Gestational Diabetes During and After Pregnancy

19. Pharmacological Treatment Options for Gestational Diabetes

Oded Langer 


Department of Obstetrics and Gynecology, St Luke’s-Roosevelt Hospital Center, University Hospital of Columbia University, New York, NY, USA

Oded Langer



The treatment goal for pregnant and non-pregnant diabetic patients is to optimize the glycemic profile. Intensified therapy, in comparison to the conventional approach, can improve perinatal outcomes. Data from non-diabetic pregnant women suggest that current targets for glucose management for pregnant women with glucose abnormalities do not approximate glucose fluctuations in healthy pregnancies. There is a lack of consensus on the medications used to achieve these targets as well. One means of assessing the viability of a pharmacologic strategy can be the rate of study participants who achieved the targeted level of glycemia.

19.1 Introduction

Gestational diabetes mellitus, or GDM, is defined as carbohydrate intolerance first diagnosed during pregnancy.1 In the United States, approximately 135–200,000 women annually develop GDM; this is in addition to those pregnant women already afflicted with either type 1 or type 2 diabetes.2 There has been a significant increase (approaching 33%) in the incidence of type 2 diabetes with its recognized parallel risk for obesity3 as well as the insidious rise of adolescent obesity in the offspring of diabetic women.4

Maternal hyperglycemia and the resultant fetal hyperinsulinemia are central to the pathophysiology of diabetic complications of pregnancy. These complications include congenital malformations, an increase in neonatal intensive care unit admission, and birth trauma. In addition, there is an increased rate of accelerated fetal growth, neonatal metabolic complications, and risk of stillbirth.56

The definition of GDM is problematic, since several million type 2 diabetic women are not diagnosed until pregnancy.1 These women are usually classified as having GDM; thus, GDM actually represents a mixture of women with abnormal carbohydrate tolerance test results in pregnancy and those with previously undiagnosed type 2 diabetes. The prevalence of GDM varies in direct proportion to the prevalence of type 2 diabetes in a given population, ethnic group, or geographic area. As a result, studies report varying rates of population prevalence and complications. In the US, reported prevalence rates range from 1 to 14%.7 The similarities between type 2 diabetes and GDM as to risk factors, metabolic abnormalities, and endocrine abnormalities provide the rationale for proposing that GDM is an “early” type 2 diabetes and thus represents the same disease with a different name.

Type 2 diabetes and GDM are heterogeneous disorders whose pathophysiology is characterized by peripheral insulin resistance, impaired regulation of hepatic glucose production, and declining β-cell function. The primary events in both are deficits in insulin secretion, followed by peripheral insulin resistance. Glucose intolerance follows β-cell dysfunction (impairment in the first phase of insulin secretion). In the second phase, the release of newly synthesized insulin is impaired. When tight glycemic control is achieved, there may follow a reversal of the effects of glucose toxicity that produce the intrapancreatic (desensitization of β-cells) or extra-pancreatic effect.811

It has become self-evident that the treatment goal for pregnant and nonpregnant diabetic patients is to optimize the glycemic profile. This is customarily performed in the pregnant diabetic woman with the trial of diet therapy and the addition of pharmacological therapy (insulin or oral antidiabetic drugs such as glyburide) when glycemic control cannot be achieved by diet alone. Therefore, investigators have chosen blood glucose control as the primary outcome variable when comparing drugs designed to reduce levels of glycemia.1215

In this chapter, I briefly discuss the pathophysiology of GDM and diabetes and how these relate to the therapies for GDM. I briefly review medical nutrition therapy and physical activity, followed by a more detailed review of pharmacologic therapies. Particular attention is paid to the sulfonylureas or oral agents, specifically regarding safety during and after pregnancy for mothers and offspring, effectiveness for glycemic control, and cost.

19.2 Pathophysiology

Autoimmunity is a major component of the pathophysiology of insulin-dependent diabetes mellitus (type 1) characterized by β-cell destruction. The autoimmune systems responsible for β-cell demise are actively functioning prior to the appearance of clinical diabetes. Markers for this deterioration are islet-cell and insulin autoantibodies, antibodies to glutamic acid decarboxylase, and other β-cell antigens. Viruses, dietary factors, and exposure to chemicals have also been implicated in the development of type 1 diabetes.

The pathophysiology of type 2 diabetes is characterized by increased hepatic glucose production, abnormal insulin secretion, and increased insulin resistance, all contributors to hyperglycemia. The increase in hepatic glucose production is a secondary phenomenon related mainly to the decrease in insulin action and increased glucagon secretion. During normal pregnancy, the marked reduction of insulin sensitivity could be compensated by a reciprocal increase in β-cell secretion. Therefore, pregnancy may be characterized as a state of hyperinsulinemia and insulin resistance as a response to the diabetogenic effects on normal carbohydrate metabolism.

Women who develop GDM have a higher insulin resistance prior to conception, often in association with obesity. Insulin resistance results in decreased glucose uptake in skeletal muscles, white adipose tissue, and the liver, as well as suppression of hepatic glucose production. The β-cell adaptation to insulin resistance is impaired in GDM women and may be a universal response to the insulin resistance, since it is found in many ethnic groups. Women with a history of GDM have an increased risk of developing type 2 diabetes later in life. The reported risk ranges from 6.8 to 92% when the results of an impaired glucose tolerance (IGT) test are combined with overt diabetes, and is 3–50% for overt diabetes alone.16 Furthermore, there is a 2–4 fold (27–38%) increased rate of metabolic syndrome in women with previous GDM. This rate is even higher in previous obese GDM (tenfold) and GDM-treated with diet (sevenfold).1721

19.3 The Rationale and Fundamental Structure of Intensified Therapy

Intensified therapy is an approach to achieving established levels of glycemic control. It incorporates memory-based self-monitoring blood glucose, multiple injections of insulin or its equivalent, diet, and an interdisciplinary team effort. These integrally related components often make the difference between success and failure in diabetes management. We demonstrated in a large prospective study that intensified therapy, in comparison to the conventional approach, resulted not only in improved perinatal outcome, regardless of ethnic origin, with similar compliance for diet and insulin therapies.2123

Diabetes-related complications can be decreased for both pregnant and nonpregnant patients with intensified therapy that results in improved glycemic control.1524 However, there is a paucity of data addressing the glucose profile in nondiabetic pregnancies. Recently, two studies of nondiabetic pregnant women addressed the characteristics of normoglycemia in day-to-day settings during the third trimester. One study using self-monitoring blood glucose25 reported a gradual increase in mean blood glucose in the third trimester. Our study25 used a system that measured continuous blood glucose in obese and nonobese nondiabetic women. These studies imply that currently recommended clinical thresholds may be associated with improved pregnancy outcome, but they are not the equivalent of the biological norm in the nondiabetic pregnant state. For example, a threshold of <140 mg/dL postprandial and/or 120 mg/dL preprandial was reported to be associated with a decreased rate of anomalies, while a mean blood glucose of <100–110 mg/dL was linked to decreased rates of large-for-gestational-age infants (LGA) or macrosomia.2628 Therefore, different thresholds of glycemia are required to minimize specific complications in the pregnant diabetic patient.

Regardless of the treatment modality used, the goal is always to achieve the established level of glycemic control that will diminish the rate of hypoglycemia and ketosis and maximize perinatal outcome. Although there is ample evidence that there is an association between diabetes control and the occurrence of maternal/fetal complications, this association does not prove cause and effect. It does, however, provide the rationale to attempt to control the glucose levels.

19.4 Diet and Exercise: Ancillary Modalities for Glucose Control

For all types of diabetes, the underlying foundation of treatment is diet. The essential principle of nutritional therapy is to achieve and maintain the maternal blood glucose profile comparable to that of the nondiabetic woman. Two current approaches are recommended: (1) decrease the proportion of carbohydrates to 40–50% in a daily regimen of 3 meals and 3–4 snacks and, (2) use of lower glycemic index carbohydrates for approximately 60% of daily intake. The assignment of daily caloric intake is similar for gestational and pregestational diabetes and is calculated based on pre-pregnancy body mass index (BMI).29

The second component of a diabetes treatment protocol is exercise. In isolation, it is not a cure for diabetes, however, exercise acts to improve insulin sensitivity and glucose tolerance. I believe that a tempered exercise program, when pregnant diabetic women are not only willing but also able (socio-economic limitations, obesity, multi-parity) to participate may improve postprandial blood glucose levels and insulin sensitivity.3031 Hypoglycemic reactions during and after exercise may be positive markers of improved insulin sensitivity. Low blood glucose necessitates adjustment of the insulin dose and carbohydrate intake. Extra monitoring is warranted after evening exercise, as glucose uptake increases for several hours after exercise and can cause nocturnal hypoglycemia.

19.5 Alternative Routes in Pharmacological Therapy

When diet therapy fails to achieve established levels of glycemic control, insulin and oral hypoglycemic and antihyperglycemic agents are the validated alternatives to treatment. When pharmacological therapy is a consideration for management, several questions need to be addressed. Who should receive it? How long should a patient remain on diet therapy before the introduction of pharmacological treatment? What is the required dose in order to achieve the established level of glycemic control?

19.6 Insulin Therapy

In GDM, opinions of authoritative bodies differ regarding the threshold of fasting plasma glucose for the initiation of pharmacological therapy (glyburide, metformin or insulin). Furthermore, the amount of insulin required to achieve targeted levels of glycemic control is still debated. This debate is, in part, due to study subjects’ differing ethnicities, as well as their rates of obesity (Table 19.1). Regardless of these confounding factors, the ultimate measure should always be the rate of study participants who achieved the targeted level of glycemia.

Table 19.1

Studies reporting the use of oral hypoglycemic and antihyperglycemic agents in pregnancy; success of therapy


Number of patients



Type of patients


Reg. insulin



Achievement of good control

Langer et al14






82 and 88%

Conway et al62 100

Prospective observational





Kremer and Duff 52

Prospective observational





Chmait et al65

Prospective observational





Gilson and Murphy66

Prospective observational






Fines et al67

Retrospective case–control






Glueck et al (2002)74

Prospective observational





Prospective and retrospective observational





39 without metformin


Hellmuth et al (2001)63

Prospective observational





68 sulfonylurea




GDM and Type-2 diabetes




tolbutamide, chlorpropramide

80% using oral hypoglycemic and 36% using insulin

Yogev et al77






27 diet-treated

Mean blood glucose similar in all groups

We evaluated 57 GDM women with normal OGTT postpartum and found a biphasic increase in insulin requirements. The first phase was characterized by a significant weekly increase up to the 30th week of gestation; from 31 to 39 weeks the insulin dose remained unchanged. Insulin requirements for obese patients were 0.9 units/kg and for nonobese subjects 0.8 units/kg. There was a significant difference in variability as measured by the coefficient of variation (45 vs. 25%, p < 0.01), respectively. These findings suggest that GDM women need weekly visits during the 20th–30th weeks of gestation for insulin adjustment. Moreover, the total insulin dose required to reach the established level of glycemic control for the majority of patients ranges from 40 to 90 units (body-weight dependent).32

Another question frequently confronted by clinicians is which form of insulin should be recommended for the pregnant diabetic patient. Human insulin became widely available in the 1980s when the preferred method of production was recombinant DNA technology. This led to the availability of mutant insulin (insulin analogs) during the mid-1990s that were designed primarily to have improved pharmacokinetic features for subcutaneous administration. In pregnancy, however, human insulin is recommended since the use of insulin analogs has not been adequately tested in GDM.

There is little or no difference between insulin lispro, insulin aspart, and human insulin in receptor binding, metabolic, and mitogenic potency with a slight increased binding of insulin lispro to the receptor for IGF-1.3336Mounting evidence of the beneficial effects of insulin lispro in type 1 and type 2 nonpregnant diabetic subjects include decreased frequency of severe hypoglycemic episodes, limited postprandial glucose excursions, and a possible decrease in glycosylated hemoglobin when the drug is administered by continuous subcutaneous infusion. In addition, insulin lispro provides greater convenience in the timing of administration (analogs administered up to 15 min after start of a meal compared to soluble insulin taken 30 min before the meal).3336

In pregnancy, data on insulin lispro are limited and abstracted from studies with relatively small sample sizes. Most of these reports demonstrated an improvement in glycemic control, an increase in patient satisfaction, a decrease in hypoglycemic episodes, but no data on maternal and neonatal outcome. This omission limits the ability to draw any firm conclusions about the efficacy of insulin lispro in comparison to human insulin in pregnancy.

19.7 Oral Antidiabetic Drugs in GDM Treatment

Oral hypoglycemic and antihyperglycemic agents are successfully used in the treatment of nonpregnant type 2 diabetes. Each may be used alone or in combination with other oral agents or insulin. Oral antidiabetic agents are convenient to use, less invasive than insulin, and relatively less expensive. Therefore, they can become the drug of choice when dietary modifications fail to reduce hyperglycemia. Oral antidiabetic agents are used in the United States especially to provide type 2 diabetes patients with support in maintaining the tight glucose control that lowers their risk for microvascular complications. Both the United Kingdom Prospective Diabetes Study (UKPDS) and the Diabetes Control and Complications Trial (DCCT) studies2337 strongly support the use of intensive therapy in patients with type 1 and type 2 diabetes to achieve and maintain near-normal HbA1c levels and to prevent diabetic complications.

Recently, opinions have shifted towards the use of these drugs during pregnancy. In fact, the use of glyburide has replaced insulin as first-line drug treatment of GDM in many obstetric practices.3538 In addition, many experts and authoritative bodies in the United States have recommended the use of glyburide (sulfonylurea) as an alternative pharmacological therapy to insulin in pregnancy.36,3942 Others, however, have recommend further evaluation.4345

The rationale is significantly lower in glyburide vs. insulin-treated by three main factors:




The UKPDS,23 the largest prospective study evaluating the impact of oral antidiabetic agents on the outcome of type 2 diabetes, demonstrated that in 70% of patients a desirable level of glucose control was achieved with the use of sulfonylurea-glyburide. The most favorable effect was obtained within the first 5 years of the disease (70% of the patients treated with glyburide achieved the desired goal). In years 3, 6, and 9, the desired goals were achieved by fewer than 55, 40, and 30% of patients, respectively, using a single agent (insulin, sulfonylurea, or metformin). With greater deterioration in β-cell function, multiple therapies will eventually be needed in the majority of patients to achieve glycemic target levels.

The study also demonstrated a 25% reduction of risk, primarily attributed to microvascular complications, and a trend toward fewer macrovascular complications after intensive therapy vs. conventional therapy. Improved glycemic control rather than a specific therapy was the primary factor responsible for the reduced risk of complications because all treatments (e.g., insulin, sulfonyurea, metformin) had similar risk reduction. The objective of the study’s glucose threshold (HbA1c < 7) was to decrease microvascular complications, however, this threshold is insufficient to decrease pregnancy-related complications. In comparison to the UKPDS success rate in achieving glycemic control in type 2 diabetes with the use of glyburide, women with GDM who characteristically have a milder glycemic profile should have an equal or greater success in achieving glycemic control with the use of antidiabetic agents.46,47

As with type 1 and type 2 diabetes, the use of oral agents is a pragmatic alternative to insulin therapy in pregnancy because of ease of administration and patient satisfaction with a noninvasive treatment. However, these reasons alone, although valid, are not adequate to introduce a new drug if improvement in pregnancy outcome as well as cost effectiveness is not associated with its use. Therefore, several relevant outcomes will be addressed.

19.8 Does Glyburide Cross the Placenta?

In order for a drug to be potentially functional and safe in pregnancy, it should not cross the placenta and/or not be detrimental to the fetus at clinically significant concentrations. We demonstrated that glyburide (glibenclamide) does not cross the human placenta from the maternal to fetal circulation in significant amounts. Since the placenta of the diabetic mother is characterized by dilation of capillaries, relatively immature villous structure and chronic disturbances in intervillous circulation, we studied the placentas of both nondiabetic and diabetic mothers. There was virtually no transport of the drug even with maternal concentrations 3–4 times higher than peak therapeutic levels. We also demonstrated that first generation sulfonylureas diffused across the placenta most freely.4851 Furthermore, in mothers treated with therapeutic plasma concentrations of glyburide, the drug was undetectable in the cord blood (using high-performance liquid chromatography) of their neonates.14 Our findings were confirmed by multiple studies, all reassuring that neither glyburide nor its metabolite cross the placenta. Several studies shed additional light on the reason why glyburide does not cross the placenta, confirming its safety in pregnancy.425254

19.9 Are Patients Who Use Oral Agents at a Higher Risk for Developing Congenital Malformations than those on Insulin?

The concern over congenital anomalies and the effect on the fetus, mainly hypoglycemia and growth stimulation, were reported as case studies using first generation sulfonylureas in small-sample retrospective studies.5557 For example, the results of a study of increased rate of congenital malformations involved 20 type 2 patients with hyperglycemia before conception (HbA1c > 8). Thus, it is impossible to define if the rate of anomalies was due to the use of the drug or the existing hyperglycemia.58 In contrast, several studies demonstrated that the cause of anomalies in oral hypoglycemic agent users is associated with altered maternal glucose metabolism, and not the drug. Towner et al, in a study of 332 type 2 patients, demonstrated that mode of therapy (oral agents or insulin) was not associated with anomalies, however level of glycemia and maternal age were significant contributors to their development.59Moreover, a recent meta-analysis failed to demonstrate an increased risk of fetal anomalies with sulfonylurea drugs.60,61

19.10 Is Glyburide as Effective as Insulin in Controlling Blood Glucose?

Several retrospective and randomized studies evaluated the efficacy of oral agents during pregnancy with an 80–85% reported success rate. The majority of studies demonstrated that these agents were comparable to insulin in their ability to achieve established levels of glycemic control and pregnancy outcome526272 (Table 19.2).

Table 19.2

Studies reporting the use of oral hypoglycemic and antihyperglycemic agents in pregnancy; neonatal outcome


Number of patients








Langer et al14





No difference in metabolic complications, congenital anomalies and perinatal mortality

12 and 13%

Conway et al62

Prospective observational





Kremer and Duff52

Prospective observational



19% Macrosomia

Chmait et al65

Prospective observational



Cesarean section 36%

7% Macrosomia

Gilson and Murphy70

Prospective observational




No significant difference in the rate between insulin and glyburide treated groups

No significant difference between insulin and glyburide groups

Fines et al67

Retrospective case–control




No difference in ponderal index between the groups

Less macrosomia in the glyburide group (5/40 vs. 11/44)

Glueck et al74

Prospective observational



GDM developed

in 7.1% of patients


Prospective and retrospective observational



GDM developed in 3% of patients treated with metformin vs. 27% without treatment


Hellmuth et al63

Prospective observational




No significant difference in neonatal morbidity. Higher rate of preeclampsia (32 vs. 10%) and perinatal mortality (11.6 vs. 1.3%) in metformin group







No significant difference in perinatal mortality, metabolic complications and congenital anomalies


Yogev at al25,77





Significant lower rate of maternal hypoglycemia In glyburide group


Although showing similar rates of success to those in our study, many studies showed significantly higher rates of adverse outcomes. In a randomized controlled trial, we compared glyburide with the traditional insulin therapy in 404 GDM women. The primary outcome was the ability to achieve established levels of glycemic control; insulin and glyburide had comparable results. Moreover, adequate glycemic control was obtained with significantly fewer hypoglycemic episodes in the glyburide group vs. the insulin group. Importantly, complications that have been anecdotally attributed to the drug due to transplacental passage were not observed. The insulin and glyburide-treated patients showed comparable results in cord-serum insulin concentrations, incidence of macrosomia, increased ponderal index, LGA infants, neonatal metabolic complications (hypoglycemia, polycythemia, and hyperbilirubinemia), respiratory complications, and cesarean delivery.14 Finally, although not measured in our study, the acceptability of the pill over an injection is an additional advantage of the drug.

Recently, the results of a large randomized study compared the use of metformin and insulin in pregnancy.73 This trial of 751 women demonstrated that the infants of mothers taking metformin showed comparable results to those in the insulin group. Although glyburide and metformin have not been compared in clinical trails, in the current study, 46% of subjects in the metformin group required supplemental insulin while in our study14 only 4% of women treated with glyburide needed insulin in order to achieve targeted levels of glycemic control. These differences may be the result of varying study criteria as well as different populations and differing target levels for glucose control achieved in each study. In fact, the rate of macrosomia and LGA in the metformin study was twofold higher than that in the glyburide study. Similar findings regarding the effect of metformin use in pregnancy in retrospective studies suggested a decreased rate of abortion and GDM in polycystic ovarian syndrome patients.74,75

19.11 Is Glyburide as Effective as Insulin at all GDM Severity Levels?

We analyzed the association among glyburide dose, severity of GDM, and selected maternal and neonatal factors. Glyburide and insulin are equally efficacious for GDM treatment at all severity levels of diabetes when fasting plasma glucose results on the oral glucose tolerance test were between 95 and 139 mg/dL. Over 80% of GDM patients requiring pharmacological intervention achieved the established levels of glycemic control with either glyburide or insulin. The majority of patients (71%) will require, on average, a 10 mg daily dose of glyburide to achieve glycemic control. Furthermore, in all disease severity levels, glyburide-treated and insulin-treated subjects had comparable success rates in achieving the targeted levels with similar pregnancy outcome.76 Again, achieving the established level of glycemic control, not the mode of pharmacological therapy, is the key to improving pregnancy outcome in GDM.

The varying reported rates of outcomes of interest in the glyburide studies (glycemic control and perinatal outcomes) may be explained by a number of factors. When comparing different studies’ success rates in achieving glycemic control, different criteria for targeted levels of glycemic control influence the results. Furthermore, different populations (ethnic and geographic groups) and sample size, as well as quality and method of glucose testing (self-monitoring, postprandial, preprandial, or mean blood glucose) will also influence the definition of success in a given study. Finally, the physician factor with respect to patient-care, provider communication, and drug administration (dose and algorithms) were shown to significantly affect the failure rate to achieve targeted levels of control. Therefore, it is not surprising that studies reported similar success rates in achieving desired levels of glycemic control for insulin or glyburide-treated patients but with unacceptable perinatal outcome in both groups, i.e., LGA and/or macrosomic rates of approximately 30–45%.

19.12 Does the Rate of Maternal Hypoglycemia Increase During Glyburide Therapy?

Hypoglycemia is the main side effect of glyburide treatment in nonpregnant women. However, the majority of type 2 diabetic persons who used this drug in the nonpregnant state are older than the average gravida. Thus, the severity of the hypoglycemia may be less pronounced in the younger age group of GDM women. In our study77 we used a continuous glucose monitoring system that recorded data every 5 min for 72 continuous hours, capturing 288 measurements/day. We found that asymptomatic hypoglycemic events, defined as more than 30 consecutive minutes of glucose values below 50 mg/dL, were found in 63% of the insulin-treated GDM compared with 28% in the glyburide-treated women. Thus, although some laboratory hypoglycemic episodes (using self-monitoring blood glucose or laboratory plasma values) may be identified during pharmacological therapy, the rate of these episodes will be significantly lower in glyburide vs. insulin-treated women (Table 19.3).

Table 19.3

Selected pregnancy outcome variables in metformin, glyburide, and insulin treatment when compared with nondiabetic women15,73


Metformin vs. insulin

Glyburide vs. insulin


LGA (%)






Macrosomia (%)






Ponderal index >2.85




Overall cesarean section (%)






Congenital malformation (%)





Preeclampsia (%)






Chronic HTN (%)






5 Min Apgar score <7 (%)






Neonatal ICU admission (%)






Hypoglycemia (%) <40 mg/dL






Polycythemia (%) >60%




Hyperbilirubinemia (%) >11 mg/dL






Hypocalcemia (%) <8 mg/dL




Respiratory complications (%)






Shoulder dystocia




LGA large-for-gestational age infants (>90th percentile); HTN hypertension; ICU intensive care unit

Macrosomia = ≥4,000 g

19.13 Is Glyburide Therapy Less Costly than Insulin Therapy in Diabetic Treatment?

Care providers must consider costs with the selection of therapy. This becomes an even more important factor when medications that are similar in their effectiveness and safety are available. Goetzel and Wilkins performed a cost analysis of insulin vs. glyburide in the treatment of GDM. They found that glyburide is considerably less costly than insulin, even when the cost of educating the new insulin user is minimized (15 min/patient). The strongest determinant was the medication cost, with an average savings/patient of $166–$200 based on year 2000 rates.78

19.14 Should Lactating Mothers Use Oral Agents?

In general, women are encouraged to breastfeed their newborn infants. A common concern is whether the drugs taken by the mother will affect the wellbeing of the child. As a rule of thumb, a concentration of drug ≥10% in the breast milk is of potential concern. When metformin was evaluated, infant blood level was 0.28% of weight, normalized to maternal dose.79 There was no trace of glyburide identified in breast milk of these infants.80

19.15 Summary

Although not universally accepted, the introduction of insulin analogs (mainly lispro), oral hypoglycemic agents (mainly glyburide) and intensified therapy has profoundly altered the management approach to treatment of diabetes in pregnancy, with outcomes comparable to the general population. The benefit of insulin analog is the reduction of nocturnal hypoglycemic episodes and postprandial levels, as well as the ease of patient use. With the establishment of efficacy of glyburide and possibly metformin, there is an equally effective alternative to insulin therapy. Glyburide is a cost-effective, patient friendly and, therefore, potentially compliance-enhancing therapy that produces perinatal outcome in GDM pregnancies comparable to the traditional insulin therapy. For GDM patients who require pharmacological therapy, glyburide is the drug of choice; thereafter, patients who fail to achieve glycemic control should begin insulin therapy.

The major obstacles to the creation of evidence-based criteria to guide benefit/risk in pharmacological therapy in obstetrics is the fear of the potential adverse drug effects on the fetus and, therefore, a resultant paucity of research. The history of the U.S. Food and Drug Administration regulations for prescription drug labeling in pregnancy adds an additional layer of difficulty. The ethical, legal, and medical rhetoric surrounding this dilemma may have exaggerated the potential for fetal harm. There may be greater risk to the fetus in withholding certain medications than in prescribing them. The current evidence-based data for both insulin lispro and glyburide support their use in pregnancy.81,82



American College of Obstetricians and Gynecologists Committee on Practice Bulletin – Obstetrics. ACOG Practice Bulletin. Clinical management guidelines for obstetrician-gynecologists. Number 30, September 2001. Gestational diabetes. Obstet Gynecol. 2001;98(3):525-538.


American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2006;29(suppl 1):S43-S48.


Mokdad AH, Serdula MK, Dietz WH, et al. The spread of the obesity epidemic in the United States, 1991-1998. JAMA. 1999;282(16):1519-1522.


Silverman BL, Rizzo TA, Cho NH, et al. Long-term effects of the intrauterine environment. Diabetes. 1996;21(suppl 2):142-149.


Suhonen L, Hiilesmaa V, Teramo K. Glycemic control during early pregnancy and fetal malformations in women with type 1 diabetes mellitus. Diabetologia. 2000;43:79-82.PubMedCrossRef


Lauenborg J, Mathiesen E, Ovesen P, et al. Audit on stillbirths in women with pregestational type 1 diabetes. Diabetes Care. 2003;26(5):1385-1388.PubMedCrossRef


US Preventive Services Task Force. Agency for Healthcare Research and Quality. Department of Health and Human Services; 1996.


Reaven GM. The role of insulin resistance in human disease. Diabetes. 1998;37:1595-1607.CrossRef


Olefsky JM. Pathogenesis of non-insulin dependent diabetes (type 2). In: DeGroot LJ, Nesser GM, Cahill JC, eds. Endocrinology. 2nd ed. Philadelphia: WB Saunders; 1989:1369-1388.


Buchanan TA, Xiang AH, Peters RK. Response of pancreatic B-cells to improved insulin sensitivity in women at high risk for type 2 diabetes. Diabetes. 2000;49:782-788.PubMedCrossRef


Catalano PM, Kirwan JP, Haugel-de Mouzon S, et al. Gestational diabetes and insulin resistance: Role in short- and long-term implications for mother and fetus. J Nutr. 2003;133:1674S-1683S.PubMed


Langer O. Maternal glycemic criteria for insulin therapy in gestational diabetes mellitus. Diabetes Care. 1998;21(suppl 2):B91-B98.PubMed


Schade DS, Jovanovic L, Schneider J. A placebo-controlled randomized study of glimepiride in patients with type 2 diabetes mellitus for whom diet therapy is unsuccessful. J Clin Pharm. 1998;38:636-641.CrossRef


Langer O, Conway DL, Berkus MD, Xenakis EMJ, Gonzales O. A comparison glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med. 2000;343(16):1134-1138.PubMedCrossRef


Langer O, Rodriguez DA, Xenakis EMJ, et al. Intensified vs. conventional management of gestational diabetes. Am J Obstet Gynecol. 1994;170:1036-1047.


Kim C, Herman WH, Vijan S. Efficacy and cost of postpartum screening strategies for diabetes among women with histories of gestational diabetes mellitus. Diabetes Care. 2007;30(5):1102-1106.PubMedCrossRef


Bo S, Menato G, Lezo A, et al. Dietary fat and gestational hyperglycaemia. Diabetologia. 2001;44:972-978.PubMedCrossRef


Lauenborg J, Mathiesen E, Hansen T, et al. The prevalence of the metabolic syndrome in a Danish population of women with previous gestational diabetes mellitus is three-fold higher than in the general population. J Clin Endocrin Met. 2005;90(7):4004-4010.CrossRef


Hofman PL, Regan F, Jackson WE, et al. Premature birth and later insulin resistance. NEJM. 2004;351(21):2179-2187.PubMedCrossRef


Weiss R, Dziura J, Burgert TS, et al. Obesity and the metabolic syndrome in children and adolescents. NEJM. 2004;350(23):2362-2374.PubMedCrossRef


Langer N. Is cultural diversity a factor in self-monitoring blood glucose in gestational diabetes? J Assoc Minor Phys. 1995;6(2):73-77.


Langer N, Langer O. Emotional adjustment to diagnosis and intensified treatment of gestational diabetes. Obstet Gynecol. 1994;84(3):329-334.PubMed


UK Prospective Diabetes Study Group 33. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet. 1998;352:837-853.CrossRef


Parretti E, Mecacci F, Papini M, et al. Third-trimester maternal glucose levels from diurnal profiles in non-diabetic pregnancies: Correlation with sonographic parameters of fetal growth. Diabetes Care. 2001;24:1319-1323.PubMedCrossRef


Yogev Y, Ben-Haroush A, Chen R, et al. Diurnal glycemic profile in obese and normal weight non-diabetic pregnant women. Am J Obstet Gynecol. 2004;191(5):1655-1660.PubMedCrossRef


Langer O, Conway DL. Level of glycemia and perinatal outcome in pregestational diabetes. J Matern Fetal Med. 2001;9(1):35-41.CrossRef


Langer O. A spectrum of glucose thresholds may effectively prevent complications in the pregnant diabetic patient. Semin Perinatol. 2002;26(3):196-205.PubMedCrossRef


Langer O. Is normoglycemia the correct threshold to prevent complications in the pregnant diabetic? Diabet Rev. 1996;4(1):2-10.


Mazze R, Langer O. Medical nutrition therapy. In: Langer O, ed. The Diabetes in Pregnancy Dilemma. Maryland: University Press of America; 2006:251-263.


Artal R. Exercise: The alternative therapeutic intervention for gestational diabetes. Clin Obstet Gynecol. 2003;46(2):479-487.PubMedCrossRef


Artal R. Exercise: the logical intervention for diabetes in pregnancy. In: Langer O, ed. The Diabetes in Pregnancy Dilemma. Maryland: University Press of America; 2006:285-295.


Langer O, Anyaegbunam A, Brustman L, et al. Gestational diabetes: insulin requirements in pregnancy. Am J Obstet Gynecol. 1987;157(3):669-675.PubMedCrossRef


Jovanovic L, Ilic S, Pettitt, et al. Metabolic and immunologic effects of insulin lispro in gestational diabetes. Diabetes Care. 1999;22:1422-1427.


Hirsch IB. Insulin analogues. N Engl J Med. 2005;352:174-183.


Gabbe SG, Graves CR. Management of diabetes mellitus complicating pregnancy. Obstet Gynecol. 2003;102:857-868.PubMedCrossRef


Saade G. Gestational diabetes mellitus: a pill or a shot? Obstet Gynecol. 2005;105:456-457.PubMedCrossRef


The Diabetes Control and Complications Trial Research Group. The effect of intensified treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.CrossRef


Ecker JL, Greene MD. Gestational diabetes – setting limits, exploring treatments. N Engl J Med. 2008;358(19):2061-2063.PubMedCrossRef


Greene MF. Oral hypoglycemic drugs for gestational diabetes. N Eng J Med. 2000;343:1178-1179 [editorial].


Cefalo RC. A comparison of glyburide and insulin in women with gestational diabetes mellitus. Obstet Gynecol Surv. 2001;56:126-127.CrossRef


Kirschbaum TH. Medical complications of pregnancy. In: Yearbook of Obstetrics, Gynecology, and Women’s Health. Mosby: St. Louis; 2002:103-106.


Koren G. The use of glyburide in gestational diabetes: an ideal example of “bench to bedside. Pediatr Res. 2001;49:734.PubMedCrossRef


American Diabetes Association. Position statement on gestational diabetes mellitus. Diabetes Care. 2004;27(suppl 1):S88-S90.


Coustan DR. Oral hypoglycemic agents for the Ob/Gyn. Contemp Ob/Gyn. 2001;April:45-63.


Jovanovic L. The use of oral agents during pregnancy to treat gestational diabetes. Curr Diab Rep. 2001;1:69-70.CrossRef


American Diabetes Association. Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care. 2000;23(suppl 2):S27-S31.


Anon. The effects of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.


Elliot B, Langer O, Schenker S, et al. Insignificant transfer of glyburide occurs across the human placenta. Am J Obstet Gynecol. 1991;165:807-812.CrossRef


Elliot B, Schenker S, Langer O, et al. Comparative placental transport of oral hypoglycemic agents: a model of human placental drug transfer. Am J Obstet Gynecol. 1994;171:653-660.CrossRef


Elliot B, Langer O, Schussling F. A model of human placental drug transfer. Am J Obstet Gynecol. 1997;176:527-530.CrossRef


Ng WW, Miller RK. Transport of nutrients in the early human placenta: amino acid, creatinine, vitamin B12. Trophoblastic Res. 1983;1:121-133.


Kremer CJ, Duff P. Glyburide for the treatment of gestational diabetes. Am J Obstet Gynecol. 2004;190(5):1438-1439.PubMedCrossRef


Nanovskaya TN, Nekhayeva I, Hankins G, Ahmed M. Effect of human serum albumin on transplacental transfer of glyburide. Biochem Pharmacol. 2006;72:632-639.PubMedCrossRef


Nanovskaya TN, Nekhayeva IA, Patrikeeva SL, et al. Transfer of metformin across the dually perfused human placental lobule. Am J Obstet Gynecol. 2006;195:1081-1085.PubMedCrossRef


Kovo N, Haroutiunian S, Feldman N, et al. Determination of metformin transfer across the human placenta using dually perfused ex-vivo placental cotyledon model [abstract]. Am J Obstet Gynecol. 2005;193(6):S85.


Kemball ML, McIvert C, Milner RDG, et al. Neonatal hypoglycemia in infants of diabetic mothers given sulfonylurea drugs in pregnancy. Arch Dis Child. 1970;45:696-701.PubMedCrossRef


Zucker P, Simon G. Prolonged symptomatic neonatal hypoglycemia associated with maternal chloropropamide therapy. Pediatrics. 1968;42:824-825.PubMed


Piacquadio K, Hollingsworth DR, Murphy H. Effects of in-utero exposure to oral hypoglycemic drugs. Lancet. 1991;338:866-869.PubMedCrossRef


Towner D, Kjos SL, Leung B, et al. Congenital malformations in pregnancies complicated by NIDDM. Diabetes Care. 1995;18(11):1446-1451.PubMedCrossRef


Gutzin S, Kozer E, Magee L, et al. The safety of oral hypoglycemic agents in the first trimester of pregnancy: a meta-analysis. Can J Clin Pharmacol. 2003;10(4):179-183.PubMed


Gilbert C, Valois M, Koren G. Pregnancy outcome after first-trimester exposure to metformin: a meta-analysis. Fertil Steril. 2006;86(3):658-663.PubMedCrossRef


Conway DL, Gonzales O, Skiver D. Use of glyburide for the treatment of gestational diabetes: the San Antonio experience. J Matern Fetal Neonatal Med. 2004;15(1):51-55.PubMedCrossRef


Hellmuth E, Damm P, Molsted-Pedersen L. Oral hypoglycaemic agents in 118 diabetic pregnancies. Diabet Med. 2001;17(7):507-511.CrossRef


Notelovitz M. Sulphonylurea therapy in the treatment of the pregnant diabetic. S Afr Med J. 1971;45(9):226-229.


Chmait R, Dinise T, Moore T. Prospective observational study to establish predictors of glyburide success in women with gestational diabetes mellitus. J Perinatol. 2004;24 (10): 617-622.


Gilson G, Murphy N. Comparison of oral glyburide with insulin for the management of gestational diabetes mellitus in Alaska native women. Am J Obstet Gynecol. 2002;187:6(S), S152 [A #336].


Fines V, Moore T, Castle S. A comparison of glyburide and insulin treatment in gestational diabetes mellitus on infant birthweight and adiposity. Am J Obstet Gynecol. 2003;189:6(S), S108 [A #161].


Velazquez MD, Bolnick J, Cloakey D, et al. The use of glyburide in the management of gestational diabetes. Obstet Gynecol. 2003;101(suppl):88S.


Pendsey SP, Sharma RR, Chalkhore SS. Repaglinde: a feasible alternative to insulin in management of gestational diabetes mellitus. Diabetes Res Clin Pract. 2002;56(suppl 1):S46 [OR103].


Jacobson GF, Ramos GA, Ching JY, Kirby RS, Ferrara A, Field DR. Comparison of glyburide and insulin for the management of gestational diabetes in a large managed care organization. Am J Obstet Gynecol. 2005;193:118-124.PubMedCrossRef


Langer O, Most O, Monga S. Glyburide: predictors of treatment failure in gestational diabetes (Abstract). Am J Obstet Gynecol. 2006;195(6):S136.


Moretti ME, Rezvani M, Koren G. Safety of glyburide for gestational diabetes: a meta-analysis of pregnancy outcomes. Ann Pharmacother. 2008;42:483-490.


Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus insulin for the treatment of gestational diabetes. N Engl J Med. 2008;358:2003-2015.PubMedCrossRef


Glueck CJ, Wang P, Kobayashi S, Phillips H, Sieve-Smith L. Metformin therapy throughout pregnancy reduces the development of gestational diabetes in women with polycystic ovary syndrome. Fertil Steril. 2002;77(3):520-525.PubMedCrossRef


Moore LE, Briery CM, Clokey D, et al. Metformin and insulin in the management of gestational diabetes mellitus: preliminary results of a comparison. J Reprod Med. 2007;52(11):1011-1015.PubMed


Langer O, Yogev Y, Xenakis EM, Rosenn B. Insulin and glyburide therapy: dosage, severity level of gestational diabetes and pregnancy outcome. Am J Obstet Gynecol. 2005;192:134-139.PubMedCrossRef


Yogev Y, Ben-Haroush A, Chen R, et al. Undiagnosed asymptomatic hypoglycemia: diet, insulin, and glyburide for gestational diabetic pregnancy. Obstet Gynecol. 2004;104:88-93.PubMedCrossRef


Goetzel L, Wilkins I. Glyburide compared to insulin for the treatment of gestational diabetes mellitus: a cost analysis. J Perinatol. 2002;22:403-406.CrossRef


Hale TW, Kristensen JH, Hacket LP, et al. Transfer of metformin into human milk. Diabetologia. 2002;45:1509-1514.PubMedCrossRef


Feig DS, Briggs GG, Kmenser JM. Transfer of glyburide and glipzide into breast milk. Diabetes Care. 2005;28:1851-1855.PubMedCrossRef


Ryan EA. Glyburide was as safe and effective as insulin in gestational diabetes. EBM. 2001;6:79.


Landon M, Durnwald C. Glyburide: the new alternative for treating gestational diabetes? Am J Obstetrics Gynecol. 2005;193:1-2.CrossRef

If you find an error or have any questions, please email us at Thank you!