Continuous Glucose Monitoring for the Evaluation of
Gravid Women With Type 1 Diabetes Mellitus
Yariv Yogev, MD, Rony Chen, MD, Avi Ben-Haroush, MD, Moshe Phillip, MD, Lois Jovanovic, MD, and Moshe Hod, MD OBJECTIVE: Tocompare the dailyglycemic prole reectedby continuous and intermittent blood glucose monitoring in pregnant women with type 1 diabetes and to compare the treatment protocols based on the two monitoring methods. METHODS: The study sample consisted of 34 gravid patients at gestational weeks 1632, with type 1 diabetes being treated by multiple insulin injections. Data derived from the continuous glucose monitoring system for 72 hours were compared with ngerstick glucose measurements performed 68 times per day. During the study period, patients documented the time of food intake, insulin injec- tions, and hypoglycemic events. Data on demographics, gravidity, parity, body mass index, hemoglobin A1c, and fructosamine levels were collected for each patient. RESULTS: An average ( standard deviation) of 780 54 glucose measurements was recorded for each patient with continuous glucose monitoring. The mean total time of hyperglycemia (glucose level greater than 140 mg/dL) un- detected by the ngerstick method was 192 28 minutes per day. Nocturnal hypoglycemic events (glucose level less than 50 mg/dL) were recorded in 26 patients; in all cases, there was an interval of 14 hours before clinical manifes- tations appeared or the event was revealed by random blood glucose examination. Based on the additional infor- mation obtained by continuous monitoring, the insulin therapeutic regimen was adjusted in 24 patients (70%). CONCLUSION: Continuous glucose monitoring can diagnose high postprandial blood glucose levels and nocturnal hy- poglycemic events that are unrecognized by intermittent blood glucose monitoring and may serve as a basis for determining treatment regimens. A large, prospective study on maternal and neonatal outcome is needed to evaluate the clinical implications of this new monitoring technique. (Obstet Gynecol 2003;101:6338. 2003 by The American College of Obstetricians and Gynecolo- gists.) The goal of management in type 1 diabetes is to maintain blood glucose and hemoglobin (Hb)A1c levels as near to normal as possible. This goal is difcult to achieve in all patients and poses an even greater challenge in pregnant women. Improved glycemic control during diabetic pregnancy has been found to decrease perinatal morbidity and mortality, 1,2 as well as the congenital malformation rate. 3 On the one hand, however, too-tight glycemic control in this patient group may be accompanied by a high inci- dence of hypoglycemia, ranging from36%to 71%. 4,5 On the other hand, as maternal glycemia increases, the risk of macrosomia, the most common and signicant peri- natal complication clearly associated with diabetes in pregnancy, increases as well. 6 Patients with diabetic pregnancy are treated with multiple insulin injections and are advised to perform selfblood glucose monitor- ing by ngerstick measurements 48 times per day. The optimal frequency of blood glucose testing in gravid patients with type 1 diabetes has not been established. The selfblood glucose monitoring method has an important limitation; it provides only a single value during the day and does not allow for continuous, lon- gitudinal monitoring. As such, it may be missing both hypoglycemic and hyperglycemic events. To counter this problem, a new technology of continuous glucose monitoring was recently developed (Mastortotoro J, Levy R, Georges LP, White N, Mestman J. Clinical results from a continuous glucose sensor multi-center study [abstract]. Diabetes 1998;47:A61). The system measures interstitial glucose levels in subcutaneous tis- sue, within a range of 40400 mg/dL. Glucose values obtained with continuous glucose monitoring have been shown to correlate with laboratory measurements of plasma glucose levels 7 and with home glucose meter values (Mastortotoro J, et al. Diabetes 1998;47:A61). The purpose of the present study was to compare the daily glycemic prole reected by continuous and inter- mittent blood glucose monitoring in pregnant women with type 1 diabetes and to determine whether treatment From the Perinatal Division and The World Health Organization Collaborating Center, Department of Obstetrics and Gynecology, Rabin Medical Center, Beilinson Campus, and Institute for Endocrinology and Diabetes, National Center of Childhood Diabetes, Schneider Childrens Medical Center of Israel, Petah Tiqva, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; and Sansum Medical Research Institute, Santa Barbara, California. 633 VOL. 101, NO. 4, APRIL 2003 0029-7844/03/$30.00 2003 by The American College of Obstetricians and Gynecologists. Published by Elsevier. doi:10.1016/S0029-7844(02)02714-X strategy protocols based on the two monitoring methods differ. MATERIALS AND METHODS The initial study sample consisted of 41 consecutive gravid women with type 1 diabetes who were recruited for this prospective study during a routine clinical visit to the Diabetes in Pregnancy Center of the Perinatal Divi- sion Unit, Rabin Medical Center between November 2001 and March 2002. Of these, 34 women (82.9%) gave consent to participate after receiving a comprehensive explanation of the study. The local ethics committee approved the study protocol. Inall cases, type 1diabetes mellitus was diagnosedbefore the onset of the current pregnancy. Gestational age ranged from 16 to 32 weeks. All patients were being treated with insulin and were under the care of a registered dietitian for individualized counseling and instructions. At entry to the study, the patients chart was reviewed for demographic data, gravidity, parity, and body mass index (BMI). Prior to sensor placement, levels of HbA1c, fructosamine, and plasma glucose were measured. The MiniMed continuous glucose monitoring system (MiniMed, Sylmar, CA) was used in all cases for 3 days. The system measures glucose levels in subcutaneous interstitial tissue. It is composed of a disposable subcuta- neous glucose-sensing device and an electrode impreg- nated with glucose oxidase connected by a cable to a lightweight monitor, which is worn over the clothing or on a belt. The systemtakes 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 en- ables the data stored in the monitor to be downloaded and reviewed on a personal computer. The patients are unaware of the results of the sensor measurements dur- ing the monitoring period. The same trained nurse placed all continuous glucose monitoring sensors. Prior to placement, the site onthe ank was prepared with an alcohol sponge, and the sensor was calibrated according to the manufacturers instructions. The patients were shown howto code the time of food intake, insulin injections, exercise periods, and symp- tomatic hypoglycemic events into the monitor. Patients were instructed to wear the continuous glu- cose monitoring device for 72 consecutive hours. During this period, they also performed ngerstick capillary glucose measurements in the morning after overnight fasting and 2 hours after meals (68 times per day) using a glucometer (Ames Glucometer Elite, Bayer Corp., Elkhart, IN) and self-coded the data into the monitor. At the end of the study period, before the nurse discon- nected the women from the sensor, plasma and glucom- eter glucose values were measured. Quality control mea- sures of glucose levels from the meter, sensor, and plasma glucose were also performed at the time of con- nection to the continuous glucose monitoring system and again at study completion. The data collected by selfblood glucose monitoring and continuous glucose monitoring for each patient were evaluated separately by a single experienced physician. The average time (in minutes) per day of sensor glucose readings of less than 50 mg/dL and greater than 140 mg/dL was calculated from the daily graphs. A hypoglycemic event was de- ned as a greater than 30-minute asymptomatic reading below 50 mg/dL or symptomatic hypoglycemia detected by meter or monitoring records. The decision regarding the insulin regimen was made twice, rst on the basis of the selfblood glucose moni- toring data and then on the basis of the continuous glucose monitoring data. To prevent bias, the two types of data were presented to the physician on different occasions. The physician was blinded to the identity of the individual patients. Continuous parameters are given as means stan- dard deviations. Pearson correlation coefcient (r) and the signicance for it (P) were calculated between the variables. Reliability coefcient was used to quantitate the consistency of the two measuring methods (self blood glucose monitoring and continuous glucose mon- itoring) applied to each subject. Paired t test was used to determine the statistical signicance of differences in mean continuous parameters. A P value equal to or less than .05 was considered statistically signicant. RESULTS Mean patient age was 26 4.7 years (range 2136 years), and mean gestational age was 25 6.2 weeks (range 1632 weeks). Mean gravidity and parity were 2.4 1.1 and 1.2 0.9, respectively. Mean BMI was 26.2 4.7 kg/m 2 , mean HbA1c level 6.1 1.2% (nor- mal range 4.55.7%), and mean fructosamine level 276 29 mg/dL (normal range 205285 mg/dL). All patients completed the 3-day study. There were no adverse events associated with the use of continuous glucose monitoring. None of the patients experienced irritation or infection at the insertion site. Although patients were blinded to the continuous glucose monitor- ing readings during the study period, they reported high satisfaction using the device concerning potential future benets of continual monitoring. An average of 780 54 glucose measurements was recorded for each patient with continuous glucose mon- 634 Yogev et al Glucose Monitoring, Gravidas, and Type 1 DM OBSTETRICS & GYNECOLOGY itoring. The mean total time of hyperglycemia (glucose level greater than 140 mg/dL) undetected by the nger- stick method was 192 28 minutes per day. Nocturnal hypoglycemic events (glucose level less than 50 mg/dL) were recorded in 26 patients; in all cases, there was an interval of 14 hours before clinical manifestations ap- peared or the event was revealed by random blood glucose examination. Mean glucose level by selfblood glucose monitoring and continuous glucose monitoring was 101 13 mg/dL and 121 13 mg/dL, respectively (P .02). The individual glucose levels varied widely during each 24-hour period, but the overall 3-day prole of each patient remained consistent in many occasions during this time period (Figure 1). Analysis of the whole study group for the total 102 days of continuous monitoring showed that all 34 pa- tients had undetected hyperglycemia by selfblood glu- cose monitoring, with a range of 74303 minutes per day (mean 192 28 minutes per day, median 166 minutes). Nocturnal hypoglycemic events (at bedtime, during the night, and in the early morning) were recorded in 26 of the 34 patients in 58 nights; symptoms occurred in 28 episodes in 17 patients. In all affected patients, there was an interval of 14 hours before clinical manifestations appeared or the event was revealed by random blood glucose examination. There was no statistically signicant correlation be- tween HbA1c and fructosamine levels and the occur- rence of hypoglycemic events. Figure 2 demonstrates a 24-hour continuous record- ing in one of the patients. In 24 of the 34 patients (70%), the physician recom- mended that the insulin regimen formulated on the basis of the selfblood glucose monitoring data be changed on subsequent evaluation of the continuous glucose monitor- ing data. The most common change made was in decreas- ing the long or intermediate-acting insulin dosage at night (mean reduction by 25% in the nighttime dose of insulin). The correlation coefcient (r) between the glucose mea- surements by the sensor and meter was .93 .04, and between the plasma glucose, meter monitoring, and sensor recording, .91 .02. The reliability coefcient was .88. DISCUSSION Despite years of meticulous study, there is still a paucity of information regarding the optimal level of glycemia in diabetic pregnancy that clinicians should target to safely Figure 1. Three-day continuous glucose monitoring prole in one of our patients, showing signicant variations in glucose levels during the day but a similar daily glycemic prole for all 3 days. Yogev. Glucose Monitoring, Gravidas, and Type 1 DM. Obstet Gynecol 2003. 635 VOL. 101, NO. 4, APRIL 2003 Yogev et al Glucose Monitoring, Gravidas, and Type 1 DM reduce maternal and perinatal morbidity. Strict meta- bolic control in patients with type 1 diabetes has been associated with an increased risk of maternal hypoglyce- mia. In our study, continuous monitoring of blood glu- cose in women with diabetic pregnancies conrmed the high occurrence rate of nocturnal hypoglycemia sus- pected in earlier studies. Rosenn et al 5 reported signi- cant hypoglycemia, dened as hypoglycemia requiring assistance fromanother person, in 71%of gravid patients with type 1 diabetes, with a peak incidence in the rst trimester. The impact of maternal hypoglycemia on hu- man fetal development and neonatal outcome has not been extensively studied. Although concern about the hazards of hypoglycemia is related primarily to the preg- nant mother, the potential effects on the developing fetus need to be considered as well. Studies in rat and mice embryos point to a possible fetal risk of malformations in the presence of short- and long-term maternal hypoglycemia. 8 These ndings were not apparent with selfblood glucose monitoring. Indeed, Data derived from continu- ous glucose monitoring led the evaluating physician to change the insulin regimen, usually by decreasing the nighttime dose of intermediate-acting insulin. In more than half the cases, the hypoglycemic events were sub- clinical, diagnosed only by continuous glucose monitor- ing, and in one fth of the patients, more than one hypoglycemic event occurred during the night. These ndings may indicate that continuous glucose monitoring is a better monitoring method than self blood glucose monitoring in detecting hypoglycemic events, which are usually asymptomatic and occur at night. Whereas stringent glycemic control may lead to hypoglycemia, too-loose control poses a risk of macroso- mia, the most common and signicant perinatal compli- cation associated with diabetic pregnancy, which can lead to an increased risk of birth injuries and asphyxia. The risk of macrosomia rises as maternal glycemia in- creases. In addition, intensied management of gesta- tional diabetes reduces the rate of perinatal complica- tions, normalizes birth weight, 9 and has a positive inuence on the congenital malformation rate. 3 Our study showed that glucose levels were above the upper normal threshold for many hours during the day. These events were related to unscheduled meals and between-meal snacks and were not detected by conven- tional selfblood glucose monitoring protocols. Despite the recent introduction of intensied treatment proto- Figure 2. A 24-hour continuous glucose monitoring trace in one of our patients demonstrating a nocturnal hypoglycemia event, with a latent phase of 1 hour before clinical symptoms appeared (marked by the patient and followed by a meal). Note the undetectable hyperglycemia by the selfblood glucose monitoring method after the meal in early morning. Yogev. Glucose Monitoring, Gravidas, and Type 1 DM. Obstet Gynecol 2003. 636 Yogev et al Glucose Monitoring, Gravidas, and Type 1 DM OBSTETRICS & GYNECOLOGY cols, high rates of macrosomia and perinatal morbidity have persisted. On the basis of our study, we speculate that this may be due to the imperfect evaluation of the daily glucose prole by selfblood glucose monitoring, which underestimates hyperglycemic events. Polansky et al 10 reported that a large dinner might be associated with a sustained postprandial state for 4.7 hours. In addition, the most rigorous monitoring protocols only require postprandial glucose measurements three times per day. Many patients indulge in large between-meal snacks, and these may be the cause of the hidden hyper- glycemia. High levels of HbA1c and fructosamine and elevated BMI (greater than 30 kg/m 2 ) were all unrelated to the total diurnal time of hyperglycemia. The lack of a strong correlation between HbA1c and glucose levels by con- tinuous glucose monitoring may indicate that plasma blood glucose levels vary signicantly day by day, and although continuous monitoring is more informative than sporadic, nonlongitudinal glucose monitoring, it cannot adequately describe daily glucose proles over an 810-week period. It is possible that HbA1c is a better predictor of preprandial than postprandial glucose lev- els, as more hours are spent in interprandial and noctur- nal periods than in the postprandial periods. In our study, we used continuous glucose monitoring as a guide for therapy adjustment. Recently, Kaufman et al 11 showed that continuous glucose monitoring could serve as a clinical tool for clinical decision making and glycemic control in children with type 1 diabetes. In another recent work, Hershkovitz et al 12 demonstrated the clinical implications of continuous glucose monitor- ing use to assess and manage asymptomatic hypoglyce- mic events in children with glycogen storage disease. Parretti et al 13 assessed the daily glycemic prole of nondiabetic, nonobese pregnant women using multiple daily ngerstick measurements. A comparison by con- tinuous glucose monitoring in our department in a non- diabetic, nonobese gravid population yielded a remark- ably similar glycemic prole (unpublished data). The present prospective study is the rst to test the application of continuous glucose monitoring on gravid women with type 1 diabetes. It showed that the diurnal glucose prole undergoes extreme changes, including both hypoglycemic and hyperglycemic events, which are unrecognized by the conventional selfblood glucose monitoring technique. Continuous monitoring proles allow the physician to identify glucose patterns and to better target insulin treatment. The treatment changes in our series would not have been made on the basis of meter data alone. At this point, we do not recommend that continuous glucose monitoring replace selfblood glucose monitor- ing, but we suggest that intermittent application of con- tinuous glucose monitoring can be used to ne-tune glycemic control, assess patient compliance, if necessary, and prevent nocturnal hypoglycemic events. Because the incidence of hypoglycemia is higher and achieving strict glycemic control is more difcult in the rst trimester of pregnancy, the frequency of continuous glucose monitoring should be increased during this pe- riod. Later applications vary individually. Importantly, this study does not indicate a clinical difference in outcome from selfblood glucose monitor- ing, and the clinical utility of continuous glucose moni- toring in improving perinatal outcome remains un- known. 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