US Pharm. 2006;31(11)(Diabetes suppl):31-36.
About
4% of pregnant patients in the United States have diabetes mellitus (DM),
making it the most common medical complication of pregnancy. Most pregnant
patients with diabetes have gestational diabetes mellitus (GDM), with glucose
intolerance developing during pregnancy. The remaining patients have been
diagnosed with DM prior to pregnancy (pregestational DM). In pregestational
DM, type 2 DM is twice as common as type 1 DM.1
Prior to the introduction of
insulin therapy, pregnant women with DM and their babies had higher rates of
morbidity and mortality. Although these outcomes have greatly improved over
the last 80 years, diabetes in pregnancy is still associated with increased
complications, especially when glycemic control is poor. Fortunately, with
optimal glycemic control and obstetrical management of the pregnant patient
with DM, outcomes comparable to those in the general population are possible.
This article introduces the pharmacist to the basic pathophysiology of
diabetes during pregnancy, discusses gestational and pregestational DM and its
management, and reviews some important counseling points to educate pregnant
patients with DM and achieve favorable outcomes.
Pathophysiology of Diabetic Pregnancy
During an
uncomplicated pregnancy, significant changes in hormonal regulation of
carbohydrate, protein, and lipid metabolism occur. Because maternal and fetal
nutritional demands increase during late gestation and lactation, adequate
nutritional stores must be present during early gestation. Normal pregnancy
has been described as a diabetogenic state because of the progressive
increase in postprandial glucose levels and insulin response during late
gestation.2 When complicated by diabetes, pregnancy becomes an even
more complex disarray of metabolic changes, as reduced insulin activity leads
to a metabolically abnormal environment.3
Pregnancy complicated by
diabetes increases not only the complexity of management required to produce
normoglycemia but also the risk of complications. Early complications
associated with hyperglycemia include spontaneous abortion, preterm delivery,
and congenital malformations, while late complications, including macrosomia,
the need for cesarean delivery, and preeclampsia, are also more common.
Additionally, microvascular and macrovascular complications can all affect and
be affected by pregnancy. Fetal prognosis and risk factors for fetal
compromise can be determined using the White classification, which is based
upon the mother's age at onset and duration of diabetes and the presence of
vasculopathy.4,5
While it is important for
pregnant patients with pregestational type 1 DM to have good glycemic control
during early pregnancy to minimize adverse outcomes, tight glycemic control
increases the risk for complications associated with hypoglycemia. Although
changes in insulin sensitivity in diabetic and nondiabetic women are often not
significant until later in gestation, various factors can increase
hypoglycemic risk early in gestation in women with diabetes. In fact, in early
pregnancy, women who are insulin dependent often require a decrease in their
insulin dosage. Other factors thought to put women with DM at risk for
complications are decreased food intake secondary to nausea, the fetus acting
as a glucose sink, and increased insulin sensitivity.6 A decreased
counterregulatory response to hypoglycemia by epinephrine and glucagon may
also have a role.7,8 Conversely, the risk for ketoacidosis is
increased in pregnant patients with type 1 DM because of their dependence on
exogenous insulin and the subtle changes in glucose metabolism and insulin
sensitivity that can occur.
Pregnant patients with type 2
DM and those who develop GDM share similar metabolic characteristics.
Abnormalities in glucose metabolism, including defects in response to insulin
secretion and decreased insulin sensitivity, as well as increased hepatic
glucose production, are all major components of the disease pathophysiology.
2 Despite the physiologic similarities of pregestational type 2 DM and
GDM, the outcomes in patients with GDM are often better than in those with
type 2 DM.4,5 Because GDM develops later in pregnancy, women with
the disease are less likely to have infants with congenital anomalies and
their risk of microvascular or macrovascular complications during pregnancy is
decreased. Regardless, patients who develop GDM are more likely to have
macrosomic fetuses and are at higher risk of preeclampsia than are patients
without DM. After pregnancy, both the mother and infant have an increased risk
of type 2 DM.9,10
Management of Pregestational DM
Nonpharmacologic
management, particularly monitoring and lifestyle modifications, is essential
in managing all types of DM. In the nonpregnant patient, type 1 DM is managed
primarily with insulin therapy, while type 2 DM is managed with oral
antihyperglycemic agents and/or insulin. In the pregnant patient with DM,
insulin is still preferred for those with type 1 DM and in those with type 2
DM that is not controlled through diet. Oral agents are sometimes used in
those who are not insulin dependent, but their use is limited because of
uncertainty regarding their safety and efficacy in pregnant patients.
Nonpharmacologic Management
Monitoring:
During pregnancy, glucose concentration and hemoglobin A1c (HbA1c) values are
lower than those of nonpregnant women; both fall by approximately 20% in
nondiabetic pregnant patients. Thus, striving for blood glucose values and
HbA1c levels at--or even below--the normal range for nonpregnant individuals is
recommended. 11 Exceptionally strict glycemic control (average
glucose values <86 mg/dL) is not recommended and should be avoided due to
adverse maternal outcomes.12 Blood glucose values recommended
for women with pregestational DM by the American College of Obstetricians and
Gynecologists (ACOG) and the American Diabetes Association (ADA) are shown in
Table 1.13,14
Frequent monitoring of blood
glucose (i.e., before and after meals and at bedtime) during pregnancy is
advised for patients with type 1 or type 2 DM to help prevent and/or treat
hypoglycemia and hyperglycemia. As pregnancy may also exaggerate rebound from
hypoglycemia, elevated morning blood glucose values may indicate nocturnal
hypoglycemia and warrant occasional nighttime blood glucose monitoring.
15,16
HbA1c values can help
determine chronic glycemic control. In nonpregnant patients, HbA1c values
depict control over the eight to 12 weeks prior to testing. In pregnant women
with pregestational DM, monitoring HbA1c is recommended every four to six
weeks, as pregnancy shortens the life span of red blood cells. Some studies
have shown that an HbA1c value of 7% or lower may not sufficiently reduce the
risk of complications in pregnant patients; therefore, a target value less
than 6%, along with close monitoring for hypoglycemia, is recommended.14
In pregnant patients with type
1 DM, urine ketones should be monitored during illness or when blood glucose
values are greater than 180 mg/dL. In both situations, there is a greater risk
of ketoacidosis, which is associated with worsened fetal outcomes.17
Nutritional Therapy and
Other Lifestyle Modifications:
Diet therapy can help the pregnant diabetic patient achieve glycemic control,
manage weight gain, and prevent adverse pregnancy outcomes, although it is not
sufficient treatment for most patients with pregestational DM. During
pregnancy, caloric requirements are approximately 300 kcal higher than basal
daily needs in nonpregnant women. Recommendations are based upon ideal body
weight and body mass index (BMI) (Table 2).13 Restricting
carbohydrates to 35% to 40% of calories is important to control postprandial
blood glucose. Complex carbohydrates are preferred over simple sugars because
they are more nutrient dense and cause less of an increase in postprandial
blood glucose.18 Daily folate and iron supplementation or a
prenatal vitamin is also recommended. Avoiding excessive weight gain and
performing moderate low-impact exercise can also improve glycemic control,
especially in pregnant patients with type 2 DM who have no contraindications (
Table 3). Patients with type 1 DM and those who are deconditioned or who
did not exercise before pregnancy should exercise more judiciously.19
Pharmacologic Management
Intensive insulin
therapy is usually considered the best method for achieving desirable glycemic
control. Some women with type 2 DM may achieve good glycemic control with diet
alone; however, those who do not, and those who took oral antihyperglycemic
agents prior to pregnancy should be treated with insulin during pregnancy.
Insulin requirements are similar in patients with type 1 or type 2 DM during
the first trimester, but as the pregnancy progresses to the third trimester,
insulin needs become proportionately greater in women with type 2 DM than in
those with type 1 DM.20
Antigenicity of insulin
preparations should be carefully considered in order to minimize the
transplacental transport of insulin antibodies. Human insulin is the least
immunogenic and is the preferred commercially available preparation. Human
regular insulin has been the most widely studied in pregnancy and is used as
the benchmark for insulin safety and efficacy in pregnant women. Of the
rapid-acting insulin analogs (i.e., lispro, aspart, glulisine), only lispro
and aspart have been studied in pregnancy and are considered safe with no
evidence of teratogenicity. Both have immunogenicity similar to that of human
regular insulin and may be advantageous in providing tight glycemic control
and lowering the risk of delayed postprandial hypoglycemia.21
The longer-acting insulin
analogs (i.e., glargine, detemir) have not been widely used or extensively
studied during pregnancy. Human recombinant insulin (isophane insulin or
neutral protamine Hagedorn [NPH]) is the preferred basal insulin, and
women taking glargine prior to pregnancy should be switched to NPH because of
concerns about the mitogenic potency of glargine. A comparison of various
insulin preparations is found in Table 4.21,22
Oral antihyperglycemic agents
are commonly used in the management of type 2 DM. However, there are several
issues that confound the use of these agents during pregnancy. While some
agents, such as glyburide and metformin, may be safe and effective
alternatives to insulin therapy, as some studies suggest, these drugs are not
FDA approved for use in pregnancy. Drugs which cross the placenta and can
cause fetal hyperinsulinemia (e.g., tolbutamide, chlorpropamide) can cause
macrosomia and prolonged neonatal hypoglycemia and should be avoided. Few or
no data are available for other oral antihyperglycemic agents.23,24
The ADA and ACOG both recommend insulin over other agents for glycemic control
in pregnant women with type 1 or type 2 DM.13,14
Intrapartum and Postpartum Management
The type of delivery, either
spontaneous or induced, as well as vaginal or cesarean, will determine the
proper recommendations for maintaining glycemic control and preventing
hypoglycemia. In general, insulin requirements usually decrease during
delivery and in the postpartum period. Because maternal hyperglycemia is the
major cause of neonatal hypoglycemia, maintenance of maternal euglycemia
during the peripartum period is crucial.25 Management of glycemic
control is more erratic in lactating diabetic women, and episodes of
hypoglycemia may be more frequent in this population. Breast-feeding may also
influence which oral antihyperglycemic agents are used in women with type 2 DM.
26
Management of GDM
To reduce the risk of maternal and fetal morbidity, especially macrosomia and related complications such as shoulder dystocia, health care providers should be vigilant about identifying women with GDM. Determining which patients to screen is controversial; some authorities suggest universal screening, while others recommend against screening patients with a low risk of GDM. Regardless, women who test positive during initial screening should undergo a three-hour oral glucose tolerance test (GTT) with a 100-g glucose load for a definitive diagnosis (Table 5 ).26,27 As with pregestational DM, both nonpharmacologic and pharmacologic management are essential to achieve optimal outcomes.
Nonpharmacologic Management
Monitoring:
Because glycemic control in patients with GDM is often managed through diet,
monitoring serves a slightly different purpose than in those with
pregestational DM. Monitoring of fasting and one-hour postprandial blood
glucose is performed to determine the degree of hyperglycemia in order to
assess fetal risk and helps determine whether and when insulin should be
initiated (Table 6).26,28 Once insulin therapy has been
initiated, more frequent monitoring may be required to help prevent
hypoglycemic complications and to guide therapy as the pregnancy progresses.
In patients with GDM, monitoring of HbA1c may be helpful as an ancillary test
to confirm that blood glucose monitoring is accurately reflecting maternal
glycemic control but has less of a role than it does in pregnant patients with
pregestational DM.
Nutritional Therapy and
Other Lifestyle Modifications:
Nutritional counseling by a registered dietitian is recommended for all
patients with GDM. Calorie allotment and carbohydrate-intake limits for
patients with GDM are similar to those of women with pregestational DM.
13,18
Exercise appears to improve
glycemic control by increasing tissue sensitivity to insulin. Women with GDM
who participate in cardiovascular exercise may have reduced fasting and
postprandial blood glucose concentrations. In some women, the initiation of
insulin may be delayed or obviated completely. The ADA encourages women with
GDM who have no contraindications to participate in moderate exercise as part
of their treatment plan.26
Pharmacologic Management
Insulin is the only
treatment recommended in the U.S. for maintaining normoglycemia in patients
with GDM who do not achieve adequate blood glucose control through medical
nutritional therapy. Approximately 15% of women with GDM require insulin
therapy. This figure includes women who have difficulty maintaining
normoglycemia and those at high risk of delivering a macrosomic infant, as
verified by ultrasound.26,29
The dose of insulin is patient
specific and varies according to degree of obesity, ethnic characteristics,
and diet. Most studies report that a total insulin dose ranging from 50 to 90
units/day is required to achieve adequate glucose control.
While oral antihyperglycemic
agents are not approved by the FDA for use during pregnancy, data are becoming
more widely available on using certain agents for managing GDM. A study of
glyburide therapy in 404 women with mild GDM who were randomized to receive
either glyburide or insulin showed similar mean blood glucose concentrations
during treatment with no differences in the frequency of macrosomia.30
A large study is underway in Australia evaluating the safety and efficacy of
metformin in GDM. Until more data on outcomes and the long-term effects on
offspring are available, use of glyburide or metformin is not recommended.
Intrapartum and Postpartum Management
As with pregestational DM, avoiding
maternal hyperglycemia is important to reduce the risk of neonatal
hypoglycemia. For patients with GDM who use insulin, insulin can usually be
withheld during delivery, and an infusion of normal saline is often sufficient
to maintain euglycemia.31 Blood glucose should be measured on the
day after delivery to ensure that the mother is no longer hyperglycemic. A
regular diet can usually be resumed after delivery. It is often beneficial for
women who experienced GDM to periodically check their blood glucose at home
and report any high values to their physician. Although most women with GDM
return to normoglycemia after delivery, their risk for overt DM, impaired
glucose tolerance, and recurrent GDM is higher than in those with unaffected
pregnancies.32
Education--Pharmacist's
Role:Preconception
counseling is one of the first steps in increasing the likelihood of a healthy
pregnancy, especially for patients with type 1 or type 2 DM.14
Glycemic control should be carefully evaluated, and adjustments in diet,
lifestyle, and medications should be made to achieve euglycemia even before a
woman becomes pregnant. Identifying a history of acute and chronic
complications of DM is also important and allows for proper monitoring and
management during pregnancy. Information on fetal and maternal complications
should be discussed with the patient, highlighting risks applicable to the
patient and her fetus.
Pharmacists need to counsel
women who take medications to prevent or treat microvascular and macrovascular
complications of DM on whether the medications are safe during pregnancy.
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers for
cardiovascular and renal protection and blood pressure control are
contraindicated during pregnancy; methyldopa or a long-acting calcium channel
blocker may be a safer alternative. Potent LDL cholesterol–lowering therapy,
such as statins, is also contraindicated during pregnancy.
Pharmacists are well
positioned to make recommendations regarding therapy for a patient's glycemic
control and to help manage complications associated with a diabetic pregnancy.
With proper education and appropriate management of a pregnant woman's DM,
excellent outcomes for both the woman and her baby can be achieved.
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