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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, St. Luke's-Roosevelt Hospital Center, University Hospital of Columbia University, New York, New York; and Perinatal Division, Department of Obstetrics and Gynecology, Rabin Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
Address reprint requests to: Y. Yogev, MD, Department of Obstetrics and Gynecology, St. Luke's-Roosevelt Hospital Center, 1000 Tenth Avenue, Suite 11A, New York, NY 10019; e-mail: ilanit{at}dlylaw.co.il.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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METHODS: All patients were evaluated using a continuous glucose monitoring system for 72 consecutive hours. The continuous glucose monitoring system measures in subcutaneous tissue interstitial glucose levels within a range of 40–400 mg/dL every 5 minutes for a total of 288 measurements per day. All patients were instructed regarding diabetic diet and assigned to pharmacological treatment as needed. Patients documented the time of food intake, insulin or glyburide administration, and all clinical hypoglycemic events. An asymptomatic hypoglycemic episode was defined as more than 30 consecutive minutes of glucose value below 50 mg/dL detected only by continuous glucose monitoring system reading without patient awareness.
RESULTS: An evaluation of 82 patients with gestational diabetes was performed; 30 were insulin-treated, 27 were managed by diet only, and 25 were patients treated with glyburide. For purposes of comparison, data were obtained from 35 nondiabetic gravid women. Asymptomatic hypoglycemic events were identified in 19 of 30 (63%) insulin-treated patients and in 7 of 25 (28%) glyburide-treated patients. No hypoglycemic events were identified in patients with gestational diabetes mellitus treated by diet alone or in nondiabetic subjects. The mean recorded hypoglycemic episodes per day was significantly higher in insulin-treated patients (4.2 ± 2.1) than in glyburide-treated patients (2.1 ± 1.1), P = .03. In insulin-treated patients, the majority of the hypoglycemic events were nocturnal (84%), whereas in glyburide-treated patients, episodes were identified equally by day and night.
CONCLUSION: Our data suggest that asymptomatic hypoglycemic events are common during pharmacological treatment in gestational diabetic pregnancies. We speculate that this finding may be explained by treatment modality rather than by the disease itself.
LEVEL OF EVIDENCE: II-2
Although hypoglycemic episodes during pregnancy are more likely to occur in patients with pregestational insulin-dependent diabetes mellitus,8–10 others have shown a high rate of maternal hypoglycemic events in patients with gestational diabetes mellitus (GDM) as well.5–7,11,12 Moreover, in pregnancy subjective symptoms of hypoglycemia such as palpitations and headaches are significantly diminished, possibly contributing to decreased awareness of hypoglycemia.13 Consequently, it would be reasonable to assume that some of the hypoglycemic episodes may be subclinical and undetectable using traditional monitoring practice. Thus, we sought to estimate the prevalence of undiagnosed, asymptomatic hypoglycemic events in pregnant diabetic patients treated by different modalities, ie, diet, insulin, and glyburide, and in nondiabetic pregnant subjects by using an original approach of continuous glucose monitoring (Mastrototaro J, Levy R, Georges LP, White N, Mestman J. Clinical results from a continuous glucose sensor multi-center study [abstract]. Diabetes 1998;47:A61).14–16
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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All patients receiving prenatal care were screened with a 50-g glucose challenge test at 24–28 weeks of gestation. A screening value greater than 130 mg/dL was followed by a 3-hour, 100-g oral glucose tolerance test (OGTT). Gestational diabetes mellitus was diagnosed according to the Carpenter and Coustan criteria.17
Treatment modalities included diet alone or a combination of diet and insulin or glyburide. Assignment to diet therapy was determined on the basis of the fasting plasma glucose level from the OGTT (95 mg/dL or less). To remain in diet therapy, the mean 2-hour postprandial glucose during treatment continues to be 120 mg/dL or less and the mean blood glucose 95 mg/dL or less. Diet control involved caloric restriction and was prescribed on the basis of 20–25 kcal/kg (obese) to 35 kcal/kg (nonobese) of actual pregnancy weight. Subjects were counseled by nutritionists about a diet regimen of 3 meals and 4 snacks daily. Diet adherence was reinforced at subsequent clinic visits. Patients with fasting plasma glucose level greater than 95 mg/dL, or who did not achieve glycemic goals on diet therapy, were assigned to insulin or glyburide therapy by physician's preference. In the women assigned to receive insulin, the starting dose was 0.7 units per kilogram per day of actual body weight at admission, given subcutaneously 3 times daily and increased weekly as necessary. The total dose was divided, with two thirds administered in the fasting state as two-thirds neutral protamine Hagedorn (NPH) and one-third rapid-acting insulin, and the remaining third of the total dose given as one-half rapid-acting insulin at dinner and one half at bedtime as NPH. The insulin treatment did not include any of the insulin analogues. In the women assigned to receive glyburide, the starting dose was 2.5 mg orally in the morning. When indicated, the dose of glyburide was increased the following week by 2.5 mg and, thereafter, by 5 mg weekly, up to a total of 20 mg when necessary to achieve glycemic control.
All patients were treated to attain the same metabolic goals: overall mean blood glucose levels, defined as mean blood glucose from diagnosis to delivery of 95 mg/dL or less, fasting blood glucose levels between 60 and 90 mg/dL, and postprandial blood glucose levels of 120 mg/dL or less.
The continuous glucose monitoring system (MiniMed, Sylmar, CA) was used in all cases. The system measures in subcutaneous tissue interstitial glucose levels within a range of 40–400 mg/dL every 5 minutes for a total of 288 measurements per day. It is composed of a disposable subcutaneous glucose-sensing device and an electrode impregnated with glucose oxidase connected by a cable to a lightweight monitor, which is worn over the clothing or on a belt. The system takes a glucose measurement every 10 seconds, based on the electrochemical detection of glucose by its reaction with glucose oxidase, and stores an average value every 5 minutes, for a total of 288 measurements each day. A communication device enables the data stored in the monitor to be downloaded and reviewed on a personal computer. The time delay between glucose values of venous plasma and subcutaneous concentrations is given with maximal 5 minutes.18 The software for the download of the sensor data takes this delay into consideration, avoiding the need for further corrections. We previously showed that the correlation coefficient (r) between the glucose measurements by the sensor and meter was 0.93 ± 0.04, and between the plasma glucose, reflectance meter monitoring, and sensor recording, 0.91 ± 0.02. The reliability coefficient was 0.88.15
To ascertain the impact of treatment modality, patients were assessed by continuous glucose monitoring at least 2 weeks after treatment was initiated. All participants were instructed to code into the monitor the time of food intake, insulin injections, exercise periods, and symptomatic hypoglycemic events. Patients were connected for 72 consecutive hours and were unaware of the results of the sensor measurements during the monitoring period. During this period, they also performed fingerstick capillary glucose measurements in the morning after overnight fasting, 2 hours after meals, and whenever a hypoglycemic event was suspected by the patient (6–8 times per day) by using a memory reflectance meter (Bayer-Dex, Elkhart, IN). For quality control, glucose determination from the reflectance meters, sensor, and plasma glucose (using the glucose oxidase enzymatic method) were performed at the initial time of connection to the continuous glucose monitoring system and again at study completion.
Hypoglycemic events were defined as follows:
Hypoglycemic episodes were further stratified into 2 subgroups: glucose value of 40 mg/dL or less and glucose value greater than 40 mg/dL, but less than 50 mg/dL.
Statistical analysis was performed with the SPSS 10.0 statistical package (SPSS Inc, Chicago, IL). Comparisons between the groups and subgroups were performed by analysis of variance with the Tukey multiple comparisons test or the Student t test for continuous data and with 
2 or Fisher exact tests for categorical data. The Pearson correlation coefficient (r) and the significance for it (P) were calculated between the variables.
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RESULTS |
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The correlation coefficient (r) between the glucose measurements by the sensor and meter was 0.94 and between the plasma glucose, reflectance meter monitoring, and sensor recording, 0.90. Mean blood glucose during the study period was similar in all GDM patients (Table 2).
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During the study period, no episodes of significant or symptomatic hypoglycemia events were identified in any of the patients. Overall, asymptomatic hypoglycemic episodes were recorded in 26 of 82 (31%) of the GDM patients in comparison with 0 of 35 in the control nondiabetic group (P < .001). Stratification by treatment modality revealed that, asymptomatic hypoglycemic events (at least 1 episode in 30 minutes) were identified in 19 of 30 (63%) insulin-treated patients and in 7 of 25 (28%) glyburide-treated patients (P = .009, odds ratio 4.4, 95% confidence interval 1.4–13.9). In contrast, no hypoglycemic events were identified in GDM patients treated by diet alone.
Stratification of asymptomatic hypoglycemic episodes into 2 subgroups—those with glucose values of 40 mg/dL or less and those with glucose values greater than 40 mg/dL but less than 50 mg/dL—revealed that insulin-treated patients had significantly more asymptomatic hypoglycemic episodes at glucose levels below 40 mg/dL (Table 2).
Further stratification by mean recorded hypoglycemic episodes per day revealed that the mean recorded hypoglycemic episodes per day for patients who had at least 1 episode of asymptomatic hypoglycemia was significantly higher in insulin-treated patients (4.2 ± 2.1) in comparison with glyburide-treated patients (2.1 ± 1.1), P = .03. In insulin-treated patients, the majority (84%) of the hypoglycemic events were nocturnal (23:00–06:00), in contrast to glyburide-treated patients, in whom episodes were identified equally by day and night (Fig. 1).
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Finally, no significant difference was found in the rate of asymptomatic hypoglycemic episodes between obese and nonobese patients in both insulin (9 obese with 4.1 ± 1.0 episodes per day versus 10 nonobese with 4.2 ± 1.1 episodes per day, P = .32) and glyburide (3 obese with 2.0 ± 1.0 episodes per day versus 4 nonobese with 2.2 ± 1.1 episodes per day, P = .60) treatment subgroups.
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DISCUSSION |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The main findings in our study are these: 1) asymptomatic hypoglycemic events are common during pharmacological treatment in GDM, 2) patients treated with glyburide had significantly fewer asymptomatic hypoglycemic events than insulin-treated patients, and 3) in patients treated with diet alone and in nondiabetic women, no hypoglycemic events were identified.
It has become axiomatic that improved glycemic control during diabetic pregnancy leads to a decrease in perinatal morbidity and mortality. On the other hand, the consequences of this treatment strategy may increase the risk of hypoglycemic events. Because there is a close relationship between maternal and fetal glucose concentrations during both early and late gestation, maternal hypoglycemia during pregnancy will therefore not only affect the mother but may also affect the fetus.
Importantly, hypoglycemic events were not found in diet-treated GDM patients or in nondiabetic pregnant women. Moreover, during the study period, significant or clinical hypoglycemic events were not identified in all patients, regardless of treatment modality.
Increased insulin resistance, diminished insulin sensitivity, and impaired insulin secretion characterize gestational diabetes. Because pregnancy is associated with insulin resistance and GDM enhances this feature, it is reasonable to assume that spontaneous hypoglycemic episodes will be minimized. Our findings may be explained by treatment modality as the side effect of pharmacological glycemic control during pregnancy rather than by the disease pathogenesis itself.
We previously demonstrated that glyburide is as safe and efficient as insulin in the treatment of GDM, with no increased neonatal and maternal side effects.19 Although glyburide-treated GDM patients did not differ from the insulin-treated GDM group by level of glycemic control, severity of GDM, age, prepregnancy weight, obesity rate, or gestational age at evaluation, significantly fewer hypoglycemic events were identified in these patients. Moreover, in the insulin-treated group, 19% of the hypoglycemic events were at glucose levels below 40 mg/dL in comparison with 8% in the glyburide-treated group. When given as a single agent, the peak plasma level of glyburide occurs within 4 hours, and its half-life is 10 hours.20 In our study, we assessed all patients at least 2 weeks after initiation of treatment modality. This ensured that there was a steady state of drug concentration (glyburide or insulin) in the plasma.
In addition, mainly nocturnal hypoglycemic events (23:00–06:00) were found among patients treated with insulin. Insulin was administered at least 3 times daily to all treated patients. One may suspect that multiple insulin administrations may be related to the high incidence of hypoglycemic events. Nevertheless, it has been demonstrated that giving insulin 4 times a day, rather than twice daily, in pregnancy improved glycemic control and perinatal outcome without increase in the risk for maternal hypoglycemia.21
A suggested approach for the reduction of the number of hypoglycemic episodes may include shortening the time lapse between daily food intakes by inserting 4 snacks. Also, adding a bedtime snack, especially in insulin-treated GDMs, will decrease nocturnal hypoglycemic episodes. Finally, human insulin (used in the current study) has a peak time of 3–4 hours. This time interval may be responsible for the hypoglycemic episode. Although not examined in our study sample, the use of insulin analogues, which have a much shorter peak time (approximately 90 minutes) with a shorter half-life, may decrease the rate of hypoglycemic events.22
The question remains, what is the clinical implication of short-time maternal hypoglycemic events for both maternal and fetal well-being in diabetic pregnancies? There is a scarcity of data concerning this question. It has been suggested that relative maternal hypoglycemia is associated with growth restriction in both animal23 and human24–26 studies. Nevertheless, in these studies the definition of maternal hypoglycemia was drawn from the OGTT rather than from the glycemic profile in pregnancy. In addition, insulin-induced hypoglycemia in the last trimester of diabetic pregnancy has been shown to increase fetal body movement, decrease the fetal heart rate variability, increase the frequency and amplitude of fetal heart rate accelerations, and cause a slight decrease in the pulsatility index of the umbilical artery and an increase in the maternal catecholamine levels.27 Others have demonstrated that fetal well-being remains unaltered despite short-time moderate maternal hypoglycemia.28 The impact of short-term maternal hypoglycemia during diabetic pregnancy on perinatal and long-term outcome of pregnancy requires further study.
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Footnotes |
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10.1097/01.AOG.0000129239.82126.a1
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REFERENCES |
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2. Landon MB, Gabbe SG. Glucose monitoring and insulin administration in the pregnant diabetic patient. Clin Obstet Gynecol 1985;28:496–506.[Medline]
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18. Thennadil SN, Rennert JL, Wenzel BJ, Hazen KH, Ruchti TL, Block MB. Comparison of glucose concentration in interstitial fluid, and capillary and venous blood during rapid changes in blood glucose levels. Diabetes Technol Ther 2001;3:357–64.[Medline]
19. Langer O, Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000;343:1134–8.
20. Groop LC, Barzilai N, Ratheiser K, Luzi L, Wahlin-Boll E, Melander A, et al. Dose-dependent effects of glyburide on insulin secretion and glucose uptake in humans. Diabetes Care 1991;14:724–7.[Abstract]
21. Nachum Z, Ben-Shlomo I, Weiner E, Shalev E. Twice daily versus four times daily insulin dose regimens for diabetes in pregnancy: randomised controlled trial. BMJ 1999;319:1223–7.
22. Simmons D. The utility and efficacy of the new insulins in the management of diabetes and pregnancy. Curr Diab Rep 2002;2:331–6.[Medline]
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24. Langer O, Damus K, Maiman M, Divon M, Levy J, Bauman W. A link between relative hypoglycemia-hypoinsulinemia during oral glucose tolerance tests and intrauterine growth retardation. Am J Obstet Gynecol 1986;155:711–6.[Medline]
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