS, Scanlon JW. Use of intravenous fluids before cesarean section: effects on perinatal glucose, insulin
, and sodium homeostasis. Obstet Gynecol
Gabbe SG, Carpenter LB, Garrison EA. New strategies for glucose control in patients with type 1 and type 2 diabetes in pregnancy. Clin Obstet Gynecol. 2007 Dec;50(4):1014–1024.
de Valk HW, Visser GH. Insulin
during pregnancy labor and delivery. Best Pract Res Clin Obstet Gynaecol
. 2011 Feb;25(1):65–76. doi:10.1016/j.bpobgyn.2010.10.002.
Kitzmiller JL, Dang-Kilduff L, Taslimi MM. Gestational diabetes after delivery. Diabet Care. 2007 Jul;30(Suppl 2):S225–S235. doi:10.2337/dc07–s221.
Kjos SL. After pregnancy complicated by diabetes: postpartum care and education. Obstet Gynecol Clin N Am. 2007 Jun;34(2):335–349, x.
Briggs GG, Ambrose PJ, Nageotte MP,
et al. Excretion of metformin
into breast milk and the effect on nursing infants. Obstet Gynecol
. 2005 Jun;105(6):1437–1441.
Glatstein MM, Djokanovic N, Garcia-Bounissen F,
et al. Use of hypoglycemic drugs during lactation. Can Fam Physic. 2009 Apr;55(4):371–373.
Castorino K, Jovanovic L. Pregnancy and diabetes management: advances and controversies. Clin Chem. 2011 Feb;57(2):221–230. doi:10.1373/clinchem.2010.155382.
Trujillo A. Insulin
treatment in pregnancy. Drug Dev Res
, Weitzen S, Slocum J, Malee M. Risk of cesarean wound complications in diabetic gestations. Am J Obstet Gynecol
Jacobsen AF, Skjeldestad FE, Sandset PM. Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium—a register-based case-control study. Am J Obstet Gynecol. 2008 Feb;198(2):233.e1–e7.
James AH, Jamison MG, Brancazio LR, Myers ER. Venous thromboembolism during pregnancy and the postpartum period: incidence, risk factors, and mortality. Am J Obstet Gynecol. 2006 May;194(5):1311–1315.
American College of Obstetricians and Gynecologists (ACOG). ACOG Practice Bulletin No. 84: prevention of deep vein thrombosis and pulmonary embolism. Obstet Gynecol. 2007;110(2 Pt 1):429–440.
Morgan ES, Wilson E, Watkins T,
et al. Maternal obesity and venous thromboembolism. Int J Obstet Anesth. 2012 Jul;21(3):253–263. doi:10.1016/j.ijoa.2012.01.002.
Stephenson ML, Serra AE, Neeper JM,
et al. A randomized controlled trial of differing doses of postcesarean enoxaparin
thromboprophylaxis in obese women. J Perinatol
. 2016 Feb;36(2):95–99. doi:10.1038/jp.2015.130.
Overcash RT, Somers AT, LaCoursiere DY. Enoxaparin
dosing after cesarean delivery in morbidly obese women. Obstet Gynecol
. 2015 Jun;125(6):1371–1376. doi:10.1097/AOG.0000000000000873.
Neubauer SH, Ferris AM, Chase CG,
et al. Delayed lactogenesis in women with insulin-dependent diabetes mellitus. Am J Clin Nutr
Hummel S, Winkler C, Schoen S,
et al. Breastfeeding habits in families with type I diabetes. Diabet Med
Finkelstein SA, Keely E, Feig DS,
et al. Breastfeeding in women with diabetes: lower rates despite greater rewards. A population-based study. Diabet Med
Ostrom KM, Ferris AM. Prolactin concentrations in serum milk and milk of mothers with and without insulin
dependent diabetes mellitus. Am J Clin Nutr
Gunderson EP. Breastfeeding after gestational diabetes pregnancy: subsequent obesity and type 2 diabetes in women and their offspring. Diabet Care. 2007 Jul;30(Suppl 2):S161–S168.
Kim C, Newton KM, Knopp RH. Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabet Care. 2002 Oct;25(10):1862–1868.
England LG, Dietz PM, Njoroge T,
et al. Preventing type 2 diabetes: public health implications for women with a history of gestational diabetes mellitus. Am J Obstet Gynecol. 2009;200:365.e1–e8.
Kjos SL, Petter RK, Xiang A,
et al. Predicting future diabetes in Latino women with gestational diabetes. Utility of early postpartum glucose tolerance testing. Diabetes
American Diabetes Association (ADA). Standards of medical care in diabetes—2011. Diabet Care. 2011 Jan;34(Suppl 1):S11–S61. doi:10.2337/dc11-S011.
Handelsman Y, Mechanick JI, Blonde L,
et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan. Endocr Pract. 2011 Mar–Apr;17(Suppl 2):1–53.
Kim C, Tabaei BP, Burke R,
et al. Missed opportunities for type 2 diabetes mellitus screening among women with a history of gestational diabetes mellitus. Am J Pub Health. 2006;96(9):1643–1648. doi:10.2105/AJPH.2005.065722.
Bennett WL, Ennen CS, Carrese JA,
et al. Barriers to and facilitators of postpartum follow-up care in women with recent gestational diabetes mellitus: a qualitative study. J Women's Health. 2011;20(2):239–245. doi:10.1089/jwh.2010.2233.
Metzger BE, Buchanan TA, Coustan DR,
et al. Summary and recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabet Care. 2007 Jul;30(Suppl 2):S251–S260. doi:10.2337/dc07-s225.
Kjos SL, Peters RK, Xiang A,
et al. Contraception and the risk of type 2 diabetes mellitus in Latina women with prior gestational diabetes mellitus. JAMA[JAMA and JAMA Network Journals Full Text]
. 1998 Aug 12;280(6):533–538.
Xiang AH, Kawakubo M, Kjos SL, Buchanan TA. Long-acting injectable progestin contraception and risk of type 2 diabetes in Latino women with prior gestational diabetes mellitus. Diabet Care. 2006 Mar;29(3):613–617.
Kiley JW, Hammond C, Niznik C,
et al. Postpartum glucose tolerance in women with gestational diabetes using levonorgestrel
intrauterine contraception. Contraception
. 2015 Jan;91(1):67–70. doi:10.1016/j.contraception.2014.08.004.
ACOG Practice Bulletin No. 190 Summary: Gestational Diabetes Mellitus Obstetrics & Gynecology:. HYPERLINK “/greenjournal/toc/2018/02000” February 2018;131(2):406–408. doi:10.1097/AOG.0000000000002498.
O’Sullivan JB, Mahan CM. Criteria for the oral glucose tolerance test in pregnancy. Diabetes
Carpenter MW, Coustan DR. Criteria for screening tests for gestational diabetes. Am J Obstet Gynecol